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Background: In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields., Methods: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included., Results: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa., Conclusions: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging., (© 2023. The Author(s).)

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF V600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF V600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF V600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF V600 mutations (including BRAF V600K ), which account for ∼10-20% of BRAF V600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: The efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM., Methods: A retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments., Results: Fifty-four patients were included: 27 (50%) female; median age 75 (range 26-94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2-46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR., Conclusions and Relevance: ICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence., Competing Interests: Competing interests: VA—Advisory Boards: BMS, MSD, Merck, Novartis, Roche, Pierre Fabre. Travel Support: BMS, Onco-sec. Speakers Fee: BMS, MSD, Merck, Novartis, Roche. GL—consultant advisor to Aduro, Amgen, Array pharmaceutical, BMS, MSD, Novartis, Roche, Pierre-Fabre. SS—consultant advisor to Astra Zeneca, MSD, Novartis, BMS, Amgen, Roche and Janssen. RS—Advisory board MSD, Novartis and speaking honoraria BMS. AM—consultant advisor to BMS, MSD, Novartis, Roche, Pierre-Fabre. DEG—advisory board and received honoraria from Amgen and from Provectus., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The treatment of non-syndromic scaphocephaly with spring-activated cranioplasty offers acceptable outcomes with the potential for reduced surgical morbidity when compared with cranial vault remodelling procedures. A disadvantage of this technique is the need for a second operative intervention to remove the implanted devices. There are many descriptions of the surgical technique for performing spring-activated cranioplasty available in the literature; however, little is documented regarding the procedures used for device removal. The published accounts of spring removal demonstrate a wide range of approaches, from the reopening and dissection of the entire previous surgical field, to attempts to limit the incisions and dissection. In this study we describe our technique for the minimally invasive removal of cranial springs used in the treatment of scaphocephaly. Our technique focuses on minimal soft tissue disruption and uses a Kirschner wire cutter to divide the spring at its mid-point so as to relieve any residual internal forces acting on the footplates., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Cleft orthognathic surgery is an important component of a comprehensive cleft care plan. Applying combined orthodontic and orthognathic treatment principles to a cohort of patients with cleft lip and palate raises many challenges not encountered in conventional orthognathic care. Cleft patients share a commonality in their midfacial anatomy that is characterized by a 3-dimensionally deficient maxilla. The residual sequelae of multiple previous surgeries along with dental differences and unhealed fistulae are considerations when embarking on treatment. This article describes many of these challenges and highlights approaches that are used to address the specific needs of this special group of patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Subungual melanoma is an uncommon type of melanoma that can be difficult to diagnose. Patients often present with advanced primary lesions and have an associated increased risk of nodal disease. Delays in diagnosis are believed to contribute to poor patient outcomes., Objective: The objective of this article is to offer an approach to assessing and managing patients who present with subungual pigmented lesions. We describe the anatomy of the nail bed to offer a rationale for our technique of nail bed biopsy, and warn of the potential to cause permanent nail dystrophy through other approaches., Discussion: Many clinicians have limited experience in assessing lesions of the nail apparatus.Subungual pigmentation has extremely broad differential diagnoses, which include a variety of benign pathologies. A systematic approach to assessment, and early referral of patients with suspicious lesions to a specialist unit, has the potential to improve patient outcomes.

Background: There were 59 unprovoked shark attacks worldwide in 2008. Twelve of these occurred in Australia, ranking it as second only to the USA. In February 2009, two attacks occurred within 72 h in Sydney, Australia., Methods: The two patients involved survived severe limb trauma. Case 1 suffered bite trauma to the lower limb and hand and underwent staged debridement and early amputation. Case 2 presented with a hand severed at the level of the wrist that was initially replanted. However, it would succumb to progressive necrosis after 12 days. We discuss the aspects of these cases that contributed to the patients' survival and ultimately good functional outcomes., Discussion: New paradigms for the management of major trauma patients have emerged over the last decade. We consider recent advances in the understanding of pre-hospital tourniquet use, rapid transit to the operating suite and damage control surgery, and examine how they impacted on the management of our patients. Very little is known about the microbiology of shark bites. Organisms from sea water, the patient's skin and the shark's mouth must all be considered when selecting appropriate antimicrobial prophylaxis. The planning of definitive surgery in severe limb trauma is dependent on the interactions of a number of factors including physical, psychological and social issues. The decision to ultimately replant or amputate the effected limb is best made in union with the patient and their family., (© 2011 The Authors. ANZ Journal of Surgery © 2011 Royal Australasian College of Surgeons.)

The World Health Organization predicts that people aged older than 65 years will comprise 20% of the world's population by 2030. One of the most commonly prescribed medications for the elderly are the bisphosphonates, which have been shown to significantly reduce debilitating and fatal fractures by preserving bone density and consequently saving governments billions of dollars annually. Despite rigorous testing, 190 million prescriptions worldwide and US$8000 million in revenue, there is a serious adverse effect called bisphosphonate-related osteonecrosis of the jaw, which is poorly described and difficult to treat. The difficulty is compounded by the inability of medical personnel to recognize and adequately refer these patients or take adequate precautions before instituting bisphosphonate therapy. A myriad of differentials and a lack of consensus on how to definitively treat these patients have made this new presentation a worrying precursor for millions of other consumers who will reach the 5-year oral half life of bisphosphonates, which is when they generally start to present. In this paper, we explore historical parallels and provide the most comprehensive review to date in the literature about the presentation, diagnosis, treatment, pathophysiology, oncogenic associations, and best practice guidelines. Legal action pursuant to bisphosphonate-related osteonecrosis of the jaw is underway on 3 continents, and we believe that every health care professional should become au fait with this condition for which our growing case series represents merely the tip of the iceberg.