A conductive, stretchable, adaptable, and self-healing, GaInSn/Ni--based composite hydrogel by incorporating a magnetic liquid metal into the hydrogel framework through crosslinking polyvinyl alcohol with sodium tetraborate.The multifunctional composite hydrogels showed outstanding performance for magnetic repair movement sensing, and EMI shielding.The online version contains supplementary material available at 10.1007/s40820-023-01043-3. Hydrogels exhibit potential applications in smart wearable devices because of their exceptional sensitivity to various external stimuli. However, their applications are limited by challenges in terms of issues in biocompatibility, custom shape, and self-healing. Herein, a conductive, stretchable, adaptable, self-healing, and biocompatible liquid metal GaInSn/Ni-based composite hydrogel is developed by incorporating a magnetic liquid metal into the hydrogel framework through crosslinking polyvinyl alcohol (PVA) with sodium tetraborate. The excellent stretchability and fast self-healing capability of the PVA/liquid metal hydrogel are derived from its abundant hydrogen binding sites and liquid metal fusion. Significantly, owing to the magnetic constituent, the PVA/liquid metal hydrogel can be guided remotely using an external magnetic field to a specific position to repair the broken wires with no need for manual operation. The composite hydrogel also exhibits sensitive deformation responses and can be used as a strain sensor to monitor various body motions. Additionally, the multifunctional hydrogel displays absorption-dominated electromagnetic interference (EMI) shielding properties. The total shielding performance of the composite hydrogel increases to ~ 62.5 dB from ~ 31.8 dB of the pure PVA hydrogel at the thickness of 3.0 mm. The proposed bioinspired multifunctional magnetic hydrogel demonstrates substantial application potential in the field of intelligent wearable devices.The online version contains supplementary material available at 10.1007/s40820-023-01043-3. Liquid metals of Ga-based alloys have attracted intensive interest because of their deformability, nontoxicity, self-healing capability, high electric/thermal conductivity, and unique surface chemistry –3. In paCurrently, miniaturized, integrated, and high-power electronic devices are being rapidly developed for wireless communication, and significantly large electromagnetic interference (EMI) is produced as an inevitable by-product , 17. EMI3C2-MXene-functionalized poly:polystyrene sulfonate (PEDOT:PSS) hydrogels [However, the EMI shielding properties of liquid metal-based composites are mainly achieved by reflecting electromagnetic waves, which will cause secondary pollution. Moreover, their limited self-healing ability hampers their applications in intelligent, flexible devices. In contrast to metal liquid-filled elastomers, hydrogels are a type of engineering material composed of a crosslinked network of hydrophilic blocks surrounded by water , demonstydrogels , ionic lydrogels , polyacrydrogels , MXene oydrogels , and mulydrogels . HoweverHerein, we present a simple ultrasonic method to fabricate PVA/GaInSn–Ni composite hydrogels with rapid self-healing capability and excellent stretchability and shape adaptability. The multifunctional composite hydrogels demonstrated high performance for magnetic repair and prototyping, body movement sensing, and EMI shielding. The abundant reversible hydrogen bonds between PVA and borate ions and the fluidity of liquid metals render the PVA/liquid metal hydrogel self-healing features in the absence of any external stimulus. In the presence of a magnetic field, broken wires can be repaired remotely by placing them in a sealed space with one end warped by the magnetic liquid metal hydrogel. The composite hydrogel could be used as a strain sensor to detect body motions and as a signature sensor that sensitively and rapidly responds to various external stimuli. The water-rich hydrogel with moderate conductivity provides absorption-dominated EMI shielding performance to the composite. Importantly, the composite hydrogel exhibited long-term stability for EMI shielding even after storage for 1 year.PVA  was purchased from Meryer Co., Ltd. Sodium tetraborate , gallium (99.9%), indium (99.9%), and tin  were obtained from Shanghai Macklin Biochemical Co., Ltd. Nickel microparticles (99.9%) were obtained from Shengshida Metal Materials. Co. Ltd., China. All reagents were used as received without further modification.The EGaInSn liquid metal alloy was fabricated by melting a mixture of Ga (68 wt%), In (22 wt%), and Sn (10 wt%) in an oil-bath pan at 150 °C for 1 h.First, PVA white powder (0.4 g) was added to 5 mL of deionized (DI) water and magnetically stirred at 80 °C for 7 h until all powders were dissolved to obtain a PVA solution (8 wt%). Thereafter, EGaInSn and Ni were added to the solutions, and then, EGaInSn–Ni was evenly dispersed in the solution by ultrasonic treatment for 2 h. Meanwhile, sodium tetraborate was dissolved in hot DI water (60 °C) and shaken well until the particles were completely dissolved to produce a solution of 4 wt%. After cooling to room temperature, the sodium tetraborate solution was slowly blended with the PVA mixture to prepare composite hydrogels. PVA-based hydrogels with different mass ratios of EGaInSn and Ni, namely 1:0.5, 1:1, 1:2, 1:4, and 1:8, are denoted as PVA/EGaInSn–0.5Ni, PVA/EGaInSn–1Ni, PVA/EGaInSn–2Ni, PVA/EGaInSn–4Ni, and PVA/EGaInSn–8Ni, respectively.A powder X-ray diffractometer  was used to record the XRD patterns. X-ray photoelectron spectroscopy (XPS) analyses were performed on a Kratos AXIS Ultra spectrometer equipped with a monochromatized Al Kα X-ray source. Fourier transform infrared (FTIR) spectra were acquired using a spectrometer . The functional groups of the PVA-based hydrogels were examined using an FTIR spectrometer (Thermo Nicolet iS10). The morphology and elemental distribution of the PVA–LM hydrogels were characterized using Scanning electron microscopy  coupled with energy-dispersive X-ray spectroscopy . The rheological behavior of the hydrogels was investigated using a Thermo HAAKE MARS 60 machine with a 20 mm parallel plate. A dynamic frequency sweep of 0.1–10 Hz was conducted at 25 °C with a fixed oscillation strain of 0.2% in the oscillation mode. The electrical resistivities of the PVA/EGaInSn–Ni and pure PVA hydrogel samples were tested using an RTS-8 four-probe resistivity meter. An LCR instrument (TH2830) operated using a LabView software was used to collect all relevant data. In the EMI shielding measurement, the composite hydrogel is cut into rectangle shape with dimensions of 22.86 mm × 10.16 mm × 3.0 mm. The EMI shielding properties of the PVA/liquid metal composite hydrogels were measured using a vector network analyzer  in the X band (8.2–12.4 GHz), and more details can be found in the Supporting Information.Figure d , the peak at 18.5 eV is associated with metallic gallium (Ga0) [1+ in Ga2O and Ga3+ in Ga2O3 [s peak at 23.8 eV is also observed in the Ga 3d spectrum, confirming the oxidation of Ga [d core-level spectrum, two distinct peaks at 443.1 (In 3d5/2) and 450.7 eV (In 3d3/2) are attributed to In0 . Similarly, in the Sn 3d XPS spectrum , the peaks centered at 484.8 and 493.2 eV are related to the metallic Sn0. These results suggest that the surface of the EGaInSn particles a mainly composed of Ga oxides and a small amount of the mixture of In and Sn oxides. The O 1s XPS spectrum  is deconvoluted into two peaks at 531.7 and 533.3 eV, suggesting the presence of intact stoichiometric oxides and oxygen vacancies, respectively [The EGaInSn particles were synthesized through an isothermal sonication process at 150 ℃ for 60 min. The long sonication process yields highly dispersed liquid metal droplets with uniform elemental distribution . A more detailed study on the surface composition of EGaInSn was performed using XPS . In the XPS spectra of Ga 3um (Ga0) , while ton of Ga . The funectively .