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Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2n Treg-KO ) of adult mice results in a robust expansion and activation of cytotoxic CD8 + T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.

Modern systemic therapy has dramatically improved outcomes for many patients with advanced metastatic melanoma. The success of these therapies has attracted much scientific interest while these therapies have made their way into the treatment of earlier stages of disease. Randomized trials have led to the approval of adjuvant immunotherapy and targeted therapy for resected stage III melanoma. However, most recently, these therapies have gained traction in the neoadjuvant setting. Promising early results led to randomized controlled trials that have now established neoadjuvant therapy as standard of care in advanced melanoma patients. Questions remain regarding the optimal choice of therapy, duration and timing of neoadjuvant therapy, extent of surgery, and the need for additional adjuvant therapy for patients who received neoadjuvant therapy. Herein we provide an overview of neoadjuvant therapy for melanoma and dilemmas to its broader applications., Competing Interests: Declaration of competing interest GMB has received clinical trial funding paid to Duke University from Delcath, Istari, Replimune, Oncosec, Checkmate. GMB has done one-time advisory board for Cardinal Health, Regeneron, Bristol-Myers-Squibb., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Background: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM., Methods: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS)., Results: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed., Conclusion: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44)., (© 2024. Society of Surgical Oncology.)

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8 + T cell activation and suppressed melanoma progression. CD63 + mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.

Modern effective systemic therapy for melanoma includes two important classes of treatment: immune checkpoint inhibitors (ICIs), comprising inhibitors of cytotoxic T-lymphocyte antigen 4, programmed cell death receptor 1, and lymphocyte-activation gene 3; and small molecule BRAF/MEK inhibitor therapy. These treatments have revolutionized the management of patients with advanced melanoma and have dramatically improved clinical outcomes. The melanoma treatment landscape continues to evolve as outcome data from completed trials continue to mature and as newer studies begin to report data. In 2022 and 2023, longer-term follow-up data for established single-agent ICI therapy has been published improving our understanding of both efficacy and durability of treatment responses. A trial of a novel combination ICI therapy has demonstrated enhanced efficacy, and a study examining the order/sequence of ICI therapy versus BRAF/MEK inhibitor therapy for first-line treatment of metastatic melanoma showed that survival is improved when patients start with ICI therapy. As the indications for these therapies have expanded to the adjuvant and neoadjuvant space, we also saw the publication of 5-year results of adjuvant therapy in resected stage III patients, new data on the role of adjuvant therapy in resected stage IIB and IIC patients, and, finally, a practice-changing trial demonstrating improved outcomes using a neoadjuvant approach for patients with macroscopic disease amenable to surgical resection. In this article, we review these articles and highlight key elements for surgical oncologists., (© 2023. Society of Surgical Oncology.)

