Cumulative Incidence and Predictors of CNS Metastasis for Patients With American Joint Committee on Cancer 8th Edition Stage III Melanoma.

PURPOSE: Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma. PATIENTS AND METHODS: Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis. RESULTS: At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined. CONCLUSION: Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.

Postoperative pancreatic fistula after distal pancreatectomy for non-pancreas retroperitoneal tumor resection.

INTRODUCTION: Short-term outcomes after distal pancreatectomy (DP) for retroperitoneal (RP) tumors are unknown. We sought to identify rates of postoperative pancreatic fistula (POPF) and morbidity after en bloc DP with RP tumor resection. METHODS: A retrospective review of 43 patients who underwent DP with RP tumor resection (1/2011-12/2017) was performed. RESULTS: Seventeen patients had RP sarcoma, 12 renal cell carcinoma, 11 gastrointestinal stromal tumor, and 3 adrenocortical carcinoma. Grade III-IV complications occurred in 7 patients. Grade B POPF occurred in 14 patients, grade C POPF in none, and biochemical leak in 6. Of 22 patients who developed radiographically evident peri-pancreatic fluid collections, 7 required percutaneous drainage. The 90-day readmission rate was 33%. CONCLUSIONS: DP with RP tumor resection is associated with high rates of clinically relevant POPF compared to historical results for DP for primary pancreatic tumors. Multi-center studies to identify targetable predictors and risk mitigation strategies for POPF in this rare high-risk population are needed.

Functional annotation of melanoma risk loci identifies novel susceptibility genes.

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and non-coding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used functional mapping and annotation (FUMA) to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5 × 10-8) identified by GWAS. The original GWAS melanoma study included 15 990 cases and 26 409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2 and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5 × 10-6. The genes associated with melanoma risk were DEF8 (P = 1.09 × 10-57), DBNDD1 (P = 2.19 × 10-42), SPATA33 (P = 3.54 × 10-38) and MC1R (P = 1.04 × 10-36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

Role of Immune Response, Inflammation, and Tumor Immune Response-Related Cytokines/Chemokines in Melanoma Progression.

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated the proportions of immune cell subsets in melanoma tumors from The Cancer Genome Atlas, followed by evaluation of the association between cytokine/chemokine expression and these subsets. We then investigated the association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated the immune cell tumor-infiltrating lymphocyte (TIL) score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA sequencing estimation of T-cell subset and pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, and IL-10, and chemokines CXCL9 and CXCL10 were positively correlated with PDCD1, CTLA-4, and CD8+ T-cell subset, but negatively correlated with tumor purity (Bonferroni-corrected P < 0.05). In multivariable analysis, higher expression levels of cytokines IFN-γ and TGFB1, but not chemokines, were associated with improved overall survival. A higher expression level of CD8+ T-cell subset was also associated with improved overall survival (hazard ratio [HR] = 0.06, 95% confidence interval [CI] = 0.01-0.35, P = 0.002). Finally, multivariable analysis showed that patients with a brisk TIL score had improved melanoma-specific survival than those with a nonbrisk score (HR = 0.51, 95% CI = 0.27-0.98, P = 0.0423). These results suggest that the expression of specific tumor cytokines represents important biomarkers of melanoma immune response.

Radiation and Its Impact on Local Recurrence in Extremity and Trunk Well-Differentiated Liposarcomas.

Patients with well-differentiated liposarcomas (WDLPS) of the extremity and trunk are treated primarily with surgical resection, with radiation used for a number of anecdotal reasons, including large size and positive margins. In this study, we evaluate the appropriate role for radiation in these tumors. A retrospective chart review of patients with extremity and trunk soft tissue liposarcomas referred to a free-standing cancer center from January 1995 to December 2011 was performed. One hundred eighty-three patients with extremity and trunk soft tissue WDLPS were identified: 61 per cent were female, median age was 60 years (range, 19-84 years) and 2 per cent had a focal area of dedifferentiation, margin status was positive in 57 per cent. Fourteen per cent of patients received radiation. Fifty patients developed recurrent disease; 28 per cent of these received radiation. Median time to recurrence was 18 years (range, 0.7-22 years). Of the 50 patients who recurred, 14 (28%) received radiation. Radiation was associated with decreased second recurrence when administered for recurrent disease (P = 0.03). On multivariable analysis, tumor size ≤ 10 cm (P = 0.014) and anatomically difficult area of resection (P = 0.008) were predictive of increased risk of recurrence. Older age (P = 0.02), dedifferentiated liposarcomas (P < 0.001), and difficult area of resection (P = 0.02) were associated with the administration of radiotherapy. Administration of radiation therapy was not associated with decreased time to recurrence in WDLPS overall; however, it should be considered in patients with recurrent disease.

