Search

Aim: Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management., Method: This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy., Results: One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median follow-up of 28.7 months (95 % CI: 21.4-38.3), ORR was 57.3 %, median DOR was 42.8 months (95 % CI, 25.8 - not reached (NR)), median PFS was 14 months (95 % CI, 8.1- 19.8), and median OS was 42.8 months (95 % CI, 30.3 - NR). One-hundred and eight patients (59 %) experienced progressive disease; 50 % (n = 54/108) with primary resistance and 26 % (n = 28/108) with secondary resistance. Fifty patients (27 %; n = 50/185) received subsequent systemic therapies (+/- local therapy) with response data; 18 (36 %; n = 18/50) received doublet platinum chemotherapy (ORR 67 %, DOR 5.0 months [95 % CI; 3.7 - NR]) and 16 (32 %; n = 16/50) were rechallenged with anti-PD-(L)1 (ORR 56 %, DOR 20.2 months [95 % CI; 8.3 - NR])., Conclusion: The most common subsequent treatment for patients with primary resistance was chemotherapy, while those with secondary resistance most frequently underwent further anti-PD-(L)1 therapy in combination with other therapies. Despite both therapies demonstrating promising ORR, doublet platinum chemotherapy had a poorer DOR compared to anti-PD-(L)1 rechallenge., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Georgina Venetia Long is supported by a National Health And Medical Research Council Investigator grant and the University of Sydney Medical Foundation. Inês Pires da Silva is supported by early career Cancer Institute New South Wales fellowship. Jeremy Mo has received travel support from Novartis, and honoraria from AstraZeneca. Caroline Gaudy-Marqueste has served as consultant and has received honoraria from Bristol-Myers Squibb, Merck Sharpe & Dohme, Pierre Fabre, and Sunpharma and travel support from Bristol-Myers Squibb, Merck Sharpe & Dohme,Pierre Fabre, and Janssen. Andrisha-Jade Inderjeeth has received honoraria from Bristol-Myers Squibb, Pfizer and Astellas. Alexander van Akkooi has served on advisory boards or as a consultant and has received honoraria from: 4SC AG, Amgen, Bristol-Myers Squibb, Merck Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, SkylineDX and Research Grants from Amgen, Merck Serono-Pfizer, SkylineDX. Anne Zaremba has received travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb. Jenny H Lee has received honoraria from MSD, AstraZeneca and travel support from Novartis, Pfizer and MSD. Jenny H Lee has served on advisory boards for MSD and Sanofi. Jenny H Lee has received a research grant from MSD. Wen Xu has served on advisory boards for Merck, MSD, BMS and Novartis and has received honorarium from Merck, MSD, BMS, AstraZeneca, and Limbic. Wen Xu has received educational support from Merck, MSD, BMS, AstraZeneca, Daiichi-Sankyo, and Eli Lilly. Wen Xu has received research funding from Merck. Celeste Lebbe has served as a consultant and has received honoraria from BMS, MSD, Peirre Fabre, Erasca and Immunocore. Celeste Lebbe has received travel support from BMS, MSD, and Pierre Fabre. Shahneen Sandhu is supported by a National Health And Medical Research Council Investigator grant and a Peter MacCallum Cancer Centre Foundation Grant. Shahneen Sandhu has served on advisory boards for Bristol Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Novartis, and Merck Serono (funds go to a research fund at Peter MacCallum Cancer Centre). Shahneen Sandhu has received institutional research grants for an investigator-initiated trial from Novartis, Genentech, Amgen, AstraZeneca, Merck Serono, Merck Sharp and Dohme, Pfizer and Senwha (funds go to a research fund at Peter MacCallum Cancer Centre). Serigne Lo has received fees for professional servces from SkylineDx BV and has received honoraria for editorial duties with The British Association of Dermatologists. Lisa Zimmer has served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis. Matteo S Carlino has served on advisory boards or as a consultant for: Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharpe & Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi, and received honoraria from Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Georgina Venetia Long is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc, BioNTech SE, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore Ireland Limited, Innovent Biologics USA Inc, Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals, Scancell Limited, SkylineDX B.V. Inês Pires da Silva declares honoraria speaker fees or advisory roles for Pierre Fabre, Merck Sharpe & Dohme, Roche, Novartis, and Bristol Myers Squibb and has served as consultant on advisory boards for MSD and Regeneron. All remaining authors have declared no conflicts of interest, (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Regional metastasis occurs in 5% of cutaneous squamous cell carcinoma (cSCC). The aim of this study is to assess the impact of margin status of regional metastases on survival., Methods: A retrospective review of 401 patients with nodal metastases from cSCC. Margin status of nodal metastases was classified as clear (>1 mm), close (<1 mm), or involved. Cox regression and Kaplan-Meier methods were used to assess associations with overall and disease-specific survival (OS and DSS)., Results: Of the 401 patients with nodal metastases (median age 75, 85.3% male), 43.6% had involved margins, 27.4% had close margins, and 28.9% had clear margins. Involved margins were significantly associated with reduced OS and DSS on univariable analysis. Multivariable analysis confirmed that involved margins independently predicted worse DSS (HR 1.92, 95% CI 1.15-3.19, p = 0.01). Other independent prognostic factors included size of deposit (HR 1.02, 95% CI 1.01-1.04, p < 0.001), number of deposits (HR 1.05, 95% CI 1.02-1.08, p < 0.001), and the presence of perineural invasion (HR 1.84, 95% CI 1.14-2.98, p = 0.01)., Conclusions: Clear surgical margins during the removal of regional metastases of cSCC improves survival outcomes. This study highlights the importance of careful preoperative evaluation to achieve a complete (R0) surgical resection., Level of Evidence: Level 3 Laryngoscope, 2025., (© 2025 The American Laryngological, Rhinological and Otological Society, Inc.)