Objective: To compare the representation of intersectional (ie, racial/ethnic and gender) identities among surgical faculty versus medical students., Background: Health disparities are pervasive in medicine, but diverse physicians may help the medical profession achieve health equity., Methods: Data from the Association of American Medical Colleges for 140 programs (2011/2012-2019/2020) were analyzed for students and full-time surgical faculty. Underrepresented in medicine (URiM) was defined as Black/African American, American Indian/Alaskan Native, Hispanic/Latino/Spanish Origin, or Native Hawaiian/Other Pacific Islander. Non-White included URiM plus Asian, multiracial, and non-citizen permanent residents. Linear regression was used to estimate the association of year and proportions of URiM and non-White female and male faculty with proportions of URiM and non-White students., Results: Medical students were comprised of more White (25.2% vs 14.4%), non-White (18.8% vs 6.6%), and URiM (9.6% vs 2.8%) women and concomitantly fewer men across all groups versus faculty (all P < 0.01). Although the proportion of White and non-White female faculty increased over time (both P ≤ 0.001), there was no significant change among non-White URiM female faculty, nor among non-White male faculty, regardless of whether they were URiM or not. Having more URiM male faculty was associated with having more non-White female students (estimate = +14.5% students/100% increase in faculty, 95% CI: 1.0% to 8.1%, P = 0.04), and this association was especially pronounced for URiM female students (estimate = +46.6% students/100% increase in faculty, 95% CI: 36.9% to 56.3%, P < 0.001)., Conclusions: URiM faculty representation has not improved despite a positive association between having more URiM male faculty and having more diverse students., Competing Interests: O.M.F. is supported by the National Institutes of Health (NIH) under Award Number 7K08CA241390. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Surgical department chairs remain conspicuously nondiverse despite the recognized importance of diverse physician workforces. However, the extent of diversity among non-chair leadership remains underexplored., Objective: To evaluate racial, ethnic, and gender diversity of surgical department chairs, vice chairs (VCs), and division chiefs (DCs) in the US., Design, Setting, and Participants: For this cross-sectional study, publicly accessible medical school and affiliated hospital websites in the US and Puerto Rico were searched from January 15 to July 15, 2022, to collect demographic and leadership data about surgical faculty. Two independent reviewers abstracted demographic data, with up to 2 additional reviewers assisting with coding resolution as necessary. In all, 2165 faculty were included in the analyses., Main Outcomes and Measures: Proportions of racial, ethnic, and gender diversity among chairs, VCs, and DCs in general surgery and 5 surgical specialties (neurosurgery, obstetrics and gynecology, ophthalmology, orthopedics, and otolaryngology)., Results: A total of 2165 faculty (1815 males [83.8%] and 350 females [16.2%]; 109 [5.0%] African American or Black individuals; 347 [16.0%] Asian individuals; 83 [3.8%] Hispanic, Latino, or individuals of Spanish origin; and 1624 [75.0%] White individuals as well as 2 individuals [0.1%] of other race or ethnicity) at 154 surgical departments affiliated with 146 medical schools in the US and Puerto Rico were included in the analysis. There were more males than females in leadership positions at all levels-chairs (85.9% vs 14.1%), VCs (68.4% vs 31.6%), and DCs (87.1% vs 12.9%)-and only 192 leaders (8.9%) were from racial or ethnic groups that are underrepresented in medicine (URiM). Females occupied more VC than chair or DC positions both overall (31.6% vs 14.1% and 12.9%, respectively) and within racial and ethnic groups (African American or Black females, 4.0% VC vs 1.5% chair and 0.6% DC positions; P < .001). URiM individuals were most commonly VCs of diversity, equity, and inclusion (DEI, 51.6%) or faculty development (17.9%). Vice chairs of faculty development were split equally between males and females, while 64.5% of VCs for DEI were female. All other VCs were predominantly male. Among DC roles, URiM representation was greatest in transplant surgery (13.8%) and lowest in oral and maxillofacial surgery (5.0%). Except for breast and endocrine surgery (63.6% female), females comprised less than 20% of DC roles. Nearly half of DCs (6 of 13 [46.2%]) and VCs (4 of 9 [44.4%]) had no female URiM leaders, and notably, no American Indian, Alaska Native, or Native Hawaiian or Other Pacific Islander individuals were identified in any surgical leadership positions., Conclusions and Relevance: While it is unclear whether promotion from VC to chair or from DC to chair is more likely, these findings of similar gender distribution between chairs and DCs suggest the latter and may partially explain persistent nondiversity among surgical chairs. Female and URiM surgical leaders are disproportionately clustered in roles (eg, VCs of DEI or faculty development) that may not translate into future promotion to department chairs.

Background: The optimal time to initiate adjuvant immune checkpoint inhibitors (ICI) following resection remains undefined. Herein, we investigated the impact of time to adjuvant ICI on survival in patients with stage III melanoma., Methods: Patients with resected stage III melanoma receiving adjuvant immune therapy were identified within a multi-institutional retrospective cohort. Patients were stratified by time to adjuvant ICI: within 6 weeks, 6-12 weeks, and greater than 12 weeks from surgery. Recurrence-free survival (RFS) was compared among time strata with Kaplan-Meier and Cox proportional hazards methods in the multi-institutional cohort., Results: Altogether, 626 patients were identified within the multi-institutional cohort: 39% of patients initiated adjuvant ICI within 6 weeks, 42.2% within 6-12 weeks, and 18.8% greater than 12 weeks from surgery. In a multivariate Cox model, adjusting for histology, nodal tumor burden, and pathologic stage, we found that increased time to adjuvant ICI was associated with improved RFS. Patients who initiated adjuvant ICI within 6 weeks of surgery had worse RFS. These findings were preserved in a conditional landmark analysis and separate subgroups of patients with (1) new melanoma diagnoses, (2) occult stage III disease, and (3) those receiving anti-PD-1 monotherapy., Conclusions: Outcomes for patients with stage III melanoma are not compromised when adjuvant ICI is initiated beyond 6 weeks from resection. Additional work is needed to better understand the underlying mechanisms and implications of timing of adjuvant ICI on long-term outcomes., (© 2023. Society of Surgical Oncology.)

