Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma.

Importance: While smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined. Objective: To determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma. Design, Setting, and Participants: This cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023. Exposure: Current, former, and never smoking. Main Outcomes and Measures: Melanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)-negative and SLNB-positive findings. Results: Of 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P < .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P < .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.

Analysis of 10-year trends in Medicare Physician Fee Schedule payments in surgery.

BACKGROUND: Medicare expenditures have steadily increased over the decades, and yet Medicare Physician Fee Schedule payments for individual services have declined. We examine trends in Medicare Physician Fee Schedule payments for office visits, inpatient visits, and surgical procedures. METHODS: The Medicare Physician Fee Schedule Look-Up Tool was queried for payment data for office visits, inpatient visits, and surgical procedures between 2013 and 2023. All data were adjusted for inflation using the Consumer Price Index. Trends in payments were calculated for 5 common procedures in each surgical specialty. Trends in aggregate national health expenditures were compared to Medicare Physician Fee Schedule payments for physician services from 2013 to 2021. RESULTS: The Consumer Price Index increased by 29.3% from 2013 to 2023. Inflation-adjusted per-visit Medicare Physician Fee Schedule payments decreased by 12.2% for outpatient office visits, 19.1% for inpatient visits, and 22.8% for surgical procedures from 2013 to 2023. This varied by surgical specialty: vascular (-25.8%), endocrine (-22.0%), general surgery (-27.0%), thoracic (-19.2%), surgical oncology (-22.1%), breast (-22.4%), urology (-2.2%), neurosurgery (-22.8%), obstetrics/gynecology (-19.9%), and orthopedics (-24.7%). Adjusted for inflation, national health expenditures increased by 33.9% for physician services from 2013 to 2021. In comparison, Medicare Physician Fee Schedule payments over the same time period 2013 to 2021 increased by 1.3% for outpatient office visits but decreased by 10.6% for inpatient visits and 9.8% for surgical procedures. CONCLUSION: Controlling rising national health expenditures is important and necessary, but 10 years of declining Medicare Physician Fee Schedule payments on a per-procedure basis in surgery would suggest that this strategy alone may not achieve those goals and could ultimately threaten access to quality surgical care. Surgeons must advocate for permanent payment reforms.

Early-stage CCNG1+ HR+ HER2+ Invasive Breast Carcinoma in Older Women: Current Treatment and Future Perspectives for DeltaRex-G, a CCNG1 Inhibitor.

Women with HR+HER2+ early-stage breast cancer are disadvantaged by the lack of clinical trials focused on women ≥70 years of age. In the past years, there has been increasing controversy on the use of toxic chemotherapy as standard of care treatment for early- stage HR+ HER2+ breast carcinoma in older women. With precision medicine coming of age, molecular profiling of tumors and circulating tumor DNA has identified target oncogenes that could be used in designing an optimal treatment for this group of women. This article reviews the current treatment of early-stage triple receptor positive breast cancer, the risks of chemotherapy in older women, and CCNG1, a novel biomarker in development for the use of DeltaRex-G, a CCNG1 inhibitor. Further, future perspectives for DeltaRex-G in older women with early stage CCNG1+ HR+ HER2+ breast cancer are discussed.

Evolving management of early stage pancreatic adenocarcinoma in older patients.

BACKGROUND: Due to the aging population, the number of older patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) will continue to rise. STUDY DESIGN: Utilizing the NCDB from 2010 to 2016, patients with early stage, clinically node negative PDAC who were ≥70 years old and had a Whipple were identified. Multivariable logistic regressions were used to determine independent factors for R0 resection and NAT. Cox-proportional-hazards regression analyses examined for the impact of NAT on the risk of death. RESULTS: Of 5086 patients, 51.7% received upfront surgery + adjuvant therapy (UFS + AT), followed by 29.9% UFS only, and the remainder NAT. NAT significantly improved OS compared to a combined cohort of those that had UFS ± AT. NAT retained its independent survival benefit when compared to only patients that had UFS + AT. CONCLUSION: For older patients diagnosed with early stage PDAC, NAT was associated with improved R0 resection rates and a significant survival benefit when compared to the current standard of care.

