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Background: Sentinel lymph node status is critical for melanoma staging and treatment. However, the factors influencing SLNB and its oncologic benefits in elderly patients are unclear., Methods: We conducted a retrospective analysis of patients aged ≥65 with clinically node-negative melanoma and Breslow depth ≥1 ​mm, using Surveillance, Epidemiology, and End Results Medicare database (2010-2018). Multivariable logistic regression assessed SLNB likelihood by demographic and clinical factors, and Cox-proportional hazard models evaluated overall and melanoma-specific mortality (MSM) for SLNB recipients versus non-recipients., Results: Of 13,160 melanoma patients, 62.29 ​% underwent SLNB. SLNB was linked to reduced all-cause mortality (HR: 0.65 [95%CI 0.61-0.70]) and MSM (HR: 0.76 [95%CI 0.67-0.85]). Older age, non-White race, male sex, and unmarried status was associated with decreased SLNB likelihood, while cardiopulmonary, neurologic, and secondary cancer comorbidities were associated with increased SLNB likelihood., Conclusions: Though less frequently performed, SLNB is associated with lower mortality in elderly melanoma patients. Advanced age alone should not contraindicate SLNB., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest regarding the publication of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (PDX) tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM., Competing Interests: CONFLICT OF INTEREST STATEMENTS: The authors declare no conflict of interest.

The objective of this study was to evaluate the feasibility of developing personalized, tumor-informed assays for patients with high-risk resectable melanoma and examine circulating tumor DNA (ctDNA) levels in relation to clinical status. Pilot prospective study of clinical stage IIB/C and resectable stage III melanoma patients. Tumor tissue was used to design bespoke somatic assays for interrogating ctDNA in patients' plasma using a multiplex PCR (mPCR) next-generation sequencing (NGS)-based approach. Plasma samples for ctDNA analysis were collected pre-/post-surgery and during surveillance. Out of 28 patients (mean 65 years, 50% male), 13 (46%) had detectable ctDNA prior to definitive surgery and 96% (27/28) tested ctDNA-negative within 4 weeks post-surgery. Pre-surgical detection of ctDNA was significantly associated with the later-stage ( P  = 0.02) and clinically evident stage III disease ( P  = 0.007). Twenty patients continue in surveillance with serial ctDNA testing every 3-6 months. With a median follow-up of 443 days, six out of 20 (30%) patients developed detectable ctDNA levels during surveillance. All six of these patients recurred with a mean time to recurrence of 280 days. Detection of ctDNA in surveillance preceded the diagnosis of clinical recurrence in three patients, was detected concurrent with clinical recurrence in two patients and followed clinical recurrence in one patient. One additional patient developed brain metastases without detection of ctDNA during surveillance but had positive pre-surgical ctDNA. Our results demonstrate the feasibility of obtaining a personalized, tumor-informed mPCR NGS-based ctDNA assay for patients with melanoma, particularly in resectable stage III disease., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown., Methods: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated., Results: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group., Conclusions: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods., Methods: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups., Results: 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity., Conclusions: Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The present study aimed to determine the isoform-specific role of the NADPH oxidases (NOX) in the endothelium-mediated vascular dysfunction associated with ageing. Endothelium-dependent [intraluminal flow- and acetylcholine (ACh)-induced] vasodilatation in human skeletal muscle feed arteries (SMFAs) of young (24 ± 1 years, n = 16), middle aged (45 ± 1 years, n = 18) and old (76 ± 2 years, n = 21) subjects was assessed in vitro with and without the inhibition of NOX1 (ML090), NOX2 (gp91) and NOX4 (plumbagin). To identify the role of nitric oxide (NO) bioavailability in these responses, NO synthase blockade (l- NG -monomethyl arginine citrate) was utilized. SMFA NOX1, NOX2 and NOX4 protein expression was determined by western blotting. Age related endothelium-dependent vasodilatory dysfunction was evident in response to flow (young: 69 ± 3; middle aged: 51 ± 3; old: 27 ± 3%, P < 0.05) and ACh (young: 89 ± 2; middle aged: 72 ± 3; old: 45 ± 4%, P < 0.05). NOX1 inhibition had no effect on SMFA vasodilatation, whereas NOX2 inhibition restored flow- and ACh-induced vasodilatation in the middle aged and the old SMFAs (middle aged + gp91: 69 ± 3; 86 ± 3, old + gp91: 65 ± 5; 83 ± 2%, P < 0.05) and NOX4 inhibition tended to restore these vasodilatory responses in these two groups, but neither achieved statistical significance (P ≈ 0.06). l- NG -monomethyl arginine citrate negated the restorative effects of NOX2 and NOX4 blockade. Only NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function (r = 0.48 to 0.93, P < 0.05). NOX2 and, to a lesser extent, NOX4 appear to play an important, probably NO-mediated, role in age-related endothelial dysfunction. KEY POINTS: The present study aimed to determine the isoform-specific role of the NADPH oxidases (NOX) in the endothelium-mediated vascular dysfunction associated with ageing. Age related endothelium-dependent vasodilatory dysfunction was evident in skeletal muscle feed arteries in response to both flow and acetylcholine. NOX2 inhibition (gp91) restored endothelium-dependent vasodilatation in the middle aged and the old skeletal muscle feed arteries, and NOX4 inhibition (plumbagin) tended to restore these vasodilatory responses in these two groups. Nitric oxide synthase inhibition negated the restorative effects of NOX2 and NOX4 blockade. NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function. NOX2 and, to a lesser extent, NOX4 appear to play an important, probably nitric oxide-mediated, role in age-related endothelial dysfunction and could be important therapeutic targets to maintain vascular health with ageing., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Background: Intratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma., Methods: Adult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy., Results: Fifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each)., Conclusions: Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies., Competing Interests: Competing interests: BDC: data safety monitoring board for Merck; institutional funding from Bristol Myers Squibb and Viralytics; honoraria from Cullinan Oncology, Nektar Therapeutics, and Clinigen. JR: none. JRH: institutional funding from Merck, BMS, Takara, and Amgen; advisory boards for BMS/Nektar Therapeutics. GAD: none. MF: advisory boards for Merck, Bristol Myers Squibb, Novartis, Nektar, Sanofi, and Array Biopharma. LF: none. KAM: consultant for ImaginAb, Oncosec, Werewolf, Xilio, Instil, IOvance, and Checkmate Pharmaceuticals; institutional funding from Merck, BMS, Roche, BioNTech, Checkmate Pharmaceuticals, IO Biotech, Regeneron, and Agenus. SH: none. MG: consultant/independent contractor (contracted directly by Viralytics). YZ and AL: employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA and stockholders in Merck & Co, Inc, Rahway, New Jersey, USA. RHIA: institutional research funding from Viralytics; in the past 3 years, employee of Seven and Eight Biopharmaceuticals Inc., (© 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.)