Objective: Prior studies have focused on the role of the learning environment on students' decisions to pursue surgery, but few have analyzed the impact of the clerkship curriculum. This study assessed surgical clerkship curricula across United States (US) medical schools and their impact on students' likelihood of pursuing a surgical residency., Design: A cross-sectional survey was developed to assess surgery clerkship characteristics. Questions included clerkship duration, number of offered and required surgical services, method of service assignment, and number of advanced clinical electives (e.g., fourth-year sub-internships) and additional surgical clinical opportunities (e.g., surgical elective rotations). Survey results were merged by the Association of American Medical Colleges with the percentages of students who matched into a surgical specialty. Linear regression models estimated the association of covariates with the percentage of students who (1) matched in surgical specialties, (2) were interested in surgery at medical school matriculation and ultimately matched into surgical residency (retention rate), and (3) were not interested in surgery at medical school matriculation but ultimately matched into surgical residency (recruitment rate)., Setting: The survey was distributed to clerkship directors and coordinators at 66 medical schools through the Association for Surgical Education (ASE) from 5/1/2021 to 8/1/2021., Participants: All US medical schools in the ASE., Results: A total of 21 medical schools responded (34.8% response rate). The overall retention rate was 36.4%, and the overall recruitment rate was 25.0%. Clerkships were 4 to 12 weeks. In 81% of programs, students submitted preferences and were assigned services. The percentage of students applying to surgical specialties was not associated with clerkship duration (p=0.79) or the number of required services (p=0.15), subspecialty services offered (p=0.33), or advanced clinical electives (p=0.24) but was associated with a program's having additional surgical clinical opportunities (p=0.02). Most of these factors were not associated with retention or recruitment rates., Conclusions: Offering more extracurricular surgical clinical opportunities was associated with having more students pursue surgical careers. Though limited by a relatively small sample size, our findings suggest that having shorter clerkships or limited subspecialty offerings may not have a significant influence on students' career choices., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Monocytes and monocyte-derived tumor infiltrating cells have been implicated in the immunosuppression and immune evasion associated with pancreatic adenocarcinoma (PDAC). Yet, precisely how monocytes in the periphery and tumor microenvironment in patients with intraductal papillary mucinous neoplasm (IPMN), a precursor lesion to PDAC, change during disease progression has not been defined. Here we functionally profiled the peripheral immune system and characterized the tumor microenvironment of patients with both IPMN and PDAC. We also tested if sera from patients with IPMN and PDAC functionally reprogram monocytes relative to that of healthy donors., Methods: Pancreatic tissue and peripheral blood were collected at the time of resection from 16 patients with IPMN and 32 patients with PDAC. Peripheral blood and pancreatic tissue/tumor were immunophenotyped using flow cytometry. Whole blood was plated and incubated with R848 (a TLR 7/8 agonist) or LPS (a TLR4 agonist) for 6 hours and TNF expression in monocytes was measured by flow cytometry to measure monocyte activation. To test if TLR sensitivity is determined by factors in patient sera, we preconditioned healthy donor monocytes in serum from PDAC (n=23), IPMN (n=15), or age-matched healthy donors (n=10) followed by in vitro stimulation with R848 or LPS and multiplex cytokine measurements in the supernatant., Results: TNF expression in R848-stimulated peripheral blood monocytes was higher in patients with low grade vs high grade IPMN (65% vs 32%, p = 0.03) and stage 1 vs stage 2/3 PDAC (58% vs 42%, p = 0.03), this was not observed after LPS stimulation. TLR activation correlated with increasing grade of dysplasia from low grade IPMN to high grade IPMN. Serum from patients with IPMN and PDAC recapitulated suppression of TNF induction after R848 stimulation in naïve, healthy donor monocytes., Conclusion: Peripheral blood monocyte TNF secretion inversely correlates with the degree of dysplasia in IPMN and cancer stage in PDAC, suggesting innate immune reprogramming as IPMNs progress to invasive disease. These effects are, at least in part, mediated by soluble mediators in sera., 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 © 2023 Eckhoff, Brown, Landa, Naqvi, Holl, Boczkowski, Fletcher, Rhodin, Giang, Sullenger, Beasley, Allen and Nair.)