−1 due to the absorption characteristic of water and stretching vibration of the –OH group, which is a typical indication of hydrogen bonding [−1. The carbonyl  and hydroxyl groups  can produce a high density of hydrogen bonds [−1.Figure  bonding . The peaen bonds , which ip core-level spectrum , the metallic indium exhibits two peaks centered at 443.7 (In 3d5/2) and 451.4 eV (In 3d3/2), with a separation of spin–orbit components d XPS spectrum , the peaks centered at 484.9 and 493.5 eV correspond to the metallic tin [s core-level spectrum has three-peak components, i.e., C–C/C=C (284.9 eV) and C–O (286.5 eV). The strong C signal indicates the presence of abundant hydrophilic groups on the PVA chains, which offer abundant crosslinking sites in the hydrogel [s peaks are deconvoluted to metal oxide, hydroxide, and lattice oxide component peaks , demonstrating the formation of mixed liquid metal oxides and the Ni oxidation states on the shell [The chemical bonding states of the PVA/EGaInSn–8Ni composite hydrogels were confirmed using XPS  values are smaller than the storage modulus (G) in the frequency range of 1–10 Hz, indicating their solid-like states. Significantly, the G″ value of PVA/EGaInSn–8Ni exceeds G′, exhibiting a liquid-like state . Therefore, Ni in the hydrogels facilitated the generation of a more liquid-like condition without damaging the complex network structure. Furthermore, for the liquid metal hydrogels with different Ni contents , the Gʹ of all composite hydrogels is less than G″, confirming their liquid-like behaviors. Therefore, for the subsequent experiments, we chose PVA/EGaInSn–8Ni as the smart sensor hydrogel.The rheological properties of the liquid metal hydrogels were studied using oscillatory rheology . For pure PVA and PVA/EgaInSn hydrogels, their loss modulus (Ms) value of 12.2 emu g−1 . The disconnected wire, in which one end is wrapped in the hydrogel, is placed in a plastic container. A permanent magnet is placed outside the plastic container. When the magnet is moved closer to the hydrogel, the entire hydrogel shifts toward the magnet. The strong adhesion between the liquid metal and PVA prevents the liquid metal droplets from leaving the hydrogels during magnetic field-driven movement. The magnet can drag the hydrogel to repair the wire conduction and finally lit the diodes up (Movie S1). In addition, the liquid metal hydrogel can be guided using the magnetic field to fill the custom-designed heart-shaped pattern  indicate the good reliability of the magnetic PVA/liquid metal hydrogel monitoring. When the PVA/liquid metal hydrogel is attached to the wrist, the current increases when bending the wrist, and the current–time curve exhibits significant stability and reproducibility  in the band (8.2–12.4 GHz) using a vector network analyzer. In everyday applications, an EMI shielding effectiveness (SE) of 20 dB can block approximately 99% of incident EM wave energy [T) of 36 dB is obtained in PVA, which shields 99.975% of EM waves  and 65.8 dB (blocking 99.9999747% EM waves) for PVA/EGaInSn and PVA/EGaInSn–8Ni hydrogels, respectively; the increase percentage is 28.3% and 83.0%, respectively. These results indicate that introducing liquid metals into the PVA hydrogel can prompt EMI shielding. In comparison with EMI shielding properties and sensor ability of state-of-the-art hydrogels (Table S1), our PVA–liquid metal composite hydrogels demonstrate the competitive performance for EMI shielding, magnetic repair and prototyping. The contributions from absorption loss (SEA) and reflection loss (SER) were analyzed to assess the EMI shielding mechanism of the hydrogels , and 62.5 dB (increase percentage of 96.8%), respectively, while the SER values decrease from 4.2 to 3.9 (decrease percentage of 7.1%) and 3.3 dB (decrease percentage of 22.0%), respectively. This demonstrates that adding liquid metals can effectively increase the absorption and decrease the reflection, and it seems that the EMI shielding mechanism mainly results from absorption. However, the calculated SER was based on the total power of EM waves, whereas SEA was based on the power of incident waves [A) and reflection (R) for the PVA, PVA/EGaInSn, and PVA/EGaInSn–8Ni composite hydrogels are shown in Fig. S12. The R values are higher than A values over the entire frequency range for the PVA and PVA/EGaInSn hydrogels, suggesting that the EMI shielding is dominated by reflection. However, in the case of PVA/EGaInSn–8Ni, the A value is higher than the R value in one-third of the X-band, indicating that introducing magnetic Ni is favorable for absorption. Although reflection dominates the EMI shielding mechanism, absorption plays an important role in the shielding contribution.EMI between electronic devices often results in equipment failure. Self-healed conductive hydrogels with good EMI properties are ideal for soft robotic applications that integrate many electronic components. The EMI shielding capabilities of PVA–liquid metal composite hydrogels (1.0 mm in thickness) were calculated by testing the scattering parameters , the R is higher than A in the frequency range of 8.2–10.7 GHz; however, the A is higher than R in the frequency range of 10.7–12.4 GHz. This illustrates that the reflection dominates in most measured frequency ranges. Most conventional EMI shielding materials show deteriorated shielding performance when placed in an air atmosphere for a long time [SET values increased from 65.8 to 75.2 dB, and SEA values increased from 62.5 to 72.9 dB. The increase percentage of SET and SEA reached 14.3% and 16.6%, respectively. However, SER values decreased from 3.3 to 2.3 dB, and the decrease percent was 28.5%. By analyzing power coefficients of A and R , PVA/EGaInInSn–8Ni presents an absorption-dominated EMI shielding mechanism after storage for one year. In an air atmosphere, hydrogels could absorb environmental water molecules to generate more free ions and dipoles, which was beneficial for EM energy dissipation and enhancing SET and SEA values.The EMI shielding performance of PVA/EGaInSn–8Ni before and after self-healing was verified Fig. g, h. Allong time , 41. NotSE values significantly increased to 65.8 dB (blocking 99.99997% of EM waves) for PVA/EGaInInSn–8Ni hydrogels, and the increase percentage reached as high as 83.0% in comparison with those of the pure PVA hydrogel. Introducing liquid metals to PVA could effectively increase the absorption loss and decrease the reflection loss, and absorption might dominate the EMI shielding mechanism. Significantly, the excellent EMI shielding performance was maintained after storage for one year, showing long-term stability. Moreover, liquid metal hydrogels could conform to objects of arbitrary geometry and recover rapidly from damage, demonstrating significant application potential in flexible electronics and artificial skin. The hydrogel served as a strain sensor to detect various body movements and a signature sensor for sensitive and rapid responses to external stimuli. Based on the above functions, the present study offers a novel strategy to develop intelligent hydrogels for multifunctional applications as well as a versatile method for fabricating liquid metal composites with extended performance.In summary, we developed a multifunctional PVA/liquid metal composite hydrogel with rapid self-healing ability, excellent stretchability, shape adaptability, magnetic prototyping, sensing capability, and good EMI shielding properties. The fluidity of liquid metal and reversible hydrogen bonds between PVA chains and borate ions enabled the PVA/liquid metal hydrogel to complete self-healing rapidly without external stimuli. The proposed PVA/liquid metal hydrogel could effectively repair broken wire joints when they were placed in a precision-sealed space under an applied magnetic field. The synergy between the moderate conductivity and inherent moisture-rich environment endowed the composite hydrogel with high-efficiency EMI shielding. The total Supplementary file1 (PDF 1523 kb)Supplementary file2 (MP4 831 kb)Supplementary file3 (MP4 284 kb)Below is the link to the electronic supplementary material.