The prognosis of a patient with a primary cutaneous melanoma is known to be related to the Breslow thickness of their tumor. This study sought to determine long-term (30-year) survival rates for the 4 American Joint Committee on Cancer 8th edition T categories by analyzing Australian registry data for 210 042 melanoma patients diagnosed from 1982 to 2014. The 30-year incidence rates of death due to melanoma and nonmelanoma (with 95% confidence intervals [CIs]) were 7.1% (95% CI = 6.9% to 7.3%) and 32.8% (95% CI = 32.3% to 33.3%), respectively. For T2 melanomas, the corresponding rates were 21.6% (95% CI = 21.0% to 22.3%) and 35.6% (95% CI = 34.7% to 36.6%), for T3 melanomas 34.2% (95% CI = 33.4% to 35.1%) and 39.6% (95% CI = 38.5% to 40.8%), and for T4 melanomas 44.3% (95% CI = 43.2% to 45.3%) and 39.6% (95% CI = 38.3% to 41.0%). A plateau in melanoma-related deaths occurred in T4 patients after 20 years, but there were ongoing melanoma-related deaths for the other T categories beyond 30 years. A progressive rise in the risk of death from other causes occurred across all T categories., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity., Objective: Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS)., Methods: Patients with CHNM and CMOS diagnosed between 2000 and 2018 were included. Locoregional control, distant metastasis-free survival, melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy., Results: Of 3007 CHNM and 10,637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs 58.5, P < .001; median Breslow thickness 1.7 mm vs 1.2 mm, P < .001; and ulceration 21.2% vs 18.2%, P < .001). CHNM had worse locoregional control (hazard ratio (HR) 1.17, P < .001) and distant metastasis-free survival (HR 1.25, P < .001) but there were no significant differences in MSS or OS. Among stage IV patients who received immune checkpoint inhibitor, CHNM had better MSS (HR 0.56, P = .001) and OS (HR 0.57, P < .001) on multivariable analyses., Limitations: Retrospective study, offset by prospective data collection., Conclusion: CHNM is associated with a distinct clinicopathological and prognostic profile., Competing Interests: Conflicts of interest Dr Saw has received honoraria for advisory board participation from MSD, Novartis, and Qbiotics and speaking honoraria from BMS and Novartis. Dr Pires da Silva has received travel support from BMS and MSD and speaker fees from Roche, BMS, MSD, and Novartis. Dr Varey has received an honorarium from Novartis. Dr Akkooi has served on advisory boards and received consultancy honoraria from Amgen, Bristol Myers Squibb, Neracare, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, and 4SC. Dr Menzies has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics. Dr Carlino has served on advisory boards for Bristol-Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai, Oncosec, and Qbiotics and honoraria from Bristol-Myers Squibb, MSD, and Novartis. Dr Long is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, and Regeneron. Dr Scolyer has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, and GlaxoSmithKline. Dr Thompson has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK, and Provectus Biopharmaceuticals, and travel and conference support from GSK, Provectus Biopharmaceuticals, and Novartis. Drs Li, Xu, Blah, Lo, Shannon, and Ch'ng have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Most patients who present with primary cutaneous melanomas have thin tumors (≤1.0 mm in Breslow thickness, ie, pT1a and pT1b). Although their prognosis is generally considered to be excellent, there is limited precise information on the association of risk of death with specific Breslow measurements in thin lesions., Objective: To assess the relative effect of a 0.8-mm Breslow thickness threshold with respect to the incidence of both melanoma-related and nonmelanoma-related death., Design, Setting, and Participants: Registry data for all Australians diagnosed with thin invasive primary melanomas between 1982 and 2014 were analyzed. Data were extracted from all 8 Australian state and territory population-based cancer registries. Dates and causes of death were obtained from the Australian National Death Index. Adults diagnosed with a first invasive primary melanoma of 1.0 mm or smaller in thickness were included., Exposure: First invasive primary melanoma between 1982 and 2014., Main Outcomes and Measures: The primary outcomes were melanoma-related deaths and nonmelanoma-related deaths. Competing-risk regression analyses and cause-specific analyses were performed to investigate the relationships between Breslow thickness subcategory (<0.8 mm versus ≥0.8 mm by 0.1-mm increments) and the primary outcomes., Results: Overall, a cohort of 144 447 participants was included. The median (range) age was 56 (18-101) years and 78 014 (54.0%) were men. Median (IQR) follow-up was 15.0 (9.5-23.3) years. Crude incidence rates of melanoma-related death 20 years after diagnosis were 6.3% (95% CI, 6.1%-6.5%) for the whole cohort, 6.0% (95% CI, 5.7%-6.2%) for tumors smaller than 0.8 mm, and 12.0% (95% CI, 11.4%-12.6%) for tumors 0.8 to 1.0 mm. The corresponding 20-year melanoma-specific survival rates were 91.9% (95% CI, 91.6%-92.1%), 94.2% (95% CI, 94.0%-94.4%), and 87.8% (95% CI, 87.3%-88.3%), respectively. On multivariable analysis, tumor thickness of 0.8 to 1.0 mm was significantly associated with both a greater absolute risk of melanoma-related death (subdistribution hazard ratio, 2.92; 95% CI, 2.74-3.12) and a greater rate of melanoma-related death (hazard ratio, 2.98; 95% CI, 2.79-3.18) than thinner tumors (<0.8 mm). Risk of death from nonmelanoma-related causes was not associated with Breslow thickness., Conclusions and Relevance: In this study, the risk of melanoma-related death increased significantly for patients with primary tumors of 0.8 to 1.0 mm in thickness. The risk of death from nonmelanoma-ralated causes was similar across Breslow thicknesses of 0.1 to 1.0 mm. This analysis suggests that a 0.8-mm threshold for guiding the care of patients with thin primary melanomas.

Background: Although most melanomas drain to the more common major lymph node basins (axilla, groin, neck), rarely they drain to deep SLN locations such as intra-abdominal and intra-thoracic (including intercostal and internal mammary) sites, which pose a higher surgical risk and complexity for procurement. Our study is aimed at determining the rate of positivity and likelihood of recurrence in these nodal sites to guide management decisions for patients with truncal melanomas which drain to these 'deep' SLN locations., Methods: Retrospective data collected between May 2008 and May 2022 including all patients with truncal melanomas who underwent lymphoscintigraphy resulting in the identification of deep SLNs in intra-abdominal and intra-thoracic sites were included. The associations between retrieval of SLNs and recurrence-free survival (RFS) and overall survival (OS) were investigated., Results: 74 patients with a total of 91 SLNs located at deep sites were included. 11 (15 %) patients with a total of 12 lymph nodes had SLNB of these deep nodes, all of which were intercostal nodes. Only 1 patient had a positive SLNB. In total, 24 (32 %) patients developed recurrence. However, the remaining patients did not recur at the deep SLN sites. There were no statistically significant associations between retrieval of deep SLNs and RFS or OS. 3-year RFS in the patients who had deep SLNB performed was 62 % compared to 54 % and 50 % in those who had no SLNB or incomplete SLNB, respectively (p = 0.63)., Conclusion: In this study omitting procurement of these deep SLNs did not result in reduced RFS or OS., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Cutaneous squamous cell carcinomas (cSCC) metastasizing to the parotid gland can cause facial nerve (FN) dysfunction secondary to direct invasion, perineural spread, or surgical ablation. This study aims to characterize the prevalence of preoperative FN involvement in metastatic cSCC to the parotid and identify risk factors resulting in FN sacrifice., Methods: Patients with parotid metastases from cSCC, treated surgically with parotidectomy with curative intent were identified through a retrospective cohort analysis of a prospectively maintained Sydney Head and Neck database from 1992 to 2021., Results: Of 408 patients identified, 39 (10%) were found to have preoperative FN weakness, of which 41% underwent concurrent temporal bone resection compared to 9.1% for the overall cohort. All patients with preoperative FN weakness underwent FN sacrifice. FN sacrifice occurred in n = 145 (36%), of which 88 (61%) required sacrifice of a trunk or division. The 5-year disease free survival and disease specific survival was worse for patients requiring sacrifice of the FN trunk compared to no sacrifice, however there was no difference in survival for patients requiring sacrifice of the FN division or branch. We found those with > 23.5 mm parotid deposits had an odds ratio of 9.9 for FN sacrifice (95% CI 3.0-32.8, p < 0.001)., Conclusions: Preoperative FN weakness was present in 10% of patients and 36% had some part of the FN sacrificed. There was no significant difference in outcomes for patients with and without preoperative FN weakness. Patients who undergo sacrifice of the FN trunk have worse survival compared to those not requiring FN sacrifice, however similar outcomes were observed in those requiring lessor degrees of FN sacrifice. The likelihood FN sacrifice rises with increasing parotid deposit size., (© 2024 Wiley Periodicals LLC.)

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.)

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF V600 -mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 ., (© 2024. The Author(s).)

