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Introduction: Clinicopathologic data-based sentinel lymph node (SLN) prediction models are used to select patients with melanoma for sentinel lymph node biopsy (SLNB). However, the temporal performance of these models is unknown. Therefore, we investigated whether the performance and clinical utility of the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center, and Friedman et al. models changed over time., Patients and Methods: Primary cutaneous melanoma cases that underwent SLNB at a single tertiary-care cancer center from 2000 to 2021 were identified from a prospectively maintained database. Calibration plots were generated. Values for estimated risks of SLN positivity and area under the receiver operator curve (AUC) were calculated. Clinical utility was assessed at thresholds between 5 and 10% using decision curve analysis., Results: In total, 2977 SLNB cases were included. The estimated risk of SLN positivity and AUCs were similar across periods for all models. However, calibration decreased over time for all models, with progressive underprediction of SLN positivity. Clinical utility also declined over time; in the most recent period investigated (2018-2021), no model offered clinical utility at risk thresholds ≤ 8%, and only the Friedman model provided clinical utility at risk thresholds of 9-10%., Conclusions: The calibration and clinical utility of three predominant models for SLN prediction declined over time. There is a need to periodically reassess the performance of SLN prognostic tools as they are applied to contemporary cohorts. Future studies are needed to determine whether findings are generalizable outside of this study cohort., Competing Interests: Disclosures: Dr. Bartlett receives institutional support from SkylineDx and Qbiotics Group. The other authors have no conflict to disclose., (© 2024. Society of Surgical Oncology.)

Introduction: Gene expression profiling (GEP) of primary cutaneous melanoma aims to offer prognostic and predictive information to guide clinical care. Despite limited evidence of clinical utility, these tests are increasingly incorporated into clinical care., Methods: A panel of melanoma experts from the Society of Surgical Oncology convened to develop recommendations regarding the use of GEP to guide management of patients with melanoma. The use of currently available GEP tests were evaluated in three clinical scenarios: (1) the utility in patient selection for sentinel lymph node biopsy; (2) the utility to guide surveillance; and (3) the utility to inform adjuvant therapy. As a basis for these recommendations, the panel performed a systematic review of the literature, including articles published from January 2012 until August 2023., Results: After review of 137 articles, 50 met the inclusion criteria. These articles included evidence related to three available GEP tests: 31-GEP, CP-GEP, and 11-GEP. The consensus recommendations were finalized using a modified Delphi process. The panel found that current evidence often fails to account for known clinicopathologic risk factors and lacks high-level data. The panel recognizes that the study of GEP tests is still evolving. The integration of GEP into routine clinical practice for predicting sentinel lymph node status and patient prognosis in melanoma is therefore not currently recommended., Conclusion: At present, GEP should be considered primarily an investigational tool, ideally used in the context of clinical trials or specialized research settings., Competing Interests: Disclosures: Giorgos Karakousis has received research funding from Merck; was the Principal Investigator (PI) of an investigator-initiated trial on neoadjuvant PD-1 therapy for clinical stage II B/C melanoma from 2019 to the present (research monies to support the trial and studies are paid to the institution); and is a member of the Advisory Boards for Merck and Bristol Myers Squibb (no direct relationships to the project). Tina J. Hieken has received research funding from Genentech and SkylineDx (current research funding is paid to the institution). Genevieve Boland is a consultant and advisor, and has received research funding. She has been a speaker for Novartis and Takeda Oncology (2019); a consultant for NW Biotherapeutics (2020), Merck (2021), InterVenn Biosciences (2021), and Ankyra Therapeutics (2021); a member of the Advisory Boards of Iovance (2021, 2023) and Merck (2021, 2022, 2023); a member of the Scientific Advisory Board and Steering Committee for Nektar Therapeutics (2020); a member of the Surgical Advisory Board for Novartis (2020); a member of the Scientific Advisory Board for Ankyra Therapeutics (2021, 2022, 2023) and Moderna (June 2024); had sponsored research agreements for Olink Proteomics, Palleon Pharmaceuticals, and InterVenn Biosciences (2021); and held stock in Ankyra Therapeutics (2021). Marc Moncrieff is an advisor and has received honoraria, travel expenses, and research funding. He was the recipient of a grant from the UK National Institute for Health and Care Research (NIHR, grant 19/102: 130886); received an honorarium and travel expenses from Novartis, Canada, in December 2019; and received an honorarium from Amgen to attend an advisory panel session in October 2019. Edmund K. Bartlett received honoraria from Excite International in 2021; received research funding and institutional research support from Skyline Dx (Rotterdam, The Netherlands, and San Diego, CA, USA) pertaining to the Merlin Assay that is ongoing; and institutional research support from Qbiotics Group. Tawnya Bowles received research funding from Genentech (2019 to the present), and was PI for a melanoma clinical research study, PI for a clinical research study conducted by Amgen (2018 to the present), PI for a clinical research study conducted by Replimune (2019 to the present), and PI for a clinical research study conducted by Natera (2020 to the present); however, she does not receive any direct funds from these sources. Cristina O’Donoghue, Keith A. Delman, Sandra Wong, and Richard L. White Jr have no conflicts of interest to declare that may be relevant to the contents of this article. Authors and reviewers have disclosed potential conflicts of interest consistent with SSO policy. Disclosures are also listed in the Appendix. Comments: Comments on this document may be sent to the SSO for consideration in future iterations of the work., (© 2024. The Author(s).)