A 46-year-old female patient was diagnosed with a rare and benign intrapulmonary schwannoma, a neurogenic tumor that represents approximately 20% of adult mediastinal tumors, with schwannomas being the most common subtype. The patient was initially asymptomatic; however, after a period of four years, the patient presented with bilateral extremity edema, chronic venous stasis, elevated right ventricular systolic pressure, and a slightly enlarged inferior vena cava. These symptoms were caused by the lung tumor compressing intrathoracic structures.This case highlights the need for early evaluation and proper management of neurogenic tumors to avoid serious symptoms and complications. It also emphasizes the importance of vigilant monitoring and prompt surgery to achieve the best outcome for patients with neurogenic tumors. Approximately 20% of adult mediastinal tumors are neurogenic tumors . These nA 46-year-old Hispanic female with a history of a benign lung tumor, diagnosed four years prior, rheumatoid arthritis, and tobacco dependence presented to the hospital complaining of progressively worsening bilateral lower extremity edema, accompanied by an ulceration on the right medial malleolus. The patient was diagnosed with a primary intra-pulmonary schwannoma via biopsy of the lung mass approximately four years prior and referred to University of California, Los Angeles (UCLA) for surgical resection. However, she could not travel for the procedure due to financial constraints. At the time of her initial diagnosis four years ago, the patient was asymptomatic and reported no lower extremity edema.On this admission, the patient reported the onset of bilateral lower extremity edema approximately six to seven months prior, which worsened over time. She first noted the appearance of a right medial malleolus ulcer about two months ago and was prescribed antibiotics by her primary care provider for possible cellulitis. However, the ulcer failed to heal despite antibiotic treatment. The patient reported experiencing mild dyspnea with exertion but denied any chest pain, syncope, shortness of breath at rest, hemoptysis, changes in vision, fever, or chills. Her current medications include dicyclomine, meloxicam, and ondansetron.Upon admission, the patient was afebrile; vitals were remarkable, with a heart rate (HR) ranging in the 105-110s and blood pressure ranging around 150/80s mmHg. There were no signs of apparent respiratory distress, with normal oxygen saturation at mid-95%. On physical examination, there were diminished breath sounds in the anterior and posterior right upper lobes, with no crackles appreciated on lung auscultation. Jugular venous distension and prominent distension of neck veins on the right side were also noted. On peripheral vascular examination, bilateral lower extremity edema was observed, extending up to the knees, with grade 2 pitting edema and clean, non-purulent ulceration on the right medial malleolus.The complete blood count (CBC) was remarkable for normocytic anemia, with a hemoglobin level of 9.6 g/dL. Otherwise, no abnormalities were noted. The comprehensive metabolic panel (CMP) results were within normal limits. The blood and wound cultures taken from the right medial malleolus ulcer were negative for growth. The chest X-ray (CXR) taken upon admission, as shown in Figure A computed tomography (CT) angiography of the chest, shown in Figure At the initial presentation four years prior, a fluorodeoxyglucose-18 positron emission tomography (FDG-18 PET) scan was obtained, as shown in Figure A CT-guided core needle biopsy performed four years prior showed that the mass tested positive for S-100, cytokeratin (CK), and AE1/AE and was negative for CD34, alpha-smooth muscle actin (SMA), and desmin on immunohistochemistry. The microscopic histology of the mass demonstrated wavy nuclei in hypercellular regions known as Antoni and hypocellular regions known as Antoni B, shown in Figure The echocardiogram during this hospitalization revealed a left ventricular ejection fraction (LVEF) of 60-65% with a mild increase in left ventricular wall thickness. The right ventricle size was normal; however, the RSVP was mildly elevated at 38 mmHg . Additionally, a mild dilation of the IVC was observed, measuring 2.8 cm . The bilateral lower extremity venous Doppler study did not reveal the presence of deep vein thrombosis. A right ankle X-ray showed evidence of soft tissue swelling at the medial malleolus.The cardiothoracic vascular surgery (CVTS) team was consulted to evaluate this lung tumor, which has increased in size and possibly compressed intrathoracic neurovascular structures. Upon thorough evaluation and complexity of the tumor, CVTS referred the patient to a tertiary care center for requiring complex surgical intervention. The patient was discharged with a recommendation to follow up with the UCLA medical team for ongoing management and monitoring. In addition, the patient was advised to use Unna boots to treat a right medial malleolus ulcer and to wear compression stockings to manage bilateral leg edema.Schwannomas, also referred to as neurilemmomas, are the most frequently occurring nerve sheath tumors. They typically originate from the sensory root of an intercostal nerve or, in less frequent cases, from the phrenic or vagus nerve -4. A retIntrapulmonary Schwannomas are a rare subtype of lung tumors that are typically benign and solitary. They can be located either centrally or peripherally within the lung tissue. These tumors' recurrence and malignant transformation rates are low -8. The mThe metabolic characteristics of schwannomas on FDG-18 PET are poorly understood and cannot be used to differentiate benign from malignant forms . ReportsThe primary treatment for intrapulmonary schwannomas is surgical resection, which is highly effective in achieving complete removal and has a low recurrence rate. Video thoracoscopy is a minimally invasive and safe approach for removing intrathoracic neurogenic tumors -16. HoweComputed tomography angiography (CTA) is a widely adopted protocol for the preoperative evaluation of patients diagnosed with neurogenic tumors in the paravertebral sulci between T5 and T12 . CTA aimOur patient, initially diagnosed with benign intrapulmonary Schwannoma based on immunochemistry and microscopic histology of the mass Figure , was asyVon Recklinghausen's disease (neurofibromatosis type 1), resulting from a Schwann cell development issue, is characterized by numerous neurofibromas on the skin and within internal organs. In a study of four cases of MPNST, 75% exhibited clinical signs of Von Recklinghausen's disease. The presence of widespread neurofibromas raises the likelihood of malignancy or future malignancy in posterior mediastinal tumors . Our patOver the four years following the initial diagnosis, the size of the patient's intrapulmonary Schwannoma grew, possibly causing symptoms such as bilateral lower extremity edema and a moderately elevated RSVP of 38 mmHg, which may be a result of compression of intrathoracic neurovascular structures. Surgical resection is the preferred method of treating intrapulmonary schwannomas, which offers a high success rate for complete removal and minimal chance of relapse ,16. ConsIntrapulmonary Schwannomas are a rare type of lung tumor that is benign. The most common symptoms include thoracic pain, respiratory symptoms, and Horner's syndrome. CT scans of the thorax are crucial in evaluating mediastinal neurogenic tumors. Schwannomas, which are benign tumors, often exhibit high FDG-18 uptake, making it difficult to differentiate them from malignant neurogenic tumors. Hence, a biopsy is necessary to establish a definite diagnosis. Surgical resection remains the primary treatment modality for intrapulmonary schwannomas. Multidisciplinary collaboration between specialties such as neurosurgery and cardiothoracic surgery is essential to optimize surgical outcomes and minimize postoperative complications.