Background: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine tumor that primarily affects elderly patients. Despite aggressive treatment, overall survival (OS) remains low., Methods: This study is a multi-institutional, retrospective review of 102 patients with MCC. We evaluated OS, disease-specific survival (DSS), and risk factors for recurrence., Results: Median age of patients was 71.46% of patients recurred. Patients with stage I disease had median 5-year OS of 59.3%, compared to 68.1% DSS. For stage III, median 5-year OS was 46.0% vs 58.2% DSS. Disease stage and advanced age were risk factors for recurrence and decreased OS. Immunocompromised status and disease stage were the strongest predictors of DSS., Conclusions: DSS is significantly better than OS for patients with MCC. Many elderly patients with newly diagnosed MCC have low remaining life expectancy, regardless of their MCC diagnosis. Patient age and overall health status should be considered to personalize care plans for patients with MCC., (Published by Elsevier Inc.)

Introduction: Anti-PD-1 antibodies are commonly used as frontline therapy for patients with metastatic melanoma. Although these medications can cause long term responses, a significant number of patients will not respond or will lose response. Optimal second-line therapy after losing response to anti-PD-1 antibodies is not well established. Therefore, we retrospectively compared the overall survival of patients who lost response to anti-PD1 antibodies between patients treated with single agent ipilimumab or ipilimumab and nivolumab., Methods: A de-identified U.S. nationwide electronic health record-derived database was reviewed for patients with advanced melanoma treated with single agent anti-PD1 antibodies in the frontline setting and who subsequently received second-line ipilimumab or combination ipilimumab and nivolumab. Overall survival from initiation of second-line therapy was compared using Kaplan Meier curves and log-rank analysis. Other known prognostic markers for melanoma were analyzed for correlation with survival in a similar fashion. Disease characteristics between the two groups were compared using chi-square analysis., Results: A total of 842 patients with advanced melanoma who received frontline anti-PD-1 antibodies were included for analysis. Of these, 57 received either ipilimumab ( n  = 22) or ipilimumab in combination with nivolumab ( n  = 35) in the second-line setting. Median survival from second-line therapy initiation for those treated with ipilimumab alone was 6 months and was 5.6 months for those treated with combination ipilimumab and anti-PD-1 antibodies, p  = 0.81., Conclusions: In this small, retrospective analysis, for patients who lost response to frontline anti-PD-1 therapy, patients treated with ipilimumab had similar survival to those who received ipilimumab in combination with anti-PD-1 antibodies.

