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pmc-8699863-1

A 15-year-old boy came to the emergency department (ED) with a two-day present-ation of abdominal pain, lack of appetite, and vomiting. On examination, the patient was found to have pain and tenderness on the right side of his abdomen. (Clinical, laboratory, radiological, and intraoperative details for all patients are described in .) SARS-CoV-2 was detected via the polymerase-chain-reaction (PCR) of his nasopharyngeal (NP) swab. Empiric intravenous (IV) antimicrobial treatment with cefotaxime and metronidazole was started and he was taken to the operating room for a laparoscopic appendectomy.

pmc-8699863-2

A 14-year-old boy presented to the ED. He had a 24-h history of nausea, diarrhoea, lack of appetite, and abdominal pain, mostly in the right iliac fossa. SARS-CoV-2 was detected via the PCR of his NP swab. On presentation to the ED, pain and tenderness on the right side of the abdomen were noted by examination. Abdominal ultrasound (US) showed findings consistent with acute complicated appendicitis. Empiric IV antimicrobial treatment with cefotaxime and metronidazole was begun and he was taken to the operating room for a laparoscopic appendectomy. An abdominal fluid culture revealed E. coli. The patient was admitted to the hospital during the first 24 h from the onset of symptoms, but the intraoperative findings of peritonitis and broad intra-abdominal inflammation may indicate that acute COVID-19 infection can speed up the disease course of acute appendicitis.

pmc-8699863-3

An otherwise healthy 15-year-old girl presented with a one-day history of generalised abdominal pain, nausea, and vomiting. An abdominal examination found pain and tenderness in the right lower quadrant. An abdominal US showed findings consistent with acute complicated appendicitis. A SARS-CoV-2 nucleic acid test was positive. The patient was initially treated conservatively for acute uncomplicated appendicitis with IV antimicrobial treatment (ampicillin plus metronidazole), but abdominal pain advanced, blood inflammation markers elevated, and therefore treatment was converted to surgery. It is possible this patient already had acute complicated appendicitis on ED admission.

pmc-8699863-4

A girl aged 12 years presented with fever, abdominal pain, and painful urination of one-day’s duration. The patient had tested positive for COVID-19 eight days before the onset of abdominal pain. SARS-CoV-2 was detected by the PCR of her NP swab. Per abdominal examination findings revealed superficial and deep tenderness in the right lower abdominal quadrant to palpation and localised tenderness to percussion. An abdominal US showed findings consistent with acute complicated appendicitis. IV antimicrobial treatment with cefotaxime and metronidazole was begun, and she was taken to the operating room for a laparoscopic appendectomy. An abdominal fluid culture revealed P.aeruginosa, Str.viridans, and Gemella morbillorum.

pmc-8699863-5

A girl aged 16 years presented with fever, abdominal pain in the epigastric and ileocecal region, nausea, lack of appetite, and vomiting of two days’ duration. Patient 5 had a recurrence of acute uncomplicated appendicitis. She had had the first episode two years previously, with acute uncomplicated appendicitis. She was treated conservatively with antibiotics; however, she was ultimately operated on laparoscopically. In her case, COVID-19 infection presumably exacerbated the course of appendicitis and resulted in abdominal pain that was a cause for diagnostic laparoscopy and further appendectomy. Unlike the four other cases in which the histology showed necrotic areas in the appendix wall, concluding that appendectomy was necessary (gangrenous appendicitis—see ), Patient 5’s surgery could have been avoided if symptoms had not persisted.

pmc-8699863-6

A girl aged five years presented with fever, abdominal pain, nausea and vomiting of one day’s duration. She had a recurrence of acute uncomplicated appendicitis. This girl had had her first episode two years previously, when she had acute appendicitis with an appendicular mass. She was treated conservatively with antibiotics; however, Patient 6 once again was treated non-surgically. In her case, the COVID-19 infection presumably exacerbated the course of appendicitis and resulted in abdominal pain.

pmc-8699901-1

We report the case of a 31-year-old Caucasian woman, gravida 3, para 1, who was referred after a second trimester fetal anatomy screening at 20 weeks gestational for a suspicion of a complex fetal cardiac malformation, for which several specialized opinions tried to reach consensus. The obstetrical history of the patient includes a previous Caesarian section with a normal course of parturition and a spontaneous miscarriage. The current pregnancy presented a low risk for aneuploidy according to the performed cell-free fetal DNA test. The classical karyotype performed after the abortion did not reveal any chromosomal abnormalities. Previous ultrasound evaluations were incongruent and reported the following findings:an isolated aortic arch anomaly (supposedly aneurysmal dilation from which the left common carotid artery emerges) and coarctation of the aorta with the anterograde flow; ventricular septal defect, coarctation of the aorta, and a vascular formation located superior from the aortic arch with the appearance of an arteriovenous fistula; aneurysmal dilation located above the pulmonary trunk bifurcation and a dilated left common carotid artery with a retrograde flow; minor ventricular septal defect with a normal ductus venosus triphasic flow. We performed fetal echocardiography, which demonstrated a mild cardiomegaly with a left deviated 72-degree heart axis, normal aspect of the four-chamber view, a small membranous ventricular septal defect, and ductal aortic coarctation; the ductus venosus flow was normal (, and ). In addition, we identified an aneurysmal structure measuring 1.63/1.25/1.16 cm with turbulent Doppler flow, situated above the emergence of the pulmonary trunk and continued by a dilated vascular structure that bifurcates in the cervical region; the aneurysm seemed connected to the left pulmonary artery as well. A dilated left subclavian artery was also suspected (, and ). In the context of complex cardio-vascular malformations, the patient requested the termination of the pregnancy by drug-induced abortion. The hands-on dissection of the fetus revealed a set of abnormalities that could stand as an anatomical basis for what has been found during the ultrasound examination. The first and the most pronounced aspect was the distention of the whole venous system of the neck and mediastinum. The specimen presented a linguo-facial vein that described a rather sinuous pathway alongside the inferior margin of the mandible (). Both the linguo-facial vein and the external jugular vein appeared with a markedly increased caliber, around 4–5 times larger than expected for this gestational age. Both left and right jugular veins and the right subclavian vein were assessed as three times larger than usual, respecting the normal relations to the neighboring structures ( and ). The confluence between the left jugular and subclavian vein into the left brachiocephalic vein was observed to be very dilated to superior and inferior, extending above the superior margin of the omohyoid muscle as well as below the inferior concavity of the aortic arch. Moreover, on the inferior side of the enlarged brachiocephalic vein, a vessel could be observed descending lateral to the left vagus nerve and communicating with the left pulmonary artery. The left pulmonary artery was observed to be dilated as well, around twice as normal (). Regarding the great vessels of the heart, there are some anomalies to be discussed. A narrowing of the aortic arch was identified distally to the emergence of the left subclavian artery ( and ). A large, patent ductus arteriosus was found, ending right at the narrowing level observed in the aortic arch (ending right at the coarctation level) (). The left subclavian artery was dilated as well, sizing as much as the ascending aorta and the aortic arch, creating the illusion of a terminal branch rather than a lateral one ( and ). Heart analysis concluded no distinct changes in heart architectural formation for this gestational age. Atrioventricular and ventriculoarterial concordance was noted. Atria and ventricles were increased in relation to the mediastinum. Surprisingly for an aortic coarctation, the right atrium was not found to be enlarged.

pmc-8699918-1

A 34-year-old woman (gravida 3, para 3) with three spontaneous vaginal deliveries was transferred to the Ulsan University Hospital from a local clinic due to severe abdominal pain accompanied by right flank pain. The patient had been previously healthy and had no specific medical or surgical history. She had an irregular menstruation cycle, and her last menstruation occurred five weeks and six days previously. The initial vital signs at the emergency room were stable; systolic and diastolic blood pressure were 114 mmHg and 68 mmHg, respectively. The initial pulse rate was 71 beats per minute. Whole abdominal tenderness with muscle guarding was noted on physical examination. Blood tests showed a low hemoglobin level (10.7 g/dL). A urinary pregnancy test was positive, and the serum β-HCG level was 7377.0 mIU/mL. Gynecological sonography found no evidence of an intrauterine pregnancy, except for normal bilateral adnexa with free fluid collection, suggestive of hemoperitoneum. After eight hours, the follow up blood test showed a lower hemoglobin level (8.6 g/dL). Two packs of packed red blood cells were transfused. We suspected a ruptured ectopic pregnancy through elevated serum β-HCG, but the ectopic mass could not be identified on pelvic ultrasound. Thus, we planned abdominopelvic computed tomography (APCT) to determine the cause of the right frank pain. Approximately 2 cm hypervascular mass in the subphrenic region, with a moderate amount of hemoperitoneum, was revealed (), which was thought to be the cause of the bleeding. Because of suspicions of a diaphragmatic ectopic pregnancy or other ruptured unknown hepatic mass, she was admitted for emergency surgery. Diagnostic laparoscopic surgery was performed in collaboration with a hepatobiliary surgeon and an obstetrician-gynecologist. On laparoscopy, about 400 mL of blood and clots were aspirated from the pelvic cavity, but both adnexa appeared normal. Approximately 20 × 10 cm tissue, suspected to be the placenta with a hematoma, had covered the diaphragm. After the removal of the placenta-like tissues, we found a 2 cm hypervascular mass attached to the diaphragm (). The mass was completely resected from the diaphragm and sent for histological examination. After the surgical mass removal, the patient was discharged without any postoperative complications, and the serum β-HCG level normalized within a month. The final pathologic diagnosis indicated that the mass was a product of conception, consistent with an ectopic pregnancy ().

pmc-8699933-1

A 68-year-old male with a history of diabetes was admitted to our hospital with a two-week history of abdominal pain, jaundice, nausea, anorexia, and episodes of loose stools. Physical examination revealed right-sided abdominal tenderness. Laboratory examination revealed slightly higher bilirubin levels (0.4 mg/dL), but serum amylase and lipase levels, and complete blood count were all within the normal range. Abdominal computed tomography demonstrated a large cystic mass in the head of the pancreas, which measured 8.1 × 7.5 × 7.4 cm, and dilatation of the common bile duct, measuring 22 mm in diameter. There was also dilatation of the pancreatic duct, measuring 5 mm in diameter. The remainder of the pancreas was grossly unremarkable. Fine needle aspiration (FNA) was performed using endoscopic ultrasound (EUS). The EUS FNA fluid test showed a CEA level > 900 ng/mL, and fluid cytology was negative for malignancy or high-grade dysplasia. Endoscopic retrograde cholangiopancreatography (ERCP) was performed with biliary stent placement, which led to the resolution of his jaundice. An extended pylorus-sparing pancreaticoduodenectomy was performed. The operation was uneventful, and the patient was discharged 4 days after surgery. Gross examination: The pancreatic head was entirely replaced by a mass lesion measuring 8.2 × 7.9 × 7.2 cm and was a unilocular cystic lesion containing gray-green turbid fluid with granular material. The cyst structure appeared to communicate with both the main and side duct branches. The cyst lining was gray-green to yellow, trabecular, and glistening to granular with few fibrous strands that arborized through the cystic structure and anchored at opposing sides of the cyst. Using a standard pancreatic cancer sampling protocol, paraffin-embedded sections of formalin-fixed tissue were studied by routine histology at the Indiana University Pathology Laboratory. Microscopic examination: Histologically, the tumor showed two components composed of an epithelial component and a spindle cell component that were intimately intermingled together. The epithelial component had features ranging from well differentiated to moderately and poorly differentiated pancreatic ductal adenocarcinoma. The majority of the epithelial component was well differentiated with simple small to large ductal structures lined by a single layer of columnar to cuboidal cells, which had small and basally located nuclei with smooth and round nuclear contours and open chromatin. They had a moderate amount of eosinophilic cytoplasm without mucinous content (). The moderately differentiated component showed a more complex glandular structure with convoluted and interconnected ducts with a single layer of cells or a cribriform-type structure including multiple layers of cells with enlarged and irregular nuclei (). Some areas showed prototypical morphology of conventional pancreatic ductal carcinoma with small and angulated ducts infiltrating the desmoplastic stroma. The poorly differentiated epithelial component was small and focal. It showed vague and poorly formed ductal structures, or solid nests to small sheets of dispersed epithelioid cells with no ductal structures (). These cells had enlarged vesicular nuclei with irregular nuclear contours and conspicuous nucleoli. The spindle cell component was highly cellular with compact spindle cells, which showed hyperchromatic and elongated nuclei with scant cytoplasm. There was rare mitosis in the epithelial component, but the spindle cell component showed frequent mitosis with up to 12 mitoses per 10 high-power fields. Frequent apoptosis was also observed in spindle cell areas. Scattered necrotic areas were present in both components. There were no osteoclast-like giant cells or rhabdomyoblasts and no osteoid formation. There were foci of hemosiderin deposition, especially in the spindle cell areas surrounding the cystic lining. None of the ducts showed papillary or mucinous features. No areas subjacent to the epithelial component showed ovarian stroma-like features. All margins were negative for tumor. Twenty lymph nodes were present, all of which were negative for metastatic tumors. The pathologic staging was pT3pN0. Immunohistochemistry: Extensive immunohistochemical studies were performed at the Indiana University Pathology Laboratory due to the mixed features of the lesion (). The epithelial component was positive for markers of pancytokeratin AE1/AE3, epithelial membrane antigen (EMA), CK7, and CK19, and negative for MUC2, MUC5, MUC6, synaptophysin, and chromogranin. Spindle cells were negative for these markers. The spindle cells were diffusely positive for vimentin and DOG1 with patchy positivity for S100. Both epithelial and spindle tumor cells were negative for the estrogen receptor, CD10, inhibin, TLE1, SOX10, Melan A, HMB45, actin, desmin, myogenin, MyoD1, STAT6, and CD117. No nuclear staining was observed for β-catenin. CD163 highlighted cells with hemosiderin deposition, consistent with histiocytes. The tumor cells were negative for CD21 and CD35 expression. P53 showed a wild type staining pattern with no complete loss or overexpression in tumor cells of both components. Cyclin D1 showed patchy nuclear staining in the epithelial component but was negative in the spindle cell component. P16 was positive in the spindle cell component but negative in the epithelial component. The spindle cells demonstrated approximately 20% positivity of Ki-67 nuclear staining, while it showed only scant (about 2%) nuclear staining in the epithelial component (). Additional immunohistochemical staining for PDL-1 (SP142), MLH1, MSH2, MSH6, and PMS2 was performed at the Caris Life Science Laboratory (Phoenix, Arizona) and showed negativity (0%) for PDL-1 expression and intact protein expression of MLH1, MSH2, MSH6, and PMS2. Molecular study: Molecular analysis of the tumor tissue was first performed by Indiana University Molecular Pathology Laboratory and showed that the tumor was microsatellite stable with no mutation in BRAF, KRAS, and NRAS genes. Additionally, the tumor tissue was sent to the Caris Life Science Laboratory (Phoenix, AZ, USA) for next generation sequencing analysis of whole exome sequencing (WES). Direct sequence analysis was performed on genomic DNA using Illumina NovaSeq 6000 sequencers. Tumor mutation burden (TMB) was low and genomic loss of heterozygosity (LOH) was also low, with 10% of the tested genomic segments exhibiting LOH. The whole exome sequencing in our case showed no pathogenic alterations in the genes, such as BRAF, ATM, BRCA1, BRCA2, PALB2, SMAD4, NRG1, and NTRK1/2/3. However, the results for AXL1, HDAC1, MED12, NOTCH1, PIK3CB, POLD2, PRKACA, PTPN11, TERT, and XRCC1 were indeterminate because of the low coverage of exons in these genes. The patient was followed up for three months after surgical resection. The last time he had an appointment for discussing the adjuvant chemotherapy. But he was then lost to follow up without receiving adjuvant chemotherapy.

pmc-8699959-1

After a multidisciplinary evaluation, at the end of November 2019, a 13-year-old girl attended the Pain Therapy Clinic of the Ospedale Pediatrico Bambino Gesù in Rome, where acupuncture is also practiced as an analgesic technique. She reported pain in the left wrist and hand, with intensity 10 on the Numeric Pain Rating Scale (NRS), pulsating, and always present, thus preventing any movement. Marked hypersensitivity and allodynia were present at the level of the left fingers, wrist and hand. Pain was present in both flexion and extension of the wrist and caused a marked reduction in strength in the left wrist and hand, making a handshake impossible for the girl. There was no redness but swelling and sweating at the level of the fingers of the left hand. The pain was so intense that it interfered with her regular attendance at school, generating social withdrawal phenomena, which are unfortunately very frequent in patients with chronic pain. Pain began three months before the consultation, after an accidental fall with trauma to the left wrist. It gradually increased and did not respond to either NSAIDs or limb immobilization. The diagnostic tests performed at the time (X-ray, Doppler ultrasound and magnetic resonance imaging) were negative, as were the blood chemistry tests ( and ). From the age of 8, the girl was followed by a pediatrician in our hospital for a history of cramps and pain in the lower limbs, especially in the ankle and left knee, both in the absence of trauma or caused by frequent falls. In the following years, clinicians found bilateral flatfoot (with subsequent surgery), mild ligamentous hyperlaxity and vitamin D deficiency. In addition, borderline cognitive level with motor coordination disorder and executive function deficit, as well as stuttering, were then diagnosed. Elements of anxiety emerged from the administration of Self Administered Psychiatric Scales for Children and Adolescents (SAFA-A, D and S) questionnaires, as highlighted in particular by the subscales “Separation anxiety” and “Generalized anxiety” [,]. Concern for one’s own health was observed, with experiences of herself as being ill; the scores indicate a propensity to somatize. There was a tone of mood oriented in a deflected sense, and insecurity. The results of the Lie scale were: 8; T: 65 [,]. In addition to pulsating headache with phono and photophobia, frontal epilepsy was also diagnosed, which could explain the frequent falls, and moreover had excluded hyperbaric oxygen therapy as a feasible regimen in this case (due to a cost/benefit evaluation, and increased exposure to oxygen toxicity during the treatment itself). Episodes of dizziness with difficulty in maintaining an upright position lasting a few hours were also observed, and on two occasions she also had an episode of unconsciousness lasting about 2 min. During the first visit, as a consequence of the mother’s need to have time to convince the recalcitrant daughter, in the meantime it was recommended to administer oral tramadol (100 mg/mL), 5 gtt in the morning and 5 gtt in order to reduce musculoskeletal pain. The reason for choosing a drug such as tramadol rather than any other pharmacological option lies in the fact that the pain was so intense that it affected the patient’s relationships []. We therefore opted for a drug that would have an immediate effect, so as to be able to undertake the acupuncture course. Subsequently, in the first two sessions, after careful disinfection of the skin with 2% chlorhexidine, and using the appropriate needles for length and diameter based on the type of acupuncture and the selected points, we used the following acupoints: TE 4 (Yang Pool), TE 5 (Waiguan), LI 5 (Yang Xi) and SI 4 (Wan Gu), all on the left side. These points were chosen on the basis of a pathology which, according to traditional Chinese medicine, was caused by cold wind. These points produced heat and dissipated the wind []. The needles were kept for 30′, with stimulation every 10′. In the third session, the girl reported a slight improvement in the painful symptoms but at the same time unbearable pain in the affected limb during the previous sessions due to the insertion and maintenance of the needles in the affected area. We decided to change strategy and to use abdominal acupuncture and stimulation of the points CV 4 (Guan Yuan), CV 12 (Zhong Wan), CV 16 (Zhong Ting), CV 17 (Shan Zong), ST 24 bilateral (Huaroumen) and KI 17 bilateral (Shang Qu), with appropriate needles and maintaining the same interspeed and time of stimulation. The needles were inserted to a depth of 0.2 cun. These new points (CV 4, CV 12, CV 16, CV 17 and KI 17), in addition to heating and dissipating the wind, re-established the correct circulation of qi []. In fact, used in combination, their purpose was to move the qi from the kidney to the extremity of the upper limb passing through the shoulder [,]. ST 24 was used to calm the patient and increase her compliance with acupuncture []. Auriculotherapy was also associated with Vaccaria seeds on the Wrist, Hand and Shenmen points, with the recommendation to stimulate them at home for 10 min, 4 times a day until the next session. Vaccaria seeds are used to stimulate certain points in auriculotherapy due to their almost spherical shape, and the absence of pharmacological properties []. The Shenmen point was chosen for its anxiolytic effect, given the patient’s psychological difficulties []. After eight sessions (two months) of abdominal acupuncture the pain completely disappeared (Numeric Pain Rating Scale value 0) and the girl regained full functional capacity of the arm and a normal life. Follow-up at three months, six months and one year demonstrated complete remission of symptoms, with constant values of NRS equal to 0. The reduction in pain, and subsequently its total disappearance, allowed the patient to resume normal school attendance, and therefore to resume a life of normal, balanced relationships.

pmc-8699977-1

Case 1 was a 2-year-old boy who was admitted to the department of hemato-oncology due to pallor without respiratory symptoms or signs including no hemoptysis. Laboratory results revealed severe anemia, and his chest radiograph and chest computed tomography scans revealed pulmonary hemorrhage as the focus of bleeding (). The patient was diagnosed with IPH and treated with corticosteroids. His clinical course was uneventful and the corticosteroid dose was gradually tapered after the first month of treatment. However, he was re-admitted due to hemoptysis. Although he had no history of allergy and low levels of specific immunoglobulin (Ig)E to cow’s milk, Heiner syndrome was nevertheless suspected, and milk avoidance was recommended. The patient has been adhering to a strict milk restriction diet and has not had any further hemorrhagic events, and is not taking corticosteroids.

pmc-8699977-2

Case 2 was a 1-year-old girl who presented with recurrent hematemesis. She was diagnosed with IPH, and systemic corticosteroids and avoidance of cow’s milk were recommended based on our clinical experience with the first case. However, due to multiple episodes of accidental milk ingestion, she experienced repetitive pulmonary hemorrhage despite corticosteroid therapy. Given the exacerbation of clinical symptoms after milk exposure, she was diagnosed with Heiner syndrome. This case demonstrated the importance of corticosteroid therapy and strict milk restriction. At 2 years after diagnosis, the patient underwent an oral milk provocation test for 5 days, and she showed no symptoms or signs of hemorrhage.

pmc-8699977-3

Lastly, case 3 was a 2-year-old boy who presented with hemoptysis. Clinical investigations were performed to rule out pulmonary tuberculosis and other infectious causes, and these all came back negative. Two years later, he was hospitalized twice for pneumonia while living abroad and probably was accompanied by pulmonary hemorrhage due to first onset of anemia. Hemoptysis recurred at the age of 3; therefore, he underwent a comprehensive work-up including lung biopsy, which confirmed pulmonary hemosiderosis. Although the patient had no history of cow’s milk allergy, milk avoidance and systemic corticosteroids were initiated. Oral milk provocation was attempted 1 year later by introducing cow’s milk and dairy products such as cheese and ice cream every day for 1 week; this led to increased sputum and pulmonary infiltrates on the chest radiograph (). As a result, this patient was diagnosed with Heiner syndrome.

pmc-8700017-1

A 20-day-old girl was admitted to the neonatal intensive care unit with a chief complaint of poor oral intake through the emergency room. She was lethargic and did not suck well with swallowing only 10 to 20 mL of formula at a time in the last two days. However, the amount of urine did not decrease, and diapers were changed 10 to 14 times per day. Vomiting and diarrhea were not observed. She was born at 38+2 weeks of gestation with 3380 g (50th–75th percentile) via cesarean section. No abnormal findings were noted during the prenatal and immediate postnatal periods. She was the first child of healthy, nonconsanguineous Korean parents, and her family history was unremarkable. At admission, her weight was 3100 g (25th–50th percentile), length was 53 cm (50th–75th percentile), and head circumference was 36 cm (50th–75th percentile). Although vital signs were appropriate for her age (heart rate 150 beats/min, blood pressure 78/50 mmHg, respiratory rate 48 breaths/min, and body temperature 36.5 °C), her lips were dry, and the capillary refill time was prolonged to 5–6 s. Physical examination revealed both thumbs in palms, frontal bossing, prominent upper lip, high arched palate, sparse frontal scalp hair, and bilateral 5th finger clinodactyly. An initial capillary blood gas analysis showed severe metabolic acidosis (pH 7.16, pCO2 28.3 mmHg, pO2 42 mmHg, HCO3−—17.3 mmol/L, base excess—17.3 mmol/L). With an impression of dehydration, 20 mL/kg normal saline was infused intravenously for over 1 h before other laboratory results were obtained. The laboratory tests at admission were as follows: serum sodium 113.3 mEq/L, serum potassium 8.79 mEq/L, serum chloride 90.8 mEq/L, total CO2 8.1 mEq/L, serum lactic acid 1.0 mmol/L, serum ketone body 24 µmol/L, blood glucose level 83 mg/dL, blood urea nitrogen 55.1 mg/dL, and serum creatinine 0.65 mg/dL. Her urinalysis revealed a specific gravity of 1.014 and pH 5.0 and was negative for white blood cells and red blood cells. Her spot urine sodium and potassium levels were 74 and 27.7 mEq/L, respectively. The serum and urine osmolality values were 232 and 229 mOsm/kg, respectively. All the results of the neonatal screening test were normal, which included TSH (1.2 mIU/L), 17-hydroxyprogesterone (1.6 ng/mL), total galactose (1.0 mg/dL), and mass spectrometry for amino acid, organic acid, fatty acid, purine, peroxisome, and carbohydrate metabolic disorders. The plasma ammonia level was within the normal limit as 97 µg/dL. The plasma renin activity and serum aldosterone level were markedly elevated to 142.0 ng/mL/h (normal range, 0.32–1.84 ng/mL/h) and 4560 ng/dL (normal range, 4.2–20.9 ng/dL), respectively. Renal ultrasonography revealed no abnormalities except mild hydronephrosis in the right kidney (). No abnormal findings were found in cardiac echocardiography or brain magnetic resonance imaging. To correct severe hyponatremia, 60 mL of 3% sodium chloride was initially intravenously administered over 8 h. Her urine output on the first day of admission was 8.45 mL/kg/h. Hyponatremia and hyperkalemia were improved with intravenous fluid and oral sodium chloride supplementation (8 mEq/kg/day). The patient consumed an adequate amount of milk (170–200 mL/kg/day), and weight gain was appropriate (40–80 g/day) after oral sodium chloride supplementation. For the genetic diagnosis of the patient, targeted exome sequencing (TES) was performed. Genomic DNA was extracted from proband blood. All exon regions of all human genes (~22,000) were captured by a Twist Human Core Exome Kit (Twist Bioscience, South San Francisco, CA, USA). The captured regions of the genome were sequenced using a NovaSeq 6000 sequencing machine (Illumina, San Diego, CA, USA). In TES, no other pathogenic/likely pathogenic single-nucleotide variants (SNVs) or small insertion and deletion variants associated with the clinical phenotypes were identified. However, her clinical phenotypes and biochemical results indicated PHA1. Therefore, we performed a chromosomal microarray (CMA) to identify deletion-encompassing genes responsible for PHA1. CMA (CytoScan Dx, Affymetrix Cytogenetics, Santa Clara, CA, USA) revealed a 203 kb heterozygous deletion at 4q31.23: arr[GRCh37] 4q31.23(148865586_149069090)x1 (). This deletion spans exons 7–9 of NR3C2 and exons 15–23 of the ARHGAP10 gene. Haploinsufficiency of the NR3C2 gene, which encodes the mineralocorticoid receptor, is responsible for ADPHA1. However, the details of the functional role of the ARHGAP10 gene in human disease remain unclear. Parental testing showed that the deletion was paternally inherited. Her father had no history of clinical PHA1 manifestation and had normal plasma electrolytes and serum aldosterone values with only slightly elevated plasma renin activity at testing.