Treatment Utilization and Outcomes for Locally Advanced Rectal Cancer in Older Patients.

Importance: The number of older patients (80 years and older) diagnosed with locally advanced rectal cancer (LARC) is expected to increase. Although current guidelines recommend neoadjuvant chemoradiation therapy (NACRT) followed by resection, little is known about management and outcomes in this older population. Objective: To assess the trends in management of older patients diagnosed with LARC who had a surgical resection. Design, Setting, and Participants: Patients 80 years and older who had a surgical resection for LARC were identified in the 2004-2016 National Cancer Database. Patients were grouped based on therapy sequence: (1) surgery followed by adjuvant therapy (AT), ie, chemotherapy or radiation; (2) surgery alone; or (3) NACRT followed by surgical resection. Data were analyzed in May 2021. Exposures: NACRT followed by surgery, and surgery with or without AT. Main Outcomes and Measures: Overall survival (OS) was assessed using Kaplan-Meier analyses with inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression were performed to examine the association of NACRT with the risk of death. Results: Of 3868 patients with LARC who underwent surgical resection, 2042 (52.8%) were male, and the mean (SD) age was 83.4 (3.0) years. A total of 2273 (58.8%) received NACRT followed by surgical resection. Factors independently associated with NACRT were more recent diagnosis, age 80 to 85 years (vs 86 years and older), fewer comorbidities, larger tumors, and node-positive disease. The Kaplan-Meier analyses with IPTW showed that 3-year and 5-year OS for NACRT (3-year: 68.9%; 95% CI, 67.0-70.8; 5-year: 51.1%; 95% CI, 49.0-53.4) vs surgery with AT (3-year: 64.4%; 95% CI, 59.0-70.2; 5-year: 43.0%; 95% CI, 37.4-49.5) vs surgery alone (3-year: 55.8%; 95% CI, 52.0-60.0; 5-year: 34.7%; 95% CI, 30.8-39.0) was significantly different (P < .001). After adjusting for confounders, patients who received NACRT were more likely to undergo an R0 resection (adjusted odds ratio, 2.16; 95% CI, 1.62-2.88), which independently improved OS (P < .001). Moreover, receipt of NACRT was independently associated with a 25% decreased risk of death (adjusted hazard ratio, 0.75; 95% CI, 0.69-0.82) compared with alternative treatment sequences. Conclusions and Relevance: Approximately 40% of older patients with LARC did not receive the current standard of care. In this cohort, NACRT was associated with a higher likelihood of an R0 resection and improved OS. Clinicians should advocate for receipt of NACRT in older patients with LARC.

Does Residual Invasive Disease in Wide Local Excision after Diagnosis with Partial Biopsy Technique Influence Survival in Melanoma? Matched-Pair Analysis of Multicenter Selective Lymphadenectomy Trial I and II.

BACKGROUND: Current guidelines recommend excisional/complete biopsy for melanoma diagnosis, owing to high rates of residual disease found at wide local excision (WLE) after partial biopsy techniques. We sought to determine any survival disadvantage associated with the presence of residual invasive melanoma in the WLE after diagnosis with a partial biopsy technique. STUDY DESIGN: Data were examined from Multicenter Selective Lymphadenectomy Trials I and II (MSLT-I and -II), 2 large melanoma trials. Patients diagnosed with excisional/complete biopsy were excluded. Clinicopathologic characteristics, melanoma-specific survival (MSS), distant disease-free survival (DDFS), and disease-free survival (DFS) of those with residual invasive melanoma in the definitive WLE and those with no residual melanoma were compared. Matched pairing was used to reduce variability between groups. RESULTS: From 1994 through 2014, 3,939 patients were enrolled in these trials and 874 (22%) were diagnosed using partial biopsy techniques. Of these, 399 (46%) had residual tumor in the WLE. Only 6 patients had residual tumor in their WLE resulting in T-upstaging of their tumor. Match-pairing formed two cohorts (1:1) of patients with and without residual invasive tumor after WLE. A total of 514 patients were paired; 288 (56%) males, 148 (28.8%) aged 60 or older, 192 (37.4%) with truncal melanomas, 214 (41.6%) had Breslow thickness 2 mm or greater, and 376 (73.2%) had positive sentinel nodes. Kaplan-Meier analysis showed no statistical difference in 10-year MSS (73.6% ± 3.3% vs 73.9% ± 3.7%, p = 0.891), DDFS (68.7% ± 3.4% vs 65.3% ± 4.0%, p = 0.548), or DFS (59.6% ± 3.7% vs 59.4% ± 3.9%, p = 0.783). CONCLUSIONS: Survival in patients with primary melanoma does not appear to be worse in patients who undergo a partial biopsy technique and are later found to have residual invasive tumor in the WLE specimen.

Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients.

Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (pilot cohort; n = 92), AJCC stage III patients given adjuvant BCG (verification cohort; n = 269), and AJCC stage III patients that are sentinel lymph node (SLN) positive receiving no immunotherapy (control cohort; n = 80). The SNP panel analysis demonstrated that the responder patient group had an improved disease-free survival (DFS) (hazard ratio [HR] 1.84, 95% CI 1.09-3.13, p = 0.021) in the pilot cohort. In the verification cohort, an improved overall survival (OS) (HR 1.67, 95% CI 1.07-2.67, p = 0.025) was observed. No significant differences of SNPs were observed in DFS or OS in the control patient cohort. This study demonstrates that SNP immune genes can be utilized as a predictive tool for identifying melanoma patients that are inherently responsive to BCG and potentially other immunotherapies in the future.

Regional Node Basin Recurrence in Melanoma Patients: More Common After Node Dissection for Macroscopic Rather than Clinically Occult Nodal Disease.

BACKGROUND: Recommended treatment for patients with sentinel lymph node (SLN)-positive melanoma has recently changed. Randomized trials demonstrated equivalent survival with close observation versus completion lymph node dissection (CLND), but increased regional node recurrence. We evaluated factors related to in-basin nodal recurrence after lymphadenectomy (LND) for SLN-positive or macroscopic nodal metastases. METHODS: An institutional database and the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were analyzed independently. Exclusions were multiple primaries, multi-basin involvement, or in-transit metastases. Patient demographics, primary tumor thickness and ulceration, lymph nodes retrieved, and use of adjuvant radiotherapy were analyzed. Multivariate analyses were performed to determine factors predicting in-basin nodal recurrence (significance p ≤ 0.05). RESULTS: The retrospective cohort (577 patients) showed an in-basin failure rate of 6.6% after CLND for a positive SLN and 13.1% after LND for palpable disease (p = 0.001). This recurrence risk persisted after adjustment for patient, tumor, and LND factors [hazard ratio (HR) 2.32; p = 0.004]. In the MSLT-I cohort (326 patients), the failure rate after CLND following SLNB was 6.2%, but 10.1% after LND for palpable recurrence in observation patients. After adjustment for other factors, macroscopic disease was associated with an increased risk of recurrence after LND (HR 2.24; p = 0.05). CONCLUSION: After LND for melanoma, in-basin recurrence is infrequent, but a clinically significant fraction will fail. Failure is less likely if dissection is performed for clinically occult disease. Further research is warranted to evaluate the long-term regional control and quality of life associated with nodal basin observation, which has now become standard practice.

Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy.

BACKGROUND: Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel. METHODS: Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical outcomes were assessed. RESULTS: CTCs were detected in 88% of blood samples from patients with melanoma. CTC-derived biomarkers and clinical variables analyzed using classification and regression tree analysis revealed that a combination of lactate dehydrogenase, CTC-mRNA biomarkers, and tumor BRAF-mutation status was indicative of clinical outcomes for patients with stage IV melanoma (n = 52). The panel stratified low-risk and high-risk patients, whereby the latter had poor disease-free (P = 0.03) and overall survival (P = 0.02). Incorporation of a DNA biomarker with mRNA profiling increased overall CTC-detection capability by 57% compared to mRNA profiling only. RNA sequencing of isolated CTCs identified significant catenin beta 1 (CTNNB1) overexpression (P <0.01) compared to nondisease donor blood. CTC-CTNNB1 was associated with progressive disease/stable disease compared to complete-responder patient status (P = 0.02). Serial CTC profiling identified subclinical disease in patients who developed progressive disease during treatment/follow-up. CONCLUSIONS: CTC-derived mRNA/DNA biomarkers have utility for monitoring CII, targeted, and combinatorial therapies in metastatic melanoma patients.