Background: Anorectal melanoma (ARM) is a rare disease with a poor prognosis. Evidence on optimal treatment is limited and surgical management varies widely. We hypothesized that the frequency of abdominoperineal resection used as primary treatment of ARM has decreased over the past several decades., Aim: To update our understanding of outcomes for patients with ARM and analyze management trends around the world., Methods: This is a multi-institutional, retrospective study of patients treated for ARM at 7 hospitals. Hospitals included both large, academic, tertiary care centers and smaller, general community hospitals. Using prospectively maintained institutional tumor registries, we identified 24 patients diagnosed with ARM between January 2000 and May 2019. We analyzed factors prognostic for recurrence and survival. We then used Cox regression to measure overall survival (OS) and melanoma-specific survival. We also performed a literature review to assess trends in surgical management and outcomes., Results: Of the 24 patients diagnosed with ARM, 12 (50.0%) had local, 8 (33.3%) regional, and 4 (16.7%) distant disease at diagnosis. Median time to recurrence was 10.4 mo [interquartile range (IQR) 7.5-17.2] with only 2 patients (9.3%) not developing recurrence following surgical resection. Median OS was 18.8 mo (IQR 13.5-33.9). One patient is still alive without recurrence at 21.4 mo from diagnosis; no other patient survived 5 years. Primary surgical management with abdominoperineal resection (APR) vs wide excision (WE) did not lead to differences in OS [hazard ratio = 1.4 (95%CI: 0.3-6.8)]. Review of the literature revealed geographic differences in surgical management of ARM, with increased use of WE in the United States and Europe over time and more frequent use of APR in Asia and India. There was no significant improvement in survival over time., Conclusion: There is wide variation in the management of ARM and survival outcomes remain poor regardless of approach. Surgical management should aim to minimize morbidity., Competing Interests: Conflict-of-interest statement: I confirm that I have no financial disclosures to declare. As the corresponding author for this manuscript, I also declare that none of my co-authors have financial disclosures to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Objectives: The relatively recent availability of effective systemic therapies for metastatic melanoma necessitates reconsideration of current surveillance patterns. Evidence supporting surveillance guidelines for resected Stage II melanoma is lacking. Prior reports note routine imaging detects only 21% of recurrent disease. This study aims to define recurrence patterns for Stage II melanoma to inform future surveillance guidelines., Methods: This is a retrospective study of patients with Stage II melanoma. We analyzed risk factors for recurrence and methods of recurrence detection. We also assessed survival. Yearly hazards of recurrence were visualized., Results: With a median follow-up of 4.9 years, 158 per 580 patients (27.2%) recurred. Overall, most recurrences were patient-detected (60.7%) or imaging-detected (27.3%). Routine imaging was important in detecting recurrence in patients with distant recurrences (adjusted rate 43.1% vs. 9.4% for local/in-transit; p = .04) and with Stage IIC melanoma (42.5% vs. 18.5% for IIA; p = .01). Male patients also self-detected recurrent disease less than females (52.1% vs. 76.8%; p < .01)., Conclusions: Routine imaging surveillance played a larger role in detecting recurrent disease for select groups in this cohort than noted in prior studies. In an era of effective systemic therapy, routine imaging should be considered for detection of asymptomatic relapse for select, high-risk patient groups., (© 2020 Wiley Periodicals LLC.)

Surgical management of external ear melanoma presents unique technical challenges based on the unique anatomy and reconstruction concerns. Surgical technique, including preservation of cartilage, is variable and impact on recurrence is unclear. Our goal was to investigate surgical approach, including extent of surgical resection and sentinel lymph node biopsy (SLNB), and the impact on recurrence. In this retrospective review of primary clinical stage 1/2 external ear melanoma, demographics, tumor characteristics, surgical resection technique (including cartilage-sparing vs. cartilage removal), and SLNB results were evaluated for recurrence risk. One hundred and fifty-six patients total had an average follow-up of 5.6 years. Twenty-nine (18.6%) patients underwent cartilage-sparing surgery and 99 (63.5%) patients underwent SLNB, 14.1% of whom had micrometastatic disease. Ten (6.4%) patients recurred loco-regionally. Recurrence was associated with Breslow depth, initial stage at diagnosis, and SLNB status. Cartilage-sparing surgery was not associated with increased recurrence. Sentinel lymph node identification rate was 100% based on clinical detection with use of lymphoscintigraphy. In addition to confirming established risk factors for melanoma recurrence, we confirm the feasibility of SLNB in stratifying recurrence risk. Although we did not see an increased recurrence risk with surgical technique and cartilage-sparing approaches, these findings are limited by small sample size.