pmc-8700032-1

A 75-year-old Caucasian woman with a history of well-controlled hypertension and hypercholesterolemia presents to the ED with complaints of a new-onset headache. She describes her headache as constant and refractory to over-the-counter pain relievers. Her physical examination is unremarkable. She has no ocular complaints, and no eye examination is performed. A non-contrast computed tomography (CT) scan of the brain is performed and reported to be normal. She is discharged with a prescription for Vicodin. Two weeks later, she returns to the ED with a worsened headache and blurred vision. The ophthalmologist on call is consulted by telephone. Visual acuity is noted to be 20/25 in both eyes (OU), pupils are round reactive to light, and no afferent pupillary defect is present. The patient has small pupils that precluded an easy view to the back of the eye with a direct ophthalmoscope. Attempts to check intraocular pressure are unsuccessful as the tonometer would not calibrate. A slit lamp examination is not done as the machine is not working. A CT and computed tomography angiogram (CTA) are performed at the recommendation of the tele-neurology doctor on call, both of which are normal. No labs are ordered. The patient is instructed to see the ophthalmologist in the morning. When the patient wakes up the next morning, her vision is worse. On examination in the ophthalmologist’s office, her visual acuity has decreased to 20/400 right eye (OD) and 20/25 left eye (OS). Giant cell arteritis (GCA) is a common disorder that presents to the ED and should be high on the differential for all elderly patients presenting with a headache, visual loss, or diplopia [,]. presents the most common presenting symptoms. Asking the right questions is crucial in preventing permanent blindness. On further questioning, the patient denied jaw claudication and temporal tenderness but did complain of ear pain and eye ache. Other historical clues that can be helpful include polymyalgia rheumatica, weight loss, fatigue, and abdominal pain due to mesenteric ischemia [,]. Laboratory evaluation should include the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count including platelet count [,]. A list of the most commonly abnormal lab values for the disease process are listed in . These laboratory tests are elevated at diagnosis in most patients and crucial to monitoring disease activity [,]. However, 20% of patients have normal laboratory testing []. CRP is much more sensitive than ESR, but the combination of all three is the most helpful and also guides management [,,]. Acute serum amyloid A (A-SAA) is less readily available but also highly sensitive []. Magnetic resonance imaging (MRI) with and without gadolinium of the orbits and temporal artery may be very helpful [,,,]. A CT scan does not pick up the vasculitis but an ultrasound of the temporal arteries may []. GCA can cause enhancement of the optic nerve or orbit on the MRI; it also can cause enhancement of the periosteum and temporalis muscle surrounding an occluded or partially occluded temporal artery [,]. If there is a history sufficiently suspicious for GCA (even if laboratory tests and imaging normal), the standard of care is to place the patient on 40 mg of prednisone (if no visual symptoms or signs) and refer for a temporal artery biopsy within two weeks [,,]. Rheumatology is then consulted, and the patient may be switched to a steroid sparing agent like methotrexate or tocilizumab (Actemra) as the prednisone is tapered slowly [,]. Monitoring always includes repeating laboratory values. If a patient has transient visual obscurations (graying or blacking out) or blurred vision due to choroidal nonperfusion or double vision, the prednisone dose should be at least 60 mg PO each morning with food [,]. If the ESR and CRP are very elevated, a significant thrombocytosis is present and/or the MRI shows extensive inflammation and/or the patient has already lost vision in one eye, the patient should be treated with high doses of IV steroids (methylprednisolone 250 mg q6 h) as an inpatient [,]. The characteristic severe visual damage is not reversible, but IV steroids usually prevent contralateral visual loss. Bilateral occipital lobe infarcts have been described. These patients can also have increased morbidity from stroke, myocardial infarctions, or aortic aneurysmal rupture if not treated [,,].

pmc-8700032-2

A 25-year-old woman with a past medical history of polysubstance abuse presents to the ED with a chief complaint of severe headaches that wake her from sleep and are present on awakening. She has tried NSAIDS without any improvement. She admits to alcohol, marijuana, and methamphetamine use and asks for Vicodin. Her physical examination is normal, and a non-contrast CT of the brain is normal. She is discharged with a limited supply of Vicodin and referred to outpatient neurology for migraine management. Her insurer is Medicaid, and she finds it difficult to visit a neurologist who will accept her insurance. She returns to the ED seven additional times with the same complaint. On her most recent visit, she complains of transient visual obscurations that gray out or black out her vision for seconds to minutes. She is again referred to Neurology and this time to Ophthalmology as well. Again, no one accepts her insurance and she presents to the ED for an eighth visit. On this visit, she complains of severe central visual loss bilaterally and on examination is unable to see more than the “big E” on the Snellen eye chart bilaterally. Her pupils are round but minimally reactive to light. No afferent pupillary defect (APD) is present. A fundoscopic exam is not obtained given that she is uncooperative (crying hysterically), there is no protocol for pupil dilation, and a non-mydriatic camera is unavailable. The ophthalmologist on call is slow to answer and the patient is admitted but unfortunately, the call group does not cover inpatients. Women of childbearing age who are overweight are the population most at increased risk for idiopathic intracranial hypertension (high intracranial pressure with no specific cause) [,,,]. It can also occur in women of normal BMI as well as men [,,]. Exposure to steroids, doxycycline, or other medications can trigger this disorder [,,]. Early morning headaches should raise concern for increased intracranial pressure and/or an intracranial mass. The headaches often get worse when laying down (gravity dependent) and can be accompanied by transient visual loss when changing from lying to sitting or standing [,,]. Increased intracranial pressure (ICP) is serious and must be addressed. Patients who complain of early morning headaches should always have their eyes examined for papilledema whether or not they have visual symptoms [,,]. High Intracranial pressure (ICP) causes insidious visual field loss that begins in the periphery and is seldom noticed early on [,,,]. In some patients, diplopia also occurs due to the sixth cranial nerve being stretched across the petrous ridge [,]. The clinical history is critically important in this case too. Key symptoms are listed in . Patients should be asked about transient graying out or blacking out of vision especially when going from lying down or sitting to standing [,,]. This patient ideally would have been referred to ophthalmology at the initial visit and had a non-mydriatic photo taken of the optic nerve. Rather than a non-contrast CT scan, an MRI/MRV of the brain would have been the imaging study of choice [,]. Venous sinus thrombosis can cause increased ICP []. While in the ED, a lumbar puncture should be performed in the lateral decubitus position to document opening pressure but also cells, glucose, and protein [,,]. An elevated protein should prompt an MRI of the spine as a spinal tumor may be causing the increased ICP [,]. The differential diagnosis also includes indolent infectious diseases, such as tuberculosis and inflammatory entities including sarcoidosis []. This is a very treatable pathophysiology, especially if identified early. Patients are placed on acetazolamide—Diamox Sequels provide extended release—and can be dosed at 500 mg PO BID [,]. When caught early, vision is preserved. Weight loss alone may recommended in mild cases with minor symptoms and preserved visual function (vision, color, visual field, and mild papilledema). Once the process has caused central visual loss, the prognosis is guarded and admission for acetazolamide, and lumboperitoneal or ventriculoperitoneal shunting is the standard of care [,,,]. Venous sinus stenting is also an option in select patients. Optic nerve sheath fenestration is also an option but most helpful before the loss of central vision [,,,].

pmc-8700032-3

A 40-year-old woman presents to the ED with neck pain and non-specific neurologic symptoms including numbness, tingling, and headaches. She denies any other symptoms. A non-contrast CT of her brain is performed, which is normal. Tele-neurology is consulted, but her symptoms do not fit the stroke protocol, so no recommendations are made. The patient is discharged without any specific instructions for follow-up. Four weeks later she returns to the ED with bilateral visual loss. She first notices visual blurring several days prior to presentation. She denies any other neurologic symptoms, has no family history of vision problems, and is otherwise healthy on no medications. On examination she is unable to see anything on the eye chart but can appreciate light. Her pupils are round, reactive to light, and without an afferent pupillary defect. The anterior segment, IOP, and eye movements are normal. The ophthalmologist on call is contacted and recommends transfer to the university hospital 90 miles away. Tele-neurology is contacted, and they recommend a CT/CTA, which are both normal. They also recommend transfer to a university. A transfer is requested but all universities in the state were on diversion and refused transfer. Attempts to see the fundus with a direct ophthalmoscope are unsuccessful. Devastating unilateral or bilateral visual loss can occur due to a wide variety of causes. The differential diagnosis includes compressive, infectious, inflammatory, toxic, vascular, neoplastic, or hereditary causes [,,]. The initial evaluation in the ED can be very helpful in guiding therapy and preserving whatever vision is present. When a patient presents with visual blurring, the first step is to determine if the problem is in the retina or the optic nerve by taking a history and performing eye signs (i.e., vitals) including red desaturation, Amsler grid testing, and fundus photography [,]. The classic symptoms of retina vs optic nerve symptoms are presented in . Once it has been determined that it is an optic nerve issue, the age of the patient will guide the work-up even more than the appearance of the nerve. Prior to the advent of MR imaging, vague neurological symptoms were difficult to evaluate. Both multiple sclerosis and neuromyelitis optica have characteristic findings on MRI and lumbar puncture [,,]. Both are serious diseases that cause both visual and/or neurologic disabilities that can be permanent. However, treatment can be sight-saving as described in . presents the most common etiologies of bilateral vs unilateral visual loss. A non-contrast CT is an inadequate test for this population. If the testing is done prior to visual loss, the patient can be treated with IV steroids and referred for outpatient initiation of definitive therapy [,,,]. Distinguishing between MS-related optic neuritis and NMO-related optic neuritis is of prime importance because early initiation of effective immunosuppressive therapy is key to preventing relapses and permanent disability—see [,].

pmc-8700032-4

A 50-year-old man presents with acute onset of double vision. His eye vitals are otherwise normal. He has a past medical history significant for diabetes, hypertension, and hypercholesterolemia. He denies headache or eye pain. The ophthalmologist on call was unable to be reached. The tele-neurologist recommended a non-contrast CT/CTA, which was reported to be normal. No additional testing was done, and the patient was discharged and told to follow-up with an ophthalmologist. One week later, the patient is found down and arrives at the ED in an ambulance. The patient never regains consciousness and passes away from a ruptured aneurysm. Managing double vision can prove equally as challenging as managing visual loss without an accurate ophthalmic examination. In a university-based ED setting, patients are typically seen in person by the ophthalmology residents on call, who are in turn supervised by a neuro-ophthalmologist. The neuro-ophthalmologist is then able to confirm a clinical diagnosis of a cranial nerve palsy or any other etiology of double vision. Depending on the diagnosis, the appropriate radiologic imaging protocol is followed and then interpreted by a neuro-radiologist. In the community-based ED setting, this stepwise evaluation and approach is not readily available. In this setting, a very helpful starting point is to take comprehensive external photos of the patient in the nine positions of gaze (i.e., straight ahead, up, down (with eyelids held up), left, right etc.). A list of the recommended diagnostic work up for common causes of double vision are presented in .

pmc-8700032-5

A 58-year-old Caucasian man did a video visit with his primary care physician, in which he complained of severe pain in the distribution of his herpes zoster that had occurred years before. No vesicles were visible. He was placed on nonsteroidal anti-inflammatory during the day and Tylenol with codeine at bedtime. Despite receiving the Pfizer COVID vaccination seven months earlier, he presented to the ED with a fever, fatigue, muscle aches, sinus congestion, and a cough. COVID PCR testing was positive, but chest X-ray was normal. A comprehensive metabolic panel and complete blood count were normal. He was discharged to quarantine at home. Two days later, the patient returned to the ED with acute loss of vision in both eyes to 20/400, no relative afferent pupillary defect was present, and fundus photography in the ED with non-mydriatic camera was normal. Additional laboratory assessments that were found to be abnormal included elevated erythrocyte sedimentation rate (40), C-reactive protein (33), and D dimers (2000). Chest CT revealed ground glass changes consistent with COVID-19; pulse ox revealed diminished saturation of 88%. A non-contrast head CT was normal, but an MRI of the brain and orbits revealed a large occipital stroke. The patient was admitted for Decadron, anticoagulation, and supplemental oxygen. Access to the monoclonal antibody was denied. The inflammatory markers and D dimer normalized, and pulmonary function improved. The visual loss was permanent. COVID-19 (SARS-CoV-2) infections classically present with symptoms of fever, cough, fatigue, muscle aches, and neurologic alterations that result in loss of smell and taste [,,]. The neurologic and ocular manifestations are less well known, and the understanding of optimal management is in evolution. It has been postulated, however, that live virus can potentially be found in the tear film [,,,]. Additionally, the virus can travel via ACE2 receptors through intact ocular epithelium and the endothelial lining of organs [,]. Ocular symptoms can be as mild as hemorrhagic conjunctivitis to as vision-threatening as retinal vascular occlusions and posterior ischemic optic neuropathy as listed in [,]. Though the literature is limited, there have been several reported cases of the latter. In these cases, the typical presentation to the ED is with complaints of acute, painless, monocular, or binocular vision loss in the setting of a previous or recent diagnosis of COVID-19 (though this has also been reported in patients with a previous COVID-19 diagnosis > 3 months) []. Oftentimes, these patients have multiple chronic conditions that make them more susceptible to a more severe disease course. Positive patients with elevated inflammatory markers (IL-6, CRP, ESR, and fibrinogen) and d-dimer are at the highest risk for visual loss [,,]. Thus, it is very important for the clinician to have a high index of suspicion for the patient that presents with elevated markers. Given that COVID-19 lowers the threshold for thrombotic complication, especially in the chronically ill, Decadron and anti-coagulation may prevent visual loss in patients with cytokine storm and hypercoagulability [,]. In certain cases, this may mean expedited complete visual recovery whereas in other instances, vision may improve spontaneously over time if at all [].

pmc-8700092-1

We herein present a case that was recently managed at our institution, the Department of Surgery of the San Camillo Forlanini Hospital of Rome, Italy. A 53-year-old man with previous history of alcohol-related liver cirrhosis presents to our department for routine follow-up. His comorbidities include hypertension managed with oral antihypertensive drugs and diabetes mellitus type 2. He has no significant allergies and never underwent any surgical procedure. He brings an ultrasound, which shows a 4 cm heterogenous mass in segment 8. His alfafetoprotein level is elevated to 76 ng/mL. He has no symptoms and looks in good performance status. We scheduled him for a triphasic CT scan, which shows a lesion of 4.3 cm with brisk arterial contrast and venous washout. According to the LIRADS classification, this lesion could be considered a class 5 with diagnostic features of hepatocellular carcinoma. The patient was discussed in our multidisciplinary tumor board including hepatobiliary and transplant surgeons, hepatologists, radiologists, pathologists, oncologists, and interventional radiologists. The plan was to submit the patient to curative intent treatments given his early presentation according to the Barcelona Clinic Liver Cancer Staging System (BCLC), namely surgical resection or liver transplantation; radiofrequency ablation was excluded given the tumor’s dimensions. Given the good performance status, the position of the lesion (which was right below the Glissonian capsule) and the liver function of the patients, the MDT decided to schedule the patient for surgery. We therefore saw the patient in clinic and discussed the procedure. Informed consent was signed, and liver function was tested using ICG retention rate. We used 0.5 mg/Kg corresponding to 40 mg in this 80 kg patient. The DICOM data of the CT scan of the patient were then submitted to our radiologist who performed a 3D reconstruction of the patient’s anatomy and the relationship of the lesion with the major vessels. Furthermore, the exact dimensions of the portal territories for segment 8 were reconstructed and showed on the model. We normally aim at the narrowest but still oncologically safe resection possible. The surgery is then planned on the model, identifying the borders of the resection and the exact location of the Glissonian pedicle to tackle and the hepatic veins to skeletonize and cut. Once the preoperative surgical plan is discussed between the surgeons and the radiologists, the patient can be scheduled for surgery. This generally happens 2 weeks from the administration of ICG to achieve a complete washout of the dye by the normal parenchyma and a retention by the tumor that will then be showed intraoperatively using the narrow band camera. The patient is scheduled for a laparoscopic anatomical segment 8 resection. In our experience, we use the so called “French position” to operate laparoscopic cases, with the patient standing in between the legs of the patient and two assistants on each side. Two screens in the operating room are dedicated to the endoscopic vision, one screen is dedicated to the intraoperative ultrasound, while one dedicated screen allows to show the preoperative surgical planning and therefore guide the resection throughout the case. We use a five-trocar technique with 1 umbilical port and 4 ports on the subcostal line. One port is epigastric and is very important for the dissection of the hepatocaval confluence. An extra 5 mm access is used to perform an extracorporeal Pringle manuever. Open laparoscopy access is gained at the level of the umbilicus. After inserting all the trocars, the narrow band camera is used to identify the HCC on the hepatic dome on segment 8, which is shining green because of the ICG administered 2 weeks before. Intraoperative ultrasound and doppler are then performed to confirm the border of the resection. Pringle manuever is prepared. Dissection is started from the hepatocaval confluence to immediately identify the middle and right hepatic veins. For segment 8 resections, no extensive right lobe mobilization is necessary unless exposure is limited. We then start our parenchymal transection using a combination of energy-based device clamp-crushing technique, CUSA dissection and bipolar coagulation. We identify the middle hepatic vein at its origin, and we carry our parenchymal transection in a cranio-caudal fashion, sweeping the liver parenchyma from the vein. This avoids any tearing on small peripheral branches of the middle hepatic vein. Slowly progressing caudally, we encroach the Glissonian pedicle for segment 8, going to the lesion and vascularizing the tumor bearing area. We test the pedicle using a bulldog clamp and checking with the doppler the absence of flow in segment 8 and the presence of flow in the remnant liver. We then ask the anesthesiologist to inject 1 mL of ICG intravenously. We will then see all the liver shining green but not segment 8, which is our resection area. Guided by the ICG we will then carry out the anatomical resection. The Glissonian pedicle is stapled, and the resection is carried out dissecting the whole resection area from the middle and right hepatic veins. Once the resection is finished, the vascularization of the remnant liver is checked both with the ICG and the doppler. A drain is generally not placed unless there are specific issues during the procedure. The patient was placed on a fast-track protocol with early feeding and mobilization and was discharged home on postoperative day 4. Follow up is now more than 1 year and the patient is currently in good health status with no signs of recurrence.

pmc-8700140-1

: A 60-year-old female was treated for NTG elsewhere but had been referred to our clinic with deterioration of the visual field. Her BCVA were 0.8 and 0.1, right and left, respectively, and she had normal intraocular pressure (IOP) (19 mmHg). Her parents were both treated for glaucoma, which could account for positive family history (treated with caution as we had not seen the parents). As both optic discs did not look glaucomatous, they looked a little pale but not excavated. The disc appearance did not match very advanced visual fields, so the patients’ drops were discontinued. The patient, seen 3 months later on follow-up visit, exhibited further deterioration of the visual fields with concomitant left vision loss. The BCVA had deteriorated to 0.2 and 0.02, right and left, respectively. An MR scan revealed olfactory groove meningioma that was successfully and subtotally removed by bilateral craniotomy. The BCVA improved to 0.9 and 0.9, right and left eye, respectively, and the VF improved significantly (RE completely, LE—significant loss remained). Summary: this is a case of rapid bilateral vision loss with regard to the BCVA and VF (too rapid for glaucoma), in addition, VF did not match optic disc appearance. Positive or “pseudo-positive” family history may be misleading, causing protracted, unnecessary topical treatment, especially in case of putative NTG.

pmc-8700140-2

: A 56-year-old male treated for POAG with high IOP (30–48 mmHg) for a couple of years but after initial success of drops, he was referred to the clinic due to high pressures (over 40 mmHg). His mother was blind due to glaucoma (confirmed). He underwent trabeculectomy in both eyes when BCVA was 0.5–1.0, but 3 years later, vision deteriorated in both eyes (especially in right eye) despite IOP being maintained around the low teens. VF loss observed over 3 years seemed to be consistent with glaucoma and the island of central vision was lost last. The rapid decrease in central visual acuity in the presence of low and stable IOP was the reason for neuroimaging. He had an MR scan done that revealed an intracranial meningioma that was totally resected by bilateral craniotomy. The right eye is blind and the left eye has some useful VF with BCVA around 0.1 and has been stable for 2 years now. Summary: this is true high tension primary glaucoma with a family history that progressed despite successful filtering surgeries. The true family history does not exclude intracranial malignancy, if the course of glaucoma is not typical (long-lasting deterioration after successful IOP drop and atypical pallor of the disc). It is difficult to determine the exact impact of high IOP vs. anterior visual pathway compression on vision loss in this patient. Additionally, disc pallor, a typical sign of compressive neuropathy, may be observed also in juvenile glaucomas or in cases with extremely high values of IOP.

pmc-8700140-3

: An 82-year-old male was treated for NTG elsewhere but referred to our clinic for consultation and for left ptosis surgery. His BCVA were 1.0 and 1.0, right and left eye, respectively, and he had normal IOP (14 mmHg). On ophthalmoscopy, both discs look glaucomatous, but the left disc more advanced. Only the left eye exhibited VF changes typical for glaucoma that corresponded ideally with a retinal nerve fiber layer thickness defect in OCT examinations. NTG was stable but unilateral. An MR scan was performed that revealed picture of 4 × 4 mm pituitary microadenoma contacting the chiasm. In three years’ observation, visual field and the tumor size remain stable. Summary: this is the case of unilateral stable glaucoma with coexisting pituitary adenoma. It is unclear if the combination of glaucoma and microadenoma is pure coincidence, or if the microadenoma is responsible for the neuropathy.

pmc-8700140-4

: A 65-year-old hyperopic female was referred to our clinic because she developed left eye pallor with consistent VF loss. Her BCVA was 1.0 with correction +4.5 DSph and 0.5+ with correction +4.5 DSph, right and left eye, respectively. The IOP was 15 and 16 mmHg, right and left eye, respectively. Her angle in gonioscopy was narrow (I/II deg.), but neither acute nor prodromal glaucoma were confirmed, which is why an MR was performed. It revealed a left optic nerve sheath meningioma measuring 11 × 12 × 7 mm involving optic nerve canal. The tumor was totally removed by left craniotomy and pathology confirmed a diagnosis of psammomatous meningioma. The patient is stable and continuously observed; the BCVA 2 years after surgery is the same, 1.0 and 0.4, right and left eye, respectively. Summary: this straightforward case of unilateral pallor of the optic disc justifies outright MR but, nevertheless, an MR may be retarded by the belief that a unilateral NTG could exist even without excavation, or by the suspicion of acute angle closure in the past. After acute angle closure in the disc, more pallor than cupping may be observed.

pmc-8700140-5

: A 70-year-old female was referred to our clinic because her NTG progressed. Her BCVA was 0.5 and 1.0, right and left eye, respectively. The IOP on glaucoma drops was 15 and 16 mm Hg, right and left eye, respectively. Both discs looked clearly glaucomatous with C/D = 0.8–0.9 with disc hemorrhage on the right side. However, the VF revealed bitemporal hemianopia hiding typical glaucomatous field loss. An MR scan was immediately performed and revealed pituitary macroadenoma (24 × 30 × 20 mm) affecting the chiasm. The tumor was removed by transsphenoidal resection. The VF improved very rapidly after surgery and has remained stable for 4 years. Summary: this is a typical case of pituitary macroadenoma affecting the chiasm with progressive VF loss and typical bitemporal hemianopia. Coexistence of true glaucoma is rare; interestingly, the progression of glaucoma was halted after the tumor was excised. The influence of the adenoma on the optic disc appearance is uncertain.

pmc-8700269-1

A young man was killed by a 30-year-old man after they had consumed alcohol and cocaine. The murderer claimed he was not capable when he committed the crime because he suffered from an alcohol-/drug-caused behavioral impairment producing neurological damage, having regularly consumed alcohol and drugs since the beginning of adolescence. In detail, he reported to have started habitually consuming alcohol, cannabis, cocaine and amphetamine when he was a teenager. The defendant also claimed to be predisposed to anti-social behavior because of genetic factors. Indeed, his forensic consultant performed a genetic testing on him focused on three genes (MAOA, COMT, SLC6A4), finding that he was a carrier of the polymorphisms of 5-HTTLPR (fragment 44 bp–SS genotype) and COMT (Leu136Leu) in homozygosity. Hence, the court requested a team of forensic experts to assess the capacity of the defendant, performing toxicology testing and a complete neuropsychiatric evaluation. Toxicology testing was performed on urine (four days after the murder), saliva (two days after the murder), blood and pubic hair (10 days after the murder). In blood and saliva, it failed to find significant levels of drugs or alcohol, while in urine it detected benzoylecgoine (322 ng/mL). In the pubic hair, significant levels of cocaine (141 ng/mg), benzoylecgonine (21 ng/mg), and ethylglucuronide in concentration >30 pg/mg were found. A full clinical/neuropsychological examination was performed. No clinical signs of neurological impairment and no signs of alcohol-dependence were observed. A personality disorder not otherwise specified was diagnosed. 3-Tesla brain MRI and brain CT-PET were also performed. In MRI imaging, a decrease in cortical thickness with larger lateral ventricles, a statistically significant volumetric asymmetry of the amygdalae (the right amygdala was smaller than the left one) and a decreased volume of the right orbito-frontal cortex (OFC) (in comparison with the left one) were observed. No ischemic lesion or anomalies in the corona radiata and in the subtentorial/cerebellar area were found. PET-CT did not find any alteration of brain perfusion or metabolism.

pmc-8700269-2

A 25-year-old man abducted, raped and robbed two women under the influence of alcohol in six months. He reported that his father often physically and psychologically abused him and his mother during his childhood and that a teenager raped him when he was a child. He was unschooled and few years before the rapes he was convicted for having stabbed a man who had insulted him. After having been released, he committed several burglaries. Moreover, he reported to have frequently beaten his wife and to have often fantasized about raping women since he was very young, even if he knew rape was illegal. Finally, he reported to have begun to consume alcohol during his childhood, albeit he never became an alcoholic. Hence, the court requested a forensic psychiatrist to assess the capacity of the defendant. A full clinical/neuropsychological examination was performed. No clinical/electroencephalographical signs of neurological impairment and no signs of alcohol-dependence were observed. An intelligence quotient (IQ) of 59 was found and an antisocial personality disorder was diagnosed. A genetic test focused on five genes (MAOA, COMT, SLC6A4, HTR1B, and DRD4) found a 3-repeat variable number of tandem repeats (VNTR) variant of MAOA and a TT genotype for the rs13212041 polymorphism of the HTR1B gene.