Background: Metastasectomy is a useful adjunct in the management of metastatic cancer. Widespread adoption of novel targeted and immunotherapies has improved the survival profiles of multiple malignancies, which has potentially altered the role of metastasectomy. This study aimed to characterize trends in metastasectomy across five primary cancers eligible for these therapies., Methods: The National Inpatient Sample was used to identify patients who underwent metastasectomy in the United States (2016-2021). Patients with procedure codes for resection of the lung, liver, adrenal gland, brain, or small bowel and concurrent diagnosis codes for secondary malignant neoplasm of that site were included. Subjects were subcategorized by primary malignancy: colorectal cancer, lung cancer, breast cancer, melanoma, or renal cancer. Sample weights were used to produce national estimates, which were incidence adjusted by primary malignancy. Trends in utilization were calculated with average annual percent change (AAPC) and linear regression coefficients., Results: Colorectal cancer was the most frequent indication for metastasectomy (n = 57,644 cases), followed by lung cancer (n = 55,090 cases), breast cancer (n = 12,616 cases), renal cancer (n = 8427 cases), and melanoma (n = 5658 cases). Utilization of metastasectomy increased over the study period for breast cancer (AAPC, +10.6%; p = .013) and melanoma (AAPC, +8.3%; p = .040) but did not change for lung cancer (AAPC, -1.6%; p = .26), colorectal cancer (AAPC, +0.3%; p = .83), or renal cancer (AAPC, +2.3%; p = .36)., Conclusions: Between 2016 and 2021, utilization of metastasectomy increased significantly for melanoma and breast cancer. The role of metastasectomy will likely continue to develop as new treatment protocols improve survival profiles for patients with metastatic disease., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Competing Interests: Disclosure: Dr. Bartlett receives institutional support from SkylineDx and the Qbiotics Group. The remaining authors have no conflicts of interest.

Importance: Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested., Objective: To determine the clinical utility of the MIA and MSKCC models., Design, Setting, and Participants: This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023., Main Outcomes and Measures,: The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm2 and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients., Results: Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all., Conclusions and Relevance: This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.

Background: For patients with melanoma, the decision to perform sentinel lymph node biopsy (SLNB) is based on the estimated risk of lymph node metastasis. We assessed 3 melanoma SLNB risk-prediction models' statistical performance and their ability to improve clinical decision making (clinical utility) on a cohort of melanoma SLNB cases., Study Design: Melanoma patients undergoing SLNB at a single center from 2003 to 2021 were identified. The predicted probabilities of sentinel lymph node positivity using the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center (MSK), and Friedman nomograms were calculated. Receiver operating characteristic and calibration curves were generated. Clinical utility was assessed via decision curve analysis, calculating the net SLNBs that could have been avoided had a given model guided selection at different risk thresholds., Results: Of 2,464 melanoma cases that underwent SLNB, 567 (23.0%) had a positive sentinel lymph node. The areas under the receiver operating characteristic curves for the Melanoma Institute of Australia, MSK, and Friedman models were 0.726 (95% CI, 0.702 to 0.750), 0.720 (95% CI, 0.697 to 0.744), and 0.721 (95% CI, 0.699 to 0.744), respectively. For all models, calibration was best at predicted positivity rates below 30%. The MSK model underpredicted risk. At a 10% risk threshold, only the Friedman model would correctly avoid a net of 6.2 SLNBs per 100 patients. The other models did not reduce net avoidable SLNBs at risk thresholds of ≤10%., Conclusions: The tested nomograms had comparable performance in our cohort. The only model that achieved clinical utility at risk thresholds of ≤10% was the Friedman model., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes., Patients and Methods: This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1., Results: Thirty patients were enrolled [60% male; median age 54 years (range, 24-78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%-17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9-26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway-related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline., Conclusions: Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved., (©2023 American Association for Cancer Research.)