Background: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA., Methods: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively., Results: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group (p = 0.091). The overall positivity rate was 16.2% in the pre-nomogram group and 14.9% in the post-nomogram group (p = 0.223). SLNB was performed less frequently in T1a melanoma patients in the pre-nomogram group (1.1%, n = 2/177) than in the post-nomogram group (8.6%, n = 17/198) [p ≤ 0.001]. This increase was particularly for melanomas with a risk score ≥ 5%, with an SLN positivity rate of 11.8% in the post-nomogram group (p = 0.004) compared with zero. For T1b melanomas with a risk score of > 10%, the SLNB rate was 40.0% (8/20) pre-nomogram and 75.0% (12/16) post-nomogram (p = 0.049)., Conclusions: In this specialized center, the SLN risk calculator appears to influence practice for melanomas previously considered low risk for metastasis, with increased use of SLNB for T1a and higher-risk T1b melanomas. Further evaluation is required across broader practice settings. Melanoma management guidelines could be updated to incorporate the availability of nomograms to better select patients for SLNB than previous criteria., (© 2024. The Author(s).)

Background: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes., Methods: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database., Results: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641)., Conclusions: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma., (© 2024. The Author(s).)

Resection, reconstruction, and rehabilitation of the mandible impact function and health related quality of life (HRQOL). In this study, we aimed to understand the impact of delayed versus immediate dental implant placement. A cross-sectional and prospective study was conducted including patients who underwent reconstruction of the mandible via osseous vascularised bone flaps and dental implants. The FACE-Q Head and Neck Cancer module and the MD Anderson Dysphagia Inventory and Speech Handicap Index were used to evaluate HRQOL. A total of 187 implants were placed in 52 patients, of which 44 patients (85%) completed questionnaires. Immediate dental implant placement was associated with superior FACE-Q appearance (p = 0.02), oral competence (p = 0.004), smile distress (p = 0.03), and satisfaction with information (p = 0.004). Dentoalveolar rehabilitation through the placement of immediate dental implants at the time of surgery was found to be associated with higher HRQOL scores related to appearance, eating and drinking, oral competence, and smile., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Health literacy (HL) comprises skills and knowledge required to understand, access, and make decisions about healthcare. Our aim was to examine associations between patient HL and time intervals (defined in the Aarhus statement) along the pathway to treatment of head and neck cancer (HNC)., Methods: A prospective cohort study was conducted from October 2018 to March 2020. Participants completed the Health Literacy Questionnaire (HLQ®) and described key events and dates along the pathway to treatment using validated questionnaires. Correlations between six diagnostic time intervals and domains of HL were explored, and factors predicting exceeding maximum acceptable timeframes were assessed using logistic regression., Results: One hundred patients with a diagnosis of HNC within the preceding 6 months were recruited. HLQ® Domain 2 (sufficient information to manage health) was significantly negatively associated with four intervals: the patient interval (first symptom to first presentation), primary care interval (first presentation to referral to secondary care), diagnostic interval (first presentation to diagnosis), and total interval (first symptom to treatment onset); correlation coefficients -0.25 to -0.27 (P < 0.05). Domain 8 (ability to find good information) was significantly negatively associated with three intervals (primary care interval, diagnostic interval, and total interval; correlation coefficients -0.23 to -0.34; P < 0.05). Higher education, age, and comorbidity levels were associated with shorter patient and diagnostic intervals., Conclusions: HL may be a potential target to improve timeliness of HNC diagnosis and reduce disparities in outcomes., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Purpose: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients., Methods: Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models)., Results: The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated., Conclusion: The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Background: Facial cancer surgery involving the midface (comprising the lower eyelids, nose, cheeks, and upper lip) can have debilitating life-changing functional, social, and psychological impacts on the patient. Midface symptoms are inadequately captured by existing patient-reported outcome measures (PROMs). PROMs are increasingly used for individual patient care, quality improvement, and standardized reporting of treatment outcomes. This study aimed to present our findings from the first phase of the development of a midface, specifically periocular and nasal, PROM., Methods: After international guidance for PROM development, the first phase comprised identification of salient issues and item generation. Fifteen patients who had midface surgery and 10 clinicians from various specialties with more than 5 years' experience treating these patients were recruited. Semi-structured interviews explored aesthetic, functional, social, and psychological outcomes, with specific attention to deficiencies in current PROMs. Thematic analysis was used to develop an item pool, and group interviews with clinicians were carried out to create and refine PROM scales., Results: Qualitative data from patient interviews were grouped into aesthetic, functional, and psychosocial domains for the eyelids and nose. Ninety-nine draft items were generated across these domains. Following focus group discussions, the final version of the midface-specific PROM contained 31 items (13 eye-specific, 10-nose-specific, eight general midface items)., Conclusions: This midface-specific PROM is valuable in assessing and comparing patient-reported outcomes in those who have undergone complex resection and reconstruction of the midface. This PROM is currently undergoing field testing., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

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).)

A biomarker is a measurable indicator of biological or pathological processes or the response to an exposure or intervention and is used to guide management decisions. In head and neck pathology, biomarkers are assessed by histological criteria and immunohistochemical and molecular studies. Surgical resection remains the mainstay of management of many head and neck malignancies. Adjuvant radiotherapy and/or systemic therapy may be administered depending on the presence of adverse prognostic factors identified on histopathological or immunohistochemical examination. In this review, we outline the clinically relevant prognostic and predictive factors in head and neck malignancies including conventionally recognised factors such as tumour size, depth of invasion, lymphovascular and perineural invasion and margin status as well as novel evolving factors such as recurrent genetic rearrangements and assessment of immune checkpoints. Practical issues are discussed to assist with recognising and reporting of these factors. A summary of useful tools such as structured pathology report formats is also included to assist with comprehensive reporting of all clinically relevant parameters, minimise risk and improve workflow efficiencies., (Copyright © 2023 Royal College of Pathologists of Australasia. All rights reserved.)

The osteocutaneous fibula free flap (FFF)'s skin paddle is commonly vascularized by the septocutaneous (SC) perforators of the peroneal artery that course through the posterior intercrural septum. However, a rare anatomical variant exists in which the skin paddle is vascularized via a separate arterial system to the fibula. We report the case of a 31-year-old man who was planned for osteocutaneous FFF reconstruction of his anterior maxilla and hard palate following resection of nasal septal chondrosarcoma. Intraoperatively, he was found to have a rare anatomical variant: the perforator to the skin paddle arose proximal to the peroneal artery, off the tibioperoneal trunk. This was a fortuitous, rare anatomical variant, as it enabled a double free flap reconstruction from a single donor site-an intraoral fasciocutaneous free flap oriented with its long axis perpendicular to that of an osseous FFF. This particular defect enabled reconstructive freedom beyond that of the standard osteocutaneous free flap, in which the skin paddle orientation is limited by the risk of kinking the septal perforator. This case report summarizes the flap raising technique and the learning points relevant to the osteocutaneous FFF with no SC perforators. The extant literature on this anatomical variant is then summarized. The average estimated rate of FFF with no SC perforators is between 3% and 25%, based on four published studies., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. Disclosure statements are at the end of this article, following the correspondence information., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Importance: Surgeons treating facial paralysis with reanimation surgery measure the outcomes of surgery and adjust treatment to each patient's needs. Our objective is to review the current subjective facial paralysis assessment tools and the emerging computer-based objective analysis, which may involve artificial intelligence. Observations: In recent years, many new automated approaches to outcome measurement in facial reanimation surgery have been developed. Most of these tools utilize artificial intelligence to analyze emotional expression and symmetry of facial landmarks. Other tools have provided automated approaches to existing clinician-guided scales. Conclusions: Newly developed computer-based tools using artificial intelligence have been developed to both improve existing clinician-graded scales and provide new approaches to facial symmetry and emotional expressivity analysis.