Infectious bursal disease (IBD) is an infectious immunosuppressive disease that affects young chickens. Instead of strict biosecurity practices, vaccination is used to control IBD. However, the disease has not been effectively managed. Variations in the observed clinical symptoms lead to confounding diagnoses. The study aimed to obtain pathological lesion data from chickens suspected of IBD virus (IBDV) infection by gross pathology, confirm IBDV infection through molecular diagnostics, and genotype the VP1 gene fragments of circulating IBDV in the field.The bursa of Fabricius, thymus, spleen, proventricular–ventricular junction, thigh muscles, and kidneys samples were collected from chickens suspected of IBDV infection from four commercial broiler farms in Central Java and The Yogyakarta Special Region Province between 2021 and 2022. The collected samples were examined histopathologically. Infectious bursal disease virus RNA was extracted from the bursa of Fabricius and VP1 gene was identified by reverse-transcriptase polimerase chain reaction (RT-PCR). The RT-PCR positive sample were sequenced and analyzed in Mega X for homology search and phylogenetic tree analysis.Macroscopic pathological lesions in the bursa of Fabricius were demonstrated by enlarged edema and thickened plica, presence of gelatinous exudate, hemorrhage, atrophy, and caseous exudate in the lumen. Moreover, the thymus had atrophy and small gray foci were observed in the spleen. Petechiae or hemorrhage was detected on the thigh muscle, and the kidney was dull and pale. Hemorrhage in the proventricular–ventricular junction was distinct. The histopathological examination of the bursa of Fabricius showed follicular vacuolization, edema, heterophilic infiltration, follicular atrophy, congestion, and hemorrhage. The thymus and spleen showed the presence of multifocal necrosis. Hemorrhage was observed in thigh muscle and mucosal part of proventricular–ventricular junction. Vacuolization was seen in renal tubules (nephrosis). Reverse transcriptase-PCR of 26 bursa of Fabricius samples from chickens suspected of IBDV infection showed four negative and 22 positive samples. Phylogenetic analysis of the VP1 gene fragment has indicated very virulent IBD (vvIBD) and belonged to B2 genotype.Infectious bursal diseases virus infection in broiler chicken generated macroscopic and microscopic primary lesions in the bursa of Fabricius and thigh muscle. Other organs such as the spleen, thymus, proventricular–ventricular junction, and kidney, were also involved. Molecular analysis of the VP1 gene confirmed the causative agent and grouped the virus into vvIBD and B2 genotype. All samples were collected from vaccinated birds therefore, the efficacy of available vaccine is required for urgent evaluation. Since most studies only focused on VP1, further exploration on VP2 gene is suggested notably for new-generation vaccines. Monitoring clinical signs’ transformation over time could assist field diagnostics. Birnaviridae family. The virus has an icosahedral symmetrical shape, is 55–65 nm in diameter, and is non-clustered. The viral genome is dsRNA with two segments: A and B. Segment A  encodes VP5 and a precursor polyprotein (VP2-VP3-VP4). This protein is autocatalytically cleaved by the viral protease VP4 into the main structural proteins of the virion VP2 and VP3. Segment A also encodes a non-structural protein VP5. [et al. [Infectious bursal disease (IBD) or Gumboro, is an immunosuppressive disease that affects young chickens. The virus is an RNA virus of the genus Avibirnavirus of the nt A 3,26 bp encodnt A 3,26 bp encodein VP5. . In B-lyein VP5. . Allan e [et al.  reported [et al. . The ver [et al. . Lesionsnt A 3,26 bp encod [et al. , 13. Chi [et al. .Infectious bursal disease virus is classified into pathogenic serotype I and non-pathogenic serotype II. Based on pathogenicity, IBDV belonging to serotype I is classified into mild, intermediate, intermediate plus, classical, variant, and very virulent strains . Due to In Indonesia, subclinical IBD cases in 1991 caused low mortality. The first outbreak of IBD reported an acute increase and expansion of IBD cases, with high mortality reaching 25% in broilers and 60% in laying hens . Based oThus, this study aimed to obtain pathological lesion data and VP1 gene characterization of the latest cases of IBD in commercial broiler farms in Indonesia. This is the first genotype analysis of IBDV VP1 gene from Indonesia.The samples were obtained from IBDV case in commercial broiler farms. There were no challenge or live animal experiment involved. Thus, ethical clearance is not required. The method has been reviewed and obtained approval from Faculty of Veterinary Medicine, Universitas Gadjah Mada, Indonesia .The study was conducted from December 2021 to October 2022. The samples were collected from commercial broiler farms in the Special Region of Yogyakarta (DIY) and Central Java. The histopathology slides were processed at the Wates Disease Investigation Center, Yogyakarta. The RT-PCR test was carried out at the Department of Microbiology, Faculty of Veterinary Medicine, Universitas Gadjah Mada University.Samples were obtained from chickens suspected of IBDV by gross pathology in four commercial broiler farms: Sragen, Wonogiri, Batang District of Central Java Province, and Sleman District of Yogyakarta Special Region Province. A total of five chickens from each farm with indicative clinical symptoms of IBD were selected. The clinical signs were recorded, and necropsies were performed to observe lesions on the bursa of Fabricius, thymus, spleen, proventricular–ventricular junction, thigh muscles, and kidneys. The collected organs were preserved in 10% formalin prior to histology slides processing. A part of the bursa of Fabricius was stored at −20°C for molecular analysis.Histology slides were processed at the Wates Disease Investigation Centre, Yogyakarta Special Region Province, according to the standard protocols of the institution. Histopathology examination was conducted at the Department of Pathology, Faculty of Veterinary Medicine, UGM.All samples were tested for the VP1 gene by RT-PCR. The genetic material of IBDV was extracted from the bursa of Fabricius using Geneaid Viral Nucleic Acid Extraction Kit II  according to the manufacturer. The VP1 gene was amplified using specific primers: Forward 5’-cta cgg gag tgg gac cta ca-3’ and reverse 5’-acc acg tgt tgg agt gaa ca-3’, which yielded a 749-bp amplicon . The polOrgan samples were collected from 26 chickens with signs of depression, trembling, whitish diarrhea, feather loss, paralysis, and dirty cloaca, with mortality rates between 3.82%–20.41%. The organs evaluated included the bursa of Fabricius, thymus, spleen, proventricular–ventricular junction, thigh muscles, and kidneys. All observed changes were recorded and are summarized in Macroscopic lesions of involved organs in IBD cases were collected from commercial broiler farms are