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s -1 ·mg -1 ; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s -1 ·mg -1 ). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated ( r  = 0.49-0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals. NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.

Background: Pembrolizumab (P) and nivolumab (N) are commonly used therapies for advanced melanoma. However, their effectiveness has never been directly compared, leaving little guidance for clinicians to select the best therapy. Therefore, we sought to retrospectively compare the overall survival of patients with metastatic melanoma treated with front line P or N in the real-world setting. Material and methods: This study included patients with advanced melanoma, diagnosed between 1 January 2011 and 31 July 2018, treated with frontline P or N who were included in a nationwide, longitudinal de-identified electronic health record (EHR)-derived database. Overall survival (OS) was estimated for each treatment group using Kaplan-Meier curves with a log-rank test. Comparison of OS was estimated using an inverse probability weighting model to reduce bias between the groups. The model was adjusted using age, sex, ECOG, LDH (elevated or not), BRAF (mutated or not), Kit (mutated or not), NRAS (mutated or not), PD-L1 expression (0% or greater), Body Mass Index, and primary site. Results: 888 patients with advanced disease who received treatment with frontline P ( n  = 486) or N ( n  = 402) were identified. Median OS for all patients treated with P was 22.6 months (m) and was 23.9 m for those treated with N ( p  = 0.91). In the inverse probability weight analysis there was no difference in survival between patients treated with P or N 1.06 (95% CI 0.84-1.33). Concluding Statement: In our retrospective, real-world analysis of patients with advanced melanoma, no statistical difference in OS was noted between patients treated with frontline P compared to N. This supports the current practice of choosing either P or N based on patient and provider preference.

Background: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi., Methods: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival., Results: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses., Conclusions: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Key Points: The present study aimed to determine the impact of ageing on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression falls progressively with advancing age in the human peripheral vasculature. Endothelial-dependent vasodilatation, typically attenuated with age, was strongly correlated with SMFA adropin protein levels. Adropin incubation restored age-related endothelial-dependent vasodilatory dysfunction and increased the phosphorylated endothelial nitric oxide synthase (eNOS)/eNOS ratio in an age-dependent manner in the SMFAs. The role of nitric oxide bioavailability was additionally indicated by NOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression. Additional evidence of a mechanistic link between declining adropin and age-related endothelial dysfunction was documented by a progressively increasing magnitude of effect of adropin-induced eNOS-mediated vasodilatation with ageing. Adropin appears to be a novel therapeutic target for facilitating the restoration of endothelial function with ageing., Abstract: The present study aimed to determine the impact of advancing age on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression and vasodilatory capacity was assesed in SMFAs from Young (27 ± 2 years, n = 10), Middle Aged (54 ± 2 years, n = 10) and Old (75 ± 2 years, n = 16) subjects. Endothelial-dependent vasodilatation, with and without adropin incubation, was assessed in response to flow-induced shear stress and ACh. Both SMFA adropin protein expression and endothelial-dependent vasodilatory function exhibited a progressive, age-related, reduction (Flow: Y: 65 ± 3%; Middle Aged: 36 ± 3%; Old: 15 ± 2%; ACh: Young: 63 ± 2%, Middle Aged: 34 ± 3%; Old: 23 ± 3%, P < 0.05). There was a strong positive correlation between SMFA adropin protein expression and both flow (r = 0.81, P < 0.05) and ACh (r = 0.78, P < 0.05). Adropin incubation in the Middle Aged and Old SMFAs restored the vasodilatory response to flow (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 47 ± 3%, P < 0.05) and ACh (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 49 ± 2%, P < 0.05). A mechanistic link between adropin and nitric oxide (NO) biovavailabilty was supported by (i) increased phosphorylated endothelial NO synthase (eNOS)/eNOS protein expression with adropin incubation only in the Middle Aged and Old SMFAs; (ii) eNOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression and (iii) a progressive increase in the magnitude of effect of adropin-induced eNOS-mediated vasodilatation with advancing age. Adropin could be a novel therapeutic target for facilitating the restoration of endothelial function via increased NO bioavailability, with advancing age., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Pelvic sentinel lymph nodes (SLNs) are commonly identified during inguinal SLN biopsy for melanoma, but retrieval is not uniform among surgeons/centers. Few studies have assessed rates of micrometastases in pelvic versus superficial inguinal SLNs. Previous studies suggested that presence of pelvic SLNs was predicted by aggressive pathologic features and that their presence portended a worse prognosis. The objectives of this study were to examine presurgical predictors of pelvic SLNs among patients undergoing inguinal SLN biopsy, assess rates of micrometastases in superficial inguinal versus pelvic SLNs, and determine whether presence of pelvic SLNs was associated with long-term outcomes. Multivariable regression was used to assess presurgical factors associated with presence of pelvic SLNs. Rates of micrometastases in superficial inguinal versus pelvic SLNs in patients who had a pelvic SLN were compared with McNemar's test. Groin recurrence, disease-free survival (DFS), and disease-specific survival were analyzed by Kaplan-Meier method. A multivariable Cox model for DFS was performed. Pelvic SLNs were retrieved in 100/537 (18.6%) superficial inguinal SLN biopsies and no preoperative factors predicted their presence. In patients with a pelvic SLN, micrometastases were present in 3.0% of pelvic versus 34.0% of superficial inguinal SLN biopsies (P<0.001). There were no differences in groin recurrence, DFS, and disease-specific survival for patients with/without pelvic SLNs in univariate analyses (all P>0.2) or in the multivariable Cox model for DFS (hazard ratio: 1.1, 95% confidence interval: 0.6-2.1). In conclusion, pelvic SLNs harbor micrometastases less frequently than superficial inguinal SLNs do, suggesting that omission of pelvic SLN biopsy may be reasonable.

Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I + II (CI+II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s -1 ·mg -1 and CI+II: 12.4 ± 0.8 pmol·s -1 ·mg -1 , P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s -1 ·mg -1 and CI+II: 8.3 ± 0.5 pmol·s -1 ·mg -1 ) and old (CI: 7.2 ± 0.4 pmol·s -1 ·mg -1 and CI+II: 7.6 ± 0.5 pmol·s -1 ·mg -1 ) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [ r = -0.56 (CI), r = -0.7 (CI+II), and r = 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = -0.71, P < 0.05). As CS activity was inversely correlated with age ( r = -0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s -1 ·mg -1 ·U CS -1 , P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s -1 ·mg -1 ·U CS -1 , respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.

Background and Objectives: Close observation may be an appropriate alternative to completion lymph node dissection (CLND) for selected patient populations, especially those with minimal tumor burden in the sentinel lymph node (SLN). In this study, we examined the practice patterns of CLND utilization., Methods: Using the National Cancer Database, we examined CLND utilization in SLN-positive patients diagnosed with clinically node-negative Stage III melanoma from 2012 to 2015. Hierarchical logistic regression models were constructed to assess the factors associated with observation after positive SLN biopsy (SLNB)., Results: Of the 131 171 patients identified, 55 688 (42.5%) underwent SLNB and 7200 (12.9%) had an SLN with a metastatic disease. CLND was performed in 57.0% of the patients with a positive SLNB. Patients were more likely to forgo CLND if the primary tumor was located on the lower extremity (odds ratio [OR], 1.65, 95% confidence interval [CI], 1.40-1.94), were older (P < 0.001), had multiple comorbidities (OR, 1.61, 95% CI, 1.19-2.20), or were diagnosed with melanoma in 2015 (OR, 1.33, 95% CI, 1.13-1.56 vs 2012)., Conclusions: CLND utilization varied based on patient factors and decreased over time. As evidence supports close observation in selected patient populations with low SLN tumor burden, monitoring is needed to ensure that CLND is performed in the appropriate patient populations. However, this will require improvements in the data collected by cancer registries., (© 2018 Wiley Periodicals, Inc.)

Aim: This study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs)., Methods: A total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP)., Results: MitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade., Conclusion: This study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age., (© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