Introduction: Centralisation of head and neck surgical services means that patients in regional and remote Australia need to travel long distances for treatment and follow-up, imparting a significant financial burden on patients and the health system., Objective: To estimate costs of travel to local outreach clinics and determine potential cost savings to patients and the health system by avoiding patient travel to major cities for head and neck surgical care., Design: Retrospective audit of three head and neck surgery outreach clinics in New South Wales, Australia over 4 years (2017-2020). Direct costs of travel from a patient's residence to their local outreach clinic were estimated. Costs of travel and accommodation to Sydney for an appointment were calculated for different travel modes. Estimated reimbursements for travel through government support schemes were calculated based on published rates., Findings: Some 657 patients attended the three clinics, accounting for 1981 appointments. Depending on mode of travel, the estimated median cost of return travel (including accommodation) to Sydney was $379 to $739 per patient per trip and the median government reimbursement ranged from $182 to $279 per trip. In comparison, the cost of return travel by car to local outreach clinics ranged from $28 to $163 per appointment. Outreach clinics were estimated to save patients a median of $285 per trip and avoided government reimbursements of $215 per trip., Discussion: Despite uptake in telehealth, outreach medical services remain an important asset for people living in regional areas to address inequities in access. However, the cost benefits are likely to be underestimated as our approach did not account for indirect costs associated with travel., Conclusion: Outreach head and neck surgical services located in regional areas can reduce the financial burden on both patients and the healthcare system. Greater investment in outreach clinics could ensure sustainability of services to promote equitable access to specialised surgical services., (© 2023 The Authors. Australian Journal of Rural Health published by John Wiley & Sons Australia, Ltd on behalf of National Rural Health Alliance Ltd.)

Squamous cell carcinoma is the most common head and neck malignancy arising from the oral mucosa and the skin. The histologic and immunohistochemical features of oral squamous cell carcinoma (OSCC) and head and neck cutaneous squamous cell carcinoma (HNcSCC) are similar, making it difficult to identify the primary site in cases of metastases. With the advent of immunotherapy, reliable distinction of OSCC and HNcSCC at metastatic sites has important treatment and prognostic implications. Here, we investigate and compare the genomic landscape of OSCC and HNcSCC to identify diagnostically useful biomarkers. Whole-genome sequencing data from 57 OSCC and 41 HNcSCC patients were obtained for tumor and matched normal samples. Tumor mutation burden (TMB), Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, frequent chromosomal alterations, somatic single nucleotide, and copy number variations were analyzed. The median TMB of 3.75 in primary OSCC was significantly lower (P < .001) than that of 147.51 mutations/Mb in primary HNcSCC. The COSMIC mutation signatures were significantly different (P < .001) between OSCC and HNcSCC. OSCC showed COSMIC single-base substitution (SBS) mutation signature 1 and AID/APOBEC activity-associated signature 2 and/or 13. All except 1 HNcSCC from hair-bearing scalp showed UV damage-associated COSMIC SBS mutation signature 7. Both OSCC and HNcSCC demonstrated a predominance of tumor suppressor gene mutations, predominantly TP53. The most frequently mutated oncogenes were PIK3CA and MUC4 in OSCC and HNcSCC, respectively. The metastases of OSCC and HNcSCC demonstrated TMB and COSMIC SBS mutation signatures similar to their primary counterparts. The combination of high TMB and UV signature in a metastatic keratinizing squamous cell carcinoma suggests HNcSCC as the primary site and may also facilitate decisions regarding immunotherapy. HNcSCC and OSCC show distinct genomic profiles despite histologic and immunohistochemical similarities. Their genomic characteristics may underlie differences in behavior and guide treatment decisions in recurrent and metastatic settings., (Copyright © 2023 United States & Canadian Academy of Pathology. All rights reserved.)

Objectives: Osteoradionecrosis (ORN) of the jaw is a potentially devastating consequence of head and neck irradiation. Despite recent advances, there are patients who fail to respond to conventional therapies. Historically, free flaps were reserved for advanced cases requiring segmental resection and composite reconstruction, with early and intermediate disease treated more conservatively. We have adopted a more active surgical approach in selected intermediate cases., Study Design: A retrospective review of patients with intermediate stage ORN who received debridement and either fascio-cutaneous or fascio-periosteal free flap reconstruction was performed. Demographic data, ORN severity, treatment, and outcomes are described., Results: From 2019, 9 cases in 7 patients were identified. All cases were Notani grade II. There were 6 Epstein stage IIa and 3 Epstein stage IIIa. The mandible was the most common site (n = 8). Of the 7 patients, 2 had oropharyngeal primaries treated with chemoradiation, and 5 had oral cavity primaries treated with surgery and adjuvant radiation therapy. Three patients had prior hyperbaric oxygen therapy, and 2 had pentoxifylline/tocopherol therapy. After debridement, the radial forearm, ulnar artery perforator, and antero-lateral thigh fascio-cutaneous free flaps were each used in 1 case and the temporoparietal fascio-periosteal free flap was used in 6 cases. There was no recurrence or progression of ORN at the site of surgery, but 2 patients developed additional sites of ORN., Conclusions: For patients with unresponsive intermediate ORN, debridement and soft tissue free flap reconstruction is an alternative to ongoing conservative management or composite resection and reconstruction., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Calculating an accurate prognosis for melanoma patients who have a positive sentinel node (SN) biopsy is important both for them and for their treating doctors to guide decision-making, particularly when adjuvant systemic therapy is being considered. The recently published EORTC-DeCOG nomograms aim to provide this via an online portal that predicts 5-year rates for recurrence, distant metastasis and overall mortality. The present study provides external validation of these nomograms., Methods/materials: De-identified data from patients with a positive SN biopsy between 2003 and 2015 were extracted from the prospectively maintained Melanoma Institute Australia (MIA) research database. ROC-curves with C-statistics, regression co-efficients and Decision Curve Net Benefit analyses were performed using the integrated private validation portal on the nomograms' hosting platform (Evidencio)., Results: Complete data were available for 352 patients. The respective C-statistics for recurrence, distant metastasis and overall mortality nomogram validations were 0.68, 0.69 and 0.66., Conclusion: The performance of the nomograms in predicting recurrence and distant metastasis was similar in the MIA and the development populations, suggesting that they are robust. However, the overall mortality nomogram performance was significantly poorer in the MIA population (C-statistic 0.66) than in the original EORTC-DeCOG derivation cohort (C-statistic 0.70) and may therefore be less reliable for clinical use., Competing Interests: Declaration of Competing Interest RAS has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. JFT has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel and conference support from GSK, Provectus Inc and Novartis. AHRV has received an honorarium from Novartis. For the remaining authors, there are no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: This study aimed to determine the diagnostic accuracy of CT and MRI in the preoperative detection of bone involvement for non-melanoma skin cancers (NMSCs) located on the scalp. This study further aimed to evaluate the predictive value of these imaging modalities in determining the need for craniectomy and to identify gaps in the existing literature., Methods: Electronic searches of the MEDLINE, Embase, Cochrane and Google Scholar databases were performed for English language studies of any type. Studies reporting detection or exclusion of histopathologically confirmed bone involvement through preoperative imaging were identified according to PRISMA guidelines. Studies reporting dural involvement, non-scalp tumours, and lacking tumour type(s) or outcome data were excluded. Outcomes were preoperative imaging result and histopathologically confirmed bone invasion. Meta-analysis was performed and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated (excluding case report and MRI data due to insufficient quality and quantity respectively)., Results: Four studies with a total of 69 patients were included in the final review, of which two studies totalling 66 patients were included in the meta-analysis. Preoperative CT had a sensitivity of 38%, specificity of 98%, PPV of 90% and NPV of 73%., Conclusions: The available data suggests that a preoperative CT finding of calvarial involvement by a scalp NMSC is likely to be real, but the absence of such a finding is unreliable. Current evidence suggests that preoperative imaging cannot exclude the necessity for craniectomy and future research is needed, particularly on the role of MRI., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Introduction: Restoration of spontaneous smiling is a key goal in facial reanimation. A major obstacle to quantifying recovery of spontaneous smiling is the current lack of a uniform and objective means of smile quantification. Objective: To compare the facial movements during smiling in patients with facial paralysis as measured by an automated application and human observers. Methods: Video recordings of 25 patients with unilateral facial palsy (FP) watching humorous videos were utilized. Application-derived smile timestamping was compared with manual observer interpretation. Internal reliability of measurements was evaluated through a test-retest approach. Results: Application-derived smile identification demonstrated almost perfect agreement with manual interpretation (kappa 0.861, p  < 0.001). There was no statistically significant difference in mean number of smiles between detection method ( p  = 0.354). Automated smile identification demonstrated a high degree of specificity (95.4%), accuracy (93.1%), positive-predictive value (94.7%), and negative-predictive value (91.8%). This method demonstrated a high degree of reliability (kappa 0.864, p  < 0.01). Conclusion: The novel "SmileCheck" mobile phone application performed accurate and reliable smile quantification in FP patients in comparison with manual observation.