Pediatric-protocol of multimodal therapy is associated with improved survival in AYAs and adults with rhabdomyosarcoma.

BACKGROUND: Multimodal therapy is the standard treatment for pediatric rhabdomyosarcoma, but for adolescents and young adults (AYAs: ages 15-39) and older adults with rhabdomyosarcoma, the use of adjuvant therapy is variable, and survival is greatly decreased compared with younger patients. METHODS: All patients with rhabdomyosarcoma who had a curative operative were identified from the 1998-2012 National Cancer Database. Regression analyses identified independent factors relating to receipt of multimodal therapy (resection + chemotherapy + radiation) and the influence of multimodal therapy on 5-year overall survival. RESULTS: Of 2,312 patients, 44% were pediatric (age < 15 years), 22% AYA (ages 15-39), and 34% adult (age ≥ 40 years). Adults received multimodal therapy least often (pediatric: 62%, AYA: 46%, adults: 24%; P < .001), even after controlling for demographic characteristics, tumor features, and stage. In the entire cohort, multimodal therapy was associated with a decreased risk of death within 5 years (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.62-0.84), with similar findings after stratification by age (pediatric: HR 0.64, 95% CI 0.48-0.85; AYA: HR 0.72, 95% CI 0.55-0.95; adult: HR 0.74, 95% CI 0.58-0.93). In AYAs only, black and Hispanic patients had an increased risk of death within 5 years (black patients: HR 1.64, 95% CI 1.14-2.37; Hispanic patients: HR 1.62, 95% CI 1.11-2.36). CONCLUSION: This first large national study suggests that multimodal therapy is independently associated with improved survival for both AYAs and adults with rhabdomyosarcoma, similar to pediatric patients, but multimodal therapy is appreciably underused. Implementation of multimodal therapy for all patients could potentially improve overall outcomes of patients with rhabdomyosarcoma.

Mycobacterium bovis Bacillus Calmette-Guérin Alters Melanoma Microenvironment Favoring Antitumor T Cell Responses and Improving M2 Macrophage Function.

Intralesional Mycobacterium bovis bacillus Calmette-Guérin (BCG) has long been a relatively inexpensive therapy for inoperable cutaneous metastatic melanoma (CMM), although intralesional BCG skin mechanisms remain understudied. We analyzed intralesional BCG-treated CMM lesions combined with in vitro studies to further investigate BCG-altered pathways. Since macrophages play a pivotal role against both cancer and mycobacterial infections, we hypothesized BCG regulates macrophages to promote antitumor immunity. Tumor-associated macrophages (M2) infiltrate melanomas and impair antitumor immunity. BCG-treated, in vitro-polarized M2 (M2-BCG) showed transcriptional changes involving inflammation, immune cell recruitment, cross talk, and activation pathways. Mechanistic network analysis indicated M2-BCG potential to improve interferon gamma (IFN-γ) responses. Accordingly, frequency of IFN-γ-producing CD4+ T cells responding to M2-BCG vs. mock-treated M2 increased (p < 0.05). Moreover, conditioned media from M2-BCG vs. M2 elevated the frequency of granzyme B-producing CD8+ tumor-infiltrating lymphocytes (TILs) facing autologous melanoma cell lines (p < 0.01). Furthermore, transcriptome analysis of intralesional BCG-injected CMM relative to uninjected lesions showed immune function prevalence, with the most enriched pathways representing T cell activation mechanisms. In vitro-infected MM-derived cell lines stimulated higher frequency of IFN-γ-producing TIL from the same melanoma (p < 0.05). Our data suggest BCG favors antitumor responses in CMM through direct/indirect effects on tumor microenvironment cell types including macrophages, T cells, and tumor itself.

Association of Surgical Treatment, Systemic Therapy, and Survival in Patients With Abdominal Visceral Melanoma Metastases, 1965-2014: Relevance of Surgical Cure in the Era of Modern Systemic Therapy.