pmc-8700282-1

A 27-year-old woman was diagnosed to have a fetus with left-sided CDH in her routine antenatal ultrasound (at 20 weeks gestation). Based on antenatal fetal imaging, the liver was in its thorax, the left lung was not visible, the right lung measured 1.95 × 1.67 cm and the lung-to-head ratio (LHR) was 1.275 (observed/expected LHR 29–33% [,], qualitative lung index/QLI 0.499), and percent predicted lung volume (PPLV) on fetal MRI was 20.5, all of which indicated poor prognosis []. Additionally, the fetal echocardiogram was suggestive of hypoplastic left heart syndrome (HLHS). The prenatal screening included amniocentesis with 46 XX karyotype and normal alpha-fetoprotein levels. The pregnancy was also complicated by polyhydramnios. An appropriate-for-gestational-age female infant was delivered by emergent cesarean section for fetal bradycardia after initial induction of labor at 39 weeks gestation. At delivery, she was apneic and floppy, and immediate cord clamping was performed. Her airway was intubated one min after birth, and a Replogle tube was placed to decompress her stomach. Her Apgar scores were 2, 5 and 8 at 1, 5 and 10 min, respectively. Her initial neonatal intensive care unit (NICU) course included gentle mechanical ventilation, followed by bedside surgical repair of CDH two weeks after birth. A postnatal echocardiogram confirmed small left-sided cardiac structures. She also had pulmonary hypertension (PHT) with supra-systemic pulmonary pressures that were managed with inhaled nitric oxide (iNO), milrinone infusion and sildenafil. She required a peripherally inserted central catheter (PICC) for parenteral nutrition and a gastrostomy tube placement to allow enteral feeding. Her respiratory support was gradually weaned to low flow nasal cannula at 0.5 L/min with 100% O2, received Palivizumab and was continued on oral sildenafil for mild residual PHT. Her microarray was normal. She was discharged home (located at a higher altitude) at 2.5 months of age, only to be readmitted two days later when she presented to the local emergency room with fussiness and emesis and developed respiratory failure, requiring endotracheal intubation. Her brain natriuretic peptide (BNP) was elevated at 4650 pg/mL and was diagnosed with pulmonary hypertensive crisis. During her second hospitalization in the NICU, she was extubated to nasal continuous positive airway pressure (CPAP) within three days after management with high settings on high-frequency oscillatory ventilation and iNO for hypoxic respiratory failure and PHT. However, she did not tolerate further wean in respiratory support, owing to worsening PHT. She had multiple episodes of PHT crisis with hypoxia and hypercarbia. To assess the V/Q status in her lungs, a nuclear medicine scintigraphy scan was performed at four months of age that showed 10% perfusion to the left lung in comparison to 90% to the right lung. A chest CT scan confirmed hypoplastic left lung. Cardiac catheterization at five months demonstrated worsening PHT, and she was restarted on iNO. Flexible bronchoscopy at five months showed gross narrowing of left mainstem bronchus and lobar bronchi. Due to continued PHT crises and an inability to remain extubated, she underwent a tracheostomy at 5.5 months. She had a BroviacTM (CR Bard, Salt Lake City, UT, USA) catheter placed for central venous access. She received several courses of dexamethasone, with minimal change in her respiratory status. At six months of age, the under-perfused left lung was emphysematous with a hyperinflated left lower lobe that caused a mediastinal shift to the right side (a). This led to compression of the right lung, further compromising gas exchange. At this stage, due to the futility of all efforts to improve her hypoxic respiratory failure and the severe ventilation/perfusion mismatch (V/Q mismatch) in her left lung, a multidisciplinary discussion involving cardiology, pediatric surgery, pulmonology and neonatology was held to determine the next steps in her management. A trial on different ventilator modalities with higher positive end-expiratory pressure (PEEP) and another course of dexamethasone did not result in any improvement (b). Given her labile nature with significant PHT and oxygenation concerns, there was concern if she would benefit from a lobectomy given the high risk of a procedure. A decision was made to trial left main bronchial plugging by placing an inflatable 5Fr bronchial blocker to determine if improving V/Q mismatch by allowing better ventilation of the better perfused right lung segments may facilitate a decrease in respiratory support. We used two separate portable video laryngoscopes (VL), one equipped with a miller 1 blade and the other with a flexible fiberoptic bronchoscope (FFB). A 5 Fr Uniblocker (Fuji Systems, Tokyo, Japan) was guided through the glottic opening under visualization by the miller 1 blade VL. The bronchial blocker was guided into its final position and the balloon was inflated with the help of FFB. The position of the bronchial blocker was confirmed by a chest radiograph (a,b). The left bronchial blocker placement resulted in an immediate improvement of her respiratory status with a decrease in oxygen requirement and improved ventilation with weaning of ventilator settings, and better inflation of the right lung (a,b). The adverse effects of the bronchial blocker placement included displacement, which required replacement under visualization by anesthesiology. Therefore, surgical exploration was subsequently performed by anterolateral thoracotomy, 80% of the emphysematous left upper lobe was resected (), a small area of the left pulmonary sequestration was also identified and a chest tube was placed. Physiological and blood gas changes are shown in . Respiratory support was weaned as tolerated, her chest X-ray improved (b) and she was discharged home two months after surgery.

pmc-8700299-1

In July 2019, a 74-year-old male patient was admitted to the Infectious Disease Section of the Verona University Hospital for investigation; he had HBV in his blood with a titer of 26,100,000 IU/mL (cobas® HBV, Roche Molecular Diagnostics, Branchburg, NJ, USA) but exhibited normal liver function. Although he displayed the hepatitis B e antigen (HBeAg), he was negative for the HBsAg, but positive for the homologous anti-HBs (ADVIA Centaur HBV assays, Siemens Healthcare GmbH, Erlangen, Germany). In August 2013, the patient received a kidney transplant for nephroangiosclerosis. At this time, the serologic screening for HBV had shown that he was HBsAg-negative, anti-HBs-positive (12 mIU/mL), HBeAg-negative and positive for antibodies to the HBeAg and to the hepatitis B core antigen (anti-HBc). No antibody markers of a hepatitis C and hepatitis D virus infection were detected; serum HBV DNA had not been determined. The indices of hepatic cytolysis were normal. The kidney donor was negative for HBV. Post-transplant, the patient received immunosuppressive induction with basiliximab, tacrolimus, mycophenolate and steroids, and was then included in the follow-up program as per protocol; the HBsAg remained negative throughout, accompanied by normal liver biochemistry. In May 2019, the patient developed chronic myeloid leukemia (CML). Before treatment with imatinib mesylate, the patient repeated the HBV serology and the HBeAg was again detected in his blood in the absence of circulating HBsAg; further testing using a real-time PCR showed that he had HBV DNA in serum at a titer of 26,100,000 IU/mL. The patient was still anti-HBs-positive (15 mIU/mL) with normal liver enzymes. A diagnosis of HBVr was made and, in July 2019, the patient started entecavir (ETV) treatment at 0.5 mg/day, which was subsequently reduced in April 2020 to 0.5 mg/48 h because of renal function deterioration. The patient underwent a close follow-up (every 2 weeks) for the first 6 months of treatment and, after, with monthly scheduling. The therapy led to a consistent decrease in viremia, reaching a plateau of 3 Log10 HBV DNA reduction after 6 months of treatment (); however, viremia did not decrease further in the following months. No classic ETV-resistant mutations were observed in the HBV reverse transcriptase (rt) gene. However, we detected the mutation rtL269I, previously reported to confer a reduced susceptibility to ETV []. On January 2021, the patient switched to tenofovir alafenamide (TAF) treatment; HBV DNA rapidly declined and reached a value of 378 IU/mL at the last FU. The single ALT elevation (107 U/L) in the 2nd month of TAF treatment was documented in the course of an infection of the residual left limb requiring surgical toileting. Unfortunately, the patient died from coronary heart disease in September 2021. The serum samples collected from July 2019 were tested for the HBsAg with the highly sensitive Lumipulse® G HBsAg-Quant assay (Fujirebio Inc., Tokyo, Japan) as well as for the HBcrAg (Lumipulse® G HBcrAg, Fujirebio Inc., Tokyo, Japan) []. The nucleotide sequences of the HBV S gene and the rt domain were determined using the Sanger sequencing method at BMR Genomics service (BMR Genomics, Padua, Italy) and analyzed using ClustalW2 software (; accessed on 23 December 2019 and on 6 December 2020) []. The HBV genotype was determined based on a reverse hybridization line probe assay (INNO-LiPA HBV Genotyping, Fujirebio Europe, Gent, Belgium) []. Despite its high analytical sensitivity for HBsAg mutants [], the HBsAg assay failed to detect a circulating HBs antigen. The HBV S gene sequence analysis identified four mutations within the a-determinant (aa 124–147) (P/T127H, Q129N, F/Y134H and G145R) and five additional mutations within the mayor hydrophilic region (MHR, aa 99–169) (T116N, P120S, C121Y, K/R160S and W165S) (). The values of the HBcrAg from baseline to the end of the follow-up were persistently above the upper limit threshold of the assay (>7.0 Log10 U/mL). Viral genotyping showed that the patient was infected with HBV genotype D.

pmc-8700368-1

We report the case of a 4-year-old male child, admitted to our clinic for generalized seizures, which persisted in spite of anticonvulsant therapy (Diazepam), with no previous acute symptoms. His personal history revealed ureterovesical junction obstruction, mild hydronephrosis, and an episode of generalized seizures approximately 2 months before the current admission for which chronic therapy with sodium valproate (Depakine) was recommended. We must mention that the brain MRI performed at that time was normal. The family history showed the presence of ageusia and anosmia in both parents. At the time of admission, the patient was intubated and mechanically ventilated and the clinical exam revealed only pallor. The laboratory tests performed on the day of admission revealed anemia (Hemoglobin—Hb 9.98 g/dL, Hematocrit—Htc 28.54%), a severely increased number of monocytes (9624/µL), and a mildly increased C-reactive protein (CRP 7 mg/L). Taking into account the family history, a real-time polymerase chain reaction (RT-PCR) of the oropharyngeal swab was performed and it tested positive for SARS-CoV-2. Moreover, both parents were confirmed with this infection. Both urine and blood cultures were negative. The serology for viral hepatitis B and C, as well as antinuclear and anti-double-strained DNA antibodies were negative. We performed a thoracic computed tomography (CT), which showed consolidation in the lower lobe of the left lung associated with an opacity in the right apex, suggesting possible atelectasis ( and ). The cranial CT revealed no pathological findings. The patient was admitted to the intensive care unit with a diagnosis of COVID-19 in a severe form. We initiated antibiotic treatment (ceftriaxone 800 mg twice a day and amikacin 100 mg twice a day), antiviral therapy (lopinavir/ritonavir 2.5 mL twice a day), corticosteroids (Dexamethasone 4 mg twice a day), anticoagulants (enoxaparin 0.2 mL in a single daily dose), and antipyretics (Paracetamol), and we continued the chronic anticonvulsant therapy with sodium valproate. The second RT-PCR performed on the third day of admission was also positive for SARS-CoV-2 infection. Unfortunately, the patient’s condition deteriorated progressively, and, after approximately 72 h of hospitalization, he developed desaturation and bradycardia. We repeated the laboratory parameters before the bradycardia event and we found leucopenia (leukocytes 3500/µL), neutropenia (neutrophils 1111/µL), mildly increased creatin kinase (280 U/L), a high ferritin level (121 ng/mL, normal ranges 7–84 ng/mL), hypoalbuminemia (3.29 g/dL), a prolonged time of prothrombin (22.3 s) and an increased international normalized ration (INR 1.74). Despite all efforts to resuscitate the patient, he died on the fourth day of admission.

pmc-8700459-1

A 43-year-old Caucasian male reported a 1-month history of spontaneous clear left side nipple discharge with a recent appearance of a homolateral painless breast swelling. There was no history of bloody discharge. Past medical history was pertinent for obesity class I (BMI: 33.3) and bilateral hypoacusia for otosclerosis. There was no family history for breast or ovarian cancer. His social history indicated no use of alcohol, but previous use (twelve years ago) of tobacco products. On physical examination, he was an overweight Caucasian male with symmetrical breasts. On palpation, there was a bilateral pseudogynaecomastia with a smooth, ill-defined left breast thickening, especially at the union of the outer quadrants. With applied pressure, a minimal clear stream of discharge fluid was elicited from the left nipple and was felt to be localized to a single duct. Digital breast tomosynthesis (DBT) with synthesized reconstructed 2D images (s2D) was performed in medio-lateral-oblique (MLO) projections for each breast and in both cranio-caudal (CC) and latero-medial (LM) projections for the left breast. The s2D images showed a regular appearance of the breast buttons without gynaecomastia, and an area of asymmetrical density at the union of outer quadrants of the left breast that was better identified at the DBT images as an area of architectural distortion with scattered peripheral punctate calcifications, sparing the nipple-areolar complex. (). A breast ultrasound (US), performed on the same day, showed in correspondence of the mammographic findings, the presence of an ill-defined, hypoechoic area of acoustic shadowing with peripheral anechoic lacunae and a close small focal ductal ectasia. () According to Breast Imaging Reporting and Data System (BI-RADS) [], these findings were classified as category 4b. An US-guided Fine-Needle Aspiration Cytology (US-FNAC) was performed. Our laboratory received 4 microscope slides fixed in alcohol and coloured with Papanicolaou stain. Microscopic examination showed atypical ductal cells with poor myoepithelium arguing for several types of proliferative non-malignant lesions but also DCIS. According to the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytopathology (1st Edition, 2020) [], these findings were classified as category C4 (). Since the Rapid On-Site Evaluation (ROSE) [] already showed this suspicious atypia, we contextually performed an US-guided biopsy (US-CNB) with a 16 Gauge (G) semi-automated core biopsy needle. Our laboratory received two specimens of breast tissue of 1.5 cm of maximum dimension who were submitted for routine processing. Microscopic examination showed breast parenchyma with fibrosis with a focal area of atypical ductal hyperplasia (ADH), p63 positive and with focal positivity for CK5/6. According to Guidelines for non-operative diagnostic procedures and reporting in breast cancer screening [], these findings were classified as category B3 (). All the findings of cytology and histology in association with the radiological assessment underlined the importance of the triple test [] and recommended us to perform surgical excision of the suspected area. Therefore, after discussing with the multidisciplinary team (MDT), according to the patient’s consent, a left subcutaneous nipple-sparing mastectomy was performed without sentinel lymph node biopsy (). Our laboratory received a specimen designated left mastectomy, weighing 90 g (). It comprised oriented fibro-fatty tissue, 8 × 4.5 × 4 cm in aggregate, which on gross examination revealed an area of small cystic formations and a whitish lesion of 0.2 cm on which random samplings were performed. Microscopic examination showed an intraductal papilloma (IP) with ADH and a single focus of DCIS solid-cribriform type, respectively. Nuclear grade was 3 (p63+, CK5/6−) with negative surgical margins. No invasive cancer was present (). The specimen was sent for immunohistochemical examination of estrogen (ER) and progesterone (PR) receptor. The tissue was positive for both ER (with 70% of nuclei staining with strong intensity) and PR (80% of nuclei staining strongly) (). Venipuncture samples were subsequently sent to an external laboratory for genetic analysis, the results of which were negative for BRCA1 and 2, and other mutations (). According to these surprising results, after a clinically and radiologically evaluation of the left axillary lymph nodes, the MDT decided not to perform axillary dissection and to administer tamoxifen as approved adjuvant hormone treatment of men with ER-positive early stage breast cancer []. The patient was noted to be doing well 6 months post-operatively and is still on follow-up at the time of writing.

pmc-8700490-1

In December 2020, an 83-year-old woman presented to the Emergency Department of our hospital with a large ulcerated and necrotic bulging lesion on her forehead. Ill-defined, dusky erythematous plaques extended on the parietal and frontal areas of the scalp and the face. Violaceous-darkish nodules were also observed. Comorbidities included chronic obstructive pulmonary disease, hypertension, diabetes, and ischemic encephalopathy. The physical examination revealed bilateral cervical lymphadenopathy. The patient’s relatives provided photographic documentation of the evolution. The lesion had emerged four months before admission as a 2 cm bruise-like patch on the forehead (a), before it rapidly developed into a large purplish plaque after 1 month (b), and then to the current presentation (c). The second lockdown in Italy and the fear of the SARS-CoV-2 contagion had led the relatives to postpone the medical evaluation. A biopsy from a violaceous nodule showed a full dermal proliferation of irregular anastomosing vascular channels lined by single or double layers of enlarged endothelial cells, which permeated between collagen bundles, causing “collagen dissection” (a,b). The endothelial cells were large and pleomorphic, with vesicular nuclei and prominent nucleoli, and were immunoreactive for CD31, CD34 and ERG (c,d), with no observed HHV8 expression or MYC overexpression. These data confirmed the diagnosis of angiosarcoma of the scalp. All routine investigations were normal. Total body computed tomography (CT) showed cervical lymphadenopathy without brain or visceral metastases. Although radiotherapy and electrochemotherapy were considered, they were not performed due to the patient’s advanced age, comorbidities, and tumor size. The patient was referred to palliative care.

pmc-8700593-1

We describe the case of an 18-year-old boy presented with ASD associated with a mild intellectual disability (patient 5 in the tables). Informed consent was obtained from all subjects involved in the study. Regarding the familial load, the paternal uncle presents an anxiety disorder treated with a selective serotonin reuptake inhibitor. The proband is the first child of unrelated and healthy parents. He attended school with support, had good global functioning and social relationships with classmates, despite his social anxiety, and had progressive improvements in his social skills. At the age of 13 years old, after his summer break, social isolation acutely worsened, associated with a confusional state, psychomotor agitation, speech impairment, visual hallucinations, cognitive regression, a loss of personal autonomy, and increased anxiety. Quetiapine up to 300 mg/day and alprazolam 0.50 mg/day were prescribed, with complete recovery. Cerebral MRI and metabolic tests were unremarkable. Array-CGH test was not significant, showing a duplication of the long arm of chromosome 6, inherited from the father. At the age of 15 years old, the patient had another acute breakdown, which was treated with quetiapine 300 mg/day and had partial recovery (only affective symptoms partly improved) until one year later, when symptoms worsened, with disorganized thought, obsessive symptoms and rumination, catatonic behaviors, associated with asthenia, reduced autonomous mobility, persistent hyporeactivity to stimuli, stiffness in the limbs and hypomymia, apathy, and isolation. Upon initial evaluation in the psychiatric ward, physical examination was unremarkable. Quetiapine was replaced with aripiprazole, with gradual titration, starting with 2.5 mg/day and 2.5 mg increases every 4 days, up to 10 mg/day, with supplementary lorazepam, resulting in a transient improvement in the clinical picture. After 2 days, the boy showed signs of psychomotor retardation, hyperreactivity to stimuli, anorexia, and asthenia. Creatine kinase (CK) was in the normal range when he was discharged. After 7 days, given the worsening symptoms associated with increased obsessive thoughts, hyperthermia, and CK elevation, the boy was admitted in an emergency department and pharmacotherapy was immediately discontinued. The patient was hospitalized in an intensive care unit for 4 weeks, then in a pediatric ward for 1 week, and finally in our hospital for 10 days. During hospitalization, limb stiffness, perioral myokymia and myoclonus, facial amimia, uncoordinated movements of the tongue and difficulty swallowing, polypnea, tachycardia, and arterial hypertension were observed. Intravenous hydration, dantrolene, clonidine, intravenous benzodiazepines, and carvedilol were administered, followed by bromocriptine therapy and intravenous lorazepam 2 mg 5 times a day. A gradual improvement in vigilance, reduction of hypertonus, and resolution of hyperthermia were observed, with gradual motor improvement. After 8 days, blood results showed a reduction in CK (404 U/L, normal CK range 0–50 UI/mL) and a mild increase in liver enzymes (ALT 72 U/L). After being discharged from our hospital, the patient carried out monthly clinical and CPK controls, and after 6 months the patient had a general assessment in our hospital, with persisting control of previous clinical manifestations.

pmc-8700620-1

A 63-year-old man was admitted to our Respiratory Disease Unit at the University Hospital—Ancona, for a 6-month exertional dyspnea and bilateral pleural effusion prevalent on the ride side, detected on chest computed tomography (CT). He was former smoker without occupational exposure to asbestos. His medical history was remarkable for asymptomatic brain aneurysm, blood hypertension, multiple lumbar disc herniation. On admission to our unit, physical examination, oxygen saturation on room air, heart rate and blood pressure were normal, whilst breathing sound was suppressed at the third right lower lung fields. The patient first underwent a repeated CT scan that allowed us to rule out a pulmonary embolism and confirmed moderate right pleural effusion with parietal and visceral pleural thickening, in the absence of significant parenchymal abnormalities (). Thoracic ultrasound (TUS) revealed hyperechogenic pleural fluid with atelectasis of basal segments of the right lower lobe (); at thoracentesis, fluid appeared cloudy and yellow coloured, and a physico-chemical exam was consistent with exudate and microbiological tests, including an acid-alcohol-fast bacilli (AAFB) search, were negative (). A subsequent medical thoracoscopy (MT) revealed the presence of yellow pleural fluid (overall 1800 mL removed) and parietal pleura hyperemia with fibrotic plaques (). Ten pleural biopsies were obtained by forceps on parietal pleura and histopathological examination documented a large lymphoplasmacytic infiltration, fibrosis, reactive mesothelial cells and vascular proliferation, in absence of neoplastic lesions or granulomas; the final diagnosis was suggestive for non-specific pleuritis (NSP). An extensive diagnostic work-up, including echocardiogram, abdominal angiography CT scan, autoimmune, viral, and bacterial serology, failed to detect any potential known cause of NSP and blood tests were normal, except for a mild elevation of C-reactive protein. Thus, the patient was diagnosed with idiopathic NSP and therapy was started with steroids (Methylprednisolone 0.5 mg/kg, tapered in one month with clinical and radiological improvement. Six months later, the patient complained chest discomfort and mild dyspnea, and CT scan showed a relapse of small amount of right pleural effusion associated with diffuse pleural thickening; a PET-FDG showed slight captation on right basal parietal pleural without abnormal captations in other organs (). Due to the limited pleural effusion and the absence of sliding at TUS, we decided not to repeat thoracoscopy, but to refer the patient to the Thoracic Surgery Unit of Sant’ Andrea University Hospital (Rome) for a surgical pleural biopsy. Histological examination revealed a diffuse fibrosing pleuritis, with occasional hyaline features, fibrinous exudate, and a dense lymphocytic and plasma cell inflammation. Interestingly, inflammatory infiltrate was diffuse but with irregular distribution throughout the histological specimen. Immunoperoxidase stains showed a marked increase of IgG4 positive plasma cells (up to 50/HPF) with an IgG4+/IgG+ ratio >40% reaching the diagnostic threshold level for IgG4 disease []. High IgG4 serum levels were found (324 mg/dL) []. Based on these findings, the patient was diagnosed with IgG4-related pleuritis (). After exclusion of systemic involvement of IgG4 disease, steroid therapy was started (Prednisone 0.5 mg/kg/d for 2 weeks, tapering up to 2.5 mg/day as a maintenance dose for an overall period of 6 months) with a complete and stable resolution of pleural effusion, improvement of respiratory symptoms and a progressive reduction of IgG4 serum levels, returned within normal limits (64 mg/dL).

pmc-8700622-1

We report the case of a 2 months old female, presented for consultation due to the presence of a lump on her left thigh, with progressive and constant growth after birth. The lesion was first described on the prenatal ultrasound at 30 weeks of gestation as a pre-femoral soft tissue mass of 20/7 mm (). The patient was delivered by cesarean section due to fetal distress but was otherwise normal at birth. Development was normal, and there was no relevant family history. On clinical examination, there was a 25/10 mm nodule on the antero-intern side of the left thigh that was firm, mobile and within the deep layers. The overlying skin was normal. There were no other lesions elsewhere on the patient’s body. The initial X-ray and ultrasound (US) showed a pre-femoral soft tissue mass that measured approximately 30/13 mm, with nonhomogeneous structure, hypoechoic areas, calcifications, and weak Doppler signal, being located anteriorly to the vascular elements of the thigh (A). Abdominal ultrasound was normal. Magnetic resonance imaging (MRI) showed a mass of 19.33/15.19/34 mm, with a nonspecific vascular involvement (B). In T1-weighted images, the MRI appearance consisted of a low signal. In T2-weighted fat-saturated images, a high signal intensity of the lesion was shown with nonhomogeneous contrast setting after intravascular contrast was administered, but with late homogenization, located on the antero-internal part of the left thigh with an important mass effect on the left vastus intermedius muscle. The lesion was considered to be probably a schwanoma of the left saphenous nerve. Elective surgery was scheduled. An italic S-shaped incision on the antero-internal face of the left thigh was performed, from the crural arch distally extended for about 6 cm. A mass of approximately 4 cm × 1.5 cm × 1.5 cm was revealed, which included the entire thickness of the sartorius muscle (A,B). In the 1/3 medial part of the tumor, dissection was performed, isolating it from the femoral vasculo-nervous package without opening the sheath of the vasculo-nervous canal. The sartorius muscle was resected at a distance of about 2 cm distal and proximal to the tumor, with complete tumor resection (C). Hemostasis was performed and adjacent tissue approximated. The excised mass was sent for pathological analysis. The patient had a favorable surgical outcome and was discharged 3 days postoperatively. At one year after surgery follow up, the child had no recurrence. Histologically, the mass in the sartorius muscle was noted as a proliferation of tapered cells arranged in an irregular spiral pattern and crossed by thin-walled vessels. In the central region, biphasic proliferation consisting of nodules with necrosis and central calcifications was observed, and between the nodules, fusiform cell proliferates arranged in small intersecting bundles (A,B). Occasional micronuclei were evident. A pseudocapsule formed by a thin layer of connective tissue <1 mm covered the mass. Neoplastic proliferation encompassed residual skeletal muscle fibers in the center of the lesion. Extracapsular and peripheral scarce mature adipose tissue were seen with isolated large-caliber blood vessels. Immunostaining revealed the following results: vimentin positive, smooth muscle actin positive in nodules with necrosis and calcifications (miotic nodules), desmin focal positive, Ki67 low (about 5 positive cells per 100 tumor cells, suggesting low cell kinetics) (D–F). Diagnosis of IM of left sartorius muscle was made.

pmc-8700649-1

Case 1 was a female child aged 7 years and 11 months. She had visited the hospital with a chief complaint of cold water pain in the anterior mandible. She had a history of trauma to the anterior primary teeth, including the lower right central incisor, right lateral incisor, and left lateral incisor, at 3 years of age. Hypomineralized areas, brownish-white in color, were observed on the labial side of her lower bilateral central incisors (). There was no past medical history. Genetic screening was not performed; the permanent tooth hypomineralization was thought to be caused by primary tooth trauma. The patient also complained of pain from air blowing and cold water, and the VAS value was 6.5. Immediately after the treatment to suppress the hypersensitivity, she no longer experienced pain with air or cold water, and VAS was zero. When patient came to the hospital one month later, her VAS score showed 4; therefore, the treatment was reapplied. After the fourth treatment, the hypersensitivity had not completely disappeared, and the VAS was 1. For the seventh treatment, patients’ VAS value of hypersensitivity pain were stable at 0.5–0. Furthermore, the surface of the brownish tooth had changed to appear almost cloudy after seventh treatment (). During the process of this treatment, discolored devitalized teeth, gingival inflammation and percussion pain did not appear. Digital analysis indicated a pre-treatment cloudiness of 6331 pixels, which was significantly reduced to 65 pixels after treatment (). In addition, the area of brown color decreased by approximately six-fold, from 12,898 to 2118 pixels. These results suggest that both cloudiness and brown color disorder were significantly improved.

pmc-8700649-2

Case 2 was a male child aged 8 years and 7 months. He visited the hospital with a chief complaint of pain in the anterior maxilla following exposure to cold water. He had a history of trauma to the anterior primary teeth at the age of one year, with composite resin repair of a fracture in the crown of the upper right primary central incisor. There was no past medical history. An abnormal position of the upper right permanent central incisor and clouding of the labial surface were observed, which were likely due to trauma to the primary teeth (). Examination results indicated a VAS value of 6 for cold water and 7.5 for air blowing. Immediately after treatment, the patient no longer felt pain with air or cold water, VAS was zero. One month later, the VAS was 4 by cold water and 5 by air. The treatment was reapplied once monthly. The hypersensitivity had become acceptable to the patient and VAS was 2 after fourth treatment. During the seven treatments, the pain did not completely disappear, the VAS by cold water was 1–2, whereas the VAS by air was 2–4. While extensive clouding remained, the color tone was obscured and improved (). During the process of this treatment, discolored devitalized teeth, gingival inflammation and percussion pain did not appear. Digital analysis showed significantly reduced cloudiness from 27,886 pixels to 7904 pixels (). The hypomineralized tooth was mostly cloudy, with a narrow area with a brown color. However, this area significantly decreased after treatment (p < 0.03). This result indicated that not only strong cloudiness but also slight brown color were significantly improved.