Background: Vasopressor use in patients undergoing autologous free tissue transfer is generally discouraged by surgeons perioperatively. This stems from concerns about the increased risk of flap failure with their use. The aim of this systematic review was to investigate the evidence and quantify any harm or benefits associated with vasopressor use., Methods: A systematic review of the literature was undertaken using OVID Medline to search 13 databases. The search strategy used Boolean operators, text word searches, truncation symbols, and adjacency searching. Terms such as "free flap," "free tissue graft," and "free tissue transfer" were used along with a list of appropriate vasopressors. The primary outcome was free flap failure, on which a meta-analysis was performed., Result: The search initially identified 1029 unique articles, which after title and abstract screening was reduced to 112, of which 15 remained after full-text screening for inclusion in the review and analysis. We analyzed data from 8427 flaps, with 6695 having received a vasopressor. Meta-analysis demonstrated that vasopressor use reduced the relative risk (RR) of free flap failure (RR: 0.70; 95% CI: 0.50-0.97; p = 0.03) but did not affect rates of other adverse events (RR: 0.81; 95% CI: 0.63-1.05; p = 0.11)., Conclusion: Vasopressor use appears beneficial for autologous free tissue transfer, with evidence that it reduced the risk of flap failure without impacting the rates of other adverse events. The use of vasopressors should, therefore, be encouraged on a case-by-case basis, depending upon the general physiological needs of the patient., Competing Interests: Declaration of Competing Interest AHRV has received honorarium from Novartis. Other authors have nothing to disclose., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved.)

Background and Objective: Mucosal melanoma of the head and neck (MMHN) are rare, aggressive neoplasms of melanocyte origin that remain incompletely understood and have a poor prognosis, with high rates of locoregional recurrence and distant metastasis. Several recent studies having expanded understanding of MMHN, we undertook a review of the latest evidence pertaining to its epidemiology, staging, and management., Methods: A literature search was conducted for peer-reviewed articles reporting and discussing the epidemiology, staging, and management of MMHN. PubMed, Medline, Embase and the Cochrane Library were searched to identify relevant publications., Key Content and Findings: MMHN remains an uncommon disease. The current TNM staging system for MMHN provides inadequate risk stratification, and consideration of an alternative staging model such as one based on a nomogram may be justifiable. Tumour resection with clear histological margins remains the cornerstone of optimal treatment. Adjuvant radiotherapy may improve locoregional control but does not appear to affect survival. Immune checkpoint inhibitors and c-KIT inhibitors demonstrate promising efficacy in patients with advanced or unresectable mucosal melanomas, and warrant further research exploring the utility of combination therapies. Their roles as adjuvant therapies have not been determined. The efficacy of neoadjuvant systemic therapy is also not yet clear, although early results suggest that it may improve outcomes., Conclusions: New insights into the epidemiology, staging and management of MMHN have transformed the standard of care for this rare malignancy. Nonetheless, the results of ongoing clinical trials and future prospective studies are required to better understand this aggressive disease and optimise its management.

The prognostic value of sentinel node biopsy (SNB) is well established and SNB was therefore adopted as a requirement for pathological staging of melanomas>1 mm thick in the American Joint Committee on Cancer (AJCC) 8th edition. Consequently, a negative SNB status became an eligibility criterion for clinical trials of adjuvant systemic therapy in resected stage IIB/C melanoma. However, since the Keynote 716 trial demonstrated an improvement in relapse-free survival (RFS) in patients with Stage IIB/C melanoma, all of whom had SNB staging, some have argued that SNB is no longer required for patients with T3 and T4 primary melanomas. The rationale for omitting SNB is that these patients will be able to access adjuvant immunotherapy regardless of SNB status, avoiding the costs and potential complications of SNB. However, this argument overlooks the prognostic value of knowing a patient's nodal status and the therapeutic benefit of SNB in regional disease control. Based on extrapolation of data from multiple sources, we demonstrate that the risk of regional node-field relapse with SNB and immunotherapy for T3b and T4 melanomas is around 7-9% but is 20-27% without SNB. Similarly, the node-field recurrence rate with SNB alone is around 14% compared to around 40% with no SNB or immunotherapy. Consequently, in the absence of prospective data, we propose that the optimal management of the regional node-field for high-risk T3b and T4 primary melanomas is likely to be achieved by combining SNB and adjuvant immunotherapy for those patients who are suitable, rather than either treatment alone., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite the widespread use of virtual surgical planning (VSP), few papers describe the modeling methods used to generate the digital simulations that underpin VSP. This paper aims to review the modeling methods that are currently available for use in VSP and the implications of their use in clinical practice. A literature review was undertaken of the two broad categories of modeling techniques; contour-based planning-namely mirroring from the contralateral side, templating from a normative database, and extrapolation from surrounding landmarks-and occlusal-based planning (OBP). The indications for each modeling method were discussed, including mandibular/maxillary reconstruction, pediatric craniofacial surgery, and orthognathic, as well as the limitations to the accuracy of modeling types. Unilateral defects of the upper/midface, wherein contour accuracy is paramount, are best reconstructed using mirroring methods, whereas bilateral defects-or cases with asymmetry due to craniofacial dysmorphology-are most suited to normative-data-based methods. Cases involving resection of the alveolar margin, in which functional occlusion is the primary outcome are best managed with OBP. Similarly, orthognathic surgery typically uses OBP, although complex cases involving asymmetry, such as clefts, may benefit from a combination of OBP and normative data methods. The choice of modeling methods is, therefore, largely driven by the defect type and the goals of reconstruction., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Background: Anterolateral thigh (ALT) and Radial forearm free flaps (RFFF) are historically the most common methods of oral reconstruction. The Superficial circumflex iliac artery perforator flap (SCIP) is an alternative providing a donor site that can be readily closed primarily with improved cosmesis in younger patients, due to its concealability., Methods: We reviewed 135 patients who received ALT, RFFF or SCIP flaps for oral reconstruction in our institution. Our aim was to compare operative and perioperative outcomes between each cohort. ANOVA and χ 2 test were used for statistical analysis., Results: There were 37 ALT, 64 RFFF and 35 SCIP reconstructions. Patients reconstructed with SCIP flaps had smaller resection volumes (P < 0.001) and earlier T and N classifications (P = 0.001, P = 0.008), and consequently reduced tracheostomy rates (P < 0.001), reduced need for enteral feeding at discharge (P < 0.001) and shorter length of stay and perioperative times (P < 0.001). SCIP flaps were more common in younger patients (P < 0.01). ALT flaps were used for more advanced disease (P = 0.001) and had larger resection volumes (P < 0.001) and increased need for assisted enteral feeding (P < 0.001). There were no significant differences in flap or donor site outcomes. There were two flap failures, both RFFF., Conclusion: Each flap plays an important role in the reconstruction of oral defects, with larger defects preferentially reconstructed with ALT flaps. SCIP appears to be a reliable alternative in small defects with excellent perioperative and postoperative outcomes., (© 2023 Royal Australasian College of Surgeons.)

