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The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAFV600E as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAFV600E mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAFV600E allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAFV600E-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAFV600Eand BRAFwild-type cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAFV600E mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAFV600E mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful.

The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAF(V600E) as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAF(V600E) mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAF(V600E) allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAF(V600E)-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAF(V600E)and BRAF(wild-type) cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAF(V600E) mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAF(V600E) mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful.

Surgery with or without radiation has always been the mainstay of treatment for patients with non-melanoma skin cancers, including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma. Until recently, there were no effective systemic therapies for patients with advanced disease. This review will focus on the landmark clinical trials that led to Food and Drug Administration (FDA) approval of Vismodegib for advanced basal cell carcinoma (ERIVANCE BCC) and pembrolizumab for advanced Merkel cell carcinoma (KEYNOTE-017). These trials have not only changed the landscape for patients with metastatic disease but also notably for patients with locally advanced disease that is either unresectable or resectable with high morbidity. Additional mention is made for the clinical trial that led to FDA approval of cemiplimab for advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1), which is already changing practice patterns, but for which longer-term data are still needed.

Background Time to treatment (TTT) varies widely for patients with gastric cancer. We aimed to evaluate relationships between time to treatment, overall survival (OS), and other surgical outcomes in patients with stage I–III gastric cancer. Methods We identified patients with clinical stage I–III gastric cancer who underwent curative-intent gastrectomy within the National Cancer Database (2006–2015) and grouped them by treatment sequence: neoadjuvant chemotherapy or surgery upfront. We defined TTT as weeks from diagnosis to treatment initiation (neoadjuvant chemotherapy or definitive surgical procedure, respectively). Survival differences were assessed by Kaplan–Meier estimate, Cox proportional hazard regression, and log rank test. Results Among the 22,846 patients with stage I–III gastric cancer, most (56%) received surgery upfront. Median TTT was 5 weeks (IQR 4–7) and 6 weeks (IQR 3–9) for patients in the neoadjuvant and surgery upfront groups, respectively. In the neoadjuvant group, increasing TTT was significantly associated with increasing median OS up to TTT of 5 weeks, with no change in median OS when TTT was > 5 weeks. In the surgery group, increasing TTT was significantly associated with increasing median OS up to 6 weeks; however, increasing TTT between 14 and 21 weeks was associated with decreasing median OS. Conclusions The relationship between time to treatment and survival outcomes is non-linear. Among patients who underwent surgery upfront, the relationship between time to treatment and OS was bimodal, suggesting that deferring definitive surgery, up to 14 weeks, is not associated with worse OS or oncologic outcomes. Mini-abstract The relationship between time to treatment and overall survival among patients was bimodal, suggesting that deferring definitive surgery up to 14 weeks is not associated with worse OS.

Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84–1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83–0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.

Background Surgical subspecialty training aims to meet the needs of practicing surgeons and their communities. This study investigates career preparedness of Complex General Surgical Oncology (CGSO) fellowship graduates, identifies factors associated with practice readiness, and explores potential opportunities to improve the current training model. Methods The Society of Surgical Oncology partnered with the National Cancer Institute to conduct a 36-question survey of CGSO fellowship graduates from 2012 to 2022. Results The overall survey response rate was 38% (221/582) with a slight male predominance (63%). Forty-six percent of respondents completed their fellowship after 2019. Factors influencing fellowship program selection include breadth of cancer case exposure (82%), mentor influence (66%), and research opportunities (38%). Overall, graduates reported preparedness for practice; however, some reported unpreparedness in research (18%) and in specific clinical areas: thoracic (43%), hyperthermic intraperitoneal chemotherapy (HIPEC) (15%), and hepato-pancreato-biliary (15%) surgery. Regarding technical preparedness, 70% reported being “very prepared”. Respondents indicated lack of preparedness in robotic (63%) and laparoscopic (33%) surgery approaches. Suggestions for training improvement included increased autonomy and case volumes, program development, and research infrastructure. Current practice patterns by graduates demonstrated discrepancies between ideal contracts and actual practice breakdowns, particularly related to the practice of general surgery. Conclusions This study of CGSO fellowship graduates demonstrates potential gaps between trainee expectations and the realities of surgical oncology practice. Although CGSO fellowship appears to prepare surgeons for careers in surgical oncology, there may be opportunities to refine the training model to better align with the needs of practicing surgical oncologists.

Background Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. Methods We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. Results A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. Conclusion Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time.

BackgroundAdherence to evidence-based guidelines for gastric cancer is low, particularly at the hospital level, despite a strong association with improved overall survival (OS). We aimed to evaluate patterns of hospital and regional adherence to National Comprehensive Cancer Network guidelines for gastric cancer.MethodsUsing the National Cancer Database (2004–2015), we identified patients with stage I–III gastric cancer. Hospital-level guideline adherence was calculated by dividing the patients who received guideline adherent care by the total patients treated at that hospital. OS was estimated for each hospital. Associations between adherence, region, and survival were compared using mixed-effects, hierarchical regression.ResultsAmong 576 hospitals, the median hospital guideline adherence rate was 25% (range 0–76%) and varied significantly by region (p = 0.001). Adherence was highest in the Middle Atlantic (29%) and lowest in the East South Central region (19%); hospitals in the New England, Middle Atlantic, and East North Central regions were more likely to be guideline adherent than those in the East South Central region (all p < 0.05), after adjusting for patient and hospital mix. Most (35%) of the adherence variation was attributable to the hospital. Median 2-year OS varied significantly by region. After adjusting for hospital and patient mix, hazard of mortality was 17% lower in the Middle Atlantic (hazard ratio 0.82, 95% confidence interval 0.74–0.90) relative to the East South Central region, with most of the variation (54%) attributable to patient-level factors.ConclusionsHospital-level guideline adherence for gastric cancer demonstrated significant regional variation and was associated with longer OS, suggesting that efforts to improve guideline adherence should be directed toward lower-performing hospitals.