An Evaluation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) Staging System for Retroperitoneal Sarcomas Using the National Cancer Data Base (NCDB): Does Size Matter?

OBJECTIVES: Retroperitoneal sarcomas (RPS) are often large at diagnosis calling into question the seventh edition AJCC size classification of <5 cm (T1) or ≥5 cm (T2). The eighth edition expands T stage into 4 categories (T1: ≤5 cm, T2: 515 cm). We evaluated the prognostic ability of the eighth edition using the National Cancer Database (NCDB). METHODS: Patients with RPS treated between 1998 and 2011 were identified from the NCDB; overall survival (OS) was compared. RESULTS: Of the 6427 patients identified, 9% had tumors ≤5 cm (n=580), 19.4% 515 cm (n=3045). With the eighth edition, stage II patients (G2/3 ≤5 cm) have a similar OS to stage IIIA patients (G2/3 5 cm10 cm) show a decrease in OS. Tumor size as a continuous variable had a modest effect on survival (HR, 1.004; P=0.04). On multivariate analysis, higher T-stage was associated with decreased OS (T4 HR, 1.3; P<0.001) but high grade and incomplete resection (R2) were stronger prognostic factors. The c-index for both editions were similar (80.13 eighth vs. 80.08 seventh). CONCLUSIONS: The eighth edition AJCC staging system for retroperitoneal sarcoma incorporates larger tumor size parameters that better characterize most patients, but tumor size alone is only a modest predictor of outcome.

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

Treatment at low-volume hospitals is associated with reduced short-term and long-term outcomes for patients with retroperitoneal sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPS) are rare tumors for which complete surgical resection remains the mainstay of treatment. The objective of the current study was to determine the impact of hospital case volume on outcomes in patients with RPS. METHODS: A total of 6950 patients with primary RPS who underwent surgical resection were identified from the National Cancer Data Base (1998-2011). Treating hospitals were classified by annual case volume; low-volume hospitals (LVHs) and high-volume hospitals (HVHs) were defined as those with ≤10 cases per year and >10 cases per year, respectively. Overall survival (OS) was compared using Kaplan-Meier curves. Cox proportional hazard models were created to compare risks. RESULTS: Of the 1131 reporting hospitals, the majority (1127 hospitals; 99.6%) were LVHs treating the majority of patients (6270 patients; 90.2%). Patients treated at LVHs were more likely to have lower grade and smaller tumors, receive radiotherapy, and undergo incomplete macroscopic (R2) resection. Patients treated at HVHs had lower 30-day readmission rates (1.8% vs 3.4%; P<.001), 30-day (1.9% vs 3.1%; P=.004) and 90-day (3.2% vs 5.7%; P=.007) mortality, longer median OS (76.2 months vs 64.2 months; P<.001), and higher 5-year OS rates (58% vs 52%; P<.001). After controlling for age, sex, insurance status, tumor size, tumor grade, surgical resection margin status, and radiotherapy administration, treatment at an HVH was found to be independently associated with a reduced risk of death (hazard ratio, 0.77; 95% confidence interval, 0.65-0.91 [P=.003]). CONCLUSIONS: Primary RPS are rare tumors, and to our knowledge few surgeons and institutions have significant experience and expertise in their multidisciplinary management and surgical resection. Although additional studies are needed, patient outcomes may be impacted by the case volume and expertise of the treating facility.

Author Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.

In the version of this article originally published, there was an error in Fig. 2b. RECIST ORR and pCR were both listed as 25%. RECIST ORR was actually 73%, and pCR was 45%. Also, an author's name was incorrect in the author list. Danny K. Wells should have been listed as Daniel K. Wells. The errors have been corrected in the print, HTML and PDF versions of this article.