Importance: Refining eligibility guidelines may identify more appropriate patients to undergo useful medical procedures., Objective: To improve cost-effectiveness in selecting patients with melanoma for sentinel lymph node biopsy (SLNB)., Design, Setting, and Participants: This hybrid prognostic study/decision analytical model was conducted among patients with melanoma who were eligible for SLNB at 2 melanoma centers from Australia and the US from 2000 to 2014. Participants consisted of 2 cohorts of patients with melanoma undergoing SLNB and a cohort of eligible patients without SLNB. Individualized probabilities of SLNB positivity generated by a patient-centered methodology (PCM) were compared with those generated by conventional multiple logistic regression analysis investigating 12 prognostic factors. Prognostic accuracy was assessed by the area under the receiver operating characteristic curve (AUROC) for each methodology and by matched-pair analyses., Interventions: Triaging appropriate patients to undergo SLNB., Main Outcomes and Measures: Total number of SLNBs performed (giving total cost) vs number of SLNB-positive outcomes (a measure of effectiveness) was evaluated. Improved cost-effectiveness through judicious patient selection was interpreted as increased numbers of SLNB-positive outcomes achieved, decreased numbers of SLNBs performed, or both outcomes simultaneously., Results: Among 7331 patients with melanoma, SLNB outcomes were assessed in 3640 Australian patients (2212 males [60.8%]; 2447 aged >50 years [67.2%]) and 1342 US patients (774 males [57.7%]; 885 aged >50 years [66.0%]); 2349 patients eligible for SLNB who did not undergo the procedure were included in the simulation. PCM-generated probabilities achieved an AUROC of 0.803 in predicting SLNB positivity in the Australian cohort and 0.826 in the US cohort, higher than corresponding AUROCs generated by conventional logistic regression analysis. In simulation, adopting many SLNB-positive probabilities as minimally acceptable patient-selection criteria resulted in fewer procedures performed or increased the expected numbers of positive SLNBs. A minimally acceptable PCM-generated probability of 8.7% elicited the same number of SLNBs as historically performed (3640 SLNBs), with 1066 positive SLNBs (29.3%), constituting an improvement of 287 additional positive SLNBs compared with 779 actual positive SLNBs (36.8% improvement). In contrast, adopting a 23.7% PCM-generated minimum cutoff probability resulted in performing 1825 SLNBs, or 1815 fewer SLNBs than the actual experience (49.9%). It resulted in the same expected number of positive results (779 SLNBs), for a 42.7% positivity rate., Conclusions and Relevance: This prognostic study/decision analytical model found that the PCM approach outperformed conventional multiple logistic regression analysis in predicting which patients would have positive results on SLNB. These findings suggest that systematically producing and exploiting more accurate SLNB-positivity probabilities could improve the selection of patients with melanoma for SLNB compared with using established guidelines, thus improving the cost-effectiveness of the selection process. Eligibility guidelines to undergo SLNB should include a context-tailored minimum cutoff probability.

Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate whether prolonged operative time is negatively associated with post-operative complications and length of stay in patients undergoing microvascular free flap reconstruction for complex head and neck defects., Methods: 342 consecutive patients undergoing microvascular reconstruction for head and neck defects between 2017-2019 at a single institution were evaluated. Operative outcomes and operative time were compared whilst controlling for patient and treatment related factors., Results: Mean operative time was 551 min and length of stay was 16.2 days. An 11% increase in the risk of a post-operative complication was observed for every additional hour of operative time (OR 1.11, 95% CI 1.03-1.21, p = 0.011) after adjusting for patient and treatment factors. A cut-off of 9 h yielded a 92% increase in complications on either side of this (OR 1.92, 95% CI 1.18-3.13, p = 0.009). Increased operative time was also associated with increased length of stay and return to theatres, but not medical complications., Conclusion: Prolonged operative time is significantly associated with increased surgical complications, length of stay and return to theatres when performing microvascular reconstructive surgery for head and neck defects., (© 2022 John Wiley & Sons Ltd.)

Purpose: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown., Experimental Design: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior., Results: Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell-enriched tumor regions associated with primary nonprogressing tumors., Conclusions: Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC., (©2022 American Association for Cancer Research.)

Optical Coherence Tomography (OCT) is a useful non-invasive diagnostic tool for diagnosing and monitoring treatment of basal cell carcinomas. We describe the use of OCT in a patient with Basal Cell Naevus Syndrome. Through measuring tumour depth on OCT, management of individual tumours was triaged accordingly using 0.4 mm tumour depth as a cut-off for surgical and non-surgical management. OCT has potential to reduce unnecessary excisions and associated morbidity in this population of patients., (© 2022 The Authors. Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

Background: The order of significance of clinicopathologic characteristics for the prognosis of patients with regional metastases from head and neck cutaneous squamous cell carcinoma (HNcSCC) is not well characterized. This study aimed to understand the impact of the known characteristics, including the presence of immunosuppression, number of deposits, largest deposit size, location and laterality of deposits, and presence of extranodal extension (ENE) on overall survival (OS) and disease-specific survival (DSS)., Methods: A retrospective study of 366 patients treated with curative intent for HNcSCC with regional metastatic disease was undertaken using recursive partitioning analysis (RPA)., Results: Using RPA modeling, the study determined that number of metastatic deposits carried the highest impact for both OS and DSS, followed by largest deposit size. The presence of ENE and immunosuppression was less significant., Conclusions: The results from this study provide new evidence for identifying and stratifying high-risk patients with metastatic HNcSCC. This information will be valuable in determining future HNcSCC staging systems., (© 2022. Crown.)