pmc-8700649-3

Case 3 was a female child aged 8 years and 7 months. She had visited the hospital with a chief complaint of cold water pain in the left side of the maxilla. The left upper second primary molar was extracted because of apical periodontitis and root resorption due to severe caries, at 4 years of age. There was no past medical history. Dark brown hypomineralization was observed on the buccal tooth surface of the first premolars (). The patient also complained of pain from air blowing and cold water, and the VAS value was 4. Immediately after the treatment to suppress the hypersensitivity, her VAS was zero. When patient came to the hospital one month later, her VAS score showed 1; therefore, the treatment was reapplied. During the seventh treatment, the hypersensitivity improved, and the VAS was 0. The dark brownish tooth surface of the first premolars was changed to pale brown (). Digital analysis significantly reduced the area of the brownish tint from 4858 to 1755 (). On the other hand, cloudiness was not detected.

pmc-8700649-4

Case 4 was a male child aged 5 years and 9 months. He had visited the hospital with a chief complaint of cold water pain in the anterior mandible. There was no history of trauma and caries in the primary teeth and no other systemic history. The cause of hypomineralization in the permanent teeth was not determined. The brownish-white in color were observed on the labial side of his lower central incisors (). The patient also complained of pain from air blowing and cold water, and the VAS value was 3. Immediately after the treatment to suppress the hypersensitivity, his VAS was zero. After one month, VAS was reduced to 0.5 and VAS was zero after four treatments. Seven treatments improved the color of the hypomineralization (). Cloudiness areas improved from 6872 to 1903, and brown areas decreased significantly from 6595 to 1667 ().

pmc-8700686-1

A 54-year old woman underwent a fine-needle aspiration biopsy (FNAB) for a 2.3 cm rapidly growing thyroid nodule (). The cytological examination showed both solid groups and discohesive oxyphilic cells (Hürthle cells) in a background featuring lymphocytes. Based on these features, the FNAB was diagnosed as a low-risk indeterminate lesion (AUS/FLUS). Five months later, the nodule grew to 3.6 cm, and thus another FNAB was performed; a diagnosis of suspicious for malignancy was rendered. The patient underwent a total thyroidectomy (nodule 4.1 × 3.4 cm) with cervical lymph node dissection, and a removal of the internal right jugular vein that was invaded by the tumor. Microscopically, a Hürthle cell carcinoma with foci of paucicellular anaplastic cancer was diagnosed (Stage IVB; cT3b cN0 Mx/pT4b pN0 M0). In particular, large epithelial cells featuring granular eosinophilic cytoplasms, hyperchromatic nuclei with evident nucleoli were arranged in a solid and trabecular pattern alternated with scattered anaplastic spindle cells and necrotic areas. Immunohistochemical stainings for pancytokeratin and PAX8 were positive in both these components. Conversely, TTF1 was expressed by Hürthle cells only. Thyroglobulin (Tg) immunostaining was negative in both Hürthle and anaplastic spindle cells (). Two years later, because of the appearance of a hacking cough, a 18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) scan was performed and revealed several millimetric lung hypermetabolic areas. Over time, the serum Tg under LT4-suppressive therapy had increased from 0.15 to 19 ng/mL. Two months later, a computed tomography (CT) scan revealed the presence of multiple lung lesions, in particular one in the medium lobe invading the airways (21 mm diameter), a second in the right inferior lobe (4 mm diameter) and a third in the left lung (9 mm diameter). A transbronchial biopsy of the largest lesion was performed, and the histology was consistent with a thyroid cancer metastasis. On January 2019, the patient came to our observation, 18FDG-PET/CT showed a further increase in the number, size and FDG uptake of the lung lesions, and the appearance of multiple lymphadenopathies in the neck and mediastinum. In particular, the lesion in the right inferior lobe had grown to 8.5 cm, with a SUV max of 50. The histology of the tumor has been reviewed by two independent pathologists who confirmed the diagnosis of ATC. The molecular test performed on the primary thyroid tumor for BRAF, NTRK and ALK mutations was negative, and chemotherapy with cisplatin plus doxorubicin was given. After three courses of treatment the disease was stable, but after three further courses the disease progressed. The patient was then given four courses of paclitaxel; however, the disease continued to progress. Immunohistochemistry for PD-L1 performed on the primary tumor was negative, but the presence of tumor-infiltrating lymphocytes (TIL) was noticed. The primary tumor was also tested for microsatellite instability-MSI using a panel of five markers (BAT25, BAT26, D2S123, D5S346 and D17S2720), and the tumor was instable for the presence of mutations of BAT-26, D2S123 and D17S2720. Based on these results, on January 2020 a treatment with lenvatinib (24 mg daily) in combination with pembrolizumab (200 mg every 21 days) was started as a salvage therapy. After five months of treatment, a partial response was achieved with a reduction by 76% of the lung lesion in the medium lobe from 8.5 cm to 2 cm and at 18FDG PET/CT a drop in SUVmax from 50 to 4.7. The treatment was continued, but lenvatinib was progressively reduced to 10 mg daily due to grade 3 diarrhea, vomiting and weight loss. After 12 months, the administration of pembrolizumab was delayed every six weeks. The lenvatinib treatment has been withdrawn several times, and the patient compliance was low. In spite of that, after 18 months of treatment all lung lesions continued to respond to therapy (PR with a reduction by 50% of the sum of the diameters of the target lesions by RECIST) (). Unfortunately, a pleural nontarget lesion showed a progression, over four months, as demonstrated by the 18FDG-PET/CT (10 mm vs. 7 mm, a 43% increase by RECIST and a SUV max of 25.8 vs. 6.5) (). The pleural lesion is being treated with stereotactic radiotherapy (42 Gy in seven fractions). The patient is still alive, and the treatment with lenvatinib and pembrolizumab is still ongoing.

pmc-8700689-1

An 11-year-old male came to our observation for his first dental visit. His medical history was negative. No symptoms were reported by the patient or his parents. The face was symmetric and no swelling of the cervical lymph nodes was observed. Intraorally, the dentition of the permanent teeth was completed, except for the third mandibular molars and the second and third maxillary molars. Bucco-lingual expansion of the jaw bones was not evident. An orthopantomogram was performed to assess the development of third molars []. Unexpectedly, the analysis revealed an intraosseous doughnut-like lesion radiopaque at the periphery and radiolucent in the center associated with the left mandibular third molar germ (a). Additional dental abnormalities were not observed. The maximum diameter of the lesion was 5.7 mm. Based on these findings, developmental abnormalities of the third molar (e.g., dilated odontoma) and odontogenic (e.g., cementoblastoma) and non-odontogenic (e.g., osteoblastoma or osteoid osteoma) tumors were considered for differential diagnoses. To better characterize the lesion, a computed tomography (CT) scan was required. The analysis established bone integrity around the lesion and its independence from the local neuro-vascular structures. In addition, it revealed, on the sagittal projection, a small gap in the proximity of the buccal surface of the mandible (b). As the most significant clinical concern related to this condition is the risk of developing pulpal necrosis, it was decided to extract the germ of the third molar and the underlying lesion. To do this, under local anesthesia, a mucoperiosteal flap was raised posterior to the mandibular right second molar. The vestibular cortical plate was removed, exposing the ovoid mass, which was removed with the germ of the mandibular tooth. The surgical flap was repositioned and sutured. Healing was uneventful. The excised lesion appeared as an empty hard spherical mass virtually devoid of content (). It was routinely processed for paraffin embedding after fixation and decalcification. Histologically (a,b), the outer hard tissue was dentin. The inner part of dentin was in continuity with basophil calcified material, which in turn was focally in contact with the bone-like matrix. The basophil calcified material focally presented a rod-like structure consistent with enamel (b, insert). More centrally, the lesion was composed of fibro-vascular tissue. The pathologic findings were considered as consistent with a dilated odontoma.

pmc-8700713-1

A 61-year-old woman was referred to our clinic complaining of an isolated, sudden, and painless visual loss in her right eye, within 24 h following a 2 h airplane flight (at 30,000 feet) from Paris to Madrid. Her medical history showed well-controlled hypercholesterolemia. Twenty-four hours later, best-corrected visual acuity (BCVA) was 20/200 in her right eye (RE) and 20/20 in her left eye (LE). There was a relative afferent pupillary defect (RAPD), color vison deficiency, and an inferior hemifield and temporal-superior quadrant scotoma (A) in the RE; funduscopic examination revealed a 360° swelling of the right optic disc, with superonasal flame-shaped hemorrhaging, venous congestion, and tortuosity. The LE was normal, with a cup-to-disc ratio of less than 0.1, suggesting “disc-at-risk”. Fundus fluorescein angiography (FFA) of the RE showed late optic-disc staining (). Cardiac and carotid Doppler ultrasound, autoimmune, and hypercoagulability tests were normal, with the exception of slightly raised serum cholesterol levels. Cranial computed tomography (CT) revealed previously unknown white matter lesions (). NA-AION associated with cerebral SVD was diagnosed. After one year of treatment with aspirin (100 mg daily), the patient developed visual disturbances in her LE, occurring during a 10 days drive in the French Alps, with a daily accumulated altitude of 1500 m. BCVA was 20/200 in her RE and 20/40 in her LE. Examination revealed edematous and flame-shaped retinal hemorrhaging at the border of the left ONH, vascular tortuosity, fluorescein leakage (during FFA), and severe widespread visual field loss with central-sparing (B), suggesting a NA-AION in the LE. At the time of publication, BCVA had decreased to 20/200 in both eyes, fundus examination showed bilateral optic disc atrophy, and spectral domain optical coherence tomography had confirmed a marked decrease in peripapillary retinal nerve fiber layer thickness in both eyes ().

pmc-8700716-1

Female, 83 years old (y/o), with hypertension, hypercholesterolemia, carotid vasculopathy (type III, AHA) and history of (h/o) smoking affected by degenerative aortic stenosis, underwent valvular replacement with a St. Jude 21 mm mechanical prosthesis in 2000. Twenty years later, she was hospitalized for respiratory distress. TTE showed left ventricle (LV) dysfunction with severe prosthetic valve stenosis (aortic acceleration time (AAT): 140 ms, transaortic maximum speed: 4.8 m/s, maximum/median gradient: 90/52 mm Hg, indexed effective orifice area (EOA): 0.3 cm2/mq, EF: 35%). TEE showed hypomobility of the anterior leaflet. Due to the shielding from the prosthesis, it was unclear if there was a thrombus or a pannus (). As it is possible to differentiate between a pannus and a thrombus due to their different radiological density (HU > 145 and > 90, respectively) [], MDCT was performed, and it showed that the anterior aortic leaflet was stuck and surrounded by hypodense tissue (Hounsfield units (HU): 203.8) interposed between native and prosthetic annuli (effective orifice area (EOA): 45 mm2, EOA/0.15) indicating a pannus (a–c). This information was of utmost importance as instead of staring anticoagulant treatment, the patient directly underwent repeat surgical repair with a bioprosthesis. The diagnosis of pannus was confirmed by pathology.

pmc-8700716-2

Female, 44 y/o, affected by mitral valve (MV) dysplasia (parachute valve with double medioposterior papillary muscle) and subaortic stenosis caused by a fibromuscular ring, underwent subaortic membrane resection and septal myectomy in 1989. Due to worsening exertional dyspnea and persistence of subaortic stenosis, a St. Jude Regent 17 mm was implanted in 2006 (40 y/o) with improvement of her physical condition. In the last 2 years, TTE detected a progressive increase of the intraventricular gradient with LV hypertrophy (maximum speed, 4.1 m/s, maximum/median gradient: 64/39 mm Hg). TEE performed in May 2020 showed normal excursion of the prosthesis’ leaflets and confirmed severe subaortic stenosis (speed: 5.5 m/s, maximum/median gradient: 120/63 mm Hg) (). New subaortic membrane formation (SAM) was suspected but not clearly detected by TEE. MDCT provided accurate 3D reconstructions of the LV outlet tract (LVOT) with a better topographic assessment of the new SAM and its surrounding structures. The SAM was located 7 mm below the aortic prosthetic annulus, with the maximum thickness of 5 mm and hemicircumferential extension along the interventricular septal surface. This information was crucial to guide surgical excision of the SAM (a,b).

pmc-8700716-3

Male, 80 y/o, with a metabolic syndrome. He underwent thromboendarterectomy because of right internal carotid artery serrate stenosis. Due to bivasal critical coronary stenosis (anterior descending (DA) and left circumflex (LCx)) and severe degenerative aortic stenosis, he underwent coronary artery bypass graft (CABG: left internal mammary artery (LIMA-IVA)) and aortic bioprosthesis implantation (Intuity 25 mm) in 2019. Ten months after surgery, he started developing intermittent fever with serial hemocultures growing Enterococcus faecalis. TTE detected paravalvular regurgitation (PVR) with focal hyperechogenic thickening of the leaflets. Diagnosis of endocarditis was made, and antibiotic treatment was started (meropenem shifted to ampicillin and ceftriaxone according to the antibiogram). TEE showed a pulsatile perivalvular pseudoaneurysm in the mitroaortic intervalvular fibrosa (). MDCT was performed a few hours later, confirming the presence of a pseudoaneurysm with the maximum axial size of 15 × 10 × 30 mm communicating with LVOT through a 5 mm window, and also detected a periaortic abscess in the anterolateral side of the vessel with longitudinal extension of 4 cm, which was only poorly detected by TEE (a–c).

pmc-8700716-4

Male, 69 y/o, with hypertension, hypercholesterolemia and previous myocardial infarction. He was affected by severe degenerative aortic stenosis and underwent trans-catheter aortic valve replacement (TAVR) with LOTUS Edge 27 mm in April 2020. TTE performed a few days after the TAV implantation detected an increased transprosthesis gradient (maximum/median gradient, 78/52 mm Hg) in the absence of fever or positive hemoculture. TEE showed hypomobility of the noncoronary cusp of the bioprosthesis (). Valve’s thrombosis was suspected and heparin administration was started. MDCT detected a paravalvular leak caused by misfolding of the prosthesis’ frame; the suspicion of valve thrombosis was also confirmed by the finding of two hypodense appositions at the lower edge of the valve. The patient underwent balloon valvuloplasty with complete resolution of the valvular dysfunction (a–c).

pmc-8700756-1

A 45-year-old, multiparous, overweight female with a history of OHP use for 13 years (levonorgestrel 0.15 mg and estradiol 0.03 mg daily) consulted the emergency room of our institution following a one-week clinical course of worsening dyspnea, general malaise, headache, and ageusia. At admission, the patient reported dyspnea at rest, associated with intermittent retrosternal oppressive chest pain radiating to the back. The physical exam revealed pulmonary aggregates on auscultation, and her vital signs showed tachypnea, tachycardia, and desaturation. Oxygen therapy was started, requiring a non-rebreathing mask at 12 L/min to maintain adequate oxygen saturation. RT-PCR test for SARS-CoV-2 was indicated. Arterial blood gases analysis showed a PAO2/FIO2 ratio of 56, and the patient was then transferred to the respiratory intensive care unit (ICU). Her COVID-19 diagnosis was confirmed with the positive results of the RT-PCR test for SARS-CoV-2 (50 copies of RNA/reaction). Laboratory test results showed positive severity predictors, including an elevation of D-dimer (>20 mg/L), troponin I (0.150 ng/mL), ferritin (2934 ng/mL), and lactate dehydrogenase (879 U/L) levels. Other admission paraclinical tests showed leukocytosis, neutrophilia, lymphopenia, mild thrombocytopenia, and elevation of transaminases more than three times the laboratory upper limit. Because of the risk of bacterial pneumonia co-infection, ampicillin-sulbactam was started as empiric antibiotic treatment. Due to significant elevation of the D-dimer, a CT pulmonary angiography (CTPA) was taken according to the YEARS protocol. The results of the CTPA showed a massive PTE with compromise to the posterior basal segmental artery of the left lower lobe, inferior lingula, and apical-posterior segment of the left upper lobe. An echocardiogram was performed, showing right ventricular dysfunction. Systemic thrombolysis with r-tPA (alteplase) 100 mg infusion over 2 h was administered according to the European Society of Cardiology guidelines. After treatment, the patient showed an improvement in her hemodynamic and ventilatory patterns. Nonetheless, during the hospital stay, the patient displayed additional complications: (1) septic shock secondary to a hospital-acquired infection requiring broad-spectrum antibiotics and hemodynamic support therapy, (2) respiratory failure with invasive mechanical ventilation support requirement and subsequent tracheostomy, and (3) severe anemia with the need for blood transfusions. The patient had an adequate response to treatment with satisfactory clinical evolution, successful extubation, and transfer to the general hospital floor. The patient was evaluated by the OB-GYN attending physician, who contraindicated the further use of estrogenic hormonal contraceptives. Finally, the patient was discharged from our institution with indefinite anticoagulation therapy with a factor-XA inhibitor. The entire hospital stay course is represented in .

pmc-8700797-1

A 74-year-old man, ASA physical class III (163 cm, 73 kg, BMI 27.4), was scheduled for tumor-wide excision, mandibulotomy, tracheostomy, and free flap reconstruction because of mouth floor squamous cell carcinoma. His medical history included hypertension and previous cystolitholapaxy for bilateral ureteral stones. The patient was taking losartan and hydrochlorothiazide and denied any drug allergies. A pre-operative chest radiograph (10 days before the surgery) showed a normal picture and an echocardiogram indicated normal left ventricular function. A mild productive cough was noted. A standard monitoring set-up (electrocardiogram, blood pressure, and SpO2) was implemented before induction of anesthesia. Pre-operative vital signs were within normal range (heart rate, 74 bpm; blood pressure, 168/85 mmHg; respiration rate, 18 times per minute; and an oxygen saturation of 94% on room air). Following pre-oxygenation, general anesthesia was induced with remifentanil (target-controlled infusion: 3 ng/mL), lidocaine (20 mg), propofol (180 mg), and succinylcholine (80 mg). Oral tracheal intubation with a 7.5 mm endotracheal tube was performed using a video-assisted intubating stylet (Trachway®, Markstein Sichtec Medical Corp, Taichung, Taiwan). Airway secretion was found during the tracheal intubation procedure. Mechanical ventilation was set at a volume-controlled mode with the following settings: tidal volume (500 mL), respiratory rate (10 times per minute), and positive end-expiratory pressure (PEEP; 4 cmH2O). Sevoflurane at an end-expiration concentration of 2% and cis-atracurium were used for the maintenance of anesthesia. An arterial line was established through a radial artery for continuous beat-to-beat monitoring. A cuffed 8.0 sized tracheostomy tube (Rota-TrachTM, Vitaltec, Taichung, Taiwan, ID 8.0 mm, OD 11.0 mm, TL 76 mm) was placed after an uneventful tracheostomy procedure. The endotracheal tube was then withdrawn without incident and no secretion impaction inside the tube was noted. However, SpO2 dropped from 100% to 96% during the course. An immediate recruitment maneuver with FiO2 1.0 was performed. When the tracheostomy was completed and ready for the second stage of the neck dissection procedure, the patient’s SpO2 continued to drop down from 96% to 89%. Peak airway pressure increased from 22 to 29 cmH2O, and EtCO2 decreased from 42 mmHg to 37 mmHg. Blood pressure was within normal range. Pure oxygen was given, and arterial blood gas (ABG) was checked, which revealed a low PaO2 (140 mmHg under FiO2 1.0). Meanwhile, physical examinations revealed that chest wall movement was normal at the left side but significantly suppressed at the right side. Lung auscultation revealed significantly diminished breath sounds over the right chest with a mixture of coarse crackles and rhonchi. Malposition of the tracheostomy tube with one-lung ventilation was immediately excluded. Since the pre-operative chest radiograph taken 10 days before was normal and the patient did not present any infection signs (fever, leukocytosis, etc.), pneumothorax was an initial impression ready to be excluded. A bedside lung POCUS with a curved transducer (2.5 to 7.5 MHz) was immediately used to evaluate the lung images. The images of the lung POCUS showed decreasing lung sliding over the right upper lung field and a reduced sandy seashore sign with intermittent lung pulse on motion mode (M-mode; A). B-line was not observed within the 2nd and 5th intercostal space. Right mainstem intubation by the tracheostomy tube was excluded by fiberoptic bronchoscopy exam (the tip was within the trachea and above the carina). While advancing the bronchoscope past the right main bronchus, however, copious sticky yellowish sputum was encountered in the bronchial branches, especially at the right upper bronchus (B). A portable chest radiography was taken and showed partial atelectasis over the right upper lobe and increased interstitial lung density, which were compatible with the ultrasound findings (C). After adequate suctioning and recruitment maneuvers, an ABG analysis was repeated (PaO2 115 mmHg under FiO2 0.5). Because of suspected pneumonia and the planned long duration of the operation, the surgery was then deferred. Sputum culture was collected and empirical antimicrobial treatment with piperacillin and tazobactam was initiated. Haemophilus influenza was isolated from the sputum culture. After a 10-day antibiotic treatment course, a repeat chest radiograph was clear, and the patient received the pre-planned surgery uneventfully.

pmc-8700985-1

Case 1: The first patient was a 79-year-old female individual with a history of hypertension, heart failure, and middle cerebral artery infarction. Blood pressure control and cardiac function were in good condition before surgery, and no neurological complications were observed. The patient’s pulmonary function test result was normal, although her chest X-ray revealed pneumonia in the right middle lobe, for which she had been treated. The patient underwent total hip arthroplasty under general anesthesia. Before the general anesthesia, monitoring using several modalities was instituted, including electrocardiography, a noninvasive blood pressure monitor, pulse oximeter, and bispectral index (BIS) monitor. The BIS was maintained at 40–60. Anesthesia was induced with propofol (2 mg/kg) and rocuronium (0.8 mg/kg), and intra-arterial cannulation was performed for continuous blood pressure monitoring. Approximately 20 min into the surgery, the patient’s oxygen (O2) saturation level dropped from 93.1% to 83.1%. While being ventilated at a fraction of inspired oxygen (FiO2) of 0.4, her arterial blood gas showed that the partial pressure of oxygen (PaO2) dropped from 161.6 to 51.2. We increased the positive end expiratory pressure (PEEP) to 10 cm H2O and FiO2 to 1.0 and performed a recruitment maneuver; however, her O2 saturation level increased only temporarily and dropped again to 81%. Upon suspecting atelectasis due to a collapsed lung, we reversed muscle relaxation and induced spontaneous respiration. The O2 saturation level recovered to 90%, and we continued the surgery with spontaneous respiration. After surgery, the patient’s O2 saturation level recovered to the preoperative state of 98%.

pmc-8700985-2

Case 2: The second patient was an 89-year-old male individual with a history of hypertension and delirium. Before surgery, his blood pressure was well controlled, and although he was taking dementia medicine, the patient was able to follow commands well. His pulmonary function test results indicated an obstructive pattern. Total hip arthroplasty was performed using the same anesthetic regimen used for the first patient. While ventilating at an FiO2 of 0.4, the patient showed an onset of hypoxia, with O2 saturation level dropping from 100% to 80% and PaO2 dropping from 129 to 53.0. This patient also showed an improvement of O2 saturation level from 81% to 88% after recovering spontaneous respiration by administering a muscle relaxant-reversing agent. His O2 saturation level improved to 90% with continuous positive airway pressure. Similar to the first patient, the second patient’s O2 saturation level improved to 98% after surgery. Neither patient developed any respiratory complications after surgery. The first patient had no notable findings on the postoperative chest X-ray, whereas the second patient showed subsegmental atelectasis on the right middle lobe compared with the preoperative findings ().

pmc-8701003-1

The patient is a 91-year-old Caucasian man with a past medical history of coronary artery disease, congestive heart failure, atrial fibrillation, hypertension, interstitial lung disease, and obstructive sleep apnea presented with a 2-week history of productive cough, fever, shortness of breath and generalized malaise. On presentation, vitals showed blood pressure of 77/35 mmHg, heart rate of 122 bpm, respiratory rate of 38 bpm, a temperature of 102 F, and oxygen saturation of 98% on 15 L of oxygen. The patient was diaphoretic, with decreased breath sounds in the right lung field, and on palpation of the abdomen, there was right upper quadrant fullness. Initial laboratory studies showed elevated white blood cells (WBC) 22.6 × 109/L with neutrophilia, bicarbonate 21 mmol/L, lactic acid 6.5 mmol/L, anion gap 17, ALT 71 IU/L, AST 69 IU/L, and ALP 450 IU/L. ECG showed atrial fibrillation with a rapid ventricular response. CXR showed acute right pleural effusion (). The patient was intubated for respiratory failure. He was also started on antibiotics (piperacillin-tazobactam and azithromycin) and intravenous normal saline with no improvement in blood pressure. The patient was then started on intravenous vasopressor support with norepinephrine and vasopressin and admitted to the intensive care unit (ICU). Due to the right upper quadrant fullness, elevated liver enzymes and fever, an abdominal ultrasound was performed, which showed an acute complex heterogeneous hypoechoic 8 × 7 × 6 cm mass-like lesion in the right hepatic lobe (). To better characterize the lesion, a CT abdomen was done. The CT showed a complex low-density right hepatic lobe subcapsular lesion measuring 13 × 8 × 7 cm, directly abutting the right anterior diaphragm, along with diffuse gross gallbladder wall thickening with cholelithiasis and a moderate right pleural effusion (). The patient underwent chest tube placement with the removal of 1600 cc of cloudy light-brown-colored fluid. Pleural fluid analysis was consistent with empyema, with WBC of 70,800 cells/mcL (61% neutrophils), glucose less than 10 mg/dL, LDH of 4821 IU/L, pH of 7.0, protein of 3.6 gm/dL, and Gram stain showing Gram-positive cocci in chains. Cytology was negative for malignant cells but showed severe acute inflammation and rare mesothelial cells. The blood culture on admission grew beta-hemolytic streptococci. The pleural fluid culture grew Streptococcus anginosus. On day two of hospitalization, the patient was scheduled for CT percutaneous drainage of liver abscess. However, the CT revealed a significant decrease in the size of the right subdiaphragmatic perihepatic collection to 1.5 cm in greatest thickness (). Due to the improvement of the hepatic collection, the CT-guided drainage of the collection was not performed. Following the persistence of pleural effusion and decreased effluent from the chest tube, an intrapleural thrombolytic was instilled via chest tube with the removal of 1.5 L exudative fluid. Repeat CXR showed improvement in the right pleural effusion (), and the patient was successfully extubated on day three of hospitalization. His hospital course was subsequently complicated by new onset and worsening respiratory distress on day eight of hospitalization requiring re-intubation. Repeat CT chest showed diffuse narrowing of the left mainstem bronchus, occlusion of right posterior segmental bronchi with atelectasis, complete collapse of the left lower lobe due to occlusion of left lower lobe central bronchi with trace right pleural effusion (). Emergent flexible fiberoptic bronchoscopy was done and showed copious thick mucopurulent secretions that were suctioned to clear. The bronchoalveolar lavage grew Candida albicans, which was not thought to be a pathogen. After two weeks of hospitalization and the inability to wean the patient from the ventilator, the patient was terminally extubated, and care was focused on comfort.