Introduction: Completion lymph node dissection (CLND) is no longer recommended routinely in the treatment of melanoma. CLND omission may understage patients for whom the distinction between stage IIIA and IIIB-C could alter adjuvant therapy recommendations. The aim of this study is to determine if stage migration has occurred with the declining use of CLND., Methods: Patients with clinically node-negative ≥ T1b cutaneous melanoma were identified from the National Cancer Database (NCDB) from 2012 to 2018. CLND utilization and changes in AJCC staging were analyzed. Patients undergoing sentinel lymph node biopsy (SLNB) alone were compared with those undergoing SLNB + CLND., Results: Overall, 68,933 patients met inclusion criteria and 60,536 underwent SLNB, of which 9031 (14.9%) were tumor positive. CLND was performed in 3776 (41.8%). Patients undergoing CLND were younger (58 versus 62 years, p < 0.0001) and more likely male (61.5% versus 57.9%, p = 0.0005). Patients were more likely to have an N classification >N1a if they received SLNB + CLND (36.8%) versus SLNB alone (19.3%), p < 0.0001. This translated to a small difference in stage IIIA patients between groups (SLNB alone 34.0%, SLNB + CLND 31.8%, p < 0.0001). Of the patients with T1b/T2a tumors who would be upstaged from IIIA to IIIC with identification of additional positive nodes, IIIC incidence was only slightly higher after SLNB + CLND compared with SLNB alone (4.4% versus 1.1%, p < 0.0001). CLND utilization dramatically decreased from 59% in 2012 to 12.6% in 2018, p < 0.0001. However, the incidence of stage IIIA disease for all patients remained stable over the 7-year study period., Conclusions: While the utilization of CLND after positive SLNB has declined dramatically in the last 7 years, stage migration that may affect adjuvant therapy decisions has not occurred to a clinically meaningful degree., (© 2023. Society of Surgical Oncology.)

Background and Methods: The Melanoma Institute of Australia (MIA) and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms were developed to help guide sentinel lymph node biopsy (SLNB) decisions. Although statistically validated, whether these prediction models provide clinical benefit at National Comprehensive Cancer Network guideline-endorsed thresholds is unknown. We conducted a net benefit analysis to quantify the clinical utility of these nomograms at risk thresholds of 5%-10% compared to the alternative strategy of biopsying all patients. External validation data for MIA and MSKCC nomograms were extracted from respective published studies., Results: The MIA nomogram provided added net benefit at a risk threshold of 9% but net harm at 5%-8% and 10%. The MSKCC nomogram provided added net benefit at risk thresholds of 5% and 9%-10% but net harm at 6%-8%. When present, the magnitude of net benefit was small (1-3 net avoidable biopsies per 100 patients)., Conclusion: Neither model consistently provided added net benefit compared to performing SLNB for all patients., Discussion: Based on published data, use of the MIA or MSKCC nomograms as decision-making tools for SLNB at risk thresholds of 5%-10% does not clearly provide clinical benefit to patients., (© 2023 Wiley Periodicals LLC.)

Objective: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma., Summary Background Data: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization., Methods: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics., Results: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients., Conclusions: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined., Objective: To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM., Evidence Review: Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45)., Findings: The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status., Conclusions and Relevance: For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

Background: Given the results of the recent KEYNOTE-716 trial, the performance of sentinel lymph node (SLN) biopsy for patients with clinical stage IIB/C melanoma has been questioned., Objective: Determine the utility of SLN status in guiding the recommendations for adjuvant therapy., Methods: Patients with clinical stage IIB/C cutaneous melanoma who underwent wide local excision and SLN biopsy between 2004 and 2011 were identified from the Surveillance, Epidemiology, and End Results database. Two prognostic models, with and without SLN status, were developed predicting risk of melanoma-specific death (MSD). The primary outcome was net benefit at treatment thresholds of 20% to 40% risk of 5-year MSD., Results: For the 4391 patients included, the 5-year MSD rate was 46%. The model estimating 5-year MSD risk that included SLN status provided greater net benefit at treatment thresholds from 30% to 78% compared to the model without SLN status. The added net benefit for the SLN biopsy-containing model persisted in subgroup analysis of patients in different age groups and with various T stages., Limitations: Retrospective study., Conclusions: A prognostic model with SLN status estimating patient risk for 5-year MSD provides superior net benefit compared to a model with primary tumor staging factors alone for threshold mortality rates ≥30%., Competing Interests: Conflicts of interest Bartlett receives institutional research support from SkylineDx and discloses an honorarium from Excite International. Karakousis is a PI of an investigator-initiated trial with institutional support by Merck and serves on the Merck advisory board. The other authors have no conflict to disclose., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Spindle cell sclerosing rhabdomyosarcoma (sc-RMS) is an extremely rare soft tissue tumor. We report an unusual case of sc-RMS in a 36-year-old patient whose tumor arose in a rectus abdominis muscle free flap that had been used for lower extremity reconstruction 18 years previously. After surgical excision of the tumor and immediate reconstruction, the patient has remained in remission and has full function of his lower extremity six months after diagnosis and treatment., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2023.)