Publisher Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.

In the version of this article originally published, there was an error in Fig. 1. In the neoadjuvant phase column, the n values for arms A and B were both reported to be 20. The n values for arms A and B were actually 12 and 11, respectively. Also, the URL underlying the accession code in the data availability section was incorrect. The URL was originally https://www.ebi.ac.uk/ega/studies/EGAS00001002698. It should have been https://www.ebi.ac.uk/ega/studies/EGAS00001003178. The errors have been corrected in the print, HTML and PDF versions of this article.

Phase II study of neoadjuvant checkpoint blockade in patients with surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

BACKGROUND: Soft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity. Within the past decade, major advances have been made in the treatment of other malignancies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma with the advent of immune-checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD1), and nivolumab (anti-PD1). The recently published SARC028 (NCT02301039), an open label, phase II, multicenter trial of pembrolizumab in patients with advanced bone and soft tissue sarcomas reported promising activity in select histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. METHODS: There is a clear need for novel and effective adjuncts in the treatment of STS. We hypothesize that immune checkpoint blockade will be effective in patients with surgically resectable primary or locally recurrent dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma when administered in the neoadjuvant setting. The primary aim of this phase II, single-center, open label, randomized non-comparative trial is to determine the pathologic response to neoadjuvant nivolumab monotherapy and combination nivolumab/ipilimumab in patients with resectable dedifferentiated liposarcoma of the retroperitoneum or undifferentiated pleomorphic sarcoma of the trunk or extremity treated with concurrent standard of care neoadjuvant radiation therapy. DISCUSSION: This study will help define the role of single agent anti-PD1 and combination anti-CTLA4 and anti-PD1 therapy in patients with surgically resectable dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT03307616 , registered October 12, 2017.

Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome.

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence.Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated.Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome.Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416-28. ©2018 AACR.

Preoperative chemoradiation therapy induces primary-tumor complete response more frequently than chemotherapy alone in gastric cancer: analyses of the National Cancer Database 2006-2014 using propensity score matching.

BACKGROUND: The benefit of preoperative chemoradiation (CXRT) over preoperative chemotherapy alone ("chemotherapy" hereafter) is unknown. By analyzing the National Cancer Database (NCDB), we investigated whether preoperative CXRT improves the incidence of primary tumor pathologic complete response (ypT0) and overall survival (OS) compared with preoperative chemotherapy in patients with gastric cancer. METHODS: Patients with non-metastatic gastric adenocarcinoma who underwent CXRT or chemotherapy followed by gastrectomy were included. Propensity score matching with a ratio of 1:1 was implemented to reduce selection bias. A conditional logistic regression model was used to compare incidences of ypT0 between groups, and Cox proportional hazards model was used to compare OS. RESULTS: We identified 8464 patients. Median patient age was 63 years; 76% were male and 79% were white. ypT0 was observed in 16.1% of patients in the CXRT group and 6.6% in the chemotherapy group (p < 0.001). After propensity score matching, a total of 2408 patients were matched. CXRT was associated with a higher incidence of ypT0 (OR 2.28, 95% CI 1.76-2.95; p < 0.0001) and higher frequency of R0 resection (92 vs. 86%; p < 0.001). However, CXRT was not associated with longer OS (HR 1.03, 95% CI 0.92-1.15; p = 0.63). Safety profiles (30-day mortality, 30-day readmission, and length of hospital stay) were equivalent between groups. CONCLUSIONS: In this study of gastric cancer patients from the NCDB, CXRT was associated with a higher incidence of ypT0 and R0 resection compared with chemotherapy, although it was not associated with a longer OS.

Nongastrointestinal Stromal Tumor Spindle Cell Sarcomas of the Colon or Rectum.