pmc-8701011-1

A 93-year-old patient visited our hospital with hypokalaemia, malnutrition, and decreased renal function detected by a family physician. Five years before her visit to the hospital, she had undergone bowel resection several times (). As a result, she had been suffering from diarrhoea for about three months, thought to be caused by SBS. The diarrhoea improved spontaneously and she had no abdominal symptoms. Then, one year before admission, watery diarrhoea appeared, and although antidiarrhoeal medication was prescribed, there was little improvement. Her past history included colonic perforation, abdominal wall hernia with strangulated ileus, and resection of about 2 m 30 cm (59.1 inches) of the terminal ileum (). Five years prior to this admission, she was diagnosed with strangulated ileus, and the small intestine was resected, 7 cm from the terminal ileum and 50 cm from the ligament of Treitz (). At presentation, the patient’s blood pressure was 95/67 mmHg, heart rate was 59 beats per minute, SpO2 as 95%, and her temperature was 36.6 °C. On physical examination, normal breath sounds and heart sounds with mild systolic murmurs were observed. The abdomen was flat and soft. Murphy’s sign was negative, and there was no costovertebral angle tenderness. Lower leg oedema was observed. The results of blood tests were as follows: white blood cell count 15.30 × 103/μ (neutrophils 78.3%, lymphocytes 15.5%, monocytes 5.6%, eosinophils 0.4%, basophils 0.2%), red blood cell count 3.34 × 106/μ, hemoglobin 11.3 g/dL, hematocrit 33.2%, platelet count 27.9 × 104/μ, total bilirubin 1.6 mg/dL, aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 48 IU/L, alanine aminotransferase (serum glutamic-pyruvic transaminase) 37 IU/L, total protein 5.2 g/dL, albumin 2.5 g/dL, blood urea nitrogen 18.7 mg/dL, creatine 1.13 mg/dL, Na 143 mEq/L, K 1.7 mEq/L, Cl 99 mEq/L, Ca 5.0 mg/dL, P 2.8 mg/dL, Mg 0.8 mg/dL, and estimated glomerular filtration rate 34.1 mL/min/L. An abdominal computed tomography showed mild oedema of the colon, and no other obvious abnormalities (). No obvious organic abnormalities were noted on imaging, but the bowel was shortened because of repeated bowel resections. Colonic specimens showed only nonspecific inflammatory findings (a,b). We believe that this inflammatory finding was due to an imbalance between the protective and aggressive factors of the intestinal tract due to ageing. After hospitalization, her electrolyte imbalance and renal function were improved by an infusion of magnesium and potassium, but the diarrhea persisted. A colonoscopy was performed and pathological specimens were taken. However, the colonoscopy, which was performed to evaluate diarrhea, did not reveal any specific findings. In addition, stool culture and histopathological examination did not reveal the exact cause. Taken together, this was likely to be de-adaptation of SBS, as a part of the clinical course. Since diarrhea and electrolyte abnormalities continued, we concluded that her bowel could not absorb nutrients, and therefore switched to central venous (CV) nutrition (delivered via a CV port), which improved her diarrhea. She was discharged in good general condition about one month after creation of the CV port.

pmc-8701217-1

A 29-year-old male, HIV-positive since 2015, severely immunosuppressed that was lost to follow-up before starting ART. He presented in March 2019 at the emergency room (ER) with a one-day history of fever, shortness of breath and cough without providing information about his HIV status. Initial assessment showed polypnea of 30 cycles per minute (cpm), hypoxia, fever (39 °C), elevated C-Reactive Protein (CRP) and bilateral middle and lower zone air space opacities on chest X-ray. He was admitted to the ward and started empirical treatment for community acquired pneumonia (CAP). Two days later, he was transferred to the ICU with aggravated tachypnea (50 cpm), severe hypoxemia (paO2 49 mmHg) despite oxygen supplementation and pneumomediastinum, bilateral pneumothorax and diffuse ground-glass opacities on thoracic-CT scan (a). The CD4+ lymphocyte count was 6/mm3 and the HIV-viral load was 18,200 copies/mL. All other microbiologic tests were negative. Treatment was then switched empirically to trimethoprim-sulfamethoxazole (TMP-SMX) 15 mg/kg of TMP each day in 3 takes plus corticosteroids for a presumed diagnosis of PJP. Later the diagnosis was confirmed by positive immunofluorescence as Pneumocystis jirovecii (P. jirovecii) in bronchoalveolar fluid (BAL). Due to refractory hypoxemia and given the high probability of barotrauma, the patient was started on venovenous-ECMO(VV-ECMO) without prior tracheal intubation. He later needed intubation due to poor bronchial clearance of secretions and completed a 14 days-period of protective IMV in an attempt to reduce extra corporeal support. He completed 21 days of therapy with TMP-SMX plus corticosteroids according to recommended PJP treatment dosage (prednisolone 40 mg two times day for 5 days, then 40 mg each day for 5 days and after that 20 mg each day for 11 days). ART was started 15 days after the ICU admission, with a significant reduction in the viral load one month later (151 copies/mL). ECMO and protective IMV were maintained for 40 days, followed by 19 days of weaning off. The pneumomediastinum and bilateral pneumothorax were managed conservatively, and a new CT-scan performed 50 days later showed great improvement (b). He was transferred to the ward after 69 days of ICU stay showing signs of significant myopathy. Three months after discharge, he was revaluated at outpatient care as fully recovered and with CD4+ lymphocyte count improvement (49/mm3).

pmc-8701217-2

A 64-year-old woman with a history of hypertension, dyslipidemia and chronic pulmonary disease presented at the ER with fever, shortness of breath and a worsening cough despite a previous complete course of antibiotics for presumed CAP. She was hypoxic, with isolated elevation of CRP and diffuse ground-glass opacities on thoracic CT-scan (a). Her status deteriorated despite antibiotics and oxygen supplementation in the Intermediate Care Unit, so she was transferred to the ICU and intubated. Three days after IMV and prone positioning, she was connected to VV-ECMO due to refractory respiratory acidemia. Anti-HIV testing was positive. Immune and viral study revealed severe immunosuppression (9 CD4+/mm3) and high serum viral load (4.050.000 copies/mL) and TMP-SMX plus corticosteroids were started for presumed PJP, at the recommended PJP treatment dosage. Diagnosis was confirmed by positive immunofluorescence for P. jirovecii in BAL. ECMO was discontinued after 10 days. During the weaning off invasive ventilation, there was recrudescence of ARDS with increased ventilatory parameters and need for prone positioning. Nosocomial infection was considered, broad spectrum antibiotics were started and bronchofibroscopy repeated, with persistently positive immunofluorescence for P. jirovecii and a positive polymerase chain reaction (PCR) for cytomegalovirus in BAL. She completed a total of 33 days of treatment with TMP-SMX and 21 days of ganciclovir with respiratory improvement and started ART. She was extubated after 83 days and was transferred to the ward after three months of ICU stay for muscular rehabilitation, without other dysfunctions. Follow-up imaging can be seen in b. She was transferred to a rehabilitation unit with a residual need of oxygen support (2 L per minute), from which she recovered after some months of pulmonary rehabilitation.

pmc-8701217-3

A 53-year-old woman, with no relevant medical history so far, was brought to the ER due to a two-month history of progressive psychomotor slowness and confusion, which had worsened in the week before. At physical examination, she was agitated and febrile. Head CT scan showed some intra-axial lesions in the left frontal and temporal lobes. The cerebral spinal fluid (CSF) had mild pleocytosis and moderately elevated proteins. The serology for HIV was positive, and the nucleic acid test of the CSF was positive for toxoplasma gondii. She was admitted in the ICU with a de novo diagnosis of HIV infection, with severe immunosuppression (CD4+ count 28 cells/mm3), clinically manifested as cerebral toxoplasmosis. On day 3, she began coughing, with respiratory hypoxemic insufficiency and bilateral diffuse glass opacities on chest-CT scan (a). The presumptive diagnosis of PJP was posteriorly confirmed with both direct dye-examination and PCR positive for P. jirovecii in BAL. She was treated with TMP-SMX for both PJP and cerebral toxoplasmosis. Following one week of appropriate medical treatment, the patient had a favorable response, and was discharged to the ward for further care. At the end of the month, she was readmitted to the ICU because of respiratory failure and elevated lactate. Respiratory secretions and gastric aspirate were both negative for tuberculosis. Other microbiology tests (including blood serologies for other common opportunistic agents) were also negative. She repeated chest-CT, and had severe deterioration in the lung opacities, with bilateral consolidation described as possible ARDS and/or nosocomial infection. As she showed no signs of clinical improvement despite corticosteroids and High Flow Oxygen Therapy (HFOT), she was intubated, had a repeat bronchofibroscopy and started broad spectrum antibiotics. The patient developed septic shock and ARDS with refractory hypoxemia and she was put on VV-ECMO. The indirect immunofluorescence was positive for P. jirovecii in BAL. She completed 21 days of treatment for PJP and 7 days of piperacillin- tazobactam, with respiratory improvement. ECMO was stopped after 12 days. Persistent fever and elevated inflammatory markers ensued, with isolation of multidrug-resistant Pseudomonas aeruginosa in respiratory secretions. Chest X-ray confirmed lobar nosocomial pneumonia. She started a targeted antibiotic course with cefepime, with good clinical, analytical, and radiological response. Roughly one week later, she was extubated to non-mechanical ventilation, and rapidly weaned off respiratory support to no oxygen supplementation. The evolution in her condition can be seen at the images in b. She was discharged to the ward after one month of ICU stay for muscular rehabilitation, already on antiretroviral therapy and free of acute infectious complications.

pmc-8701217-4

A 36-year-old male, overweight and with HIV infection diagnosed in 2009, with poor adherence to appointments and complete discontinuation of ART in the three months before admission. The patient presented at the ER with a 3-week history of worsening cough, dyspnea, and fever. Initial assessment showed hypoxia, fever (39 °C), elevated CRP, 6 CD4+ lymphocytes/mm3 and several ground glass opacities on thoracic CT-scan (a). He started empirical treatment with TMP-SMX plus corticosteroids at the recommended PJP treatment dosage and was admitted to the ward. The need for oxygen support increased in the next few hours and the patient responded poorly to HFOT. Twenty-four hours later he was admitted to the ICU and VV-ECMO was started. No tracheal intubation was performed. PJP was confirmed by positive immunofluorescence in BAL. After 9 days of ECMO support the patient became delirious and agitated, which caused flow problems in the extracorporeal circuit and eventually led to the need for sedation and subsequent intubation. He completed 21 days of treatment, initially with TMP-SMX, then changed to atovaquone plus primaquine due to hematologic toxicity. ECMO support was maintained for 26 days. He was transferred to the ward for rehabilitation after 37 days of ICU stay, and already on ART. The follow-up CT-scan can be seen in b. All four patients are being followed and regularly observed as part of our Infectious Diseases program and are functional and radiologically recovered, a summary of the patients’ characteristics and evolution is presented in .

pmc-8701381-1

Case History: A 52-year-old white male inmate with a history of non-steroidal anti-inflammatory drugs (NSAIDs) therapy and enalapril therapy for hypertension was admitted to the emergency room for repeated lipothymia in the absence of sweating, with hematemesis from the previous evening and melaena from three days before. The patient was hemodynamically unstable with acute anemia. The hemoglobin value upon admission was 6g/dL, while the procalcitonin in the blood was not evaluated. Therefore, a computed tomography (CT) scan of the abdomen was performed, which revealed a narrow lumen of the second portion of the duodenum; furthermore, the esophagus-gastro-duodenoscopy (EGDS) examination revealed multiple sub-centimeter lymph node formations in the stomach with normodistended walls due to insufflation, and fundus and gastric bodies occupied by food residues and clots; at the level of the first duodenum, there was an ulcerated lesion covered by a large clot. After a worsening of the condition, the patient was transferred to Intensive Care, was intubated and underwent therapy to restore hemodynamic balance. On the fifth day, the hemodynamics were unstable, and the anemia persisted. An emergency gastroscopy was performed in resuscitation, which revealed the absence of blood in the esophagus, stomach, and duodenum, and ulcerative lesion of the duodenal bulb with circumferential extension to the intestinal wall. Conditions precipitated due to common complications of hypovolemia. Hemorrhagic shock and peritonitis due to enterobiasis were assessed as causes of death. After 72 h, an autopsy was performed in accordance with the recommendations on the harmonization of forensic autopsy rules of the Committee of Ministers of the Council of Europe (1999) and according to the commonly accepted criteria for sudden cardiac death (SCD). Femoral blood was analyzed for alcohol (ethanol) and volatiles by head-space gas chromatography coupled with a flame ionization detector (GC/HS-FID). All post-mortem specimens were screened for the presence of the main different classes of drugs (pharmaceuticals and illegal drugs), using immunological or chromatographic methods as appropriate. A systematic toxicological analysis (STA) was performed by the LC-MS/MS system (API 3200 triple quadrupole ABI-SCIEX) in multiple reaction monitoring (MRM) mode.

pmc-8701660-1

A nine day old male newborn was admitted to our hospital due to fever and poor general condition. The pregnancy was complicated by threatened miscarriage and placental abruption. He was born at 36 weeks + 1 day of GA by spontaneous delivery. Perinatal cardiotocographic monitoring was negative. Neonate blood gas analyses and cardiorespiratory adaption were normal, and the Apgar score was 7 and 8 at 1′ and 5′ minutes, respectively. Birth weight was 2950 g. The subsequent early postnatal period was complicated by transient hypoglycemia; neonatal clinical assessment was normal, postnatal weight loss was within normality range (<10%), and the neonate was discharged on the fourth day of life. The mother was tested for SARS-CoV-2 at admission in the obstetric ward with a negative result and a positive result at discharge, without any symptoms. At day nine, the baby developed fever (38 °C) and poor feeding. The nasopharyngeal swab, tested for SARS-CoV-2 by qualitative realtime PCR (AllplexTM SARS-CoV-2 Assay, Seegene), was positive; thus, he was admitted to our COVID-19 center. In the subsequent 24 h, he developed progressive respiratory failure and diarrhea with enterorrhagia and was admitted to the PICU. Surgical evaluation with abdominal X-ray and ultrasound excluded the suspicion of volvulus or necrotizing enterocolitis; echocardiography and electrocardiogram were normal although the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and Troponin T (TnT) were elevated (). The baby was supported with noninvasive ventilation, and treatment with antibiotic wide coverage (ampicillin plus gentamycin plus metronidazole) was started. In the subsequent days, the neurological condition deteriorated with impaired consciousness and pathological spontaneous motricity, and we observed worsening of respiratory failure leading to intubation and mechanical ventilation on day three. The chest radiograph and CT scan showed a picture of bilateral interstitial pneumonia with an extensive area of atelectasis in the basal site. On the nasopharyngeal swabs (NPS) and bronchoalveolar lavage (BAL), SARS-CoV-2 viral load was assessed by quantitative realtime PCR (Quanty COVID-19 assay, Clonit Srl, Milan, Italy), revealing a high viral load at admission (). SARS-CoV-2 variant determination was performed by realtime PCR single-nucleotide-polymorphism (SNP) detection approach (COVID-19 Variant Catcher, Clonit Srl, Milan, Italy, CE IVD). N501Y mutation and HV69-70 deletion, suggesting VOC 202012/01 Lineage B.1.1.7 variant (also known as UK variant), were detected. Thus, we started anti SARS-CoV-2 hyperimmune plasma day three and four, plus dexamethasone 0.15 mg/kg/die and remdesivir 2.5 mg/kg day 5 and 1.25 mg/kg for nine more days. Because of the neurological impairment, a lumbar puncture was performed and was normal, with negative microbiological results including SARS-CoV-2. The metabolic test on blood and liquor were normal. Immunological screening showed no abnormalities. The EEG showed hypovolted brain electrical activity with a discontinuous pattern; no electrographic or electroclinical seizure was recorded. The cerebral CT scan was normal; the brain MRI showed deep medullary vein thrombosis associated with cytotoxic edema in the deep periventricular white matter (fan-shaped configuration) (, and ), thus, treatment with enoxaparin 100 UI/kg q 12 was started. The clinical condition progressively improved; after thirteen days the baby was extubated and in four more days became oxygen independent, able to feed on the breast, with neurological and EEG improvement. Extended thrombophilic screening including homocysteine, anticardiolipin antibodies, antiphospholipid antibodies, anti-beta-2-glycoprotein antibodies, protein S, protein C, activated protein C resistance, lupus anticoagulant, factor XIII, von Willebrand factor antigen, Factor V Leyden (G1691A) mutation, factor II prothrombin (G20210A), MTHFR (C677T) mutation all were normal. Genetic investigation of CFTR (Cystic Fibrosis Transmembrane conductance Regulator) showed normal results. After 39 days, the nasopharyngeal swab for SARS-CoV became negative, and the baby was discharged after 42 days. At the five month follow-up visit, the baby was doing well, without any clinical problems. A T1-weighted MRI showed significant reduction in linear hyperintense lesions, normal intensity of periventricular white matter, and enlargement of lateral ventricles (, and ).

pmc-8701878-1

A 5-year-old boy with a molecularly confirmed diagnosis of DMD was referred for further clinical evaluation because of ID, ASD, joint hyperlaxity, and morphogenetic anomalies. A history of epilepsy with tonic–clonic seizures, photosensitivity, and moderate elevation in serum creatinine phosphokinase (CPK) levels following physical exercise was reported in his mother. He was born from non-consanguineous parents after an uneventful dizygotic twin pregnancy. A cesarean section was performed at 35 weeks of gestation due to a twin pregnancy. His birth weight was 2080 g (50th centile), and his Apgar scores were 81 and 95. His parents reported initial concerns during the child’s first year of life. A lack of eye contact, visual tracking, and social interest were noted from early on, associated with delayed milestones. He reached head control at 3 months and could not roll over and sit up without support till the age of 14 months; he walked independently at 4 years of age. On EEG, focal spikes over the frontal region and the left temporal region and generalized spike-and-wave complexes during sleep were detected in the absence of overt epilepsy. A brain MRI showed normal results. Following the detection of an increased CPK level (13,000 UI/L) and elevated liver enzymes (AST 272 U/L, ALT 388 U/L), muscular dystrophy was suspected at the age of 4 years and the child underwent the genetic analysis of the dystrophin gene. The deletion of exons 46-51 of the gene was detected through MLPA, consistent with the diagnosis of DMD. The mother was found to be a heterozygous carrier, as expected from her increased CPK level. When evaluated at the age of 5 years, the child presented with severe developmental delays and autistic features, including poor eye contact, the absence of protodeclarative pointing, attention deficit, and inadequate social-communicative abilities. He could not follow simple instructions and a cognitive test could not be performed. Joint hyperlaxity and peculiar facial traits were noted, including a high forehead, epicanthic folds, deep-set eyes, an elongated face, and large ears. Notwithstanding the reported high rate of cognitive impairment and neurobehavioral abnormalities in DMD, the complexity of the whole clinical phenotype of our patient—in particular, the association of motor delay and severe ID with ASD and the distinctive facial dysmorphisms—led us to hypothesize comorbidity with an additional genetic condition, namely, with FXS. Following array-CGH analysis, which detected no additional CNVs, except for the deletion formerly identified in the dystrophin gene, the child underwent FMR1 molecular analysis. He was found to be a mosaic carrier of a large premutation (PM) with 170 CGGs and of an MFM with an expansion above 200 CGG triplets, confirming the clinical hypothesis of FXS (). His unaffected mother was heterozygous for a normal allele with 20 CGGs and a premutation allele with 80 triplets. The boy is currently receiving a rehabilitation program with slight improvement shown, especially in his motor skills.

pmc-8701878-2

This 7-year-old girl is the only child of non-consanguineous parents. She was born at 39 weeks of gestational age via an urgent cesarean section due to maternal premature rupture of the membranes (PROM). At birth, she presented respiratory distress and her Apgar scores were 51 and 85. Her birth weight was 3550 g (75th centile), her length was 53 cm (90th centile), and her OFC 36.5 cm (around 98th centile). Soon after birth, she developed spontaneous tremors of the upper limbs, axial hypotonia, and apnea episodes treated with phenobarbital and oxygen, respectively. A brain ultrasound and MRI were normal. EEG displayed continuous activity, with occasional sharp elements in the right temporo-occipital area. Audiometric and fundus oculi examinations were both normal. She reached head control at 3.5 months, sitting position at 10 months, and non-autonomous standing station at 15 months. Up to 15 months, she presented difficulties in handling objects with coarse grip. Language was poor with very few words developed at 13 months. Psychomotor delay was accompanied by macrocephaly: until 4 months of age, OFC was at the 98th centile and from 8 to 10 months it was abundantly above the 98th centile. Upon physical examination, she presented with a broad and rounded forehead, a small nose with saddle root and anteverted nostrils, a reverse epicanthus, sparse eyebrows in the medial portion, fetal finger pads, ligamentous hyperlaxity, and a sandal gap with prominent heel (). Upon clinical evaluation performed at 4 years and 5 months of age, the young girl pronounced few simple words, walked with a broad-based gait and showed a lack of sphincter control. Negative results came from the direct nucleotide sequencing analysis of the following genes: lamin A/C, SEPN1, NFIX, EZH2, NSD1, SETD2, COL6A1, COL6A2, and COL6A3. Array-CGH revealed a “likely benign” 9q21.31 duplication of approximately 200 kb, with no associated genes accessed on 18 January 2021 and accessed on 18 January 2021). Parental origin was not investigated. Molecular analysis for FXS revealed heterozygosity for a normal allele of 29 CGG repeats and a series of expanded alleles in the range of PM and FM (between 73 and >200 CGGs). After the diagnosis of FXS in the proband was established, the parents were also examined with the following results: her father carried the 29 CGG allele, while her mother had a normal allele of 23 triplets and a PM of 121–131 CGG triplets. As the diagnosis of fragile X syndrome could not explain all the clinical findings of the proband, a trio WES was undertaken and revealed the presence in the proband of a de novo heterozygous variant c.592G>A p.(Glu198Lys) in the PPP2R5D gene (NM_006245.3). This variant is reported in HGMD (Human Gene Mutation Database; CM153575) [] and never in GnomAD (Genome Aggregation Database). The same variant was previously reported de novo in patients affected by moderate/severe ID [,].

pmc-8701878-3

Patient 3 is a 33-year-old man who is the second child of non-consanguineous parents. He started walking and saying his first words at the age of 2. At the age of 10 years he suffered his first seizure episodes and when he was 22 years old he had a coma episode following a severe seizure crisis. Brain angio-MRI showed temporo-mesial sclerosis, left A1 segment agenesis with origin of the left anterior vertebral artery from the right circle, asymmetry of the supratentorial ventricular system due to the prevalence of the right trigone, and an occipital horn. He is currently still undergoing anticonvulsive treatment with valproic acid, oxcarbazepine, and topiramate. His character is calm, with a few nervous jerks (due to seizure medication). Presently, he attends a day center and practices sport (judo) and recreational activities (dancing). Family history revealed two further male patients (both sons of a maternal cousin) affected by ID of an unknown cause and diagnosis. Physical examination showed an elongated face, high forehead, wide and anteverted ears, a long and flat philtrum, midface hypoplasia, joint hyperlaxity, and hypotonia. A molecular analysis of the FMR1 gene and array-CGH were performed, revealing an FMR1 MFM allele (>200 CGGs) (A). Following this result, his mother was tested and found to be heterozygous for a normal allele of 30 CGG triplets and a PM allele with 79 CGGs. She underwent menopause at 39 years and had a spontaneous fracture of the femur at 50 years. Computerized bone mineralometry showed severe osteoporosis. No history of seizures was reported in the mother. The proband’s sister was found to carry a PM of the FMR1 gene and she had a first unaffected daughter and a second son affected by FXS. Additionally, array-CGH revealed a chromosome 2p25.3 deletion spanning around 500 kb, again derived from his premutated mother (B). The deleted region on chromosome 2 was included between positions 1,145,059 and 1,670,349 (according to Genome Browser Assembly hg19, GRCh37, February 2009) and encompasses the SNTG2, TPO, and PXDN genes, and possibly MYT1L. There were no specific probes in this last locus at the 44 K resolution of the employed array. Due to the association of the MYT1L gene with ID and seizures and since the clinical presentation of the proband was complicated by severe convulsions, we quantified the MYT1L transcript levels in the proband and his mother in order to verify if there was a “positional effect” of the microdeletion on chromosome 2. The results of real-time PCR revealed a decreased level of MYT1L transcript in the proband when compared to his mother and neurotypical controls (C).

pmc-8701891-1

A 59-year-old Lithuanian male presented to our department due to deterioration of cognitive functions that had been observed for 2–3 years and gotten worse over the past three days. The patient could not perform some simple tasks in everyday life and lost his previous interests. He maintained some independence though, such as being able to go to the supermarket and do housework unsupervised. Past medical history was significant for dyslipidaemia, arterial hypertension, and stroke at the age of 36 with mild right hemiparesis. He also experienced several episodes of aphasia, which could be considered as transient ischemic attacks (TIAs). The patient had a history of smoking for a long time. He was born full-term and healthy; his parents, four siblings, and two offspring did not have any relevant health problems and no hereditary diseases were identified among family members. On neurological examination, mild bilateral dysmetria was observed and the mental examination revealed executive dysfunction and pronounced cognitive slowing. Mini–Mental State Examination (MMSE) score was 25, Frontal Assessment Battery (FAB) score was 5, phonemic fluency (words beginning with P) was 4 in one minute, and semantic fluency (animals) was 3 in one minute. Laboratory blood tests revealed significant dyslipidaemia (total cholesterol level—7.55 mmol/L, low-density lipoprotein level—5.82 mmol/L). Cerebrospinal fluid analysis was unremarkable. Low grade bilateral internal and external carotid artery stenosis was detected on carotid ultrasound. Brain magnetic resonance imaging (MRI) revealed communicating hydrocephalus, most likely due to brain atrophy and secondary brain changes, with no obvious cause of obstruction in the ventricles (Huckman index was equal to 66; the width of the third ventricle was equal to 10 mm), and extensive leukoencephalopathy, Fazekas scale score 2–3, lacunar lesions in the dorsal part of pons, thalamus bilaterally, and right cerebellar hemisphere (). Since the patient developed early onset progressive dementia, had a stroke at a young age, several TIAs, and brain MRI was significant for extensive leukoencephalopathy, genetic testing by next generation sequencing for inherited cerebral small vessel disease was performed. On follow-up, the patient began manifesting positive psychiatric symptoms (hallucinations, delusions, anxiety) at the age of 60 that required several hospitalisations to the psychiatric ward. Cognitive functions further deteriorated from baseline MMSE score of 25 to 14 in 3 years, and the patient gradually became fully dependent in daily life. He also developed bladder and bowel incontinence and gait apraxia at the age of 62. In parallel, brain MRI showed evolution of findings: communicating hydrocephalus and leukoencephalopathy were progressing over time (HI was equal to 82, the width of the third ventricle was equal to 11 mm, Fazekas scale score 3), and new lacunar ischemic lesions and hemosiderin deposits appeared ().

pmc-8702017-1

Patient 2.II.1 (a right) is a male diagnosed at the age of 34 years old. He presented with high serum ferritin levels (but <1000 µg/L) and high serum iron. In addition, he had hypogonadotropic hypogonadism treated with testosterone and moderate hepatic steatosis. As expected for an iron overload disease, the hepcidin levels of the patient were low (0.1919 ng/mL). One year later, serum ferritin levels peaked to 3942 µg/L. Magnetic resonance shows no evidence of iron overload in the heart while in the liver revealed increased iron concentration of 47 µmol/g indicative of hepatic iron overload (normal values <36 µmol/g). Iron chelation with Desferoxamine was used as the main therapeutic treatment. Initially, phlebotomies were performed in combination with iron chelation but had to be stopped due to intolerance. Iron chelation treatment ended in 2020 and the patient is now asymptomatic. The patient will continue with maintenance therapy. Patients A.II.1 and A.II.2 (b upper first panel) are two male brothers of Asian origin diagnosed with HH at 35 and 37 years old respectively. Both presented with high levels of serum ferritin and iron, while in both patients, the hepcidin levels were 0.2395 and 0.0111 ng/mL respectively. Hepatic magnetic resonance showed a severe hepatic iron overload (282.97 µmol Fe/g and 265 µmol Fe/g). The treatment option for both patients consisted of weekly phlebotomies in combination with iron chelation (Desferoxamine). A.II.1 proband started the phlebotomies in January 2019 (weekly) and the Desferoxamine treatment in May 2019. In February 2021, after 100 phlebotomies and approximately 22 g of iron removal the ferritin levels dropped to normal levels, but transferrin saturation remained high. A.II.2 proband started the phlebotomies in July 2017 (once a month) and the Desferoxamine treatment in January 2018 (initial dose of 1080 mg/day that eventually was increased to 2160 mg/day in May 2018). At the last data available (February 2021), the patient accumulated a total of 46 phlebotomies that removed a total amount of 9 g of iron and resulted in the normalization of ferritin and transferrin saturation parameters. The iron depletion was partially confirmed by the last hepatic magnetic resonance performed to the A.II.2 patient that showed a moderate iron overload (70.33 µmol Fe/g).