New Findings: What is the central question of this study? We sought to determine whether human skeletal muscle feed arteries (SFMAs) express TRPV 1 channels and what role they play in modulating vascular function. What is the main finding and its importance? Human SMFAs do express functional TRPV 1 channels that modulate vascular function, specifically opposing α-adrenergic receptor-mediated vasocontraction and potentiating vasorelaxation, in an endothelium-dependent manner, as evidenced by the α 1 -receptor-mediated responses. Thus, the vasodilatory role of TRPV 1 channels, and their ligand capsaicin, could be a potential therapeutic target for improving vascular function. Additionally, given the 'sympatholytic' effect of TRPV 1 activation and known endogenous activators (anandamide, reactive oxygen species, H + , etc.), TRPV 1 channels might contribute to functional sympatholysis during exercise. To examine the role of the transient receptor potential vanilloid type 1 (TRPV 1 ) ion channel in the vascular function of human skeletal muscle feed arteries (SMFAs) and whether activation of this heat-sensitive receptor could be involved in modulating vascular function, SMFAs from 16 humans (63 ± 5 years old, range 41-89 years) were studied using wire myography with capsaicin (TRPV 1 agonist) and without (control). Specifically, phenylephrine (α 1 -adrenergic receptor agonist), dexmedetomidine (α 2 -adrenergic receptor agonist), ACh and sodium nitroprusside concentration-response curves were established to assess the role of TRPV 1 channels in α-receptor-mediated vasocontraction as well as endothelium-dependent and -independent vasorelaxation, respectively. Compared with control conditions, capsaicin significantly attenuated maximal vasocontraction in response to phenylephrine [control, 52 ± 8% length-tension max (LT max ) and capsaicin, 21 ± 5%LT max ] and dexmedetomidine (control, 29 ± 12%LT max and capsaicin, 2 ± 3%LT max ), while robustly enhancing maximal vasorelaxation with ACh (control, 78 ± 8% vasorelaxation and capsaicin, 108 ± 13% vasorelaxation) and less clearly enhancing the sodium nitroprusside response. Denudation of the endothelium greatly attenuated the maximal ACh-induced vasorelaxation equally in the control and capsaicin conditions (∼17% vasorelaxation) and abolished the attenuating effect of capsaicin on the maximal phenylephrine response (denuded + capsaicin, 61 ± 20%LT max ). Immunohistochemistry identified a relatively high density of TRPV 1 channels in the endothelium compared with the smooth muscle of the SMFAs, but because of the far greater volume of smooth muscle, total TRPV 1 protein content was not significantly attenuated by denudation. Thus, SMFAs ubiquitously express functional TRPV 1 channels, which alter vascular function, in terms of α 1 -receptors, in a predominantly endothelium-dependent manner, conceivably contributing to the functional sympatholysis and unveiling a therapeutic target., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Background: Cutaneous carcinosarcoma is a rare tumor with distinct malignant epithelial and mesenchymal cell populations. The histologic subtypes of epithelial and mesenchymal components in cutaneous carcinosarcoma are variable, as an assortment of carcinomatous and sarcomatous patterns have been described in the literature., Methods: Clinical information was obtained from patient charts and archival slides were retrieved and reviewed., Results: We present a novel series of six distinct cases of cutaneous carcinosarcoma and review the literature. Our cases consisted of basal cell, pilomatrical, squamous cell, and trichoblastic variants. These cases occurred in elderly men on sun exposed skin with treatment and follow up was available for 4 of 6 cases. The four cases were treated with Mohs micrographic surgery with mean follow up of nine months., Conclusion: We report six cases of cutaneous carcinosarcoma with distinctive clinical and histologic characterization not previously described in a single series., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy., Results: There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses., Experimental Design: Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks., Conclusions: Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

Although advancing age is often associated with attenuated skeletal muscle blood flow and skeletal muscle feed arteries (SMFAs) have been recognized to play a regulatory role in the vasculature, little is known about the impact of age on the vasodilatory capacity of human SMFAs. Therefore, endothelium-dependent and -independent vasodilation were assessed in SMFAs (diameter: 544 ± 63 μm) obtained from 24 (equally represented) young (33 ± 2 yr) and old (71 ± 2 yr) subjects in response to three stimuli: 1) flow-induced shear stress, 2) ACh, and 3) sodium nitropusside (SNP). Both assessments of endothelium-dependent vasodilation, flow (young subjects: 68 ± 1% and old subjects: 32 ± 7%) and ACh (young subjects: 92 ± 3% and old subjects: 73 ± 4%), were significantly blunted (P < 0.05) in SMFAs of old compared with young subjects, with no such age-related differences in endothelium-independent vasodilation (SNP). In response to an increase in flow-induced shear stress, vasodilation kinetics (time constant to reach 63% of the amplitude of the response: 55 ± 1 s in young subjects and 92 ± 7 s in old subjects) and endothelial nitric oxide synthase (eNOS) activation (phospho-eNOS(s1177)/total eNOS: 1.0 ± 0.1 in young subjects and 0.2 ± 0.1 in old subjects) were also significantly attenuated in old compared with young subjects (P < 0.05). Furthermore, the vessel superoxide concentration was greater in old subjects (old subjects: 3.9 ± 1.0 area under curve/mg and young subjects: 1.7 ± 0.1 area under the curve/mg, P < 0.05). These findings reveal that the endothelium-dependent vasodilatory capacity, including vasodilation kinetics but not smooth muscle function, of human SMFAs is blunted with age and may be due to free radicals. Given the potential regulatory role of SMFAs in skeletal muscle blood flow, these findings may explain, at least in part, the often observed attenuated perfusion of skeletal muscle with advancing age that may contribute to exercise intolerance in the elderly.