Because of the low incidence of nongastrointestinal stromal tumor (non-GIST) spindle cell sarcomas of the colon or rectum, the clinical behavior and ideal surgical treatment of these tumors and patient outcomes are poorly defined. The purpose of this study was to characterize these tumors and to determine the best surgical approach. We identified 1056 patients with non-GIST spindle cell sarcomas of the colon or rectum (1998-2010) in the National Cancer Database and collected data for each patient that included patient and tumor characteristics, tumor site (colon vs rectum), surgery type, and outcomes. The median overall survival was significantly longer in patients with rectal tumors than in those with colon tumors (P < 0.01). Patients with colon tumors who underwent anatomic surgical resection showed a trend toward longer median survival than those with no surgical treatment [hazard ratio (HR), 1.94; P = 0.09] or who underwent local excision (HR, 1.74; P = 0.09). Patients with rectal tumors did not benefit from anatomic surgical resection, but there was a trend favoring local excision (HR, 0.55; P = 0.06). Local sphincter-sparing procedures should be considered for rectal non-GIST tumors whenever technically feasible.

Salvage Surgery for Recurrent Retroperitoneal Well-Differentiated Liposarcoma: Early Reoperation may not Provide Benefit.

PURPOSE: Current evidence regarding salvage resection for recurrent retroperitoneal (RP) sarcomas generally lacks detailed histology-specific analyses, but the aggressiveness of these tumors varies widely by histology. We investigated associations between timing and extent of salvage surgery and survival outcomes in patients with recurrent RP well-differentiated liposarcoma (WDLPS). METHODS: The University of Texas MD Anderson Cancer Center Surgical Oncology sarcoma database was reviewed to identify patients with RP WDLPS who underwent surgical resection for first recurrent disease (salvage surgery) in 1995-2015. Medical records were retrospectively reviewed to identify factors associated with overall survival and disease-free survival. RESULTS: We identified 52 patients who underwent salvage surgery for RP WDLPS for first local recurrence; 28 (54%) underwent salvage surgery within 6 months after recurrence. Concomitant organ resections were performed in 32 (62%) patients, 4 (13%) of whom had pathologic invasion of resected organs. After R0/R1 resections (n = 45), 38 (84%) experienced a second local recurrence. Multivariable analyses revealed that organ invasion at the primary surgery [hazard ratio (HR) 13.08; p = 0.005] and disease-free interval < 1 year (HR 3.64; p = 0.044) were associated with shorter overall survival. Recurrence-to-salvage interval < 6 months was associated with shorter disease-free survival (HR 2.18; p = 0.025). Concomitant organ resection was associated with a longer hospital stay: ≥ 14 days (odds ratio 21.58; p = 0.007). CONCLUSIONS: Early salvage surgery may not always be the best approach for recurrent RP WDLPS patients. Because organ invasion is rare among recurrent RP WDLPS patients and concomitant organ resection is associated with a longer hospital stay, preservation of uninvolved organs should be considered.

Surgeon symptoms, strain, and selections: Systematic review and meta-analysis of surgical ergonomics.

BACKGROUND: Many surgeons experience work-related pain and musculoskeletal symptoms; however, comprehensive reporting of surgeon ailments is lacking in the literature. We sought to evaluate surgeons' work-related symptoms, possible causes of these symptoms, and to report outcomes associated with those symptoms. MATERIALS AND METHODS: Five major medical indices were queried for articles published between 1980 and 2014. Included articles evaluated musculoskeletal symptoms and ergonomic outcomes in surgeons. A meta-analysis using a fixed-effect model was used to report pooled results. RESULTS: Forty articles with 5152 surveyed surgeons were included. Sixty-eight percent of surgeons surveyed reported generalized pain. Site-specific pain included pain in the back (50%), neck (48%), and arm or shoulder (43%). Fatigue was reported by 71% of surgeons, numbness by 37%, and stiffness by 45%. Compared with surgeons performing open surgery, surgeons performing minimally invasive surgery (MIS) were significantly more likely to experience pain in the neck (OR 2.77 [95% CI 1.30-5.93]), arm or shoulder (OR 4.59 [2.19-9.61]), hands (OR 2.99 [1.33-6.71], and legs (OR 12.34 [5.43-28.06]) and experience higher odds of fatigue (8.09 [5.60-11.70]) and numbness (6.82 [1.75-26.65]). Operating exacerbated pain in 61% of surgeons, but only 29% sought treatment for their symptoms. We found no direct association between muscles strained and symptoms. CONCLUSIONS: Most surgeons report work-related symptoms but are unlikely to seek medical attention. MIS surgeons are significantly more likely to experience musculoskeletal symptoms than surgeons performing open surgery. Symptoms experienced do not necessarily correlate with strain.