Importance: Systemic therapy for metastatic melanoma has evolved rapidly during the last decade, and patient treatment has become more complex. Objective: To evaluate the survival benefit achieved through surgical resection of melanoma metastatic to the abdominal viscera in patients treated in the modern treatment environment. Design, Setting, and Participants: This retrospective review of the institutional melanoma database from the John Wayne Cancer Institute at Providence St Johns Health Center, a tertiary-level melanoma referral center, included 1623 patients with melanoma diagnosed as having potentially resectable abdominal metastases before (1969-2003) and after (2004-2014) advances in systemic therapy. Main Outcomes and Measures: Overall survival (OS). Results: Of the 1623 patients identified in the database with abdominal melanoma metastases, 1097 were men (67.6%), and the mean (SD) age was 54.6 (14.6) years. Of the patients with metastatic melanoma, 1623 (320 [19.7%] in the 2004-2014 period) had abdominal metastases, including 336 (20.7%) with metastases in the gastrointestinal tract, 697 (42.9%) in the liver, 138 (8.5%) in the adrenal glands, 38 (2.3%) in the pancreas, 109 (6.7%) in the spleen, and 305 (18.8%) with multiple sites. Median OS was superior in surgical (n = 392; 18.0 months) vs nonsurgical (n = 1231; 7.0 months) patients (P < .001). The most favorable 1-year and 2-year OS was seen after surgery for gastrointestinal tract (52% and 41%) and liver (51% and 38%) metastases, respectively. Multivariable analysis found increasing age (hazard ratio [HR], 1.01; 95% CI, 1.00-1.01; P = .02) and the presence of ulceration (HR, 1.21; 95% CI, 1.01-1.45; P = .04) were associated with a worse OS. Alternatively, treatment with metastasectomy (HR, 0.59; 95% CI, 0.46-0.74; P < .001) and metastases involving the gastrointestinal tract (HR, 0.65; 95% CI, 0.48-0.87; P = .004) were associated with a better OS. The systemic treatment era did not significantly affect outcomes (HR, 0.82; 95% CI, 0.67-1.02; P = .15). Overall, patients with gastrointestinal tract metastases undergoing complete, curative resection derived the greatest benefit, with a median OS of 64 months. Conclusions and Relevance: To our knowledge, this series is the largest single-institution experience with abdominal melanoma metastases, demonstrating that surgical resection remains an important treatment consideration even in the systemic treatment era.

Insights into Local Tumor Microenvironment Immune Factors Associated with Regression of Cutaneous Melanoma Metastases by Mycobacterium bovis Bacille Calmette-Guérin.

Mycobacterium bovis bacille Calmette-Guérin (BCG) is listed as an intralesional (IL) therapeutic option for inoperable stage III in-transit melanoma in the National Comprehensive Cancer Network Guidelines. Although the mechanism is unknown, others have reported up to 50% regression of injected lesions, and 17% regression of uninjected lesions in immunocompetent patients after direct injection of BCG into metastatic melanoma lesions in the skin. BCG and other mycobacteria express ligands capable of stimulating the γ9δ2 T cells. Therefore, we hypothesized that γ9δ2 T cells play a role in promoting BCG-mediated antitumor immunity in patients treated with IL-BCG for in-transit cutaneous melanoma metastases. Indeed, we found γ9δ2 T cell infiltration in melanoma skin lesions during the course of IL-BCG treatment. Gene expression analysis revealed that BCG injection elicits the expression of a vast array of chemokines in tumor lesions, including strong expression of CXCL9, 10, and 11, a set of chemokines that attract T cells expressing the CXCR3 chemokine receptor. In corroboration with our hypothesis, approximately 85% of γδ T cells express high levels of CXCR3 on their surface. Importantly, the injected tumor lesions also express genes whose protein products are the antigenic ligands for γδ T cells (BTN3A1 and MICB), and the cytokines that are the typical products of activated γδ T cells. Interestingly, we also found that γδ T cells infiltrate the regressed lesions that did not receive BCG injections. Our study suggests that γ9δ2 T cells may contribute to melanoma regression induced by IL-BCG treatment.

Impact of Completion Lymph Node Dissection on Patients with Positive Sentinel Lymph Node Biopsy in Melanoma.