Background: In-transit metastases (ITMs) affect approximately 4% of patients with cutaneous melanoma. This study sought to identify clinical and pathological characteristics that predict further recurrence and survival following resection of ITMs., Patients and Methods: Patients (n = 573) who underwent surgical resection of their first presentation of ITM following previous surgical treatment of an American Joint Committee on Cancer (AJCC) stage I-II melanoma between 1969 and 2017 were identified from an institutional database. Clinicopathological predictors of patterns of recurrence and survival following ITM resection were sought., Results: The median time of ITM development was 2.4 years after primary melanoma resection. ITMs were most frequently located on the lower limb (51.0%). The most common melanoma subtype associated with ITM development was nodular melanoma (44.1%). After surgical resection of a first ITM, 65.4% of patients experienced recurrent disease. Most recurrences were locoregional (44.7%), with distant metastasis occurring in 23.9% of patients. Lower limb ITMs were more frequently associated with subsequent ITMs [odds ratio (OR) 2.41, p = 0.0002], and the lowest risk of distant metastasis (p < 0.0001) compared with other primary sites. Primary melanomas and ITM on head and neck, as well as the presence of ulceration, were associated with worse survival., Conclusions: Recurrence after surgical resection of a first ITM was common. Patterns of recurrence differed according to anatomical site; further ITM recurrences were more likely for lower limb ITMs, which were also associated with longer distant recurrence-free survival. Distant metastasis was more common for ITM on the head and neck, with worse survival., (© 2022. Crown.)

Long-term health-related quality of life (HRQOL) and functional outcomes following mandibular and maxillary reconstruction are lacking. To determine these outcomes, a cross-sectional study of patients with a history of cancer who underwent jaw reconstruction was undertaken. Participants were identified from a database of jaw reconstruction procedures at the Chris O'Brien Lifehouse (Sydney, Australia). Eligible patients had at least one month follow-up, were aged ≥18 years at surgery, and had history of malignancy. HRQOL was measured using the FACE-Q Head and Neck Cancer Module (FACE-Q H&N). Functional outcomes were measured using the FACE-Q H&N, MD Anderson Dysphagia Inventory (MDADI) and Speech Handicap Index (SHI). Ninety-seven questionnaires were completed (62% response rate). Mean age of respondents was 63.7 years, 61% were male, and 64% underwent radiotherapy. Treatment with radiotherapy was associated with worse outcomes across 10/14 FACE-Q H&N scales, three MDADI subscales and one composite score, and the SHI. Mean differences in scores between irradiated and non-irradiated patients exceeded clinically meaningful differences for the MDADI and SHI. Issues with oral competence, saliva, speaking, and swallowing worsened with increasing time since surgery. Younger patients reported greater concerns with appearance, smiling, speaking, and cancer worry. Women reported greater concerns regarding appearance and associated distress. History of radiotherapy substantially impacts HRQOL and function after jaw reconstruction. Age at surgery and gender were also predictors of outcomes and associated distress. Pre-treatment counselling of patients requiring jaw reconstruction may lead to improved survivorship for patients with head and neck cancer.

Background: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) surgical risk calculator (SRC) is an open access calculator predicting patients' risk of postoperative complications. This study aims to assess the validity of the SRC in patients undergoing microsurgical free flap reconstruction at an Australian tertiary referral centre., Methods: This is a retrospective cohort study of 200 consecutive patients treated up to November 2020. SRC-predicted rates of postoperative complications and hospital length of stay (LOS) were compared to those observed for the ablative and reconstructive components of the procedure. The performance of the SRC was assessed using Brier scores, area under the receiver operating characteristic (ROC) curve (AUC), and the Hosmer-Lemeshow test., Results: For both ablative and reconstructive components, the SRC discriminates well for pneumonia and urinary tract infection, and it is calibrated well for readmission and sepsis, but it does not discriminate and calibrate well for any single outcome. SRC-predicted hospital LOS and actual LOS did not correlate well for the reconstructive component, but they correlated strongly for the ablative component., Conclusions: The SRC is a poor predictor of postoperative complication rates and hospital LOS in patients undergoing head and neck microsurgical reconstruction., Competing Interests: Declaration of Competing Interest No conflicts of interest have been declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: To present an institution's experience and survival outcomes for patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) and perineural spread (PNS)., Method: Retrospective study of patients with HNcSCC and PNS treated between January 2010 and August 2020 from the Sydney Head and Neck Cancer Institute database, Sydney, Australia; a high-volume, tertiary, academic head and neck centre. Patient demographics, primary site, involved cranial nerves, treatment modality, loco-regional failure and survival data were obtained., Results: Forty-five patients were identified, of which 32 patients were male (71%). Mean age at diagnosis was 68.7 years (range 43-90). Median follow-up was 16.1 months (range 1-107). The trigeminal nerve was most frequently involved (n = 30, 66.6%) followed by facial nerve (n = 13, 28.9%). Most patients underwent surgery followed by radiotherapy (n = 33, 73%) and eight received definitive radiotherapy. The median overall survival (OS) was 4.5 years (95% CI 3.71-5.38), median disease-specific survival 5.1 years (95% CI 4.21-5.97) and median disease-free survival (DFS) was 1.7 years (95% CI 1.11-2.22). The estimated 5-year OS and DFS were 45% and 25%, respectively. Patients treated with surgery and adjuvant radiotherapy with a clear proximal nerve margin had favourable DFS (P = 0.035) and trended towards better OS (P = 0.134) compared with patients with an involved nerve margin. Patients treated surgically with involved proximal nerve margins had similar outcomes compared with patients with treated definitive radiotherapy (HR 0.80, 95% CI 0.29-2.22, P = 0.664)., Conclusion: The likelihood of achieving a clear proximal nerve margin should be a strong consideration in the selection of appropriate patients for primary surgery., (© 2022 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thind, Ashford, Strbenac, Mitchell, Lee, Mueller, Minaei, Perry, Ch’ng, Iyer, Clark, Gupta and Ranson.)