The purpose of this study was to determine if heat inhibits α2-adrenergic vasocontraction, similarly to α1-adrenergic contraction, in isolated human skeletal muscle feed arteries (SMFA) and elucidate the role of the temperature-sensitive vanilloid-type transient receptor potential (TRPV) ion channels in this response. Isolated SMFA from 37 subjects were studied using wire myography. α1 [Phenylephrine (PE)]- and α2 [dexmedetomidine (DEX)]-contractions were induced at 37 and 39°C with and without TRPV family and TRPV4-specific inhibition [ruthenium red (RR) and RN-1734, respectively]. Endothelial function [acetylcholine (ACh)] and smooth muscle function [sodium nitroprusside (SNP) and potassium chloride (KCl)] were also assessed under these conditions. Heat and TRPV inhibition was further examined in endothelium-denuded arteries. Contraction data are reported as a percentage of maximal contraction elicited by 100 mM KCl (LTmax). DEX elicited a small and variable contractile response, one-fifth the magnitude of PE, which was not as clearly attenuated when heated from 37 to 39°C (12 ± 4 to 6 ± 2% LTmax; P = 0.18) as were PE-induced contractions (59 ± 5 to 24 ± 4% LTmax; P < 0.05). Both forms of TRPV inhibition restored PE-induced contraction at 39°C (P < 0.05) implicating these channels, particularly the TRPV4 channels, in the heat-induced attenuation of α1-adrenergic vasocontraction. TRPV inhibition significantly blunted ACh relaxation while denudation prevented heat-induced sympatholysis without having an additive effect when combined with TRPV inhibition. In conclusion, physiological increases in temperature elicit a sympatholysis-like inhibition of α1-adrenergic vasocontraction in human SMFA that appears to be mediated by endothelial TRPV4 ion channels.

Unlike cardiac and skeletal muscle, little is known about vascular smooth muscle mitochondrial respiration. Therefore, the present study examined mitochondrial respiratory rates in smooth muscle of healthy human feed arteries and compared with that of healthy cardiac and skeletal muscles. Cardiac, skeletal, and smooth muscles were harvested from a total of 22 subjects (53 ± 6 yr), and mitochondrial respiration was assessed in permeabilized fibers. Complex I + II, state 3 respiration, an index of oxidative phosphorylation capacity, fell progressively from cardiac to skeletal to smooth muscles (54 ± 1, 39 ± 4, and 15 ± 1 pmol·s(-1)·mg(-1), P < 0.05, respectively). Citrate synthase (CS) activity, an index of mitochondrial density, also fell progressively from cardiac to skeletal to smooth muscles (222 ± 13, 115 ± 2, and 48 ± 2 μmol·g(-1)·min(-1), P < 0.05, respectively). Thus, when respiration rates were normalized by CS (respiration per mitochondrial content), oxidative phosphorylation capacity was no longer different between the three muscle types. Interestingly, complex I state 2 normalized for CS activity, an index of nonphosphorylating respiration per mitochondrial content, increased progressively from cardiac to skeletal to smooth muscles, such that the respiratory control ratio, state 3/state 2 respiration, fell progressively from cardiac to skeletal to smooth muscles (5.3 ± 0.7, 3.2 ± 0.4, and 1.6 ± 0.3 pmol·s(-1)·mg(-1), P < 0.05, respectively). Thus, although oxidative phosphorylation capacity per mitochondrial content in cardiac, skeletal, and smooth muscles suggest all mitochondria are created equal, the contrasting respiratory control ratio and nonphosphorylating respiration highlight the existence of intrinsic functional differences between these muscle mitochondria. This likely influences the efficiency of oxidative phosphorylation and could potentially alter ROS production.