Background: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN + ) in this population are poorly characterized., Objective: To determine factors associated with SLN + in patients with T1a melanoma., Methods: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN + were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years., Results: Of the 965 patients identified, the overall SLN + was 4.4% (N = 43). Factors associated with SLN + were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm 2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm 2 (N = 38) had a SLN +  rate of 18.4%., Limitations: Retrospective study., Conclusion: SLN + is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN + ., Competing Interests: Conflicts of interest Faries serves on the advisory boards for Novartis, Bristol Myers Squibb, Merck, Sanofi, Array Bioscience, and Nektar Biofarma. Shannon, Sharon, Straker, Carr, Sinnamon, Bogatch, Thaler, Kelly, Vetto, Fowler, DePalo, Miura, Zager, and Karakousis have no conflicts of interest to declare., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Completion lymph node dissection (CLND) for microscopic lymph node metastases has been replaced by observation; however, CLND is standard for clinically detectable nodal metastases (cLN). CLND has high morbidity, which may be reduced by excision of only the cLN (precision lymph node dissection [PLND]). We hypothesized that same-basin recurrence risk would be low after PLND., Methods: Retrospective review at four tertiary care hospitals identified patients who underwent PLND. The primary outcome was 3-year cumulative incidence of isolated same-basin recurrence., Results: Twenty-one patients underwent PLND for cLN without synchronous distant metastases. Reasons for forgoing CLND included patient preference (n = 11), comorbidities (n = 5), imaging indeterminate for distant metastases (n = 2), partial response to checkpoint blockade (n = 1), or not reported (n = 2). A median of 2 nodes (range: 1-6) were resected at PLND, and 68% contained melanoma. Recurrence was observed in 33% overall. Only 1 patient (5%) developed an isolated same-basin recurrence. Cumulative incidences at 3 years were 5.0%, 17.3%, and 49.7% for isolated same-basin recurrence, any same-basin recurrence, and any recurrence, respectively. Complications from PLND were reported in 1 patient (5%)., Conclusions: These pilot data suggest that PLND may provide adequate regional disease control with less morbidity than CLND. These data justify prospective evaluation of PLND in select patients., (© 2022 Wiley Periodicals LLC.)

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma 1 . We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate 2 . The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial 1 , provide further confirmation of the efficacy and safety of this new immunotherapy regimen., (© 2022. The Author(s).)

Pelvic sarcomas are a rare and heterogenous group of tumors divided into two groups: soft tissue sarcomas and bone sarcomas. Soft tissue sarcomas of the pelvis include most commonly liposarcoma, leiomyosarcoma, gastrointestinal stromal tumors, malignant peripheral nerve sheath tumors, and solitary fibrous tumors. Bone sarcomas of the pelvis most commonly include osteosarcoma and chondrosarcoma. Multidisciplinary treatment at a center experienced in the treatment of sarcoma is essential. Management is dictated by histologic type and grade. Surgical resection with wide margins is the cornerstone of treatment for pelvic sarcomas, although this is often challenging due to anatomic constraints of the pelvis. Multimodal treatment is critical due to the high risk of local recurrence in the pelvis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Radiation-associated sarcomas (RAS) are rare but aggressive malignancies. We sought to characterize the histology-specific presentation and behavior of soft tissue RAS to improve individualized prognostication., Methods: A single-institutional prospectively maintained database was queried for all patients with primary, nonmetastatic RAS treated with surgical resection from 1982 to 2019. Patients presenting with the five most common RAS histologies were propensity-matched to those with sporadic tumors of the same histology. Incidence of disease-specific death (DSD) was modeled using cumulative incidence analyses., Results: Among 259 patients with RAS, the five most common histologies were malignant peripheral nerve sheath tumor (MPNST; n = 19), myxofibrosarcoma (n = 20), leiomyosarcoma (n = 24), undifferentiated pleomorphic sarcoma (UPS; n = 55), and angiosarcoma (AS; n = 62). DSD varied significantly by histology ( P = .002), with RAS MPNST and UPS having the highest DSD. In unadjusted analysis, RAS MPNST was associated with increased DSD compared with sporadic MPNST (75% v 38% 5-year DSD, P = .002), as was RAS UPS compared with sporadic UPS (49% v 28% 5-year DSD, P = .004). Unadjusted DSD was similar among patients with RAS AS, leiomyosarcoma, or myxofibrosarcoma and sporadic sarcoma of the same histology. After matching RAS to sporadic patients within each histology, DSD only differed between RAS and sporadic MPNST (83% v 46% 5-year DSD, P = .013). Patients with RAS AS presented in such a distinct manner to those with sporadic AS that a successful match was not possible., Conclusion: The aggressive presentation of RAS is histology-specific, and DSD is driven by RAS MPNST and UPS histologies. Despite the aggressive presentation, standard prognostic factors can be used to estimate risk of DSD among most RAS. In MPNST, radiation association should be considered to independently associate with markedly higher risk of DSD.