Objective: To determine the feasibility and impact of neoadjuvant therapy (NT) in patients who present with advanced melanoma amenable to surgical resection., Summary Background Data: Given current effective systemic therapy for melanoma, the use of NT is being explored in patients with advanced melanoma with disease amenable to surgical resection., Methods: Prospective data from 3 institutions was obtained in patients with clinically evident Stage III/IV melanoma who underwent NT. The primary objective was to compare recurrence-free survival between patients who had pathologic complete response (pCR) to those with persistent disease., Results: NT was offered to 45 patients, with 43 patients initiating various NT regimens including PD-1 antagonist (PD-1) therapy (N = 16), PD-1 plus ipilimumab (N = 10), BRAF/MEK inhibitor therapy (N = 14), a combination of those three (N = 1), and talimogene laherparepvec (TVEC) (N = 2). Thirty-two (74.1%) patients underwent surgery whereas 11 patients did not undergo surgery for these reasons: clinical CR (N = 7), progressive disease not amenable to resection (N = 3), and ongoing therapy (N = 1). 12 of 32 patients (37.5%) had pCR with these therapies: PD-1 (N = 4), PD-1 plus ipilimumab (N = 2), BRAF/MEK (N = 4), combination (N = 1), and TVEC (N = 1). At median follow-up of 16.4 months there was only 1 recurrence in the pCR group and patients with a pCR had significantly improved recurrence-free survival compared to patients without pCR (p = 0.004)., Conclusions: Despite variability in NT regimens across institutions, NT for melanoma is feasible and associated with improved prognosis in patients who achieve a pCR. Maximizing rates of pCR could improve prognosis for patients with advanced melanoma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Background: Patients with single primary melanomas have an increased risk of developing subsequent melanomas. Secondary tumors diagnosed within and after 3 months are termed "synchronous" and "asynchronous," respectively., Objective: To compare tumor distributions and survival characteristics between patients with second primary melanomas and those with single primary melanomas., Methods: Retrospective cohort study. Data were collected from an institutional database from 14,029 patients with a diagnosis of a primary melanoma seen between 1970 and 2004., Results: The synchronous and asynchronous cohorts demonstrated significantly improved survival probabilities compared with the single primary cohort (P = .04 and .002, respectively). Single primary lesions (2.2 ± 2.3 mm) were significantly thicker than the first-identified synchronous (2.0 ± 1.7 mm) and asynchronous (1.7 ± 1.3 mm) lesions. Synchronous lesions were more likely to be anatomically concordant compared with asynchronous lesions (55.7% vs 38.2%, P < .001)., Limitations: Single-center study design and incomplete records for second primary melanoma Breslow depth and histopathology., Conclusion: Patients with second primary melanomas demonstrated a significant survival advantage and thinner lesions compared with those with single primary melanomas. Our reported tumor distributions support the role of full body skin examinations, with attention to the region of initial diagnosis., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022. Published by Elsevier Inc.)

Background: Antitumor mechanisms of CD4 + T cells remain crudely defined, and means to effectively harness CD4 + T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4 + T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy., Methods: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8 + T-cell and B-cell knockout, CD4 + T-cell depletion, CD4 + T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans., Results: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4 + T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8 + T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy., Conclusion: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4 + T-cell help for antitumor CD8 + T cells, and implicates eosinophils as antitumor effectors of CD4 + T cells., Competing Interests: Competing interests: MCB, AD, DMA, DDB, SKN, and MG own intellectual property related to Lerapolturev, which has been licensed to Istari Oncology. MCB, AD, MG, and DDB received consultancy fees from Istari Oncology; MG and DDB hold equity in Istari Oncology. All other authors declare they have no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Multiple randomized controlled trials have influenced the current standard of care for patients with cutaneous melanoma. Since the development of targeted and immune therapy, studies of adjuvant therapy for patients with resected stage III/IV melanoma have led to the approval of combined B-raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase inhibitors for patients with a BRAF mutation, and cytotoxic T-lymphocyte associated protein-4 or antiprogrammed cell death-1 therapy for patients without a BRAF mutation. This article discusses the details of the trials that have influenced these treatment decisions, in addition to discussing ongoing trials and possible future directions., Competing Interests: Disclosure Dr Beasley: received clinical trial funding from Istari Oncology, Delcath, Oncosec Medical, Replimune, and Checkmate Pharmaceuticals paid to Duke University. Served one time on the advisory boards for Cardinal Health and Regeneron. Giorgos Karakousis: PI of Investigator Initiated Trial with institutional support by Merck. Advisory board: Merck., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome-heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity and contributes to the development of adaptive resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti-PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti-PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti-PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti-PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