Background: We evaluated the role of intraoperative radiation therapy (IORT) during radical resection of locally advanced colorectal cancer (CRC)., Methods: We retrospectively evaluated all patients with CRC treated with IORT at our institution from 2001 to 2010. IORT was delivered using high-dose-rate brachytherapy (median 12.5-Gy). We analyzed factors associated with postoperative morbidity, local control (LC), and overall survival (OS)., Results: One hundred patients were evaluated with 70% received IORT for recurrent tumors. R0 resection rate was 58%. Postoperative Grade ≥3 complications (33%) were independently associated with transfusions ≥3 units packed red blood cells (P = 0.016) and body mass index (BMI) ≥35 (P = 0.0499). Eighty-two patients underwent external beam radiation therapy (EBRT) before IORT. Five-year LC was 94%, for primary and 56%, for recurrent tumors, respectively (P = 0.007). Microscopic positive (R1) margins were not associated with LC (P = 0.316). BMI ≥30 (P = 0.048) and post-discharge complications (P = 0.041) were independent risk factors for worse LC. Median post-IORT OS was 67.7 (95% CI 51.1-84.3) months for all patients., Conclusion: For patients with primary or recurrent locally advanced CRC, treatment with radical surgery and IORT achieved excellent LC outcomes irrespective of microscopic margin status. IORT may be indicated for tumors suspected to have close or positive microscopic margins., (© 2014 Wiley Periodicals, Inc.)

We aimed to prospectively assess limb volume change (LVC) and associated symptoms in patients with melanoma undergoing sentinel lymph node biopsy and/or therapeutic lymph node dissection. Limb volume was measured preoperatively and postoperatively at 6 and 12 months using a perometer (1000 mol/l). LVC was calculated and used to define three groups: less than 5%, 5-10%, and greater than 10%. A 19-item lymphedema symptom questionnaire was administered at baseline, 6, and 12 months. One hundred and eighty-two patients were enrolled. Twelve months after axillary surgery, 9% had LVC 5-10% and 13% had LVC greater than 10%. Twelve months after inguinofemoral surgery, 10% had LVC 5-10% and 13% had LVC greater than 10%. There was a significant seven- to nine-fold increase in symptoms for patients with LVC greater than 10% compared with those with LVC less than 5% (P<0.05). On multivariate analysis, therapeutic lymph node dissection versus sentinel lymph node biopsy (odds ratio=3.18; P<0.01) and borderline significance for lower-extremity versus upper-extremity procedures (odds ratio=1.72; P=0.07) were associated with LVC greater than 5%. LVC greater than 5% is common at 12 months following nodal surgery for melanoma and is associated with symptoms. Informed consent for melanoma patients undergoing lymph node surgery should include a discussion of the risks of postoperative lymphedema.

Purpose: We evaluated clinical features and survival outcomes among patients with signet ring and mucinous histologies of colorectal adenocarcinoma by using data from the National Cancer Data Base (NCDB)., Methods: Patients aged 18-90 years with colorectal adenocarcinoma diagnosed between 1998 and 2002 were identified from the NCDB. Site-stratified (colon vs. rectum) survival analysis was performed by multivariate relative survival adjusted for multiple clinicopathologic and treatment variables., Results: The study included 244,794 patients: 25,546 (10%) with mucinous, 2,260 (1%) with signet ring, and 216,988 (89%) with nonmucinous, non-signet ring adenocarcinoma. Mucinous and signet ring cancers were more frequently right-sided (60% and 62%, respectively) than were nonmucinous, non-signet ring adenocarcinomas (42%, P < 0.001). Signet ring histology was associated with a higher stage (P < 0.001), and 77.2% of signet ring tumors were high-grade lesions, compared with 20% of mucinous and 17% of non-signet ring, nonmucinous adenocarcinomas (P < 0.001). After adjustment for covariates, signet ring histology was independently associated with higher risk of death [hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51, and HR 1.57, CI 1.38-1.77, for tumors located in the colon and rectum, respectively]. Mucinous tumors of the rectum (HR 1.22, CI 1.16-1.29), but not the colon (HR 1.03, CI 1.00-1.06), were associated with increased risk of death., Conclusions: Signet ring cell adenocarcinomas of the colon and rectum and mucinous adenocarcinomas of the rectum are associated with poorer survival. These aggressive histologic variants of colorectal adenocarcinoma should be targeted for research initiatives to improve outcomes.

Patients with locally advanced esophageal carcinoma have consistently poor survival following surgery with associated high systemic and local-regional failure rates. Neoadjuvant therapeutic strategies have been employed in an attempt to improve outcome with variable success. Randomized trials of either neoadjuvant chemotherapy or chemoradiotherapy have shown conflicting results regarding survival and local-regional control. Future efforts should focus on identifying novel agents and targets to improve therapeutic efficacy.