BACKGROUND: Whether patients with positive SLNB should undergo complete lymph node dissection (CLND) is an important unanswered clinical question. STUDY DESIGN: Patients diagnosed with positive SLNB at a melanoma referral center from 1991 to 2013 were studied. Outcomes of patients who underwent CLND were compared with those who did not undergo immediate CLND (observation [OBS] group). RESULTS: There were 471 patients who had positive SLNB; 375 (79.6%) in the CLND group and 96 (20.4%) in the OBS group. The groups were similar except that the CLND group was younger and had more sentinel nodes removed. Five-year nodal recurrence-free survival was significantly better in the CLND group compared with the OBS group (93.1% vs 84.4%; p = 0.005). However, 5-year (66.4% vs 55.2%) and 10-year (59.5% vs 45.0%) distant metastasis-free survival rates were not significantly different (p = 0.061). The CLND group's melanoma-specific survival (MSS) rate was superior to that of the OBS group; 5-year MSS rates were 73.7% vs 65.5% and 10-year MSS rates were 66.8% vs 48.3% (p = 0.015). On multivariate analysis, CLND was associated with improved MSS (hazard ratio = 0.60; 95% CI, 0.40-0.89; p = 0.011) and lower nodal recurrence (hazard ratio = 0.46; 95% CI, 0.24-0.86; p = 0.016). Increased Breslow thickness, older age, ulceration, and trunk melanoma were all associated with worse outcomes. On subgroup analysis, the following factors were associated with better outcomes from CLND: male sex, nonulcerated primary, intermediate thickness, Clark level IV or lower extremity tumors. CONCLUSIONS: Treatment of positive SLNB with CLND was associated with improved MSS and nodal recurrence rates. Follow-up beyond 5 years was needed to see a significant difference in MSS rates.

Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades.

Mucosal melanoma represents a distinct minority of disease sites and portends a worse outcome. The ideal treatment and role of adjuvant therapy remains unknown at this time. We hypothesized that a combination of neoadjuvant and adjuvant therapies would improve survival in these aggressive melanomas. Our large, prospectively maintained melanoma database was queried for all patients diagnosed with mucosal melanoma. Over the past five decades, 227 patients were treated for mucosal melanoma. There were 82 patients with anorectal, 75 with sinonasal, and 70 with urogenital melanoma. Five-year overall survival and melanoma-specific survival for the entire cohort were 32.8 and 37.5 per cent, respectively, with median overall survival of 38.7 months. One hundred forty-two patients (63.8%) underwent adjuvant therapy and 15 were treated neoadjuvantly (6.6%). There was no survival difference by therapy type or timing, disease site, or decade of diagnosis. There was improved survival in patients undergoing multiple surgeries (Hazard Ratio [HR] 0.55, P = 0.0005). Patients receiving neoadjuvant therapy had significantly worse survival outcomes (HR 2.49, P = 0.013). Over the past five decades, improvements have not been seen in outcomes for mucosal melanoma. Although multiple surgical interventions portend a better outcome in patients with mucosal melanoma, adjuvant treatment decisions must be individualized.

Predictors and Survival Impact of False-Negative Sentinel Nodes in Melanoma.

BACKGROUND: The status of the sentinel lymph node in melanoma is an important prognostic factor. The clinical predictors and implications of false-negative (FN) biopsy remain debatable. METHODS: We compared patients with positive sentinel lymph node biopsy (SNB) [true positive (TP)] and negative SNB with and without regional recurrence [FN, true negative (TN)] from our prospective institutional database. RESULTS: Among 2986 patients (84 FN, 494 TP, and 2408 TN; median follow-up 93 months), the incidence of FN-SNB was 2.8%. While calculated FN rate was 14.5% [84 FN/(494 TP + 84 FN) × 100], when we accounted for local/in-transit recurrence (LITR) this rate was 8.5% [46 FN/(494 TP + 46 FN) × 100 %]. On multivariate analysis, male gender (OR 2.0, 95% CI 1.1-3.6, p = 0.018), head/neck primaries (OR 2.5, 95% CI 1.3-4.8, p < 0.006), and LITR (OR 3.5, 95% CI 2.1-5.8, p < 0.001) were associated with FN-SNB. Melanoma-specific survival (MSS) for the FN group was similar to the TP group at 5 years (68 vs. 73%, p = 0.539). However, MSS declined more for the FN group with a longer follow up and was significantly worse at 10 years (44 vs. 64%, p < 0.001). On multivariate analysis, FN-SNB was a significant predictor of worse MSS in melanomas <4 mm in Breslow thickness (HR 1.6; 95% CI 1.1-2.5, p = 0.021). CONCLUSIONS: Male gender, LITR, and head and neck tumors were associated with FN-SNB. FN-SNB was an independent predictor of worse MSS in melanomas <4 mm in thickness, but this survival difference did not become apparent until after 5 years of follow-up.