Background: Although adult guidelines are often applied to children, age-specific surgical margins have not been defined for pediatric melanoma., Procedure: Patients &lt;20 years of age with invasive, cutaneous melanoma were identified using the 2004-2016 National Cancer Database and categorized as undergoing wide (&gt;1 cm) or narrow (≤1 cm) excision. Unadjusted overall survival (OS) was compared using the Kaplan-Meier method and log-rank test. Multivariable Cox proportional hazard models were used to estimate the effect of excision margin on OS after adjustment for available covariates., Results: In total, 2081 patients met study criteria: 1338 (64.3%) patients underwent wide excision whereas 743 (35.7%) underwent narrow excision. Unadjusted OS was improved in the narrow-excision group (log-rank p = .01), which was consistent among patients with thicker (&gt;1 mm) and thinner (≤1 mm) tumors. After adjustment for patient and tumor characteristics, we found no evidence of a difference in OS for patients who underwent narrow excision compared to patients who underwent wide excision (adjusted hazard ratio 0.57, 95% confidence interval 0.32-1.01, p = .053). There was no interaction between excision margin width and Breslow depth (p = .85), indicating that the effect of excision margin width on OS does not differ based on Breslow depth., Conclusions: In this analysis, wide excision (&gt;1 cm) does not appear to be associated with improved survival in children with melanoma regardless of tumor characteristics. Although further studies are needed to define optimal excision margins in pediatric melanoma, this study suggests that more narrow margins (≤1 cm) may be acceptable., (© 2022 Wiley Periodicals LLC.)

The presence of lymph node metastases is a well-studied prognostic factor for cutaneous melanoma. Characterization of melanoma lymph node metastases and their association with survival in multiple, large observational studies has led to recognition of the following high-risk features: quantity of lymph node metastases (number of nodes), size of the nodal tumor deposit (in mm), and extracapsular extension. Despite increasing utilization of these features in the design of randomized clinical trials, in addition to their role in contemporary clinical decision-making, current staging systems lag behind, only accounting for the quantity of lymph nodes with metastases. Herein, we review the prognostic role of melanoma lymph node metastases and their high-risk features, current reporting standards, how such features have been utilized in practice-changing trials, and best practices for future clinical trial design and clinical decision-making., 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 Rhodin, Fimbres, Burner, Hollander, O’Connor and Beasley.)

Background: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined., Methods: Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables., Results: Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and > 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with > 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%., Conclusions: A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials., (© 2022. Society of Surgical Oncology.)

Background: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes., Methods: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS)., Results: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND., Conclusion: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma., (© 2022. Society of Surgical Oncology.)

Background: We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells. In the current study, prelerapolturev and postlerapolturev tumor biopsies and blood were evaluated for biomarkers of response., Methods: The following analyses were performed on tumor tissue (n=11): (1) flow cytometric assessment of immune cell density, (2) NanoString Digital Spatial profiling of protein and the transcriptome, and (3) bulk RNA sequencing. Immune cell phenotypes and responsiveness to in vitro stimulation, including in vitro lerapolturev challenge, were measured in peripheral blood (n=12)., Results: Three patients who received anti-PD-1 therapy within 30 days of lerapolturev have a current median progression-free survival (PFS) of 2.3 years and had higher CD8+T cell infiltrates in prelerapolturev tumor biopsies relative to that of 7 patients with median PFS of 1.6 months and lower CD8+T cell infiltrates in prelerapolturev tumor biopsies. In peripheral blood, four patients with PFS 2.3 years (including three that received anti-PD-1 therapy within 30 days before lerapolturev and had higher pretreatment tumor CD8+T cell infiltrates) had significantly higher effector memory (CD8+, CCR7-, CD45RA-) but lower CD8+PD-1+ and CD4+PD-1+ cells compared with eight patients with median PFS 1.6 months. In addition, pretreatment blood from the four patients with median PFS 2.3 years had more potent antiviral responses to in vitro lerapolturev challenge compared with eight patients with median PFS 1.6 months., Conclusion: An inflamed pretreatment tumor microenvironment, possibly induced by prior anti-PD-1 therapy and a proficient peripheral blood pretreatment innate immune response (antiviral/interferon signaling) to lerapolturev was associated with long term PFS after intratumoral lerapolturev in a small cohort of patients. These findings imply a link between intratumoral T cell inflammation and peripheral immune function., Trial Registration Number: NCT03712358., Competing Interests: Competing interests: GMB reports clinical trial funding from Istari Oncology, Delcath, Oncosec Medical, Replimune, and Checkmate Pharmaceuticals paid to Duke University. AnS receives research funding paid to the institution from Bristol Myers Squibb, Immunocore, Merck, Pfizer Advisory roles; and has served on advisory boards for Array, Novartis, Iovance, and Regeneron. MCB, DDB and MG are paid consultants of Istari Oncology, Inc. and MG and DDB are scientific advisors for Istari Oncology; DDB and MG hold equity in Istari Oncology. MCB, DDB, MG and SKN own intellectual property related to this research, which has been licensed to Istari Oncology. Duke University (Licensor of PVSRIPO) has a financial interest in Istari Oncology. All other authors declare they have no competing interests., (© 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.)