shown in Obtained histopathological changes involving organs are grouped according to lesion type . ObserveThe RT-PCR analysis revealed 22 out of 26 bursal samples positive for the VP1 gene. The sequences were analyzed against the VP1 gene sequence available in GenBank. Homology analysis indicated variations in amino acid residues 166, 167, 360, 399, 401–404, 410, and 412 . The phyet al. [et al. [The clinical symptoms observed in this study are consistent with those reported elsewhere. Chickens infected with IBDV exhibit general weakness, whitish diarrhea, dirty cloaca, and tremors –28. Theset al. , or expeet al. . Furtheret al. . The mor [et al.  reported [et al. , 51% [25 [et al. .et al. [et al. [The bursa of Fabricius is the primary organ affected by IBDV infection and generally presents with inflammation, edema, hyperemia, hemorrhage, and atrophy . Bursal et al.  consiste [et al.  reported [et al. . Liver l [et al. . In an e [et al. .et al [et al. [Histopathological lesions from bursal samples  exhibiteet al . Furtheret al , 43. Widet al . Challenet al . Howeveret al . Other det al . Multifo [et al. . A previ [et al. . The ren [et al. .The molecular analysis could only confirm 22 samples by RT-PCR, possibly the viral load was too low because samples were collected after peak infection . This evBased on sequence analysis, some variations were detected in amino acid residues D242E, T287A, L360M, and E393D of all isolates in this study. Mutations in residues D242E, T287A, L360M, and E393D were reported to alter pathogenicity from classic to very virulent strain , 52, 53.et al. [et al. [et al. [The phylogram of the VP1 gene included IBDVs from serotype I  and serotype II (BII). Based on the VP1 gene sequence, IBDV is divided into genogroups B1 (non-vvIBD) and B2 (vvIBD) . By contet al.  divided et al. , the VP1et al. ; Wibowo  [et al.  that the [et al.  suggeste [et al. .Our study has limitations. The genetic properties of identified vvIBD strains must be further explored. Moreover, this study should include a larger area of samples and include cases from layer farms.Broiler chickens infected with IBDV showed specific macroscopic and microscopic lesions in the bursa of Fabricius and thigh muscle. Moreover, other organs such as the spleen, thymus, proventricular–ventricular junction, and kidney were affected. Molecular analysis of the VP1 gene fragment has grouped the virus into vvIBD of B2 genotype. This study has provided evidence of the latest IBDV genotype circulating in broilers in Indonesia. Most studies on IBDV have focused on the VP1 gene; however, some studies have suggested using VP2 for generating more effective IBDV vaccines. Periodic monitoring of the latest isolate for the probability of genome mutation and clinical signs update of IBD field cases. Because all samples were obtained from vaccinated chickens, our findings provide a new outlook regarding vaccine efficacy.BAD: Collected samples, performed laboratory work, analyzed the data, and drafted the manuscript. KP: Supervised the molecular work and reviewed the manuscript. MHW: Designed the study, supervised all the laboratory work and the analysis, and reviewed the manuscript. All authors have read, reviewed, and approved the final manuscript.


Breast cancer (BC) remains a major challenge for oncology today, impacting the lives of countless individuals worldwide. Yet, in the journey toward improved outcomes and personalized care, a beacon of hope has emerged in the form of neoadjuvant systemic therapy (NST). NST is used in early stage BC to predict outcomes and increase eligibility for breast conserving surgery, recommended for patients with triple negative (TN) or human epidermal growth receptor 2 positive (HER2+) diseases. Magnetic resonance imaging (MRI) is an essential tool for assessing breast tumors, axillary lymph node status and response to NST, aiding in surgical decision-making. The goal of this Special Issue is to analyze closely related cutting-edge diagnostic and therapeutic approaches in early stage BC receiving NST, based on a collection of review and research articles with the latest evidence.As we said, neoadjuvant systemic therapy has revolutionized the approach to early stage BC in HER2+ and TN patients. Giffoni et al.  providedTN BC is known for its aggressive nature, poor prognosis, and early relapse and historically treatment has heavily relied on chemotherapy. However, recent advancements in biologic and targeted therapies are reshaping early stage TN BC treatment strategies as showed by Garufi et al. . The aut®, a classification system that incorporates the number, type, and distribution of CD3+ and CD8+ immune cells. The score was initially developed for the prognosis of colon cancer, but it is now widely used in clinical research for prognostic and predictive evaluation in many types of solid tumors. As a first clinical validation of the prognostic potential of the Immunoscore® in patients with BC, the authors assessed this test in BC in the neoadjuvant setting. The presence of high CD3+, CD8+ TILs, and a high Immunoscore® is predictive of better treatment responses. Patients with these characteristics are more likely to achieve pCR, which is a favorable prognostic index. These findings have significant clinical implications, as they suggest that assessing TILs and Immunoscore® could help tailor treatment strategies for BC patients.In their research article, Rapoport et al.  highlighMRI is an essential diagnostic tool for evaluating NST response and can influence the surgical management. In their reviews, Panico et al. and Conti et al. ,5 emphasThe use of MRI can also be useful for assessing the response to NST in specific biological tumor subtypes as demonstrated in the research article of Panthi et al. . They asIn parallel with the necessity of an adequate “T” staging after NST, it is also important to define the “N” stage, indeed it represents the main prognostic factor affecting the rate of recurrence and the therapeutic management so that a correct staging of the axillary lymph node status is fundamental. Di Paola et al.  in theirIn a prospective research article, Rella et al.  explore Finally, an important clinical issue to consider in selecting NST in BC is the likelihood of cancer recurrence. Rabinovici-Cohen et al. , in theiThe combination of these research and review articles collected in this Special Issue give an overview that allows us to better comprehend the wide and heterogeneous field of neoadjuvant treatment in early stage breast cancer. They provide a detailed and up-to-date view of the main advances in the field of pharmacological neoadjuvant treatment in early stage BC, and also in relation to tumor molecular subtypes, tumor staging (T) and lymph node assessment (N).The possibility of predicting pathological complete response and recurrence rate using clinical and radiologic information was also discussed promising new frontiers in personalized care and outcome.