pmc-8702017-2

Patient B.II.1 (b upper second panel) is a male of 46 years old diagnosed in 2012 with hemochromatosis that presented with hyperferritinemia and severe hepatic iron accumulation (300 µmol Fe/g) detected by hepatic magnetic resonance. The patient also suffers from dyslipidemia and internal hemorrhoids. The patient does not consume alcohol and is an ex-smoker as of May 2014. Genetic analysis shows that this patient is a carrier for the Cys282Tyr mutation in the HFE gene. Secondary to the hemochromatosis, the patient presents with severe chronic arthropathy in feet, spine (spondylarthrosis) and hands. The treatment initially was monthly erythroapheresis (later, the rate of erythroapheresis was reduced to once every two months). In January 2015, phlebotomies were introduced as part of the treatment. In May 2017, the hepatic magnetic resonance showed no sign of hepatic iron overload.

pmc-8702083-1

A 65-year-old woman with a noncontributory medical history was referred to the Oral Surgery Unit, Policlinico Umberto I, “Sapienza” University of Rome, Italy, to undergo surgical reconstructive therapy peri-implantitis lesion localized around the mandibular left distal implant ( and ). The patient’s written detailed informed consent was obtained for the diagnostic and therapeutic approach and the use of the documentation for research purposes and publishing. The procedure involved the prosthetic superstructure removal, oral and buccal full-thickness mucoperiosteal flaps incision, surface debridement and decontamination, and guided bone regeneration of an infra-bony defect using a mineralized dehydrated bone allograft and resorbable membrane in the non-submerged mode of wound healing []. During open-flap debridement of the infected implant surface with sodium bicarbonate air powder abrasion (PROPHYflex™ 3 with periotip, KaVo, Biberach, Germany) (), rapid onset swelling arose on the left cheek as well as in the periorbital space. The procedure was stopped immediately and the surgical area was rinsed with sterile saline solution to remove all residual bicarbonate particles. Before repositioning and suturing the flap, intra- and extra-oral inspection and palpation of the face and neck were performed to determine the spread and extension of entrapped air. Extra-oral examination revealed slight asymmetry of the face and complete left eyelid ptosis due to swelling of the left periorbital space and cheek (). A crackling sensation with no tenderness was detectable on palpation of the subcutaneous tissue in the swelling area. Visual acuity, light reflex, and extraocular movements were intact. Intraoral examination showed no swelling or crepitus in the mandibular region because air, spreading upwards alongside the buccinator muscle insertion, was entrapped into the upper and middle loose spaces of the face. The patient complained of experiencing only slight discomfort but no pain and no difficulty swallowing, breathing, or speaking. Therefore, computed tomography was deemed unnecessary to avoid undue radiation exposure. Subcutaneous emphysema diagnosis was based on the sudden onset during air-powder debridement of soft tissue swelling associated with crepitus in the absence of erythema, oedema, significant pain, or lymphadenopathy. In the lack of signs or symptoms of serious complications, close observation was performed. The patient was reassured that the swelling should reduce spontaneously in 2–3 days and subside within 7–10 days with no complications or morbidity. After an adequate observation period, the patient was discharged with a prescription for 875 mg of amoxicillin plus 125 mg of clavulanic acid (Augmentin; GlaxoSmithKline, London, UK) twice daily and 250 mg of metronidazole (Flagyl; Zambon, Milan, Italy) three times daily for ten days. The antibiotic protocol was adopted to prevent the potential aerobic and anaerobic polymicrobial infection due to the dissemination in subcutaneous tissues from peri-implantitis lesion microbiota []. Furthermore, to reduce the probability of complications, the patient was advised to avoid coughing, sneezing, and nose-blowing, which could increase intraoral pressure. Follow-up visits were scheduled every two days to monitor the progressive swelling reduction and complete resolution, which was obtained spontaneously after a week without any complications.

pmc-8702094-1

A 23-year-old man was admitted to our cardiomyopathy clinic for repetitive ventricular ectopic beats. He was hemodynamically stable with no other relevant symptoms. He never experienced syncope and was unaware of any case of cardiomyopathy or sudden cardiac death in his family. Remarkably, his medical history included an episode of acute myocarditis one year before. At that time, he was admitted to the emergency department of a different hospital with chest pain, troponin rise, and T wave inversion in the inferolateral leads on ECG (). An urgent coronary angiogram revealed normal coronary arteries. Then, a cardiac magnetic resonance (CMR) was performed, showing a non-dilated left ventricle (LV) with low-normal ejection fraction (EF), as well as normal RV dimensions and function. T2-weighted images highlighted the presence of mid-wall myocardial edema involving the interventricular septum, where mid-wall late gadolinium enhancement (LGE) was also noted on post-contrast images (). Endomyocardial biopsy was proposed, though the patient did not provide informed consent. The patient was discharged with a diagnosis of acute myocarditis, with a recommendation for close clinical follow-up. When re-assessing the patients at his 1-year follow-up, echocardiography showed an initial reduction of LV EF, with an area of hypo-akinesia involving the lateral wall, and preserved RV dimensions and function. A new CMR study was performed, which confirmed the mildly reduced LV EF with no evidence of myocardial edema. Post-contrast images, however, revealed a diffuse circumferential subepicardial LGE involvement of the LV myocardium (). To exclude a left-dominant variant of arrhythmogenic cardiomyopathy, in which this LGE pattern has been reported with CMR, genetic testing and accurate family screening were then performed. His 56-year-old mother and 30-year-old sister, both asymptomatic, were also found to have inverted T waves in the inferolateral leads on ECG and a mildly reduced LV EF on echocardiogram. Performing CMR on those two subjects, a pattern of LGE very similar to the one detected in the proband was detected (). No relevant clinical findings were identified by exploring the paternal side of the family. To our knowledge, this was the only documented case of a “myocarditis-like” onset of arrhythmogenic cardiomyopathy among the family members. Molecular testing was carried out by analyzing a panel of target genes through an NGS-based procedure. The MAF threshold was set to 5% using Illumina Variant Interpreter Software. Genetic testing identified a heterozygous variant in DSP (c.5428C>T, p.Gln1810Ter). According to the American College of Medical Genetics (ACMG), the variant was classified as likely pathogenic (class IV). The same mutation was found in the patient’s relatives with a positive phenotype (), and a diagnosis of familiar left-dominant arrhythmogenic cardiomyopathy was finally made. The patient, as well as his mother and sister, started therapy with β-blocker drugs, and the proband also received an implantable cardioverter-defibrillator.

pmc-8702215-1

An 8-year-old Caucasian girl was referred to our clinic for joint hyperlaxity, skin hyperextensibility and delayed wound healing. She was the second child of non-consanguineous parents, born preterm (29 weeks + 6 days) with an urgent Cesarean section due to maternal pre-eclampsia and placental abruption. Birth weight was low but appropriate for gestational age (930 g; 11th centile), and prematurity requested prompt admission to the neonatal intensive care unit. Twelve hours after birth, she experienced small bowel perforation due to meconium ileus, which required resection surgery and subsequent ileostomy without local complications. In the subsequent weeks, bilateral retinal detachment likely due to the retinopathy of prematurity was also diagnosed and promptly treated with laser photocoagulation and subsequent vitrectomy at 2 months of age. Additionally, she was diagnosed with bilateral cataract presumably secondary to prematurity. For this complication, she underwent surgery by the age of 18 months and 3 years to the left and right eye, respectively. The ophthalmologic prognosis was complicated by high-grade myopia and visual deficit. According to the last evaluation, she had a visual acuity of 3/10 in the left eye and a partial blindness in the right one (she only perceives lights), treated with daily topic ocular β-blockers. At the age of 7, she had a right traumatic femoral bone fracture after a minor trauma (a fall from a chair), requiring surgical treatment. On examination, the girl was found to be overweight (weight 75–90th centile; BMI 75th centile—CDC charts [], with generalized joint hypermobility (Beighton score: 9/9) (a), skin hyperextensibility, multiple atrophic and post-surgical dystrophic scars (b), multiple ecchymoses in her lower limbs, absence of lingual frenulum, mild right-convex thoracic scoliosis, bilateral genu valgum-recurvatum, cubitus valgus with elbows hyperextensibility and bilateral pes planus. She had no strength deficit, with global hypotonia but normal muscular trophism and deep tendon reflexes. However, she had a global hypotonia. Intellectual abilities were normal. She was able to walk, with the help of a crutch. On both legs, soft, velvety skin and subcutaneous tissues had been long misdiagnosed as a mild lymphedema. Parents also reported easy bruising for their daughter. None of her family members presented with similar signs or symptoms. Chest, spine and limb radiography confirmed the orthopedic abnormalities. Global respiratory function with spirometry, abdominal and supra-aortic trunk ultrasounds and video-electroencephalography all resulted normal. A comprehensive cardiovascular evaluation evidenced a mild mitral valve insufficiency without clinical relevance. No other vascular or lymphatic anomalies were detected. Multidisciplinary follow up, including pediatric, oculistic, psychiatric and cardiovascular evaluations, has been continued for 5 years. She reports no pain. She attends school with good cognitive and social skills and weekly swimming sessions. Support insoles were prescribed without a clear clinical improvement.

pmc-8702325-1

A 12-year-old girl developed abdominal pain and reported frequent bloody stools for over a month. She had been diagnosed with moderate left-sided UC at nine years of age. Remission was initially induced with prednisolone, and she remained in remission with azathioprine due to mesalazine intolerance. She experienced moon face and increased appetite as side effects while taking prednisolone. She was later diagnosed with a UC relapse based on colonoscopic findings of marked erythema and the absence of vascular pattern. Because of the side effects of previous prednisolone therapy, the patient and her guardian declined further steroid therapy. We decided to induce remission with GMA. However, securing two blood vessels for GMA was expected to be difficult because of the patient's small anthropometric measurement (height: 134.9 cm, weight: 31.7 kg). Therefore, we elected to perform GMA with the single-needle method. She underwent GMA once per week for 10 weeks. A 17-gauge dialysis puncture needle (outer diameter: 1.4 mm, length: 25 mm) was inserted into the right elbow (). The dialysis console processed a blood flow rate of 40 mL/min (total blood volume: 1,800 mL). In this case, the treatment time was 90 minutes. No decrease in blood pressure was observed during this procedure. Heparin was used as an anticoagulant. All 10 GMA treatments were completed without puncture failure or poor blood removal. Additionally, no side effects were observed. However, the patient did not attain remission with GMA. After an unsuccessful attempt of oral tacrolimus therapy, remission could be achieved and has maintained with infliximab (5 mg/kg, every 8 weeks) for 10 months.

pmc-8702359-1

A 60-year-old female presented to our tertiary medical center for a second opinion regarding the incidental pathology finding of stage III nonmucinous appendiceal adenocarcinoma after an emergent appendectomy for perforated appendicitis at an outside hospital four months prior. Her initial pathology revealed primary nonmucinous, moderately differentiated, stage III, pT4pN1aM0, appendiceal adenocarcinoma, involving 1 of 3 periappendiceal lymph nodes with extensive lymphovascular space invasion. Mismatch repair protein was intact. She completed staging computed tomography (CT) and colonoscopy. On imaging, there was no evidence of distant metastasis, but a small right ovarian cyst and calcification of the gallbladder wall were noted (). The ovarian cyst had been evaluated intraoperatively at the index operation by a gynecologist, and it was deemed that no intervention was needed at that time. Completion right hemicolectomy and possible right oophorectomy followed by adjuvant FOLFOX (folinic acid, fluorouracil, and oxaliplatin) were recommended. However, she opted to forgo any treatment at that time. The patient was asymptomatic in the interim. The patient represented to clinic with CT findings of growth in the right ovarian cyst, from 4 to 11 cm, with a new 6 cm complex cystic/solid mass along the left pelvic sidewall (). On presentation, she complained of lower abdominal fullness and cramping with intermittent bloating and early satiety. Her exam was mostly unremarkable except for the fullness in bilateral adnexa. Her case was presented at the multidisciplinary tumor board. At that time, her pathology was also reviewed (). We recommended completion right hemicolectomy as well as resection of adnexal masses, which were concerning for malignancy. We also discussed the possibility of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy if peritoneal metastasis was discovered on exploration. In addition, she was recommended to undergo cholecystectomy at the same time. Intraoperatively, the patient was found to have diffuse carcinomatosis. Cytoreductive surgery included right hemicolectomy, cholecystectomy, and total abdominal hysterectomy and bilateral salpingo-oophorectomy with en bloc resection of the adnexal masses. This was followed by HIPEC with mitomycin C. The peritoneal carcinomatosis index (PCI) was 20, and the completeness of cytoreduction score (CC) was 1 due to subcentimeter implants on the small bowel serosa from the jejunum to the terminal ileum. The patient had an uneventful postoperative recovery and was discharged on postoperative day 6. Surprisingly, pathology revealed primary gallbladder adenocarcinoma, moderately to poorly differentiated, arising in a background of high grade biliary intraepithelial neoplasm and porcelain gallbladder. The carcinoma extended through the visceral peritoneum onto the serosal surface and into the pericystic soft tissue on the hepatic bed surface (). All tumor deposits collected from the operation were consistent with metastasis from the biliary origin. With this new finding, her case was rediscussed at tumor board. The original appendiceal specimen slides were reviewed and found to be similar histologically to the gallbladder adenocarcinoma (). The possibility of synchronous gallbladder and appendiceal primaries was discussed but given the morphological resemblance between the two and the pattern of spread, primary gallbladder adenocarcinoma with carcinomatosis was the most likely diagnosis. The patient completed four cycles of gemcitabine and cisplatin before switching to FOLFOX after surveillance imaging demonstrated disease progression. Shortly after receiving the first cycle of FOLFOX, she presented with an acute abdomen secondary to perforated viscus and underwent emergent laparotomy. She was subsequently transitioned to hospice.

pmc-8702361-1

The female patient was 4 years old when she came to our attention. She was brought to the practice by her parents because she complained of hypersensitivity to heat and cold, even during normal breathing. The patient had never undergone a dental examination or treatment.

pmc-8408423-1

A 33-year-old female living in Fresno, California presented to the hospital with progressively worsening diplopia and headache for 5 days. Chart review showed that she had been diagnosed with coccidioidal meningitis three years ago when she presented with similar headaches and reduced visual acuity. Computed tomography (CT) of the head at the time showed hydrocephalus. CSF opening pressure was 52 cm H2O. Coccidioides complement fixation titer of the CSF was positive at 1:16. She was started on oral fluconazole 1000 mg daily for adequate CNS penetration and a ventriculoperitoneal shunt was placed at that time. She was eventually discharged home but lost to follow-up. In the Emergency Department on Day 0, her vital signs were stable within normal range. Physical exam was benign, other than oblique diplopia. CT of the head showed hydrocephalus and a right posterior parietal ventriculoperitoneal shunt tube (). Lumbar puncture was performed on Day 1. Opening pressure was 17 cm H2O. CSF analysis revealed leukocytes of 51/uL with 69% lymphocyte predominance, glucose 23 mg/dl, protein 324 mg/dl. CSF studies showed positive Coccidioides complement fixation at 1:32 and VDRL 1:32. Fungal culture of CSF was negative. RPR titer was 1:32. Upon further investigation, the patient had been diagnosed with syphilis about 2 years ago when she presented to an Emergency Room with vaginal pain and swelling. RPR at that time was positive at 1:16, but the patient had already left the Emergency Department and did not receive any treatment. The Department of Public Health also confirmed that she had never received appropriate treatment for syphilis. She was started on Fluconazole 1000 mg daily to treat CNS infection with Coccidioides as well as Penicillin G 4 million units IV every 4 hours for 14 days to treat neurosyphilis. Unfortunately, her mental status continued to decline requiring intubation for airway protection. On Day 20, she underwent external ventricular drain (EVD) placement due to worsening hydrocephalus on repeat imaging. Subsequent imaging on Day 22 showed worsening ventriculomegaly with bifrontal hemorrhage despite EVD placement (). Due to lack of neurological improvement and poor prognosis, her family elected to transition to comfort-focused care, and she was discharged on a hospice on Day 30.

pmc-8646964-1

A 25-year-old man presented to our epilepsy center for evaluation of seizures. He was born at term without any developmental delays and had no risk factors for epilepsy including traumatic brain injury, brain surgery, febrile seizures, central nervous system infections, or family history of seizures and no significant past medical or psychiatric comorbidities. Three years prior to his presentation he had his first seizure. He did not remember the event, but while attending basic training in the Army, he was reportedly found in the shower confused by his fellow soldiers. There was no tongue bite or urinary incontinence, but he was disoriented afterward for much of that day. He had another episode within the same month while he was performing physical training exercises, whereby he collapsed and remained confused for hours, but no report of witnessed convulsions. An evaluation at that time was unrevealing. He had 12 episodes in the next 3 years. They were all similar, some associated with lateral tongue laceration suffered during the event. He was seizure-free for 6 months and then began to have spells at least monthly. He denied an aura or premonition preceding his seizures. His wife reported at night that he would “cry” at the onset and then appears to have clonic jerking bilaterally and symmetrically, up to 3 minutes in duration. He was reported to be distressed for a few minutes after the episodes. Brain MRI was reportedly normal and EEG abnormal, but the reports were unavailable. He had been taking levetiracetam 3000 mg daily with topiramate 50 mg daily. He had also tried valproic acid but reportedly had abnormal labatory studies so this was discontinued. At his appointment, it was determined that he would continue his current regimen of levetiracetam, and topiramate was increased to 100 mg total daily. A presumptive diagnosis of epilepsy was made upon clinical grounds though the classification included focal epilepsy localized to the frontal head region or genetic generalized epilepsy manifest as recurrent nocturnal generalized tonic-clonic seizures. At his follow up appointment, a high-resolution 3-T brain MRI was performed and was normal without intracranial abnormalities. EEG demonstrated 3–4 Hz generalized polyspike-and-wave discharges supporting a clinical diagnosis of genetic generalized epilepsy. The patient and his wife had recorded a video of his habitual seizures, which was reviewed an epileptologists (WOT). As noted in the video, he appears agitated and combative and is thrashing his extremities in a non-rhythmic and discontinuous manner with side to side head movements with eyes closed (). He and his wife were clear that this was the semiology of his typical seizure. The side to side head movements, eye closure, and discontinuous nonrhythmic hypermotor activity suggested FS . He was subsequently admitted to the epilepsy monitoring unit for LTVEM for differential diagnosis and classification of recurrent events. During the admission, EEG redemonstrated interictal generalized spike and polyspike and slow wave complexes noted previously. He had one seizure with clinical semiology suggesting a focal to bilateral tonic-clonic seizure due to head version, yet lateralized and focal seizures are known to occur in genetic generalized epilepsies . Despite the appearance of focal features, the ictal EEG demonstrated a generalized seizure onset. Immediately following a definitive diagnosis of epilepsy with electroclinical support from a electroclinical bilateral tonic-clonic seizure, he exhibited the exact same post-ictal behavior that was witnessed in clinic while reviewing the smartphone video. This behavior observed on the smartphone video was therefore able to be linked to his habitual postictal state with violent thrashing that simulated a FS (). In discussion with the patient and his wife, the difference between his seizure and a postictal state with confusion and combativeness was underscored to define a sequence of events rather than separate events. LTVEM was therefore able to establish a diagnosis of genetic genealized epilepsy despite the history suggesting focal epilepsy and the smartphone video suggesting a FS.

pmc-8647200-1

A 60-year-old Japanese male patient without any past medical history presented with dyspnea for 5 days in June 2019 (before the COVID-19 outbreak). He had no history of cigarette smoking, alcohol consumption, or sick contacts. He had a frequent cough, tachypnea (40 breaths per minute), low-grade fever (37.2°C), and hypoxemia (PaO2, 50.2 mm Hg on room air). He did not have wheezes or lung crackles and abnormal heart sounds on auscultation. Edema, skin rash, muscle weakness, myalgia, and arthralgia were absent. Blood tests revealed leukocytosis (10,300 cells/μl with 76% neutrophils, 2.0% eosinophils, and 14.0% lymphocytes) with high C-reactive protein levels (5.27 mg/dl). He had normal liver and renal function tests (aspartate aminotransferase 25 IU/L, normal <38 IU/L; alanine aminotransferase 30 IU/L, normal <40 IU/L; blood urea nitrogen 13.6 mg/dl, normal <20 mg/dl; and creatinine 1.04 mg/dl, normal <1.10 mg/dl) and no elevation of creatinine kinase (155 IU/L, normal <170 IU/L). Autoimmune screening did not identify any abnormalities, including anticyclic citrullinated peptide, anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-proteinase 3 (PR3) antibodies, anti-myeloperoxidase (MPO) antibodies, anti-Scl-70 antibodies, anti-Sjögren's syndrome-related antigen A (SSA/Ro52) antibodies, anti-aminoacyl-transfer RNA synthetase (ARS) antibodies, anti-Jo-1 antibodies, and anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Chest X-ray and computed tomography (CT) scan showed diffuse ground-glass opacification and consolidation in bilateral lung fields (Figure ). On the day of admission, the patient's condition deteriorated rapidly and he received noninvasive intermittent positive pressure ventilation (NPPV). The diagnosis of rapidly progressive interstitial lung disease with autoimmune disorders, such as severe inflammatory myopathy-related interstitial lung disease, could not be ruled out. Based on the diagnosis of ARDS of unknown etiology (PaO2/FiO2 235 with a positive end-expiratory pressure of 5 cmH2O), high-dose (1000 mg/day) intravenous (IV) methylprednisolone therapy was initiated. Empiric antibiotics (IV piperacillin-tazobactam and levofloxacin) were also given, although blood culture and urinary pneumococcal and Legionella antigen tests were negative. After 3 days of steroid pulse therapy, the patient improved dramatically and was weaned from NPPV and, thereafter, from oxygen support. The dose of IV methylprednisolone was reduced to half every 3 days and later it was switched to oral prednisolone (60 mg/day), which was also gradually reduced. Chest CT scan taken on the 13th day of admission revealed almost complete disappearance of abnormal shadows from the lung field (Figure ). He was discharged without dyspnea on the 26th day of admission. The steroid was tapered down gradually and discontinued 7 months after discharge. Although the patient had been asymptomatic for a while, he had a relapse of dyspnea in 10 months later after the first onset of ARDS. Upon the second admission, he had hypoxemia (PaO2 64 mm Hg) on O2 5L/min via face mask and started receiving NPPV therapy. Chest CT scan showed a mixture of diffuse ground-glass opacification and consolidation similar to roentgenological patterns observed previously (Figure ). The findings of physical examination and blood tests were not significantly different from the previous admission except that he had grasping pain in both thighs, proximal muscle weakness in extremities, and elevation of serum creatinine kinase (1741 IU/L). He had no skin eruptions, such as nail-bed telangiectasia, heliotrope rash, Gottron's papules, Raynaud's phenomenon, and hyperkeratotic lesions on his fingers (mechanic's hands). The short-tau inversion recovery sequence (STIR) of magnetic resonance imaging (MRI) showed inflammatory changes in both hamstring muscles (Figure ). However, the Euroline myositis line blot assay showed negative results for either myositis-specific antibodies (Jo-1, PL-7, PL-12, EJ, SRP, Mi-2, MDA5, and TIF1-γ) or myositis-associated antibodies (Ku, PM-Scl100, Scl-70, and SSA/Ro52). From these findings, the diagnosis of ARDS that relapsed along with an initial manifestation of seronegative PM was made. After 3 days of high-dose (1,000 mg daily) IV methylprednisolone therapy, the patient's dyspnea and muscle weakness improved dramatically and NPPV therapy was discontinued. Additionally, the diffuse abnormal shadows on the chest CT scan (Figure ) and the high signal on STIR MRI of the hamstring muscles (Figure ) disappeared. The dose of IV methylprednisolone was gradually reduced to 40 mg/day prednisolone, when the patient was discharged without respiratory and muscular symptoms on the 26th day of the second admission (Figure ). The steroid was tapered down gradually and discontinued 6 months after discharge.

pmc-8647806-1

A 70-year-old Caucasian woman with medical history significant for stage III chronic kidney disease, transitional cell ureteral cancer status post-left-sided nephroureterectomy, and three-year history of Waldenstrom's macroglobulinemia (WM) presented with complaints of right-sided weakness associated with paresthesias, dysarthria, and blurry vision of three weeks duration. Magnetic resonance (MRI) imaging of the brain demonstrated an enhancing, hypercellular mass centered in the left thalamus with additional foci of signal abnormality and enhancement in the cortex of the left frontal lobe and subcortical white matter (Figure ). These findings were concerning for an intracranial neoplastic process, especially given her history of WM. Regarding her oncological history, she was initially diagnosed with WM at the age of 67 after workup for complaints of chronic fatigue revealed elevated IgM levels (3370 mg/dl) as well as serum hyperviscosity. Bone marrow biopsy showed a low-grade B-cell lymphoma with plasmacytic differentiation and 60%–70% bone marrow involvement. Neoplastic cells were found to be lambda restricted and negative for CD5, CD10, and CD23 by flow cytometry. An increased number of lambda predominant cells were confirmed by flow cytometry and CD138 immunostaining. The patient was started on first-line therapy with the Bruton tyrosine kinase inhibitor ibrutinib; however, due to worsening adverse effects after 6 months of therapy she transitioned to rituximab, an anti-CD20 monoclonal antibody. Unfortunately, the patient was found to have worsening IgM levels and serum viscosity while on rituximab monotherapy over the next 6 months. Thus, she was restarted on ibrutinib while continuing rituximab every 3 months and had significant improvement on this combination of therapy. She completed two years of maintenance rituximab and reduced-dose ibrutinib (140 mg) at time of presentation with the most recent IgM levels of 299 mg/dl prior to the onset of her previously mentioned neurological symptoms. Given her MRI findings, computed tomography (CT) imaging of the head, chest, abdomen, and pelvis was completed, which revealed multiple intracranial lesions but no evidence of lymphadenopathy or neoplastic process elsewhere. She further underwent lumbar puncture for cerebral spinal fluid (CSF) analysis with flow cytometry showing mostly T cells without evidence of B-cell non-Hodgkin lymphoma. As there remained high suspicion for central nervous system (CNS) lymphoma, the patient ultimately had a left parietal stereotactic brain biopsy with pathology findings of diffuse aggressive B-cell non-Hodgkin lymphoma (Figure ). Immunohistochemical studies were positive for CD20, CD23, BCL-6, MUM1, and LE1 (Figure ) with approximately 80% of cells expressing Ki-67 proliferation antigen (Figure ). Fluorescent in situ hybridization (FISH) analysis was negative for c-MYC, BCL-6, or BCL2 gene rearrangements. Lastly, mutation testing using next-generation sequencing returned positive for MYD88 L265P mutation. The patient was placed on oral dexamethasone 4 mg four times daily with noticeable improvement in her speech and mobility. Due to the patient's poor renal function, she was not a candidate for induction therapy with methotrexate. Thus, she began treatment with whole brain radiation therapy (WBRT) to 30.6 Gy while continuing systemic treatment with ibrutinib. A repeat MRI of the brain two months later demonstrated near resolution of the patient's lymphoma with findings of only a few small foci of nonspecific enhancement adjacent to the biopsy cavity within the left thalamus (Figure ). There was no evidence of intracranial mass effect, midline shift, or abnormal extra-axial collection.