Pump-probe microscopy of melanin in tumors has been proposed to improve diagnosis of malignant melanoma, based on the hypothesis that aggressive cancers disaggregate melanin structure. However, measured signals of melanin are complex superpositions of multiple nonlinear processes, which makes interpretation challenging. Polarization control during measurement and data fitting are used to decompose signals of melanin into their underlying molecular mechanisms. We then identify the molecular mechanisms that are most susceptible to melanin disaggregation and derive false-coloring schemes to highlight these processes in biological tissue. We demonstrate that false-colored images of a small set of melanoma tumors correlate with clinical concern. More generally, our systematic approach of decomposing pump-probe signals can be applied to a multitude of different samples.

Introduction: B cells are key regulators of immune responses in melanoma. We aimed to explore differences in the histologic location and activation status of B cell follicles in sentinel lymph nodes (SLN) of melanoma patients., Methods: Flow cytometry was performed on fresh tumor draining lymph nodes (LN). Paraffin slides from a separate cohort underwent NanoString Digital Spatial Profiling (DSP)®. After staining with fluorescent markers for CD20 (B cells), CD3 (T cells), CD11c (antigen presenting cells) and a nuclear marker (tumor) was performed, regions of interest (ROI) were selected based on the location of B cell regions (B cell follicles). A panel of 68 proteins was then analyzed from the ROIs., Results: B cell percentage trended higher in patients with tumor in LN (n=3) compared to patients with nSLN (n=10) by flow cytometry. B cell regions from a separate cohort of patients with tumor in the (pSLN) (n=8) vs. no tumor (nSLN) (n=16) were examined with DSP. Within B cell regions of the SLN, patients with pSLN had significantly higher expression of multiple activation markers including Ki-67 compared to nSLN patients. Among 4 patients with pSLN, we noted variability in arrangement of B cell follicles which were either surrounding the tumor deposit or appeared to be infiltrating the tumor. The B cell follicle infiltrative pattern was associated with prolonged recurrence free survival., Conclusion: These data suggest a role for B cell follicles in coordinating effective adaptive immune responses in melanoma when low volume metastatic disease is present in tumor draining LN., (Copyright © 2022 Therien, Beasley, Rhodin, Farrow, Tyler, Boczkowski, Al-Rohil, Holl and Nair.)

The smallest Platonic hydrocarbon, tetrahedrane, has been subject to frequent theoretical and experimental study for 50 years, but its infrared spectrum and synthetic pathway remain a mystery. The recent partial attribution of the ultraviolet extinction bump observed in the interstellar medium (ISM) of the Milky Way galaxy to hydrogenated T-carbon, a larger tetrahedral cluster formed from tetrahedrane and C 4 monomers, has brought renewed interest to the molecule. Similarly, as a polycyclic hydrocarbon, tetrahedrane is similar in structure to the molecules proposed to be responsible for the so-called unidentified infrared bands (UIRs) observed in all kinds of astronomical environments. Furthermore, tetrahedrane's ν 2 and ν 7 fundamental vibrational frequencies, with values of 3210.6 cm -1 (3.11 μm) and 752.5 cm -1 (13.29 μm) as computed in the present quantum chemical study, have substantial intensities of 59 and 183 km mol -1 , respectively. These come tantalizingly close to, but potentially distinct from, the 3.3 and 13.2 μm regions of the infrared spectrum typically included in the UIRs. As such, tetrahedrane or related clusters of these polycyclic aliphatic hydrocarbons may have a role to play in both of these sets of observations and could even help to explain the relation between them. Regardless, if tetrahedrane is present in the ISM, the highly-accurate theoretical data reported herein should help to aid in its identification and may assist in guiding future synthetic experiments as well.