The Great Debate session at the 2022 Melanoma Bridge congress (December 1–3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate. The Great Debate session at the 2022 Melanoma Bridge congress (December 2–3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.The combination of nivolumab and ipilimumab was assessed in the phase III CheckMate 067 trial of 945 patients with previously untreated unresectable stage III/IV melanoma. After a follow-up 6.5 years, combination treatment with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab alone was associated with significantly better overall response rate (ORR) and median overall survival (OS) than ipilimumab alone . This miLAG-3 is a marker of T cell exhaustion, with exhausted CD8+ and CD4+ T cells progressively co-expressing multiple inhibitory checkpoints during chronic antigen stimulation . ResponsStrong T cell receptor (TCR) signalling results in higher LAG-3 expression, meaning that the effect of LAG-3 blockade is amplified in conditions of strong immunogenic signalling . ConversGiven this, relatlimab in combination with nivolumab may be a better treatment option in patients who would otherwise be candidates for single-agent nivolumab or nivolumab plus low-dose ipilimumab. In addition, patients with or without BRAF-mutated melanoma, as well as those with acral and mucosal melanoma, a high tumour burden, or M1a/b baseline metastases, all benefit from nivolumab plus relatlimab versus nivolumab alone . The effNivolumab plus relatlimab is superior to single-agent nivolumab across patient populations, with the added toxicity consistent with single-agent therapy and largely manageable. This combination should replace nivolumab plus low dose ipilimumab. Nivolumab plus higher-dose ipilimumab still has a role in special populations, e.g., patients with brain metastases, but even then only until data indicating otherwise become available. The use of nivolumab plus ipilimumab should be limited to second-line or salvage therapy, as in the SWOG 1616 trial which reported improved PFS and a higher ORR with nivolumab plus ipilimumab versus ipilimumab alone in patients with advanced melanoma refractory to anti-PD-1/PD-L1 treatment . HoweverMultiple trials across multiple years in various melanoma patient populations have proven the benefit of nivolumab plus ipilimumab over nivolumab alone. This includes in patients with liver metastases , uveal mIn a comparison of ipilimumab 3 mg/kg compared with ipilimumab 10 mg/kg in patients with advanced melanoma, the higher dose was associated with significantly improved OS but with more treatment-related adverse events . HoweverIn patients with metastatic melanoma, choice of first-line therapy is critical given that the response to second-line therapy is never as good. For patients who do not respond to nivolumab and relatlimab, options for second-line treatment need to be considered. Most patients today have received adjuvant PD-1 treatment and so need a different option to nivolumab plus relatlimab. In the future, the best first-line option may be triplet or quadruplet therapy. For example, the interleukin-6 receptor blocking antibody, sarilumab, is being investigated in combination with ipilimumab, nivolumab and relatlimab in a phase II study of patients with unresectable stage III/IV melanoma. The discussion now is how to optimise checkpoint blockade. Second-line therapy will not be another checkpoint inhibitor but will involve an alternative approach, such as tumour-infiltrating lymphocyte (TIL)-based therapy or bispecific antibodies. These may be developed to have affinity to both cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and PD-1 receptors, allowing higher dosing with less toxicity. Other bispecific antibodies include XmAb104, which simultaneously targets PD-1 and the immune co-stimulatory receptor, ICOS, and bavunalimab (formerly XmAb 22841), that simultaneously targets CTLA-4 and LAG-3. These two agents will be assessed in combination in a phase Ib/II study in patients with metastatic melanoma refractory to prior immune checkpoint inhibitor therapy and with or without central nervous system (CNS) involvement. Anti-LAG-3 has good tolerability, so will have a role as second-line therapy in combination with newer agents. Examples include ImmTAC® molecules, which are engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively target these cancer cells via an anti-CD3 immune-activating effector function, and could be combined with LAG-3 inhibitors. Off-the-shelf therapeutics, e.g., allogeneic natural killer (NK) cells with a bispecific innate cell engager, may also be a well-tolerated option which could be combined with LAG-3 or PD-1 blockade , high LDH or high tumour burden.More data is needed in relation to the long-term benefit of LAG-3 based therapy.In many centers, combined anti-PD-1 based immunotherapy is the most frequently used treatment regimen for patients with unresectable metastatic melanoma. This is most typically nivolumab plus ipilimumab in both Europe and the US, with nivolumab plus relatlimab also available in the US. However, anti-PD-1 monotherapy also remains a well-established regimen of choice.Future clinical trials in metastatic melanoma are likely to have several major aims. These include increased efficacy of first-line treatments, identifying new immune checkpoint inhibitors with increased efficacy or reduced toxicity, and defining the therapeutic role of specific vaccine-based and cellular products. Choice of therapy in the control arm of any clinical trial must be an established standard of care treatment in metastatic melanoma, with acceptable toxicity and proven survival benefit  as compared with previous treatments.The two pivotal trials used to support the use of anti-PD-1 based combination therapy over monotherapy are the CheckMate 067 trial of nivolumab plus ipilimumab and RELATIVITY 047 trial of nivolumab plus relatlimab. In the CheckMate 067 trial, PFS rates at 6.5 years were 34% with nivolumab plus ipilimumab in combination versus 29% with nivolumab alone and 7% with ipilimumab alone [In the RELATIVITY 047 study, median PFS was significantly improved with nivolumab plus relatlimab compared to nivolumab monotherapy  [In a post-hoc descriptive analysis of CheckMate 067, 6.5-year MSS rates were 56% with the combination, 48% with nivolumab and 27% with ipilimumab . The comIn conclusion, anti-PD-1 monotherapy remains an established standard of care in metastatic melanoma with a proven survival benefit over previous treatments, whereas any OS and MSS benefit of combination immune-checkpoint blockade over monotherapy is still unproven. Moreover, combination therapy is associated with a significant additional toxicity burden compared with monotherapy. As a result, single-agent anti-PD-1 treatment should still be considered an acceptable comparator arm in clinical trials.The time has now arrived that PD-1 blockade with nivolumab or pembrolizumab alone can no longer be considered a standard of care or an appropriate control arm for clinical studies in metastatic melanoma. The combination of nivolumab plus relatlimab resulted in significantly better PFS than nivolumab alone in the RELATIVITY 047 study and this was maintained from 1-year to 2-years of follow-up . In addiIn the neoadjuvant setting, nivolumab plus relatlimab resulted in a pCR rate of 57% and overall pathologic response rate of 70% among 30 patients with resectable stage III/IV melanoma [In a cross-trial