Background: Risk-based thresholds to guide management are undefined in the treatment of primary cutaneous melanoma but are essential to advance the field from traditional stage-based treatment to more individualized care., Methods: To estimate treatment risk thresholds, hypothetical clinical melanoma scenarios were developed and a stratified random sample was distributed to expert melanoma clinicians via an anonymous web-based survey. Scenarios provided a defined 5-year risk of recurrence and asked for recommendations regarding clinical follow-up, imaging, and adjuvant therapy. Marginal probability of response across the spectrum of 5-year recurrence risk was estimated. The risk at which 50% of respondents recommended a treatment was defined as the risk threshold., Results: The overall response rate was 56% (89/159). Three separate multivariable models were constructed to estimate the recommendations for clinical follow-up more than twice/year, for surveillance cross-sectional imaging at least once/year, and for adjuvant therapy. A 36% 5-year risk of recurrence was identified as the threshold for recommending clinical follow-up more than twice/year. The thresholds for recommending cross-sectional imaging and adjuvant therapy were 30 and 59%, respectively. Thresholds varied with the age of the hypothetical patient: at younger ages they were constant but increased rapidly at ages 60 years and above., Conclusions: To our knowledge, these data provide the first estimates of clinically significant treatment thresholds for patients with cutaneous melanoma based on risk of recurrence. Future refinement and adoption of thresholds would permit assessment of the clinical utility of novel prognostic tools and represents an early step toward individualizing treatment recommendations., (© 2022. Society of Surgical Oncology.)

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients., Competing Interests: Competing interests: ZE: Advisory boards: Array, Pfizer, OncoSec, Regeneron, Genentech, Novartis, Natera. Research funding: Novartis, Pfizer, Boehringer-Ingelheim. JFT: Advisory boards: BMS Australia, MSD Australia, GSK, Provectus Inc. Travel support: GSK, Provectus Inc and Novartis. TJH: Research funding: Genentech, SkylineDX. EKB: Research funding: SkylineDx, Honorarium: Excite International inc. DEG: Honoraria: BMS, Novartis, Q biotics. GK; Advisory Board: Merck. AVA: Advisory Boards: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC Research funding: Amgen, Merck-Pfizer. JV: Speaker: Caste Biosciences. GB: Research funding: Istari Oncology, Delcath, Oncosec Medical, Replimune, Checkmate Pharmaceuticals. ROB: Advisory boards: Amgen, BD/BARD, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi Genzyme. Research funding: Bristol-Myers Squibb, SkyLineDx. Speaker honorarium: Roche and Pfizer. Shareholder in SATMEG Ventures AB. NIK: Advisory boards: Bristol-Myers Squibb, AstraZeneca, Regeneron, Array, Immunocore, Merck, Incyte, Jounce Therapeutics,Pfizer,Novartis, Nektar,Castle Biosciences, Instil Bio. Research funding: Bristol-Myers Squibb, Merck, Novartis, Celgene, Replimune, Amgen, Regneron, HUYA, GlaxoSmithKline Stocks: Bellicum Pharmaceuticals, Amarin Corporation, Asensus Surgical., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: A neural network-based model (i31-GEP-SLNB) that uses clinicopathologic factors (thickness, mitoses, ulceration, patient age) plus molecular analysis (31-gene expression profiling) has become commercially available to guide selection for sentinel lymph node (SLN) biopsy in cutaneous melanoma, but its clinical utility is not well characterized., Objective: To determine if use of the i31-GEP-SLNB model is associated with clinical benefit when used to select patients for SLN biopsy., Design, Setting, and Participants: This decision-analytic study used data derived from a published external validation study of the i31-GEP-SLNB prediction model. Participants included patients with primary cutaneous melanoma., Main Outcomes and Measures: The primary outcome was the net benefit associated with using the i31-GEP-SLNB model for SLN biopsy selection compared with other selection strategies (SLN biopsy for all patients and SLN biopsy for no patients) at a 5% risk threshold. Analyses were stratified by American Joint Committee on Cancer (AJCC) T category. The reduction in the number of avoidable SLN biopsies and relative utility were also calculated., Results: Compared with other SLN biopsy selection strategies, use of the i31-GEP-SLNB model had greater net benefit for patients with T1b (+0.012), T2a (+0.002), and T2b melanoma (+0.002) but not for those with high-risk T1a (-0.003) disease. The improvement in relative utility was +22% in patients with T1b, +1% in T2a, and +2% in T2b melanoma. Compared with SLN biopsy for all patients, use of the model would equate to a 23% decrease in SLN biopsies among patients with T1b disease without an SLN metastasis with no increase in the number of patients with an SLN metastasis left untreated; among patients with T2a and T2b melanoma, the net decrease in avoidable biopsies compared with SLN biopsy for all was 3% and 4%, respectively., Conclusions and Relevance: The findings of this decision-analytic study suggest that i31-GEP SLNB has significant potential for risk-stratifying patients with T1b melanoma if using a 5% risk threshold; its role among patients with T1a and T2 melanoma or using other risk thresholds requires further study. A prospective validation study confirming the added clinical benefit and cost-effectiveness of i31-GEP-SLNB compared with free clinicopathologic-based prediction models is needed in patients with T1b melanoma.

Competing Interests: Declaration of Competing Interest None.