Adrenalectomy for Metastatic Melanoma: Current Role in the Age of Nonsurgical Treatments.

Surgical resection of metastases to the adrenal gland can improve overall survival of patients with stage IV melanoma, but its relative value with respect to current nonsurgical therapies is unknown. We hypothesized that surgery remains an optimal first-line treatment approach for resectable adrenal metastases. A search of our institution's prospectively collected melanoma database identified stage IV patients treated for adrenal metastases between January 1, 2000, and August 11, 2014. The 91 study patients had a mean age of 60.3 years at diagnosis of adrenal metastasis and 24 had undergone adrenalectomy. Improved survival was associated with an unknown primary lesion, surgical resection, and nonsurgical therapies. Median overall survival from diagnosis of adrenal metastases was 29.2 months with adrenalectomy versus 9.4 months with nonoperative treatment. Adrenalectomy, either as complete metastasectomy or targeted to lesions resistant to systemic therapy, is associated with improved long-term survival in metastatic melanoma.

A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients.

Circulating cell-free(cf) microRNAs (miRNAs) have been reported to exist in plasma. MicroRNA-210(miR-210) is known to play important roles in the tumor hypoxic state. We hypothesized that the expression levels of cf-miR-210 in plasma would predict early clinical recurrence in melanoma patients. A direct miRNA assay on plasma (RT-qPCR-DP) was developed to improve cf-miRNA assay logistics, eliminate RNA extraction, and reduce specimen amount required. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) melanoma tissues (n = 108) and assessed by RT-qPCR. Plasma (10 µl; n = 264) was procured from AJCC Stage III/IV patients in phase III clinical trials. A RT-qPCR-DP was performed to detect cf-miR-210. MiR-210 was significantly higher in metastatic tumors compared to primary tumors. Cf-miR-210 was significantly higher in melanoma patients versus healthy donor controls. In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012). ROC curve analysis demonstrated that patients with elevated cf-miR-210 were more likely to have disease recurrence. Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001). Lactate dehydrogenase (LDH) level was also assessed within patients, and the AIC values for proportional hazards regression models of cf-miR-210(120.01) and LDH (122.91) demonstrated that cf-miR-210 is a better recurrence indicator. We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

Combined intralesional Bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma.

The introduction of numerous immunotherapeutic agents into the clinical arena has allowed the long-time promise of immunotherapy to begin to become reality. Intralesional immunotherapy has demonstrated activity in multiple tumor types, and as the number of locally applicable agents has increased, so has the opportunity for therapeutic combinations. Both intralesional Bacille Calmette-Guérin (ILBCG) and topical 5% imiquimod cream have been used as single agents for the treatment of dermal/subcutaneous lymphatic metastases or in-transit melanoma, but the combination has not previously been reported. We used this combination regimen in 9 patients during the period from 2004 to 2011 and report their outcomes here. All patients were initially treated with ILBCG, followed by topical imiquimod after development of an inflammatory response to BCG. In this retrospective study, we examined their demographics, tumor characteristics, clinical and pathologic response to treatment, associated morbidities, local and distant recurrence, and overall survival. The 9 patients (8 male) had a mean age of 72 years (range, 56-95 y). Mild, primarily local toxicities were noted. Five patients (56%) had complete regression of their in-transit disease and 1 had a partial response. The 3 others had "surgical" complete responses with resection of solitary resistant lesions. The mean interval between the first treatment and complete resolution of in-transit disease was of 6.5 months (range, 2-12 mo). With a mean follow-up of 35 months (range 12-58 mo), 7 patients (78%) had not developed recurrent in-transit disease. Two patients (22%) have died of nonmelanoma causes, and none have died due to melanoma.