pmc-8647807-1

The case study is devoted to investigating of penile pain in a 41-year-old married man. According to medical evaluation, the pain extended to the perineal and inguinal regions and it was reported to be more acute during erection. The patient was referred by urologist for sonographic evaluation of penis and testes. The pain had started 3 days before the urologist examination, following his first full erection for intercourse, after his positive COVID-19 polymerase chain reaction (PCR) test. The patient did not have any other urologic symptoms such as discharge, hematuria, or dysuria. He denied any trauma to the penis, previous pelvic tumor, pelvic surgery and history of recent immobilization. He did not use vasoconstrictive drugs. The patient reported positive nosopharyngeal swab test for COVID-19 three weeks earlier. He had mild symptoms of COVID-19 infection including muscle pain, fever, cough, and fatigue. He had received conservative treatment and had not taken any anti-coagulants, antivirals, and corticosteroids. His medical history did not show any significant underlying disease and any risk factor for cardiovascular disease. He also did not have history of previous deep vein thrombosis. In physical examination of the penis and testes, no pathologic finding was detected such as skin tissue changes, discoloration, edema, tenderness, or palpable nodularity. Ultrasound evaluation showed thrombosis of deep dorsal penile vein while the superficial dorsal penile vein, iliac veins, and inferior vena cava were intact (Figures ,,). Laboratory tests revealed slightly increased D-dimer level(may be due to inflammatory process of COCID-19 infection), normal levels of fibrinogen, anti-thrombin III, protein S, Protein C, anti-cardiolipin antibodies and normal count of platelets and white blood cell counts. Also Tests were negative for anti-phospholipid-IgG, IgM, and lupus anti-coagulant (Table ). Immediately after sonographic diagnose of deep dorsal penile vein thrombosis, the Rivaroxaban treatment was started with the dosage of 15 mg twice a day. Two months after starting the treatment, patient's symptoms were completely disappeared and he had no penile pain during erection and sexual disturbances anymore. Ultrasound evaluation revealed no evidence of acute deep dorsal penile vein thrombosis. Old partial thrombosis at the proximal part of the vein was seen. A little pain at the site of the partial thrombosis with the pressure of the ultrasound probe was noted (Figures ,,).

pmc-8649078-1

A 45-year-old male was admitted to the emergency department with postural instability and dysarthria. To lessen his instability and avoid to fall, the patient widened his support polygon. He had also reported dyspnea at effort, which occurred 3 days prior to his admission. He had a history of rheumatic mitral stenosis, since 2005, for which he benefited from a percutaneous mitral dilation in the same year. He also reported a Penicillin allergy. Initial examination found the patient conscious. His heart rate was 125 b/m, blood pressure was 135/85 mm Hg. He was polypneic and orthopneic with a respiratory rate of 28 breaths/min, an O2 saturation of 96% on ambient air with the presence of bilateral crackles. He had a fever measured at 39.5C. Cardiac auscultation revealed a low-pitched diastolic rumble, well heard at the apex. The neurologic examination revealed unsteady gait and the patient was unable to perform Romberg's test. The ECG showed coarse-mesh atrial fibrillation with an average ventricular rate of 90 cycles per minute (). No abnormalities were detected on the chest x-ray. Transthoracic echocardiogram (TTE) found rheumatic changes of the mitral valve including: commissural fusion and thickening, producing “dog leg deformity” of the anterior mitral leaflet (-A). The mitral valve area was 0,8 cm2 (-B) and the pressure gradient across the mitral valve was 22 mmhg (-E). We noted a mobile vegetation measuring 11,7 mm of length, located in the posterior leaflet of the mitral valve (-C). The left atrium was dilated at 47 cm2 while size and function of the left ventricle was normal. Pulmonary arterial systolic pressure (PASP) was important (-F) and the filling pressures of the left ventricle were elevated. In addition to that, we reported moderate aortic stenosis and regurgitation and mitral regurgitation at grade A. Three sets of blood cultures were made, coming back negative as well as the HACEK organism's serologies (Haemophilus; Actinobacillus; Cardiobacterium; Eikenella; and Kingella). It was decided to perform a brain MRI based on the clinical findings. It showed a recent ischemic stroke involving the right peduncular territory associated with chronic lacunar infarcts (). Signs of inflammatory response were noted, high white blood cell count at 14 770/mm3 in addition to C reactive protein (CRP) at 67 mg/l, Ferritin was elevated at 839 μg/l. The kidney function was normal. Further investigations were realized to precise the extension of infective endocarditis, all coming back normal. No point of entry for the pathogen was detected. The patient was admitted to the cardiology unit. The diagnosis of infective endocarditis was made, based on the modified Duke criteria (1 major clinical criteria +3 minors clinical criteria). Given the negative blood culture endocarditis and the history of penicillin allergy, it was decided to start an antibiotic therapy combining: Vancomycin at 30mg/kg/day for 6 weeks (Vancomycin serum concentrations of 15–20 mg/L were aimed) and Gentamicin at 3mg/kg/day for 2 weeks, in addition to intravenous diuretics (80 mg of Furosemide as bolus followed by a maintenance dose of 40mg/12hours) with a strict control of kalaemia. Finally, for his supraventricular arrythmia, Enoxaparin was started at a curative dose (100 UI/kg/12h). The tolerability was good and no adverse events were reported. Within 4 days, fever disappeared. The postural instability and the dysarthria were less important than in his admission. Routine TTEs showed a regression of the vegetation and a normalization of the left ventricular pressures. The patient was satisfied after the improvement of his clinical condition. He was addressed after that to the cardiovascular surgery department for a surgical treatment of his valve disease.

pmc-8649079-1

A 29-year-old female patient, gravida 1, para 1, with no significant pathological history, had presented herself in consultation complaining of a left cervical swelling that had been evolving for 11 months in a context of general state conservation. The mass was increased in size rapidly after the end of the breastfeeding period (three months). The clinical examination at admission found normal vital signs, and Body mass index of 26.3 kg/m2. Family history was unremarkable for cancer. The patient was used a combined oral contraceptive for menstrual regulation. The cervical examination showed a postero-lateral mass of the left neck measuring 6 cm in diameter, painless, of firm consistency, unilobed, soft, adherent to the superficial and deep plane. There was no palpable cervical lymphadenopathy or inflammatory signs of the adjacent skin. A cervical magnetic resonance imaging (MRI) was performed, revealing a mass of the left posterior cervical soft parts, at the expense of the trapezium muscle, tissue, oval, of regular contours, well-defined, measuring 41 × 68 × 81 mm, enhanced after injection of Gadolinium, with multiple homolateral supraclavicular and lateral cervical lymph nodes (). The monotest, in the absence of an IRD tuberculin skin intradermoreaction, was negative. A biopsy of the mass with Tru-cut® was performed, concluding a desmoid tumor. Abdominopelvic and thoracic computed tomography, indicated for staging, showed the absence of other progressive lesions elsewhere. In view of these clinical, radiological and pathological findings, a large resection of the tumor was indicated. The patient was installed in the supine position. Access to the posterior neck area was via a direct surgical approach (Fusiform incision). The mass was found to originate from the trapezius muscle without local infiltration of surrounding structures. A sharp dissection over the mass of the tumor away from the muscle was not possible. Complete excision of the mass was accomplished involving the fascia and trapezius muscle (). A close suction drain was placed. The safety margins are macroscopically healthy with a resection at 1.5 cm macroscopic distance from the palpable area of the tumor. The post-operative outcomes were simple without any complications and the drain was removed on the second postoperative day. The patient was discharged from the hospital on postoperative day 5, and the functional result was considered satisfactory without any impairment noted. The pathology examination of the surgical specimen showed proliferation of spindle-shaped cells arranged in long fascicles in a collagenous stroma. This proliferation infiltrates the striated muscle, with negative excision margins. An immunohistochemistry staining was performed, demonstrating cytoplasmic labeling with anti AML antibody, and nuclear labeling of tumor cells with anti-beta-catenin antibody. This pathological and immunohistochemical aspect highlights the diagnosis of a desmoid tumor (). The case was analyzed by a multidisciplinary committee, and it was decided to follow the patient without any adjuvant treatment given its long-term side-effects and the safety margins are healthy. After a three month, the clinical and radiological follow-up examinations were unremarkable. The outcome was favorable without local or distant tumor recurrence.

pmc-8649209-1

The participant in this study was a 24-year-old man who was in a motor vehicle accident that led to a severe TBI two years ago. According to the report of the spiral brain CT scan, the primary lesion was located in the left frontotemporal area due to contusion, and a few lacunar infarcts were seen in the left basal ganglia. Before the accident, he was an active member of a music band and was involved in bodybuilding activities. He was hospitalized for 48 days after the accident. Following discharge from the hospital, he received regular rehabilitation, including electrical stimulation of the wrist and knee extensors and ankle dorsiflexors, resistance training, and aerobic and endurance conditioning (e.g., walking on treadmill and stationary bike). At the time of the first visit to the research clinic, he could not independently walk or stand up from a chair and was using a wheeled walker for mobility and an ankle foot orthosis to prevent drop foot. The clinical examination was performed by an experienced physical therapist. The participant had right (RT) hemiplegia with full and strong grasping and gripping but without the ability to write. Other impairments were aphasia, bradykinesia, and dyscoordination of movements of RT upper (i.e., finger to nose) and lower (i.e., heel to shin) extremities. Also, deep tendon reflexes were increased with no spasticity in his muscles. He was dependent in some activities of daily living (ADL) (e.g., dressing, toilet use, and feeding).

pmc-8649573-1

A 53-year-old man presented with a pruritic rash on the trunk as well as on the upper and lower extremities. Examination was notable for lichenified papules throughout the trunk and extremities, most notably on the back. Biopsies of the rash showed mild spongiosis with an underlying superficial and deep perivascular infiltrate (). Due to failure of topical halobetasol, topical tacrolimus, oral antihistamines, prednisone, and mycophenolate mofetil, dupilumab was initiated at standard dosing. Within 3 months, the patient noticed a dramatic improvement of his rash and pruritus, complaining only of mild pruritus between injections and minimal residual post-inflammatory hyperpigmented macules. Dupilumab was stopped after 1 year due to insurance reasons, and the initial pruritic rash returned. After insurance reapproval, dupilumab was restarted with complete resolution of his rash and pruritus.

pmc-8649573-2

A 48-year-old woman presented with a 5-year history of intense pruritus and rash significantly impacting her daily life. Examination showed few excoriated papules and subtle lichenification on the upper back, elbows, dorsal forearms, thighs, and fingers. Biopsy revealed mild epidermal spongiosis with a perivascular lymphocytic infiltrate containing rare eosinophils, consistent with DHR (). After failing multiple therapies including topical betamethasone, topical tacrolimus, and oral mycophenolate mofetil, dupilumab was initiated with improvement in severity and duration of flares within the first 6 months. Due to slight progression of her baseline blurry vision and headaches, the dose was decreased to 200 mg every 2 weeks. The patient experienced subsequent flaring of her rash, so the dose was increased back to 300 mg every 2 weeks with resolution of her pruritus and rash and no further exacerbation of her ocular symptoms. Ultimately her ocular symptoms were evaluated by an ophthalmologist and deemed to not be consistent with dupilumab-induced conjunctivitis nor glaucoma.

pmc-8649573-3

A healthy 43-year-old woman presented with a 1-year history of a pruritic rash affecting her legs and abdomen. On exam, the patient was noted to have erythematous, blanchable papules coalescing into small plaques on her abdomen and distal part of the legs. Biopsy of the rash revealed an unremarkable epidermis and superficial perivascular lymphocytes with abundant interstitial eosinophils consistent with DHR. Patch testing was performed, which was 2+ for nickel sulfate and 1+ for p-tert-butylphenol formaldehyde resin, but the rash was persistent even with allergen avoidance. After failing multiple topical regimens, including triamcinolone and clobetasol, as well as oral prednisone, the patient was initiated on mycophenolate mofetil therapy, with excellent control but poor gastrointestinal tolerance. Her rash subsequently recurred, so dupilumab was started at standard dosing, and 5 months after starting dupilumab the patient's rash and pruritus had resolved without any side effects.

pmc-8649573-4

A 68-year-old man presented with a 6-month history of a pruritic rash that began on his back and legs and spread to his knees, elbows, shoulders, and chest. Patch testing showed 1+ positivity for both sodium laurel sulfate and benzaprene #4, which were deemed not clinically relevant. On examination, he had scattered erythematous scaly patches on the upper chest, shoulders, and back with overlying excoriation. Biopsy of the right shoulder showed an unremarkable epidermis and a sparse perivascular and interstitial mixed infiltrate containing scattered interstitial eosinophils, consistent with a DHR (). Oral prednisone initially cleared the rash, but it recurred on discontinuation. The rash was also recalcitrant to trials of topical steroids, oral antihistamines, and topical tacrolimus; therefore, he was transitioned to dupilumab at standard dosing. After 3 months, the patient reported complete clearing of the rash and pruritus. He did note occasional eye dryness, which was well-managed with artificial tears.

pmc-8649573-5

A 75-year-old man presented with a 1-year history of recurrent diffuse, pruritic rash. Examination revealed a generalized eruption of erythematous papules with minimal scale on the extremities and trunk particularly the flanks. Initial differential diagnosis included hypersensitivity dermatitis, contact dermatitis, non-bullous pemphigoid, atopic dermatitis, and Grover disease. A biopsy was performed on the left part of the chest and revealed a predominantly perivascular inflammatory infiltrate with occasional eosinophils consistent with DHR. A direct immunofluorescence test was negative. The patient failed multiple therapies, including topical triamcinolone, clobetasol, and hydroxyzine. Oral prednisone helped but was discontinued due to steroid-induced diabetes. The patient was started on dupilumab 300 mg injections every 14 days and within 4 months, his dermatitis and pruritus resolved. Due to cost, the injections were spaced to every 30 days, and he continued to experience resolution of his symptoms without any side effect from the medication.

pmc-8649573-6

A 78-year-old man presented with a 5-year history of extreme pruritus. No significant dermatitis was observed aside from faint pink patches on the upper chest and lower back with mild lichenification. Patch testing was performed and revealed 1+ positivity to potassium dichromate, but no culprit allergens were identified. A biopsy taken from the right part of the chest revealed mild acanthosis and minimal spongiosis with a perivascular lymphocytic infiltrate containing rare eosinophils in the presence of a negative direct immunofluorescence test, consistent with a DHR. The patient failed multiple therapies including topical corticosteroids, antihistamines, doxepin, narrow-band UV-B light, doxepin, gabapentin, butorphanol, and aprepitant. Azathioprine was poorly tolerated due to fatigue. The patient was then started on dupilumab with dramatic improvement in his pruritus and a 50%-60% reduction of the rash within the first 2 months with no associated side effects. His condition remains stable on this medication. Additional clinical information is summarized in .

pmc-8651769-1

A 31-year-old gravida 4 para 0 African American woman at 22-weeks gestation presented with vaginal bleeding to an outside hospital. Her obstetric history was significant for 2 therapeutic abortions and 1 spontaneous abortion. During prenatal care, the fetus was noted to have a unilateral dysplastic kidney. The patient’s family history was significant for two family members with cervical cancer and two family members with endometrial cancer. She was placed on bedrest with inpatient admission. 48 h after admission she developed pelvic pain and uterine contractions. She expelled a mass vaginally measuring 11 × 9 × 5 cm with no fetal contents. The pathology from the outside facility showed a showed a highly cellular tumor composed of spindle-shaped cells and bizarre multinucleated giant cells with focal myxomatous change with mitotic count is greater than 50 per 10 high power field (Positive for CD10, SMA, ER, PR, EMA) with the differential diagnosis including endometrial stromal sarcoma and undifferentiated uterine sarcoma. The patient underwent examination under anesthesia, demonstrating a 3 × 3 cm defect of the posterior vaginal wall with active bleeding, which was sutured for hemostasis. The cervix was long, closed, and high with no evidence of bleeding and the fetus was intact with normal heart tones. She was discharged in stable condition. At 27-weeks, the patient was referred to our institution for maternal-fetal medicine, and gynecology oncology consultation. On initial evaluation, she reported no prior abnormal gynecology history and no history of infertility issues. She denied dyspareunia and bulk symptoms prior to or during pregnancy, and her periods before pregnancy were normal. A pap smear at 27-weeks gestation was normal and negative for human papilloma virus. Her intake physical exam at our institution revealed a normal pelvic exam with no evidence of residual vaginal mass, and an ultrasound revealed no intrauterine myomas. Given the differential diagnosis included an endometrial stromal sarcoma, an undifferentiated uterine sarcoma, and a primary vaginal sarcoma, the patient underwent magnetic resonance imaging (MRI) without contrast of the chest, abdomen, and pelvis at 27 weeks. MRI findings were notable for a peri-centimeter cyst in the cervix consistent with a Nabothian cyst, a multiloculated cystic structure in the fetal abdomen consistent with dysplastic kidney, and an anterior placenta. There was no evidence of metastatic disease. Due to the inability to ascertain whether the cancer had originated in the uterus, cervix or vagina, the patient desired definitive management for possible uterine sarcoma. In consultation with maternal fetal medicine and gynecology oncology specialists, the decision was made to proceed with a cesarean hysterectomy at 36 weeks. Betamethasone 12 mg intramuscularly was given for two doses 24 h apart with the first dose at 35 weeks and 6 days gestational age. At 36 weeks and 1 day, she underwent planned exam under anesthesia of the vaginal canal with cesarean hysterectomy, bilateral salpingectomy, and peritoneal biopsies. She delivered a male infant weighing 2520 g with Apgars of 9 and 9. Operative findings were notable for normal appearing pelvic organs. There were no palpable or visibly enlarged pelvic/periaortic lymph nodes or evidence of metastatic disease throughout the peritoneal cavity. The neonate was admitted to the NICU post-delivery for prematurity. Neonatal US confirmed a right multi-cystic dysplastic kidney. He was transferred out of NICU on day 2 of life, and discharged home with his mother. The final surgical pathology report was benign: no malignant or neoplastic cells were seen. The patient was seen at her 6-week postpartum visit and was doing well with a normal pelvic exam. At a follow-up surveillance visit 3 months postpartum, she was noted to have a 1 cm posterior vaginal wall lesion; biopsy results showed a high-grade sarcoma. The tumor was estrogen receptor and progesterone receptor positive. Computer tomography (CT) with contrast of the chest, abdomen, and pelvis showed no evidence of metastatic disease. The patient underwent an upper vaginectomy and proctoscopy. Operative findings were notable for 1.5 cm polypoid lesion in the posterior vagina wall 5 cm distal to the posterior vaginal apex. A 1 cm surgical margin was obtained circumferentially around this lesion where feasible, and surgical pathology showed high-grade sarcoma () of the polyp lesion with negative surgical margins. The tissue removed from this excision showed residual sarcoma, morphologically similar to the original pathology from the outside hospital pathology. All other vaginal biopsies were also negative for malignancy. Marker seeds were placed in the proximal and distal margins of the areas where the sarcoma was excised. She was treated adjuvant high dose rate vaginal brachytherapy using a multi-channel vaginal cylinder. She received a biologically equivalent 2 Gy dose (EQD2) of 45 Gy to the whole length of the vagina and 60 Gy to the post-operative bed (). A CT scan 36 months after surgery continue to show no evidence of disease. She remains disease free 58 months after completion of vaginal brachytherapy.

pmc-8654049-1

A 55-year-old male with a history of type 1 diabetes mellitus (T1DM) and unspecified autoimmune disease who presented with acute onset of confusion as well as concrete visual hallucinations and behavioral change. There were no reports of any headache, fever, or stroke-like symptoms. His only outpatient medications were insulin and low-dose steroids. The patient was initially admitted to an outside hospital where magnetic resonance imaging (MRI) of the brain revealed multifocal areas of restricted diffusion with areas of corresponding T2 hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences (Figure ). There was a concern for stroke in multiple vascular territories with concern for vasculitis. Initial workup was unremarkable, and the patient was started on methylprednisolone for presumed primary central nervous system (CNS) vasculitis. He was transferred to our institution for further management by the Neurology service. His initial neurologic exam was notable for encephalopathy, manifesting as inattention, disorientation to place and time, and stupor. He was only able to follow simple appendicular commands. Cranial nerve exam revealed left lower facial droop. He had full strength in bilateral upper extremities and 4/5 strength in bilateral lower extremities. Initial differential diagnosis included autoimmune vasculopathies, primary CNS vasculitis, and infectious meningoencephalitis given his mental status changes, reported visual hallucinations, and multifocal strokes. Steroids were initially held on admission to our institution until further workup could be performed. Extensive rheumatologic labs were ordered, and only rheumatoid factor and anti-CCP were found to be mildly elevated. A contrast-enhanced MRI of the brain demonstrated evolving areas of restricted diffusion with multifocal new areas of restricted diffusion in multiple vascular territories (Figure ). There was also incomplete suppression of CSF signal on FLAIR with multiple areas of abnormal leptomeningeal enhancement, suggestive of a superimposed inflammatory process affecting the meninges (Figures , ). In addition, there was abnormal vessel wall thickening and enhancement, particularly involving the intracranial carotid arteries as well as anterior cerebral arteries (ACA) and middle cerebral arteries (MCA) (Figure ). Computed tomography angiography (CTA) of the head also demonstrated areas of vessel irregularity and multifocal areas of narrowing, particularly involving the ACA (Figure ). On further review of the initial lab work and neuroimaging, it was felt that a primary CNS vasculitis was unlikely. Rather, findings were more suspicious for a meningoencephalitis complicated by acute stroke. A lumbar puncture (LP) was subsequently performed, which demonstrated a lymphocytic pleocytosis (WBC 25 K/cumm, 80% lymphocytes), normal CSF glucose of 64 mg/dl, elevated protein of 104 mg/dl, and increased opening pressure of 28 cm H20. Infectious studies (including Syphilis screen, bacterial cultures, fungal cultures, HSV PCR, and flow cytometry) and inflammatory markers (including oligoclonal bands and IgG index) were unremarkable; however, India ink was performed on the CSF, which revealed a small number of encapsulated yeasts. He was subsequently diagnosed with cryptococcal meningoencephalitis and started on the appropriate anti-fungal regimen with amphotericin B and flucytosine. He required daily LPs to ensure opening pressure remained less than 20 cm H2O. The patient was treated with four weeks of amphotericin B and flucytosine followed by eight weeks of fluconazole. Prior to discharge to an inpatient rehabilitation facility, the patient’s mental status was notably improved and near his neurologic baseline.

pmc-8654049-2

A 35-year-old male with a history of hyperlipidemia and seizure disorder presented to an outside hospital following a breakthrough seizure, where he was incidentally also found to have punctate areas of acute cerebral infarcts in multiple vascular territories. Additional workup revealed the presence of a left atrial thrombus and newly diagnosed atrial fibrillation. He was ultimately discharged to home on apixaban. The patient then re-presented a month later for evaluation of transient diplopia, expressive aphasia, daily right temporal headaches, and right facial and left leg weakness. MRI of the brain showed new areas of diffusion restriction in the left cerebellar hemisphere and left medial occipital lobe (Figure ). CTA showed no signs of carotid occlusion or stenosis. The etiology of his multifocal strokes was thought to be related to his newly diagnosed atrial fibrillation and left atrial thrombus. The patient was then transferred to our hospital for further evaluation. His initial NIH stroke scale was 8 (primary deficits were including unilateral facial palsy, bilateral lower extremity pronator drift and ataxia). Stroke labs, including lipid panel and hemoglobin A1C, were unremarkable. MRI of the brain with contrast showed a new infarct in the splenium of the corpus callosum in addition to prominent generalized meningeal enhancement (Figure ). MRI of the spine with contrast showed possible meningeal enhancement as well as punctate areas of encephalomalacia in the C3-4, C7, and T3 spinal levels. A bedside LP revealed a mildly elevated opening pressure of 24 cm H20, lymphocytic pleocytosis (WBC 150 K/cumm, 61% lymphocytes), protein 170 mg/dl, hypoglycorrhachia of 15 mg/dl, and presence of cryptococcal antigen. Other notable CSF labs included the presence of 11 oligoclonal bands. He was diagnosed with cryptococcal meningoencephalitis and started on a four-week course of amphotericin B and flucytosine. A repeat LP after several days of treatment showed a normal opening pressure of 14 cm H20, mildly improved pleocytosis (WBC 130 K/cumm, 84% lymphocytes), protein 172 mg/dl, and glucose 14 mg/dl. He did not require any additional lumbar punctures, and his symptoms (including headaches and left lower extremity weakness) gradually improved. The patient was discharged to an inpatient rehabilitation facility prior to returning home. Though our patient in Case 1 had a history of an unknown autoimmune disease, our patient in Case 2 had no history of autoimmune disease or other existing immunodeficiency. Both patients developed multiple cerebral infarcts in multiple vascular territories in the setting of cryptococcal meningoencephalitis, though our patient in Case 2 also had recently diagnosed with atrial fibrillation which further confounds the underlying etiology of his strokes.

pmc-8654052-1

A 71-year-old male presented with a two-week history of painless right submandibular swelling that was not associated with fever. The patient had underlying hypertension and diabetes mellitus that were regularly treated. On examination, a right submandibular swelling with normal overlying skin measuring 6 × 5 cm that was non-tender, mobile, and firm in consistency was noted (Figure , ). The swelling is ballotable by bimanual palpation. There was no other swelling palpable in the neck region. Intraorally, pus was noted at the Wharton’s duct orifice, and no sialolith was palpable. Preoperative blood investigations (complete blood count, serum urea and electrolytes, and serum uric acid), electrocardiography, and chest radiographs were normal. Computed tomography (CT) of the neck was performed as part of the preoperative assessment, which showed opacity in the right submandibular gland and duct (Figure , , ). A diagnosis of right submandibular stone was made. The patient subsequently underwent excision of the right submandibular gland under general anesthesia. Intraoperatively, the right submandibular gland was indurated (Figure ). During the excision, the surgeon noted another firm bulge along the submandibular duct that turned out to be a few smaller pieces of stones within the duct (Figure ). The size of the largest stone was 25 mm. Postoperative recovery was uneventful. Histopathology examination revealed severe acute-on-chronic sialadenitis with multiple calculi.

pmc-8654059-1

A seven-year-old otherwise healthy female sustained bilateral elbow trauma after a fall with outstretched elbows and landing with force on the floor (kindergarten facility at the climbing frame). The neurovascular status of both upper extremities was intact upon the arrival of the patient to the Trauma Unit. Clinical examination revealed loss of any active movement in both elbow joints in every plane. The joint was locked in a relatively extended position with the forearm neutral to a slightly supinated position. The patient had no sign of swelling or hematoma. Clinical suspicion was guided to a complex elbow injury, possibly with the participation of various bony structures. A gross estimation of the patient's potential hyperlaxity was performed except for the elbow joints using the Beighton scale without significant clinical findings []. Neurovascular status of the upper limbs was thoroughly re-examined, but no sign of neural or vascular impairment or compromise was found. Plain radiographs with standard projections (anteroposterior [AP] and lateral views) confirmed posterolateral elbow dislocation bilaterally with no signs of evident fractures. Identification of the bony structures was performed, and meticulous control and confirmation of the secondary ossification centers expected for the patient's age was done to exclude any secondary damage (Figures -). In the emergency department, the upper limbs were immobilized in a provisional plaster with the elbows in a light hyperextension and neutral rotation of the forearms to reduce any movement and relieve the pain. The reduction was achieved under sedation in the operating theater and muscle relaxation with the patient in the beach chair position and with access to fluoroscopy during the whole procedure. The maneuver included gentle manipulation of the joints by slightly rotating, distracting and giving a flexion jerk to the joint. The audible and palpable "click" sign and the complete restoration of the arch of motion with the appropriate imaging confirmed the reduction as well as achievement of ligamentotaxis. Postoperatively, the patient retained both elbows in a functional position, stabilized with dorsal braces and collar and cuff to suspend the extremities (Figures -). Removal of any support took place in three weeks post-reduction, followed by mild kinesiotherapy and gradual return to moderate athletic activities. The patient achieved a full range of motion with no pain and excellent ligament stability. At the six-week follow-up, new radiographs were obtained, with normal findings.