Purpose: Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors., Experimental Design: We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD., Results: We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline., Conclusions: In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Sentinel lymph node biopsy (SLNB) is often omitted in selected patients with advanced primary melanoma, although the justification/criteria for omission have been debated., Objective: We sought to determine whether assessment of frailty could serve as an objective marker to guide selection for SLNB in patients with advanced primary melanoma., Methods: Patients presenting with clinical stage IIC (ulcerated, > 4 mm Breslow thickness) cutaneous melanoma from January 1999 through June 2019 were included. Frailty was assessed using the Memorial Sloan Kettering Frailty Index (MSK FI), a composite score of functional status and medical comorbidities. Five-year melanoma-specific survival (MSS) and overall survival (OS) were estimated using Cox regression, and predictors of OS were identified using competing risk models., Results: MSS did not differ between patients who did (n = 451) or did not undergo SLNB (n = 179) [63.2% vs. 65.0%, p = 0.14]; however, omission of SLNB was associated with decreased 5-year OS (29% vs. 44%, p < 0.001). In a multivariable competing risk model, selection for SLNB omission was an independent predictor of death from non-melanoma causes (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.3, p < 0.001). After incorporation of the MSK FI score into the multivariable model in this subset, MSK FI (HR 2.4, 95% CI 1.5-4.1, p < 0.001), but not SLNB omission, was an independent predictor of poorer OS., Conclusion: We observed worse OS in patients with thick melanoma selected not to undergo SLNB, which was attributed to death due to non-melanoma causes. Formal assessment of frailty may provide an objective prognostic measure to guide selective use of SLNB in these patients., (© 2021. Society of Surgical Oncology.)

Treatment options for patients with advanced sarcoma remain limited. Promising responses to checkpoint inhibition have been observed, but responses to single-agent PD-1 inhibition are rare. We report on two patients with multiply recurrent myxofibrosarcoma treated with the combination of regionally administered melphalan ( via isolated limb infusion) and pembrolizumab. Both patients had recurrent disease after multiple surgical resections and radiation. Analysis of primary tumors demonstrated microsatellite stable tumors with few mutations. After combination treatment, one patient had a significant partial response of 6 months duration, the second patient had a complete response of 2 years duration. Post treatment biopsies demonstrated immune infiltration into the tumor. These promising responses in patients with multiply recurrent myxofibrosarcoma have prompted the development of an investigator-initiated clinical trial to formally study the combination of regional melphalan and pembrolizumab in a systematic fashion (NCT04332874)., Competing Interests: CK reports receiving research funding from Merck, Amgen, and Agios; SD’A reports research funding from Amgen, EMD Serono, Incyte, Merck & Co., Nektar, Bristol-Myers Squibb, and Deciphera; consultancy for Amgen, EMD Serono, GlaxoSmithKline, Immune Design, Incyte, Merck & Co., Nektar, and Immunocore; reimbursement for travel expenses from EMD Serono, Merck & Co., Adaptimmune, and Immunocore. The remaining 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 © 2021 Bartlett, D’Angelo, Kelly, Siegelbaum, Fisher, Antonescu and Ariyan.)

Background: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown., Methods: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models., Results: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment., Conclusions: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients., Lay Summary: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma., (© 2021 American Cancer Society.)

Objective: We sought to define the prognostic significance of histologic subtype for extremity/truncal liposarcoma (LPS)., Background: LPS, the most common sarcoma, is comprised of 5 histologic subtypes. Despite their distinct behaviors, LPS outcomes are frequently reported as a single entity., Methods: We analyzed data on all patients from a single-institution prospective database treated from July 1982 to September 2017 for primary, nonmetastatic, extremity or truncal LPS of known subtype. Clinicopathologic variables were tested using competing risk analyses for association with disease-specific death (DSD), distant recurrence (DR), and local recurrence (LR)., Results: Among 1001 patients, median follow-up in survivors was 5.4 years. Tumor size and subtype were independently associated with DSD and DR. Size, subtype, and R1 resection were independently associated with LR. DR was most frequent among pleomorphic and round cell LPS; the former recurred early (43% by 3 years), and the latter over a longer period (23%, 3 years; 37%, 10 years). LR was most common in dedifferentiated LPS, in which it occurred early (24%, 3 years; 33%, 5 years), followed by pleomorphic LPS (18%, 3 years; 25%, 10 years)., Conclusions: Histologic subtype is the factor most strongly associated with DSD, DR, and LR in extremity/truncal LPS. Both risk and timing of adverse outcomes vary by subtype. These data may guide selective use of systemic therapy for patients with round cell and pleomorphic LPS, which carry a high risk of DR, and radiotherapy for LPS subtypes at high risk of LR when treated with surgery alone., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown., Study Design: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared., Results: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin-only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86)., Conclusions: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Clinicians caring for patients with sarcoma founded the field of cancer immunotherapy. Despite this, contemporary success with immunotherapy for sarcoma has been limited. Here, we review immunotherapy for sarcoma including Coley's toxins, interleukin-2, adoptive cell transfer, and checkpoint blockade. We detail recent and ongoing efforts to combine checkpoint blockade with other immune modulators, surgery, or radiation. These results, along with ongoing investigations, have identified immunotherapeutic approaches as a promising avenue for progress in advanced sarcomas., (© 2020 Wiley Periodicals LLC.)