This review describes the current body of literature and ongoing clinical trials examining neoadjuvant immune checkpoint inhibitors (ICI) for patients with resectable stage III and IV melanoma. Based on prior success in treating metastatic melanoma and as adjuvant therapy, ICIs are being explored in the neoadjuvant setting. There have been initial trials and there are many ongoing trials examining neoadjuvant ICI. Herein, we will review the clinical feasibility and efficacy of various neoadjuvant ICI regimens, explore pathologic and cellular responses, and present factors associated with predictive tumor response.

Background: In 2014, technetium-99m tilmanocept (TcTM) replaced technetium-99m sulfur colloid (TcSC) as the standard lymphoscintigraphy (LS) mapping agent in melanoma patients undergoing sentinel lymph node biopsy (SLNB). The aim of this study was to examine differences in mapping time, intra-operative identification of sentinel lymph node (SLN), and false negative rate (FNR) between patients who underwent SLNB with TcTM compared to TcSC., Methods: Patients who underwent SLNB between 2010 and 2018 were retrospectively identified. Patient demographic, tumor, and imaging data was stratified by receipt of TcSC (n = 258) or TcTM (n = 133). Student's t test and χ 2 test were used to compare characteristics and outcomes., Results: Both cohorts were similar in demographic, primary tumor characteristics, and total number of SLN identified (TcTM 3.56 vs. TcSC 3.28, p = 0.244). TcTM was associated with significantly shorter LS mapping times (51.8 vs. 195.1 min, p < 0.01). There was no significant difference in the number of patients with positive SLN (TcTM 11.3 vs. TcSC 17.4%, p = 0.109) and the FNR was similar between both groups (TcTM 25% vs. TcSC 22%)., Conclusion: TcTM was associated with significantly shorter LS mapping time while identifying similar numbers of SLN. Our results support further study to ensure similar FNR and oncologic outcomes between agents., (© 2021 Wiley Periodicals LLC.)

Malignant melanoma recurrence remains heterogeneous in presentation, ranging from locoregional disease (i.e., local recurrence, satellites, in transit disease) to distant dermal and visceral metastases. This diverse spectrum of disease requires a personalized approach to management and has resulted in the development of both local (e.g., surgery, radiation, intralesional injection) and systemic (intravenous or oral) treatment strategies. Intralesional agents such as oncolytic viruses may also evoke local immune stimulation to induce and enhance the antitumor immune response. Further, it is hypothesized that these oncolytic viruses may convert immunologically "cold" tumors to more reactive "hot" tumor microenvironments and thereby overcome anti-PD-1 therapy resistance. Currently, talimogene laherparepvec (T-VEC), a modified herpes virus, is FDA-approved in this population, with many other oncolytic viruses under investigation in both preclinical and trial settings. Herein, we detail the scientific rationale, current landscape, and future directions of oncolytic viruses in melanoma., Competing Interests: The authors declare no conflict of interest. GMB has received clinical trial funding paid to Duke University from Delcath, Istari, Replimune, Oncosec, Checkmate. GMB has done one-time advisory board for Cardinal Health, Regeneron. SKN is an inventor on patents licensed to Istari Oncology Inc., (© 2022 The Author(s). Published by IMR Press.)

Since the observation that clearance of all visible and microscopic tumors from cutaneous melanoma is critical to prevent a recurrence, wide surgical margins have been central to surgical dogma. In the last several decades, more conservative margin widths have been vigorously studied by surgical investigators to lessen wound complications, the need for reconstruction, and healthcare costs. This review summarizes surgeon-led clinical trials that define current guidelines and highlights the challenges to initiate and perform trials today., (© 2021 Wiley Periodicals LLC.)

Background: Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined., Methods: Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated., Results: Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients., Conclusion: Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences., (© 2021. Society of Surgical Oncology.)