comparison of nivolumab plus either relatlimab (RELATIVITY 047) or ipilimumab (CheckMate 067), the benefit:risk ratio, presented as the ratio of PFS improvement to toxicity × 100, favoured nivolumab plus relatlimab . In anotFor future trials in melanoma, there should be no single agent anti-PD-1 arm as the single control arm. In both the metastatic and neoadjuvant settings, nivolumab plus relatlimab combination appears most active and less toxic than nivolumab plus ipilimumab, although the two combination approaches should be directly compared to make a strong definitive statement. A triplet combination of nivolumab/ipilimumab/relatlimab may become a future experimental arm in clinical trials. However, ultimately a better understanding of biomarkers is needed to help guide treatment choices among all these regimens in combination or as single agents Fig. .Fig. 2IsKey points:Choice of therapy in the control arm of a clinical trial must be an established standard of care, with acceptable toxicity and proven survival benefit.Anti-PD-1 monotherapy has a proven survival benefit over previous treatments, without the additional toxicity burden of combination therapy.In both the metastatic and neoadjuvant settings, nivolumab plus relatlimab appears most active and less toxic than nivolumab monotherapy, which may no longer be the gold standard of care.Five-year survival rates for stage III melanoma in different cohorts range from 80% in stage IIIA to 30% in stage IIID, which justifies the use of adjuvant treatment. Studies of adjuvant therapy in high-risk melanoma (dabrafenib and trametinib in COMBI-AD and pembrolizumab in KEYNOTE 054) have shown HRs of 0.51–0.61 for reduced risk of relapse and 0.56–0.62 for distant metastases in stage III disease , 18. ThePrevention of recurrence is considered to be more important than concerns of adverse events or quality of life by patient who are candidates for adjuvant melanoma treatment. In a real-world survey of over 900 patients, approximately 25% with stage III disease declined adjuvant therapy, with the most cited reasons in descending order of frequency being age, presence of comorbidities, fear of relapse, fear of adverse events and loss of quality of life . However“perioperative”, since patients received treatment with pembrolizumab both before and after surgery, so it is not a pure neoadjuvant approach. These may be practice-changing data, with meaningful reductions in recurrence seen with just three cycles of pre-surgery pembrolizumab and no additional toxicity compared with conventional adjuvant therapy. It is unclear whether this may become a replacement for or an alternative to ipilimumab plus nivolumab.Alternative options to the current approach include improved selection of high-risk patients who will benefit from adjuvant treatment, e.g., through the use of nomograms, risk prediction scores and gene expression profiling (GEP). Another option is neoadjuvant therapy with or without adjuvant treatment. In the OpACIN-neo study, two cycles of neoadjuvant nivolumab plus ipilimumab had a pathologic response rate (pRR) of 77% . In the Only around 20% of all patients with stage III melanoma have palpable lymph nodes or skin metastases and are therefore candidates for neoadjuvant treatment. In the future, there may be even fewer candidates due to more effective adjuvant stage II treatment. To date, there are no neoadjuvant trials in stage IIB/C melanoma. Adjuvant treatment remains an important option, although a neoadjuvant approach represents a valuable alternative for selected patients.The goal of adjuvant therapy is to improve the OS of curatively treated patients. However, even after 5 years of follow-up we have not seen a statistically significant OS benefit, according to prespecified boundaries, with adjuvant immunotherapy or targeted therapy in melanoma. This does not mean we should stop adjuvant therapy completely, but better selection of patients that will truly benefit is needed.Adjuvant targeted or immunotherapy benefits less than 20% of patients with stage III melanoma, i.e., 80% of patents are treated for no clinical benefit but at a significant financial cost and exposure to adverse events. In COMBI-AD, the absolute difference in RFS rate at 4 years was 16% (4-year RFS of 54% with dabrafenib plus trametinib and 38% with placebo) . SimilarAn OS difference is also unlikely to be observed after even longer-term follow-up. Among patients with distant recurrence, approximately 20% will have distant metastases that can be salvaged with local therapy (radiotherapy or surgery) . ResponsThe same applies in stage II melanoma, where even less absolute benefit is of only around 10% of patients seeing a RFS or DMFS benefit with adjuvant immunotherapy . WithoutFurthermore, the neoadjuvant arm involved 15 cycles of pembrolizumab after surgery, i.e., neoadjuvant plus adjuvant, and it is not known whether this is needed for all patients. In the PRADO trial, patients with major pathologic response (MPR) had 2-year RFS and DMFS rates of 93% and 98%, without therapeutic lymph node dissection (TLND) and adjuvant therapy .Vice versa, adjuvant systemic therapy improved the RFS and DMFS rates of patients with no response to neoadjuvant checkpoint inhibition. In PRADO, 2-year RFS rate was 71% in non-responders, which compares with a 2-year RFS of 37% in non-responders, who did not receive adjuvant therapy in the OpACIN-neo study . This abIn conclusion, adjuvant therapy for all patients with resectable stage II/III melanoma is not a valid option, because for these whole unselected cohorts there will be no OS benefit, and this at high financial and adverse event costs of patients treated for no benefit. A neoadjuvant approach is the way forward to solve this dilemma. Identifying non-responders after neoadjuvant therapy might become a strong biomarker for identifying patients with stage III disease who need adjuvant therapy. In stage II melanoma, a neoadjuvant approach still needs to be developed Fig. .Fig. 3IsKey points:Data suggest adjuvant treatment has a survival benefit with good tolerability in high-risk melanoma.Even after 5 years of follow-up we have not seen a statistically significant OS benefit with adjuvant immunotherapy or targeted therapy in melanoma so better selection of patients that will truly benefit is needed.Adjuvant treatment remains an important option, although a neoadjuvant approach represents a valuable alternative for selected patients.Stage II melanoma represents around 15% of patients with melanoma, with around one‐half of these patients having stage IIB or IIC disease and so being at higher risk of recurrence . The numAnti-PD-1 therapy reduces recurrence and distant metastasis. In the KEYNOTE 716 trial, adjuvant pembrolizumab significantly improved RFS and DMFS (both HR 0.64) versus placebo after 27 months of follow-up in patients with stage IIB or IIC melanoma . SimilarHowever, even without a proven OS benefit, adjuvant therapy may still be important. Although OS was rated the most important factor by patients when surveyed about attitudes to treatment decision-making, reduction of relapse was prioritized over risk of toxicity . As suchIn conclusion, resectable stage IIB/C melanoma has a significant risk of recurrence. Anti-PD-1 therapy improves RFS and DMFS and most likely also PRFS2. No OS benefit has been reported in any peri-surgical (neoadjuvant or adjuvant) anti-PD-1 trial but reduction in relapse is in itself considered a significant