Testing for BRAF mutations in metastatic melanoma is pivotal to identifying patients suitable for targeted therapy and influences treatment decisions regarding single agent versus combination immunotherapy. Knowledge of BRAF V600E immunohistochemistry (IHC) results can streamline decisions during initial oncology consultations, prior to DNA-based test results. In the absence of formal guidelines that require pathologist initiated ('reflex') BRAF mutation testing, our institution developed a local protocol to perform BRAF V600E IHC on specimens from all stage III/IV melanoma patients when the status is otherwise unknown. This study was designed to evaluate the application of this protocol in a tertiary referral pathology department. A total of 408 stage III/IV melanoma patients had tissue specimens accessioned between 1 January and 31 March in three consecutive years (from 2019 to 2021), reported by 32 individual pathologists. The BRAF mutation status was established by pathologists in 87% (352/408) of cases. When a prior BRAF mutation status was previously known, as confirmed in linked electronic records (202/408), this status had been communicated by the clinician on the pathology request form in 1% of cases (3/202). Pathologists performed BRAF V600E IHC in 153 cases (74% of cases where the status was unknown, 153/206) and testing was duplicated in 5% of cases (20/408). Reflex BRAF IHC testing was omitted in 26% of cases (53/206), often on specimens with small volume disease (cytology specimens or sentinel node biopsies) despite adequate tissue for testing. Incorporating BRAF IHC testing within routine diagnostic protocols of stage III/IV melanoma was both feasible and successful in most cases. Communication of a patient's BRAF mutation status via the pathology request form will likely improve implementation of pathologist initiated BRAF mutation testing and may result in a reduction of duplicate tests. To improve pathologist reflex testing rates, we advocate for the use of an algorithmic approach to pathologist initiated BRAF mutation testing utilising both IHC and DNA-based methodologies for stage III/IV melanoma patients., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Primary scalp melanomas are associated with a higher rate of brain metastasis than primary cutaneous melanomas occurring at other head and neck and body sites, but the reason is unclear. Spread to brain parenchyma via emissary veins draining from the scalp to dural sinuses has been suggested. We sought to examine the locations of metastases from primary scalp and nonscalp head and neck melanomas to determine whether there was anatomical evidence supporting direct venous spread to the brain. Data from patients who developed distant metastases from cutaneous head and neck melanomas (CHNMs) between 2000 and 2018 were analyzed. Anatomical sites of primary scalp melanomas and their respective intracranial metastases were compared. Times to first brain and nonbrain metastases were investigated for scalp and nonscalp primary CHNMs. Of 693 patients with CHNMs, 244 developed brain metastases: 109 (44.7%) had scalp primaries and 135 (55.3%) had nonscalp primaries. There was no significant association between anatomical sites of scalp primary melanomas and brain metastases (Cramer's V = 0.21; Chi-square P = 0.63). Compared with nonscalp CHNMs, scalp melanomas had no greater propensity for the brain as the first distant metastatic site ( P = 0.52) but had a shorter time to both brain metastasis (76.3 vs. 168.5 months; P < 0.001) and nonbrain metastasis (22.6 vs. 35.8 months; P < 0.001). No evidence was found to support a direct vascular pathway for metastatic spread of scalp melanomas to the brain. The increased incidence of brain metastases from scalp melanomas is probably driven by aggressive biological mechanisms., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: pT3/4 head and neck cutaneous squamous cell carcinomas (HNcSCCs) are associated with poor outcomes, including local recurrence, metastasis and death. Whilst surgery remains the standard treatment for advanced HNcSCC, novel systemic therapies, such as immunotherapy, are being used earlier in the treatment paradigm. It is imperative that the clinical outcomes of surgery are clearly described so that conventional and emerging treatment modalities can be better integrated and sequenced in the management of pT3/4 HNcSCC., Methods: Patients with confirmed pT3/4 HNcSCC undergoing curative surgical resection between 2014-2020 were identified retrospectively from a prospectively maintained research database. The primary outcomes of interest were locoregional control (LRC), disease-specific survival (DSS), and overall survival (OS). The secondary outcome was surgical complication rate., Results: A total of 104 patients (median age 74, range 41-94 years) were included, 90% of which had pT3 tumors; 36.5% received adjuvant radiotherapy. Median follow-up was 24.3 (range 1.0-84.3) months. LRC at 5 years was 62.0%, DSS at 5 years was 83.7%, and OS at 5 years was 71.9%. Median time to recurrence was 8.4 months. LRC was reduced in the presence of margin involvement and previous treatment (radiotherapy/surgery). The major surgical complication rate was 9.6%., Conclusions: More than 60% of patients treated surgically for pT3/4 head and neck cSCC were alive and free of disease at 5 years posttreatment. High-risk features such as margin involvement and having had previous treatment (radiotherapy/surgery) should be used to guide adjuvant therapy., (© 2022. The Author(s).)

Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg -1 and nivolumab 3 mg kg -1 . In patients achieving major pathologic response (MPR, ≤10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Head and neck angiosarcoma (HN-AS) is a rare and aggressive, representing <1% of all head and neck malignancies. It is characterized by a high rate of local recurrence and poor 5-year survival (10-54%). Australian data in this rare disease is lacking. We aim review the clinical outcomes of HN-AS from two high volume head and neck cancer units in Australia., Methods: Retrospective chart review., Results: A total 26 patients were identified, consist of predominantly male patients (81%) with a mean age of 77 year old. Most of the HN-AS arises from the scalp (62%). The 5-year overall survival (OS) and disease free survival (DFS) were 41% and 15%, respectively. Patients treated with upfront surgery with adjuvant therapy has better OS and DFS compared with patients receiving upfront chemoradiotherapy (median OS 3.63 vs. 0.53 years, P = 0.011 and median DFS 1.19 vs. 0.33 years, P = 0.001). There is no difference in OS or DFS for the sites of HN-AS or age of patients. Recurrences were noted in 15 patients (57.7%). For those with metastatic disease, the most common site was the lung (80%) with a median time to development of distant disease of 2.7 years (range 1.8-3.6 years). In patients who underwent salvage treatment, the median survival (post-salvage) was 1.3 years (0-2.8 years)., Conclusion: This is the first Australian report of treatment patterns and outcomes of patients with HN-AS. Our cohort confirms that HN-AS is a slowly progressive disease with poor survival. Patients treated with surgery and adjuvant radiotherapy in this series had better outcomes compared with those treated with chemoradiotherapy alone. The role of neoadjuvant chemotherapy is an area of ongoing research., (© 2022 Royal Australasian College of Surgeons.)

Introduction: The optimal time interval between diagnostic excision of a primary cutaneous melanoma and sentinel node (SN) biopsy is unknown. The current study sought to determine whether this interval influenced the SN-positivity rate, recurrence or survival., Methods: Data collected from 2004 to 2014 for a Dutch population-based cohort of patients with melanoma who underwent SN biopsy (SNB) within 100 days of initial diagnosis (n = 7660) and for a similarly specified cohort from a large Australian melanoma treatment centre (n = 3478) were analysed. Time to SNB was analysed continuously (in weeks) and categorically (per month). The effects of SNB timing on SN-positivity were assessed using multivariable logistic regression, and its effects on recurrence-free survival (RFS) and overall survival (OS) were assessed using Cox proportional hazard regression analyses. Advanced modelling using a multivariable Cox model with penalised splines for modelling the continuous effects of time to SNB on RFS and OS was also performed., Results: In neither the Dutch nor the Australian cohort was there a significant association between time to SNB and SN-positivity in either cohort, nor was there an impact of time to SNB on RFS or OS in either cohort. The spline-based HR curves for RFS and OS confirmed these findings., Conclusions: The time interval between diagnostic excision of a primary melanoma and SNB did not influence the SN-positivity rate or survival outcomes. This provides reassurance that neither early nor delayed definitive wide excision and SNB will adversely affect prognosis., Competing Interests: Conflict of interest statement RAS has received fees for professional services from Merck Sharp & Dohme, GlaxoSmithKline Australia, Bristol-Myers Squibb, Dermpedia, Novartis Pharmaceuticals Australia Pty Ltd, Myriad, NeraCare and Amgen. JFT has received honoraria for Advisory Board participation from Merck Sharpe & Dohme Australia and Bristol Myers Squibb Australia, honoraria and travel expenses from GlaxoSmithKline and Provectus Inc, and conference attendance support from Novartis. RPMS has received honoraria for advisory board participation from Merck, Sharp and Dohme, Novartis and Qbiotics and speaking honoraria from Bristol-Myers Squibb. AJS has received honoraria for advisory board participation from Qbiotics, Novartis and Stryker. The other authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)