pmc-8654060-1

We present the case of a 42-year-old man who presented to the emergency department with a complaint of abdominal pain and diarrhea for 3 days. The abdominal pain started in the periumbilical region and was shifted to the right lower quadrant of the abdomen. The pain started gradually and had been progressing in severity. He described the pain as a stabbing in nature. It was exacerbated by movement and food intake. The pain was partially relieved by oral analgesic medications like paracetamol. The pain was associated with low-grade fever and decreased appetite. The patient also complained of diarrhea with five bowel motions/day. The stools were watery with no mucus or blood. He reported that diarrhea developed after he received an oral antibiotic therapy (cefuroxime) for a recent upper respiratory tract infection. The past medical history of the patient was remarkable for diabetes mellitus that was well-controlled with oral antidiabetic agents. He did not undergo any previous abdominal surgeries. He had a smoking history of 15 pack-years. He had never drunk alcohol before. He worked as a taxi driver. The family history was unremarkable for any inherited gastrointestinal disorders. Upon examination, the patient appeared sick. He was not pale, jaundiced, or cyanosed. Vital signs revealed tachycardia (115 bpm), low-grade fever (37.5℃), normal respiratory rate (14 bpm), and maintained blood pressure (122/80 mmHg). The oxygen saturation was 99% on room air. Abdominal examination revealed a soft abdomen with diffuse tenderness. However, the tenderness was more pronounced in the right iliac fossa with a positive rebound sign. Further, the Rovsing sign was positive. Initial laboratory investigation revealed elevated leukocyte count and elevated inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein. The renal and hepatic profiles were within the normal limits (Table ). In light of the aforementioned clinical information, the patient was diagnosed as having acute appendicitis. A CT scan with intravenous contrast was performed to confirm the diagnosis. The scan demonstrated colonic wall thickening with edematous haustral folds suggestive of pseudomembranous colitis. Further, an endoluminal lesion was observed in the cecum with an average size of 6 cm. The lesion was well-defined and had a homogenous fat density with no solid component. The mass was causing a partial colonic obstruction. Such findings conferred the diagnosis of cecal lipoma (Figure ). The patient was prepared for an emergency laparoscopy for further evaluation and management. The operation was done under general anesthesia and the patient was placed in the supine position. Limited segmental rection of the cecum with appendectomy was performed. The estimated blood loss was 10 mL and the total operative time was 100 minutes. The patient tolerated the operation with no complications. He had an uneventful recovery. Histopathological examination of the resected sample revealed the diagnosis of cecal lipoma and the associated acute appendicitis. The patient was discharged on the fifth postoperative day. After 3 months of follow-up, the patient remained asymptomatic with no active issues.

pmc-8654062-1

A 29-year-old, non-lactating, and non-gravid woman presented with a complaint of a lump in her right breast. The patient also complained of low-grade fever and unilateral pain in breast tissue. The general physical examination showed a one-centimeter erythematous and tender mass in the right breast tissue. There was no nipple discharge, axillary lymphadenopathy, or external draining sinuses. The primary care physician evaluated the patient and called for a USG for the assessment of the affected breast, which demonstrated an ill-defined lesion with thin fluid streaks in the lower outer quadrant, suggesting an inflammatory lesion (Figure ). At the same time, cystic fluid from her breast was aspirated, and the bacterial culture test showed no growth of any microorganisms after 48 hours. The cytology revealed predominantly neutrophils and degenerating cells in a hemorrhagic background, which suggested an acute suppurative inflammatory process of the affected breast as shown in Figure . Based on the clinical features, imaging findings, and cytology reports, a presumptive diagnosis of acute mastitis with underlying bacterial abscess was established. Subsequently, she was being prescribed a course of antibiotics and antipyretics for one week. However, instead of improving, her condition worsened over time. Therefore, the physician decided to repeat the ultrasound-guided fine-needle aspiration and cytology (FNAC). The sonomammogram of the right breast revealed an ill-demarcated hypoechoic irregular lesion involving the parenchyma of the right breast in the outer lower and adjoining upper quadrants. The lesion measured 34.4 millimeters on a long axis with no fluid components as shown in Figure . The repeated cytological examination also showed cellular clusters comprising histiocytes and epithelioid-like cells. Hence, based on these findings, the treating physician concluded that the ongoing clinical picture was more suggestive of tuberculosis of the breast. Therefore, after discussing with the patient, a therapeutic trial of an anti-tuberculosis therapy (ATT) was prescribed for four weeks. However, instead of any clinical improvement, her condition worsened over time and she had to visit her physician again just after three weeks. Her re-assessment by sonomammography was performed, which indicated an ill-demarcated hypoechoic irregular lesion, measuring 44.7×35.4 millimeters in the outer lower and adjoining upper quadrants of the right breast with thin fluid streaks as shown in Figure . The sonologist concluded that these findings were consistent with an infectious or inflammatory lesion. Afterward, the primary care physician referred her to a teaching hospital for a surgical consult. So, re-evaluation of the patient was performed by a detailed history, thorough general physical examination, and routine laboratory investigations. It was then planned to perform incision and drainage of pus collection and excisional tissue biopsy after surgical resection of the mass. The excisional biopsy material was sent for histopathology and pussy discharge for acid-fast bacilli (AFB) smear. After surgery, she received broad-spectrum antibiotics (ceftriaxone and moxifloxacin) for two weeks. The subsequent histopathology showed areas of acute and chronic inflammation along with predominant lobulocentric granulomatous inflammation as shown in Figure . These findings were suggestive of idiopathic granulomatous mastitis as an etiology. Concurrently, the AFB smear also came out to be negative. Hence, a final diagnosis of idiopathic granulomatous mastitis was established. Afterward, corticosteroids (prednisolone) were also added to the drug dosage regimen of this patient. The patient was followed up after one month, and during this period her symptoms had started to resolve. The medical team agreed to advise her to follow up until the complete resolution of her disease, and she was followed up monthly for the next three months. During these follow-up visits, we evaluated the patient for improvement in the clinical symptoms. Finally, a USG scan was performed, which showed complete resolution of the lesion with no abnormal findings. Table describes the timeline of all these events.

pmc-8654064-1

A 58-year-old man, with no relevant medical history, presented with a history of an enlarging painless mass at his right groin region for the past three months (Figure ). The patient did not have any other complaints or symptoms. Physical examination revealed a firm, skin-colored and mobile tumor with well-defined margins (5 cm largest diameter). There were no palpable adenomegalies. The patient was referred to the General Surgery department by a urologist, with suspicion of a soft-tissue tumor. An MRI described a “focal subcutaneous lesion with nodular morphology of 4.7 cm and no malignancy features”. Based on clinical and image findings, it was decided to perform an excisional biopsy. Despite the apparent benign characteristics, the lesion was surgically removed along with the surrounding adipose tissue, preserving the margins. There were no complications related to the procedure. Grossly, it was a subcutaneous nodular non-capsulated solid lesion, multilobulated, well-circumscribed, greyish-yellowish, without necrotic areas (Figure ). Microscopically, a variable amount of atypical bland spindle cells and mature adipocytes were seen, with multinucleated floret-like cells in a myxoid stroma with ropey collagen bundle cells. Sclerosing areas were not disclosed (Figure ). On immunohistochemistry, the tumor was stained for CD34, S100, and MDM2 (focal-weak), whereas CDK4 expression was absent (Figure ). Based on these findings, an atypical pleomorphic lipomatous tumor was diagnosed.

pmc-8654068-1

A 15-year-old female patient was referred by a pediatric cardiologist to our pediatric cardiac surgery clinic with a confirmed diagnosis of CCL syndrome since birth by a dermatologist. Her cardiovascular symptoms started one month before the presentation with a history of recurrent episodes of shortness of breath, palpitations, and chest pain. The severity of the symptoms has increased in the past few weeks. At the time of referral, she was on furosemide 10 mg twice daily and enalapril 10 mg once daily. Her parents are phenotypically normal. All her siblings, five brothers and two sisters, are free from the disorder. Also, the patient has a remarkable family history, as her cousin is a 20-year-old male with the same disorder. There is consanguinity between parents in the family. On general examination, she had a senile appearance with generalized inelastic, loose, and sagging skin. Vital signs revealed a heart rate of 114 beats per minute, respiratory rate of 20 breaths per minute, blood pressure of 123/73 mmHg, oxygen saturation (SpO2) of 100% in room air, and temperature of 36 °C. On cardiac examination, the precordium was hyperactive, the first and second heart sounds were obscured, and pansystolic murmur grade III/VI radiating to the axilla was detected. The hematological studies were within normal limits. Electrocardiogram (ECG) showed sinus tachycardia with right atrial enlargement and right ventricular hypertrophy (Figure ). Chest x-ray showed cardiomegaly with subsegmental atelectasis (Figure ). For more assessment and operative plan, transesophageal echocardiogram (TEE) revealed severe mitral and tricuspid valve prolapse with malcoaptation causing severe regurgitation of both valves with pulmonary hypertension and severe dilatation of both right and left atria (Figures -). After the patient’s condition was discussed in the heart team meeting, the plan was set for mitral and tricuspid valve repair versus replacement, depending on the intraoperative findings. Also, the patient was planned to be counseled by a medical geneticist. The case was discussed with the patient and her family as they were involved in the clinical decision. Procedure Under general anesthesia, midline sternotomy was carried out, and the thymus was resected due to its enormous size. Standard cannulation was accomplished through the ascending aorta and superior and inferior vena cava with snugging around each cannula. Consequently, standard cardioplegic arrest with full flow of cardiopulmonary bypass (CPB) was achieved as the patient was cooled down to a temperature of 30 °C. The aortic valve was immediately examined after the aorta was transversely opened, and it had some significant enlargement and dilatation of the leaflet, but the valve was manually competent; thence, no intervention was done to the aortic valve. Both atria were significantly enlarged; thereupon, right and left atrial appendages were resected in combination with atrioplasty (Figures , ). The left atrium was opened, the mitral valve was examined and showed significant myxomatous changes of both anterior and posterior leaflets, and the valve was irreparable. Hence, the decision was made intraoperatively to replace the mitral valve with a 33-mm St. Jude Medical Epic porcine valve prosthesis (Figure ). After this, through an incision into the right atrium, the tricuspid valve was found to have a cleft at the septal leaflet and the anterior leaflet with significant dilation of the annulus. Accordingly, commissural tricuspid annuloplasty was performed. The tricuspid valve test rendered a competent valve. After completing the procedure, the patient was fully rewarmed and weaned off CPB. Intraoperative TEE showed trace tricuspid regurgitation, and the prosthetic valve was well seated at the mitral position. With these findings, the patient was decannulated, chest tubes and pacer wire were inserted, and closure was performed. She was transferred to the cardiac surgery intensive care unit (CSICU) in a stable condition. During the first 15 hours in the CSICU, the chest tubes drained blood in a total of 1,450 mL (right lower pleura), 300 mL (mediastinum), and 1,330 mL (left lower pleura). Afterward, the patient received five units of packed red blood cells (PRBCs), seven units of fresh frozen plasma (FFP), two units of cryoprecipitated antihemophilic factor (Cryo), two units of platelets, and two doses of intravenous protamine sulfate (50 mg per dose). The bleeding was then controlled (Table ). The patient was shifted from the CSICU to the ward on postoperative day 3 (POD 3). All chest drains were removed subsequently, and laboratory work was within normal limits. Predischarge transthoracic echocardiogram (TTE) showed no significant changes, and the patient was planned to be discharged home on POD 6 in satisfactory condition.

pmc-8654073-1

An 11-year-old boy was diagnosed with Crohn’s disease at the age of nine years. Since then, he was on a regular infliximab transfusion regimen at monthly intervals at a dose of 5 mg/kg for maintenance of remission of disease as symptoms relapse by the end of each month. He presented to the Maternity and Children Hospital in Al-Ahsa, Eastern Province in Saudi Arabia, complaining of palpitation for one year. The palpitations were intermittent at the beginning of the year but then worsen progressively over the last month. They were associated with easy fatigability and chest discomfort, with no history of cyanosis or chest pain. There was no history of a similar condition or history of cardiac disease or sudden death in the family. In addition, these symptoms occur with the manifestation of tachycardia during infliximab transfusion with no respiratory or mucocutaneous involvement or other signs of anaphylaxis. This transfusion reaction is managed by slowing the transfusion rate and premedication with steroids and antihistamines. Upon examination of the child, he appeared pale, underweight (with weight of 18 kg below the third centile) but not distressed. He had sinus tachycardia (150-160 beats/min) with maintained blood pressure (98/59 mmHg). chest examination revealed hyperdynamic precordium with pan-systolic murmur grade III out of VI at the apex with radiation to left mid-axillary line with no thrill. Rest of the examinations were unremarkable. Laboratory investigations showed microcytic hypochromic anemia related to the drop of iron profile and thrombocytosis, with positive anti-Saccharomyces cerevisiae antibodies for Crohn’s disease and negative antibodies for infliximab (Table ). ECG and Holter 24 hours monitor were done and showed intermittent sinus tachycardia with no dysrhythmias (Figure ). Echocardiography showed dilated left ventricle with ejection fraction of 21% and fraction of shorting of 10% associated with severe mitral regurgitation (Figure and Video ). The patient was diagnosed with acute heart failure secondary to dilated cardiomyopathy. He started on anti-failure medications controlling three parameters pre-load, after-load, and enhancing myocardial contractility by diuretics furosemide (1 mg/kg/dose twice a day initially), spironolactone (1 mg/kg/dose twice a day), enalapril (0.35 mg/kg/day divided three times a day) and digitoxin (2.5 mcg/kg/day once daily), respectively. Aspirin was added as an anticoagulant. In addition, the patient started on intravenous iron to improve anemia which was not responding to oral iron supplementations or dietary management. The patient was discharged home with the previous plan and kept on regular follow-up with pediatric cardiology with no need for cardiac surgery at the present time. In addition, he kept on regular follow up with pediatric hematology to assess the improvement in hemoglobin and response parental iron. Finally, the patient referred to a tertiary hospital for further follow-up with pediatric gastroenterology and the possibility of starting a different anti-tumor necrosis factor agent ustekinumab.

pmc-8654078-1

In September 2020, a 42-year-old male was referred to our Department of Internal Medicine because of a finding in a chest X-ray. The patient was healthy with no previous hospitalizations and worked as a nurse at our institution. He was not taking any medications, had no smoking history, and was presenting no malignancy-related symptoms (fatigue, unintended weight loss, or changes in bowel habits). He had seen an anesthesiologist before being seen by a surgeon due to an inguinal hernia, a minor condition. The anesthesiologist noticed the pulmonary lesion. A chest X-ray showed a solitary pulmonary nodule in the right mid-lung that was 2 cm in diameter (Figure ). The patient was asymptomatic, as mentioned above, and had a previous chest X-ray that was normal. In a physical examination, his temperature was 36.7°C, blood pressure was 138/78 mm Hg, heart rate was 76 beats per minute, and oxygen saturation was 98% in room air. In auscultation, heart and lung sounds were normal. Both oropharyngeal and abdominal examinations were normal, and he had no periodontal disease. The patient was admitted to the hospital for further investigation. Blood tests were normal, with a white blood cell count of 9,430 leucocytes/mm3 with 63% neutrophils, hemoglobin level of 153 g/L, and platelet count of 205 × 109/L. C-reactive protein was 83 mg/dL (normal range: <5 mg/dL). A reverse-transcription polymerase chain reaction (RT-PCR) test was negative on hospitalization day 1 (Table ). As mentioned, a chest X-ray showed a solitary pulmonary nodule in the right upper lobe. Our patient presented with a solitary pulmonary nodule, which raised the suspicion of a primary lung tumor or metastasis of unknown origin. For further radiological characterization and assessment of the pulmonary node, the patient underwent a thoracic CT scan, which revealed ground glass opacities that suggested either inflammatory or infectious conditions (Figure ), similar to atypical pneumonia. A second RT-PCR was performed on hospitalization day 3, and the result was positive. Based on these data, we established a diagnosis of COVID-19 pneumonia in an asymptomatic patient. The first test for the qualitative detection of IgG against SARS-CoV-2 (a chemiluminescent microparticle immunoassay) was negative on hospitalization day 3. On day 5, the examination was normal, the patient’s oxygen saturation was 98%-99% in room air, and laboratory blood tests were normal, so we discharged the patient with no treatment, but he was attended in a follow-up in our outpatient clinic with a new chest X-ray and new laboratory blood tests on day 10 after discharge. The chest X-ray showed complete resolution of pneumonia, and laboratory blood tests were normal, with C-reactive protein < 5 mg/dL and a positive test for IgG against SARS-CoV-2.

pmc-8654082-1

A female patient aged 27 years presented with a slow-growing abdominal lump of nine months duration. There were no other symptoms except for fullness of the abdomen after taking food and weight loss. Clinical examination revealed large, non-tender, soft cystic swelling occupying the entire upper abdomen. On radiological investigations, ultrasonogram (USG)-complex cystic mass with internal septation was present. Contrast-enhanced computed tomography (CECT) abdomen showed a large multiseptated cystic lesion occupying almost the entire abdomen and adhered to the pancreas with mass effect. The lesion was well defined, lobulated, hypodense in nature, and associated with main pancreatic duct dilatation. There was also portal vein thrombosis with portal cavernoma on the CECT abdomen (Figure ). USG-guided FNAC revealed straw-colored aspirate with mature lymphocytes; no atypical cells were noted. Cyst amylase and carcinoembryonic antigen (CEA) were within the normal range (Figure ). After complete preoperative workup, the patient underwent surgical exploration. On exploration, there was a large multiloculated cystic lesion extending through gastrocolic omentum, pushing the stomach up and transverse colon downwards with hundreds of cystic spaces containing lymphatic fluid (Figure ). Cysts were decompressed, and the entire lesion was excised. The anterior surface of the pancreas was forming the base of the lesion. Postoperatively patient had continued lymphatic discharge from the abdominal drain, and the patient was discharged with it (Figure ). Final histopathological examination showed unremarkable pancreatic tissue with attached lesion consisting of dilated lymphatic spaces with lymphatic follicles in the wall, with congested blood vessels and fibrocollagenous tissue with chronic inflammatory infiltrate. Cytocentrifuged smears from fluid show lymphocytes, and no malignant or atypical cell was seen. The patient was followed regularly in outpatient department, and drain output gradually decreased over two weeks and was removed (Figure ).

pmc-8654092-1

A 58-year-old woman with a past medical history of diabetes and hypertension presented to our clinic for evaluation of an enlarging left breast mass that she first noticed three years ago. She stated that the mass started to progressively increase in size in the past few months. She also reported a weight loss of 34 pounds over the last nine months. On physical exam, she had a palpable breast mass of approximately 3 centimeters in the tail of the left breast. Rest of physical exam was unremarkable. Review of labs showed WBC of 8.8/mL with absolute lymphocyte count of 4400/mL, hemoglobin of 12g/dl and platelet count of 316K. Prior mammograms and ultrasounds had revealed stable intramammary lymph nodes at the site of the present lesion on the left breast over the last three years with no suspicious calcifications or architectural distortions. There were no palpable ipsilateral or contralateral axillary lymphadenopathy. The mass was subsequently percutaneously biopsied. Histopathology showed diffuse atypical small lymphocytic cells (Figure ). Immunohistochemical staining revealed neoplastic lymphoma cells positive for CD20 (Figure ), CD5 (Figure ), CD23 (Figure ), PAX5, CD4, BCL2 and negative for CD3, CD10, BCL1, and BCL6. The final pathologic diagnosis was consistent with primary small lymphocytic lymphoma of the breast rather than chronic lymphocytic leukemia. This was unexpected. Bone marrow biopsy was done and histopathology revealed diffuse involvement with small lymphocytic lymphoma (Figure ). Fluorescence in situ hybridization (FISH) studies revealed trisomy 12 cytogenetic abnormality. Computed tomography (CT) imaging revealed extensive mediastinal lymphadenopathy (Figure ) and retroperitoneal lymphadenopathy (Figure ). The final clinicopathologic diagnosis was small lymphocytic lymphoma (Stage 4) with breast and bone marrow involvement. She was subsequently treated with the FCR regimen comprising of fludarabine, cyclophosphamide and rituximab which resulted in clinical and radiologic remission. The breast mass was no longer palpable and repeat CT scans did not reveal any evidence of any pathologic lymphadenopathy.

pmc-8654094-1

This is a case of 41-month-old infant girl who presented with weight loss and intractable diarrhea associated with oral feeding. She is a product of full-term pregnancy, delivered through spontaneous vaginal delivery, with a birth weight of 2 kg, and she did not require admission to the neonatal intensive care unit (NICU). The pregnancy was uneventful. Parents are first-degree cousins, and the patient has two older healthy siblings. At the age of six months, she presented to another hospital afebrile with a loss of weight and had watery, non-bloody diarrhea, six to seven times per day. Both endoscopy and biopsy from the duodenum were normal according to the mother. The patient was initially misdiagnosed with cow milk protein allergy, so hypoallergenic formula was given but there was no improvement, then after two months, she was switched to amino acid-based infant formula 200 ml five times per day. In the beginning, there was an improvement, but with time, she stopped gaining weight again. At the age of 10 months, she came to the gastroenterology and genetics teams at our facility with chronic diarrhea, poor growth, and abnormal hair. Her weight and height were 5.30 kg (<3rd percentile) and 61 cm (<3rd percentile), respectively. The diagnosis of THES was confirmed by whole exons sequence (WES) analysis, which identified the homozygous variant (c.1201G > A) p. (Glu401Lys) in the SKIV2L gene. Upon literature review, we did not find the mentioned variant mutation in any previous literature (Table ). At 12 months of age, she was admitted for dehydration and nasogastric tube (NGT) feeding due to poor weight gain. Her body measurements upon admission were 5.64 kg (<3rd percentile) for the weight, and her height was 63 cm (<3rd percentile). Upon examination, she had some dysmorphic features such as a depressed nasal bridge, broad forehead, low set ears, and scanty dry hair. During her admission, she was having watery diarrhea with mucus two to three times a day. She was managed with intravenous fluid and the clinical nutritionist prepared a high-calorie formula. The nutrition therapy plan was to provide 180 ml of hypoallergenic baby formula (0.67 kcal/ml) every four hours orally, as much as she can tolerate, and if she did not complete her meal, give the rest through the NGT. This plan provided her with 192 ml/kg fluids and 135 kcal/kg/day energy. Her laboratory workup results were sodium 138 mmol/l, potassium 3 mmol/l, chloride 113 mmol/l, aspartate aminotransferase (AST) 40 units/l, alanine aminotransferase (ALT) 30 units/l, and gamma-glutamyl transferase (GGT) 32 units/l. Her immunoglobulins workup showed low immunoglobulin E <25 au/ml, and normal immunoglobulin G and A levels. She was improving and gained 100 grams in two days. On the seventh day of admission, she was able to tolerate oral feeding, so the patient was discharged on the same plan and to add 1 ml of medium-chain triglycerides oil every other day. At the age of 21 months, the mother reported in a follow-up visit that her daughter’s weight has been improved and reached 7.8 kg, but still under the third percentile. The patient was continued on hypoallergenic baby formulas and a regular diet. At the age of 41 months, the patient presented with progressive bullous itchy skin rash, and fluid-filled vesicles on erythematous background with red erosions and fissures all over the body but sparing abdomen and back. It was associated with cough, rhinorrhea, fever, and decreased urine output and oral intake, but without gastrointestinal complications. The diagnosis of bullous impetigo was made, and the patient was admitted. Amoxicillin, clavulanate, and diphenhydramine were administered intravenously with topical clindamycin and tretinoin cream. The patient showed clinical improvement in three days. The patient was discharged on oral Augmentin, Mupirocin, and Loratadine (Figure ). On follow-up evaluation at the age of 41 months, her weight and height were 10 kg (<3rd percentile) and 85 cm (<3rd percentile), respectively. She was able to tolerate normal oral feeding. She did not show any signs of intellectual disability, and she is developmentally up to her age now. She is active and plays with her cousins. She can speak and understand both Arabic and English, and according to the mother she is starting to memorize songs.

pmc-8654106-1

A 49-year-old female patient was admitted with complaints of fever, abdominal bloating, and losing weight for one year. She was diagnosed with cirrhosis and was treated at a local hospital. Three months ago, the patient deteriorated; thus, peripheral blood test, bone marrow (BM) aspiration, and bone marrow biopsy were performed. The results showed lymphocytosis in the marrow. Therefore, the patient was referred to our center. On physical examination, she had a fever (about 38°C), mild pallor, swollen legs, mild hepatomegaly, and huge splenomegaly. There was no purpura and no peripheral lymphadenopathy. There were no clinical infections and no joint damage. Complete hemogram revealed hemoglobin of 117 g/L, platelet count of 82 G/L, total leukocyte count of 12.63 G/L with 65% lymphocytes, and 30% neutrophils. The peripheral blood smear showed lymphocytosis and thrombocytopenia (Figure ). The lymphocytes were predominantly large lymphocytes, which were having abundant cytoplasm containing coarse azurophilic granules and clumped chromatin. Her biochemical examination was fairly normal. Serological examination revealed no evidence of HIV, HBV, HCV, EBV, CMV, or dengue infection. The results of cultures of fungi and bacteria in blood were negative. The ultrasound of the abdomen confirmed mild hepatomegaly and huge splenomegaly. Bone marrow imprint smears showed 33% lymphocytes (lymphocytosis) (Figure ). The lymphocytes displayed a medium to large size with a moderate amount of cytoplasm containing numerous azurophilic granules and a round nucleus with clumped chromatin. Bone marrow biopsy displayed an increasing level of cell density and lymphocytic infiltration in hematopoietic compartments with nonuniform size and similar morphology lymphocytes seen in peripheral smear (Figure ). The erythroid, myeloid, and megakaryocytic series were suppressed. Cytogenetics revealed a normal karyotype. Flow cytometric analysis of the bone marrow showed that 49.5% of cells were of lymphoid origin. These lymphoid cells were positive for T-cell markers, including CD2, CD8, CyCD3, CD5, CD7, CD56, CD16, and TCR gamma delta. The cells expressed CD4-. These findings were suggestive of T-cell large granular lymphocytic leukemia. After being treated with methotrexate for one month, the clinical condition was ameliorated. The patient had no fever and splenomegaly regression, and the peripheral blood revealed an increasing proportion of neutrophils (65%). Therefore, the patient was given outpatient treatment and kept being examined monthly.

pmc-8654109-1

A 34-year-old man with no previous history of chronic illness and a non-smoker presented with a history of headache, fatigue, diarrhea, vomiting, and insomnia for three days. During the initial examination, he was conscious and alert. His blood pressure (BP) was 111/71, pulse rate (PR) 40, respiration rate (RR) 14/min, body temperature 36.7, and oxygen saturation (SpO2) 96% under ambient oxygen conditions. The patient had a clear chest, without any crepitating sounds in the cardiovascular system (CVS; S1+S2+0). An abdominal exam showed a soft and lax abdomen, and both lower limbs were normal. The status of the central nervous system (CNS) was normal, all cranial nerves were intact, and chest X-ray and chest CT scans were performed (Figures -). EKG showed sinus rhythm, first-degree heart block with prolonged QT interval, and bigeminy (Figure ). Echo revealed a normal echo study (Figure ). General clinical and blood parameters of the patients are shown in Table . Due to the COVID-19 pandemic, all patients reporting to the hospital with fever were routinely tested with the PCR test for COVID-19. Also, a nasopharyngeal swab was tested by RT-PCR and proved to be positive for SARS-CoV-2.