Identification of preoperative factors associated with outcomes following surgical management of intra-abdominal recurrent or metastatic GIST following neoadjuvant tyrosine kinase inhibitor therapy.

BACKGROUND: The role of surgical resection in the treatment of patients with metastatic/recurrent gastrointestinal stromal tumors (GIST) is unclear. The aim of this study was to identify preoperative factors associated with oncologic outcomes for recurrent/metastatic GIST after tyrosine kinase inhibitor (TKI) therapy. METHODS: We identified 107 patients with metastatic or recurrent GIST treated with TKIs and surgical resection (2002-2012). Patients that underwent palliative or incomplete resection were excluded. Complete resection was achieved in 87 patients which comprise the analytic cohort. Univariate and multivariate analyses were conducted to identify risk factors for GIST-specific survival (DSS) and time-to-recurrence (TTR). RESULTS: At a median follow-up of 51 months (91 months for survivors), median DSS was 74 months and TTR was 21 months. By univariate analysis, unifocal disease, duration of TKI < 365 days, and no evidence of radiographic progression were associated with improved TTR and DSS. Multivariate Cox regression demonstrated that evidence of radiographic progression was associated with shorter DSS (HR 2.53, 95%CI = 1.27-5.06, P = 0.008) and increased risk of recurrence (HR 3.33, 95%CI = 1.91-5.82, P < 0.001). CONCLUSIONS: Patients with unifocal disease and radiographic evidence of response to TKI therapy may achieve improved oncologic outcomes when complete surgical resection is achieved following treatment with TKI.

Comparative Performance of the 7th and 8th Editions of the American Joint Committee on Cancer Staging Systems for Soft Tissue Sarcoma of the Trunk and Extremities.

BACKGROUND: The 8th edition American Joint Committee on Cancer (AJCC) staging for soft tissue sarcomas of the trunk/extremities divides T stage into four categories and upstages nodal disease to stage IV. We used the National Cancer Database (NCDB) to evaluate the prognostic power of the new system. METHODS: A total of 26,144 patients were identified from the NCDB from 2004 to 2013. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard models. RESULTS: Including T3 (10 cm > × >15 cm) and T4 (> 15 cm) categories resulted in an increased number of patients classified as stage III (5120 as IIIA [19.6%] and 4280 as IIIB [16.4%], vs. 7882 [30.1%] previously), and there was a small increase in the number of patients classified as stage IV (2776 [10.6%], vs. 2565 [9.8%] previously). In the 7th edition, the hazard ratio (HR) for death increases with stage, with large incremental increases between stages II-III and III-IV. In the 8th edition, the HR for death demonstrates smaller incremental increases between each stage. Five-year OS for 7th edition T1 and T2 patients was 78.8 and 58.8% (p < 0.01), respectively, versus 62.6, 53.5, and 56.1% for T2, T3, and T4 patients, respectively, in the 8th edition (p < 0.01). Patients with isolated nodal disease (n = 211) had a better 5-year OS than those with distant metastases (33.1% vs. 12.4%, p < 0.001). CONCLUSIONS: The AJCC 8th edition uses T stage to more accurately stratify OS in patients with large, high-grade tumors (T3/4) compared with those patients with T2 tumors, which facilitates risk assessment. The distinction between T3 and T4 may not be clinically significant. Patients with metastatic nodal disease have a survival outcome intermediate to those with stages III and IV disease.

Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014.

BACKGROUND: No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed. METHODS: Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use. RESULTS: This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival. CONCLUSIONS: Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018;124:998-1007. © 2018 American Cancer Society.

Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial.

BACKGROUND: Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. METHODS: We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775. FINDINGS: Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2-not estimable] vs 2·9 months [95% CI 1·7-not estimable]; hazard ratio 0·016, 95% CI 0·00012-0·14, p<0·0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]). INTERPRETATION: Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib. FUNDING: Novartis Pharmaceuticals Corporation.