Background: The purpose of this study is to report the additional prognostic information and cost associated with sentinel lymph node biopsy (SLNB) for patients with T1b melanoma., Patients and Methods: An institutional database was queried for patients with T1b melanoma (0.8-1.0 mm or < 0.8 mm with ulceration) with at least 5 years of follow-up. Results of SLNB, completion lymphadenectomy (CLND), recurrence, and melanoma-specific survival (MSS) were assessed. Institutional costs of melanoma care were converted to Medicare proportional dollars. A Markov model was created to estimate long-term costs., Results: Among the total 392 patients, 238 underwent SLNB. Median follow-up was 10.5 years. SLNB was positive in 19 patients (8.0%). Patients who underwent SLNB had higher 10-year nodal recurrence-free survival (98.6% vs. 91.2%, p < 0.001) but not MSS (94.4% vs. 93.2%, p = 0.55). Ulceration (HR 4.7, p = 0.022) and positive sentinel node (HR 11.5, p < 0.001) were associated with worse MSS. Estimates for 5-year costs reflect a fourfold increase in total costs of care associated with SLNB. However, a treatment plan that forgoes adjuvant therapy for resected stage IIIA melanoma but offers systemic therapy for a node-basin recurrence would nullify the additional cost of SLNB., Conclusions: SLNB is prognostic for T1b melanoma. Its impact on the overall cost of melanoma care is intimately tied to systemic therapy in the adjuvant and recurrent settings.

Background: Indiscriminate use of adjuvant therapy in stage IIIA melanoma is controversial. We sought to model the clinical impact and cost of implementing a gene expression profile (GEP) test to guide adjuvant therapy., Study Design: A Markov decision-analysis model was created to represent resected stage IIIA melanoma with 3 treatment options: observation (OBS), adjuvant pembrolizumab for all patients (ALL), and selective adjuvant therapy (SEL). In the SEL option, only high-risk patients based on GEP stratification were treated with pembrolizumab. Cost of adjuvant therapy was normalized to reflect Medicare reimbursement schedules. The primary outcome was cost per mortality avoided at 10 years., Results: Model projections for 10-year overall survival were 68% for OBS, 73% for SEL, and 76% for ALL. The estimated incremental cost-per-mortality-avoided (compared to OBS) was $2.1 million for SEL and $2.4 million for ALL. These translate to costs of $583.0K and $697.1K per life-year for the SEL and ALL strategies, respectively., Conclusions: Routine adjuvant pembrolizumab for stage IIIA melanoma is costly, and risk-stratification by GEP only marginally improves the value of therapy., (Copyright © 2020 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Two RCTs found no survival benefit for completion lymphadenectomy after positive sentinel lymph node biopsy compared with observation with ultrasound in patients with melanoma. Recurrence patterns and regional control are not well described for patients undergoing observation alone., Methods: All patients with a positive sentinel node biopsy who did not have immediate completion lymphadenectomy were identified from a single-institution database (1995-2018). First recurrences were classified as node only, local and in-transit (LCIT) only, LCIT and nodal, or systemic. Regional control and factors associated with recurrence survival were analysed., Results: Median follow-up was 33 months. Of 370 patients, 158 (42·7 per cent) had a recurrence. The sites of first recurrence were node only (13·2 per cent), LCIT only (11·9 per cent), LCIT and nodal (3·5 per cent), and systemic (13·8 per cent). The 3-year postrecurrence melanoma-specific survival rate was 73 (95 per cent c.i. 54 to 86) per cent for patients with node-only first recurrence, and 51 (31 to 68) per cent for those with initial systemic recurrence. In multivariable analysis, ulceration in the primary lesion (hazard ratio (HR) 2·53, 95 per cent c.i. 1·27 to 5·04), disease-free interval 12 months or less (HR 2·38, 1·28 to 4·35), and systemic (HR 2·57, 1·16 to 5·65) or LCIT and nodal (HR 2·94, 1·11 to 7·79) first recurrence were associated significantly with decreased postrecurrence survival. Maintenance of regional control required therapeutic lymphadenectomy in 13·0 per cent of patients during follow-up., Conclusion: Observation after a positive sentinel lymph node biopsy is associated with good regional control, permits assessment of the time to and pattern of recurrence, and spares lymphadenectomy-related morbidity in patients with melanoma., (Published by John Wiley & Sons Ltd.)