Background: Although sentinel lymph node (SLN) biopsy is a standard procedure used to identify patients at risk for melanoma recurrence, it fails to risk-stratify certain patients accurately. Because processes in SLNs regulate anti-tumor immune responses, the authors hypothesized that SLN gene expression may be used for risk stratification., Methods: The Nanostring nCounter PanCancer Immune Profiling Panel was used to quantify expression of 730 immune-related genes in 60 SLN specimens (31 positive [pSLNs], 29 negative [nSLNs]) from a retrospective melanoma cohort. A multivariate prediction model for recurrence-free survival (RFS) was created by applying stepwise variable selection to Cox regression models. Risk scores calculated on the basis of the model were used to stratify patients into low- and high-risk groups. The predictive power of the model was assessed using the Kaplan-Meier and log-rank tests., Results: During a median follow-up period of 6.3 years, 20 patients (33.3%) experienced recurrence (pSLN, 45.2% [14/31] vs nSLN, 20.7% [6/29]; p = 0.0445). A fitted Cox regression model incorporating 12 genes accurately predicted RFS (C-index, 0.9919). Improved RFS was associated with increased expression of TIGIT (p = 0.0326), an immune checkpoint, and decreased expression of CXCL16 (p = 0.0273), a cytokine important in promoting dendritic and T cell interactions. Independent of SLN status, the model in this study was able to stratify patients into cohorts at high and low risk for recurrence (p < 0.001, log-rank)., Conclusions: Expression profiles of the SLN gene are associated with melanoma recurrence and may be able to identify patients as high or low risk regardless of SLN status, potentially enhancing patient selection for adjuvant therapy.

Background: Adjuvant radiation therapy (RT) can decrease lymph node basin (LNB) recurrences in patients with clinically evident melanoma lymph node (LN) metastases following lymphadenectomy, but its role in the era of modern systemic therapies (ST), immune checkpoint or BRAF/MEK inhibitors, is unclear., Patients and Methods: Patients at four institutions who underwent lymphadenectomy (1/1/2010-12/31/2019) for clinically evident melanoma LN metastases and received neoadjuvant and/or adjuvant ST with RT, or ST alone, but met indications for RT, were identified. Comparisons were made between ST alone and ST/RT groups. The primary outcome was 3-year cumulative incidence (CI) of LNB recurrence. Secondary outcomes included 3-year incidences of in-transit/distant recurrence and survival estimates., Results: Of 98 patients, 76 received ST alone and 22 received ST/RT. Median follow-up time for patients alive at last follow-up was 44.6 months. The ST/RT group had fewer inguinal node metastases (ST 36.8% versus ST/RT 9.1%; P = 0.04), and more extranodal extension (ST 50% versus ST/RT 77.3%; P = 0.02) and positive lymphadenectomy margins (ST 2.6% versus ST/RT 13.6%; P = 0.04). The 3-year CI of LNB recurrences was lower for the ST/RT group compared with the ST group (13.9% versus 25.2%), but this reduction was not statistically significant (P = 0.36). Groups did not differ significantly in in-transit/distant recurrences (P = 0.24), disease-free survival (P = 0.14), or melanoma-specific survival (P = 0.20)., Conclusions: In the era of modern ST, RT may still have value in reducing LNB recurrences in melanoma with clinical LN metastases. Further research should focus on whether select patient populations derive benefit from combination therapy, and optimizing indications for RT following neoadjuvant ST.

While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition., Competing Interests: Declaration of interests A.K.S. received research funding from Bristol Myers Squibb, Immunocore, and Merck. J.H.S. received research funding from A(∗)STAR Singapore, Curegenix, and Leap. J.H.S. has also received research funding and served on the scientific advisory board for OncoMed. B.A.H. received research funding from OncoMed, Merck, and Leap. B.A.H., N.C.D., and B.T. are authors on a patent describing paracrine Wnt ligand signaling as a predictive marker for cancer immunotherapy. V.N.D. is an employee of EDDC/A(∗)STAR and is an author on a patent on combining ETC-159 with pembrolizumab. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation., Methods: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections., Results: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months., Conclusion: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients., Trial Registration Number: NCT03712358., Competing Interests: Competing interests: SKN owns intellectual property related to this research, which has been licensed to Istari Oncology, Inc. DDB and MG have financial interest in Istari Oncology, Inc. Duke University (Licensor of PVSRIPO) has a financial interest in Istari Oncology, Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)