benefit by many patients.The proportion of patients with stage II melanoma who benefit from adjuvant therapy is limited and the vast majority with stage IIA/B disease do well without treatment; overtreatment is an issue given that only 12% with stage IIA disease, 18% with stage IIB and 25% with stage IIC benefit from adjuvant treatment .Adjuvant therapy in stage II disease is a controversial topic and this can in part be attributed to the unpredictable nature of relapse, which may or may not be salvageable. Patients with stage IIB and IIC melanoma have a high risk of recurrence after 24 months with poor outcomes . PembrolIn KEYNOTE 716, 16% of pembrolizumab-treated patients had grade 3–4 treatment-related adverse events, which is not a trivial proportion. Similarly, grade 3–4 treatment-related toxicity occurred in 10% of nivolumab-treated patients in the CheckMate 76 K study . AlthougTo date, we do not have data showing an OS benefit of adjuvant therapy in stage II disease. We do not know whether treating later will be equal in benefit to treating early. Those patients most likely to experience side effects cannot be predicted. Similarly, we do not have biomarkers for disease recurrence. More data on patterns of recurrence are required.Alternatives to adjuvant therapy include careful observation or enrolment in clinical trials, although opportunities for study enrolment are limited. Targeted therapy may still be an option, as previously shown by a benefit with vemurafenib versus placebo in patients with stage IIC/IIIB melanoma . ProspecImmunotherapy can offer the ‘gold star’ of a potential cure, but more data and rigorous biomarkers are needed to avoid overtreatment. It is essential that treatment goals and outcomes, including potential side effects and risks of recurrence with and without adjuvant therapy, are discussed with each individual patient Fig. .Fig. 4StKey points:Anti-PD-1 therapy improves RFS and DMFS in resectable stage IIB/C melanoma.Although no OS benefit has been reported in any peri-surgical (neoadjuvant or adjuvant) anti-PD-1 trial, reduction in relapse is in itself a significant benefit for many patients.However, the vast majority patients with stage IIA/B disease do well without treatment and more data and rigorous biomarkers are needed to avoid overtreatment.The majority of patients diagnosed with early-¯stage melanoma are at low likelihood of relapse and will never require treatment beyond the primary site. A wide excision is recommended with margins based on the primary tumour thickness –40. OngoThe second Multicenter Selective Lymphadenectomy Trial (MSLT-II) reported that CLND did not result in a MSS benefit versus observation in patients with melanoma and sentinel-node metastases . This reIn long-term follow-up of MSLT-II, 80.2% of basins were free of nodal recurrence at 10 years in the observation arm, supporting that there is a therapeutic value of SLNB in patients with melanoma . Risk fahttps://melanomarisk.org.au/SNLForm) [Risk prediction tools which use conventional biomarkers, such as the Melanoma Institute Australia Prediction Tool for Sentinel Node Metastasis Risk (SNLForm) , or combSNLForm) . Low-risIn a retrospective study of 1377 patients with pT1–pT4b primary cutaneous melanoma, the optimal maximum tumour deposit size cut-point was 0.7 mm for the pT1b-pT4a SLN-positive subgroups, but there was no cut-point for SLN-positive patients with pT4b melanoma . Nodal rAdjuvant therapy reduces risk of recurrence and improves survival following initial treatment and in whom there is no evidence of disease. However, clinical benefit is only possible if residual sub-clinical disease exists. It is important to recognize that absolute benefit is a function of hazard ratio and overall risk of recurrence. Moreover, since toxicity may occur in any patient who receives adjuvant therapy, with the potential for lifelong sequalae, it is critically important to weigh the potential benefits, risks, and alternatives of any potential treatment strategy. SLNB is an important staging technique that improves regional control, may have a therapeutic benefit, and helps clinicians and patients make more informed treatment decisions.In the metastatic setting, surgery may be selectively deployed, with long-term survival following metastasectomy in highly selected patients having a limited but important role, while the consolidation or resection of resistant clones in the setting of systemic therapy can help mitigate/palliate symptoms, such as pain, bleeding, or obstruction, and facilitate considerations for additional systemic and/or other approaches.To conclude, despite exciting times in this era of effective systemic therapy, there is still a significant role for surgery across the continuum of melanoma that continues to evolve and is unlikely to completely disappear.Clearly surgery is required for resection of primary melanoma. However, beyond this, the number of surgical interventions in melanoma could be reduced by up to 80% in Europe over the next 5 years. Importantly, lymphocytes are primed and ‘educated’ in the lymph nodes so their removal should be avoided where possible.Wide excision for primary cutaneous melanoma is recommended with margins based on the primary tumour thickness . HoweverPositive sentinel node staging used to provide an indication for CLND, although this is no longer the case since the MSLT-II and DECOG trials showed no OS benefit , 48. A pWith regard to TLND, this has largely been replaced by neoadjuvant immunotherapy, as shown by the PRADO trial in which patients with MPR in their index lymph node after neoadjuvant nivolumab and ipilimumab did not receive TLND or adjuvant therapy; 2-year RFS was 93% in these patients . NeoadjuFurther surgical uses include resection of In-transit metastases, which can mostly be treated with immunotherapy  although there is a still an occasional need for excision of oligometastatic disease. Distant metastases can be treated with neoadjuvant checkpoint inhibition, with only around half needing resection. Escape lesions are very rare and will be treated by organ specialist surgeons. Palliative interventions for local control may be sometimes needed but are also rare; neoadjuvant immunotherapy and radiation therapy may also have a role in these patients.To conclude, melanoma surgery will be reduced by > 60% in the short term and by > 80% in the next 5 years, being replaced by (neo)adjuvant therapies and the use of SLNB replacement technologies. Neoadjuvant immunotherapy will replace the standard adjuvant therapy model and reduce TLND, metastasis resections, and SLNB , 50 adjuvant therapies and the use of SLN biopsy replacement technologies.Neoadjuvant immunotherapy will replace the standard adjuvant therapy model and reduce TLND, metastasis resections, and SLN biopsy.The Melanoma Great Debate included the presentation of counterpoint views from leading experts on five contemporary clinical issues in the management of melanoma. Given the format and nature of the debates, presentations were not intended as a rigorous and/or systematic assessment of the field but instead allowed the opportunity to highlight some important questions and current controversies. These debates are obviously more nuanced than the simple for or against/yes or no format encourages; however, it is hoped that these discussions can help focus attention on these issues, stimulating further research needed to improve our understanding of different therapeutic approaches.