Importance: The performance of prognostic gene expression profile (GEP) tests for cutaneous melanoma is poorly characterized., Objective: To systematically assess the performance of commercially available GEP tests in patients with American Joint Committee on Cancer (AJCC) stage I or stage II disease., Data Sources: For this systematic review and meta-analysis, comprehensive searches of PubMed/MEDLINE, Embase, and Web of Science were conducted on December 12, 2019, for English-language studies of humans without date restrictions., Study Selection: Two reviewers identified GEP external validation studies of patients with localized melanoma. After exclusion criteria were applied, 7 studies (8%; 5 assessing DecisionDx-Melanoma and 2 assessing MelaGenix) were included., Data Extraction and Synthesis: Data were extracted using an adaptation of the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS-PF). When feasible, meta-analysis using random-effects models was performed. Risk of bias and level of evidence were assessed with the Quality in Prognosis Studies tool and an adaptation of Grading of Recommendations Assessment, Development, and Evaluation., Main Outcomes and Measures: Proportion of patients with or without melanoma recurrence correctly classified by the GEP test as being at high or low risk., Results: In the 7 included studies, a total of 1450 study participants contributed data (age and sex unknown). The performance of both GEP tests varied by AJCC stage. Of patients tested with DecisionDx-Melanoma, 623 had stage I disease (6 true-positive [TP], 15 false-negative, 61 false-positive, and 541 true-negative [TN] results) and 212 had stage II disease (59 TP, 13 FN, 78 FP, and 62 TN results). Among patients with recurrence, DecisionDx-Melanoma correctly classified 29% with stage I disease and 82% with stage II disease. Among patients without recurrence, the test correctly classified 90% with stage I disease and 44% with stage II disease. Of patients tested with MelaGenix, 88 had stage I disease (7 TP, 15 FN, 15 FP, and 51 TN results) and 245 had stage II disease (59 TP, 19 FN, 95 FP, and 72 TN results). Among patients with recurrence, MelaGenix correctly classified 32% with stage I disease and 76% with stage II disease. Among patients without recurrence, the test correctly classified 77% with stage I disease and 43% with stage II disease., Conclusions and Relevance: The prognostic ability of GEP tests among patients with localized melanoma varied by AJCC stage and appeared to be poor at correctly identifying recurrence in patients with stage I disease, suggesting limited potential for clinical utility in these patients.

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care., Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies., Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed., Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility., Conclusions and Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

An ambiguous pathologic report can present a clinical dilemma to the treating surgeon. We describe lesions ranging from the potentially benign to the likely malignant. Correctly identifying features associated with higher-risk lesions has proven challenging given the overall good prognosis and low rate of events. An appropriate treatment plan generally requires discussion between the surgeon and an experienced dermatopathologist. When clinically indicated, additional testing may be used to further support or refute a diagnosis of melanoma. The indications for these techniques, the data to support their use, and the strengths and weakness of each are reviewed., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Patients with advanced sarcoma have limited treatment options. Talimogene laherparepvec (T-VEC) has been shown to increase tumor-specific immune activation via augmenting antigen presentation and T-cell priming., Objective: To examine whether T-VEC in combination with pembrolizumab is associated with increased tumor-infiltrating lymphocyte infiltration and programmed death-ligand 1 expression and thus with increased antitumor activity in patients with locally advanced or metastatic sarcoma., Design, Setting, and Participants: This open-label, single-institution phase 2 interventional trial of T-VEC plus pembrolizumab enrolled 20 patients with locally advanced or metastatic sarcoma between March 16 and December 4, 2017, for whom at least 1 standard systemic therapy had failed. The median duration of therapy was 16 weeks (range, 7-67 weeks). Reported analyses include data through December 14, 2018., Intervention: Patients received pembrolizumab (200-mg flat dose) intravenously and T-VEC (first dose, ≤4 mL × 106 plaque-forming units [PFU]/mL; second and subsequent doses, ≤4 mL × 108 PFU/mL) injected into palpable tumor site(s) on day 1 of each 21-day cycle., Main Outcomes and Measures: The primary end point was objective response rate (ORR; complete response and partial response) at 24 weeks determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, criteria. Secondary end points included best ORR by immune-related RECIST criteria, progression-free survival rate at 24 weeks, overall survival, and safety., Results: All 20 patients (12 women [60%]; median age, 63.5 years [range, 24-90 years]) were evaluable for response. The study met its primary end point of evaluating the best ORR at 24 weeks determined by RECIST, version 1.1, criteria; the best ORR was 30% (95% CI, 12%-54%; n = 6). The ORR overall was 35% (95% CI, 15%-59%; n = 7). The incidence of grade 3 treatment-related adverse events was low (4 patients [20%]). There were no grade 4 treatment-related adverse events or treatment-related deaths., Conclusions and Relevance: In this phase 2 clinical trial, treatment with T-VEC plus pembrolizumab was associated with antitumor activity in advanced sarcoma across a range of sarcoma histologic subtypes, with a manageable safety profile. This combination therapy met its predefined primary study end point; further evaluation of T-VEC in combination with pembrolizumab for patients with select sarcoma subtypes is planned., Trial Registration: ClinicalTrials.gov identifier: NCT03069378.

Background: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD-1 inhibition., Methods: Patients undergoing initial treatment with PD-1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan-Meier and landmark analyses., Results: Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow-up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3-2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2-2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months)., Conclusions: Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD-1 inhibitor monotherapy. Combined, these biomarkers can widely risk-stratify patients for treatment failure and survival., (© 2019 American Cancer Society.)