Pathological Margin Clearance and Survival After Pancreaticoduodenectomy in a US and European Pancreatic Center

Background: The optimal definition of a margin-negative resection and its exact prognostic significance on survival in resected pancreatic adenocarcinoma remains unknown. This study was designed to assess the relationship between pathological margin clearance, margin type, and survival. Methods: Patients who underwent pancreaticoduodenectomy with curative intent at two academic institutions, in Amsterdam, the Netherlands, and Boston, Massachusetts, between 2000 and 2014 were retrospectively evaluated. Overall survival, recurrence rates, and progression-free survival (PFS) were assessed by Kaplan–Meier estimates and multivariate Cox proportional hazards analysis, according to pathological margin clearance and type of margin involved. Results: Of 531 patients identified, the median PFS was 12.9, 15.4, and 24.1 months, and the median overall survival was 17.4, 22.9, and 27.7 months for margin clearances of 0, < 1, and ≥1 mm, respectively (all log-rank p < 0.001). On multivariate analysis, patients with a margin clearance of ≥1 mm demonstrated a survival advantage relative to those with 0 mm clearance [hazard ratio (HR) 0.71, p < 0.01], whereas survival was comparable for patients with a margin clearance of < 1 mm versus 0 mm (HR: 0.93, p = 0.60). Patients with involvement (0 or < 1 mm margin clearance) of the SMV/PV margin demonstrated prolonged median overall survival (25.7 months) relative to those with SMA involvement (17.5 months). Conclusions: In patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, a margin clearance of ≥1 mm correlates with improved survival relative to < 1 mm clearance and may be a more accurate predictor of a complete margin-negative resection in pancreatic cancer. The type of margin involved also appears to impact survival. Electronic supplementary material The online version of this article (10.1245/s10434-018-6467-9) contains supplementary material, which is available to authorized users

Cutting Through Confusion: Multimodality Therapy in Borderline Resectable and Locally Advanced Pancreatic Cancer

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Fine Needle Aspiration Cytology of Malignant Digestive System Gastrointestinal Neuroectodermal Tumor in a Lymph Node Metastasis from a Previously Diagnosed Liver Primary: A Case Report and Review of Literature

Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare neoplasm. Immunohistochemically, GNET typically demonstrates neural differentiation but lacks melanocytic differentiation, making it distinct from clear cell sarcoma of the soft tissues (CCS). Herein we report for the first time the cytomorphologic features of lymph node metastasis from presumably liver GNET. A 36‐year‐old female presented with fevers, night sweats, loss of appetite, and a 20‐lbs weight loss. Radiographic imaging showed a 13 cm heterogeneously enhancing mass in the right lobe of the liver and a hypermetabolic 0.9 cm periportal lymph node on positron emission tomography–computed tomography (PET/CT). Initially, a CT‐guided liver biopsy was performed followed by right hepatic lobectomy and portal lymphadenectomy. The liver biopsy and resection showed an S100‐protein and SOX10 positive malignant neoplasm and genomic profiling of liver biopsy revealed EWSR1‐CREB1gene rearrangement. These findings in conjunction with the morphologic and immunohistochemical profile were diagnostic of GNET. Two months later, she presented with recurrent lymphadenopathy in the upper abdomen. Fine needle aspiration of the periportal nodal mass revealed single and clusters of primitive, large to medium‐sized neoplastic cells with round to oval nuclei, high nuclear‐cytoplasmic ratio, vesicular chromatin, and prominent nucleoli. The tumor cells were S100 protein and SOX10 positive, consistent with metastasis of the patient's recently diagnosed malignant digestive system GNET. Palliative chemotherapy was administered but the patient died a few days later, 4 months from the initial diagnosis. Awareness of this entity and judicial use of ancillary studies including molecular testing are essential for achieving accurate diagnosis

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors

Radiological dynamics and SITC-defined resistance types of advanced melanoma during anti-PD-1 monotherapy: an independent single-blind observational study on an international cohort

Background Although the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world data regarding differences in these resistance subtypes with respect to radiological dynamics and clinical manifestations.Methods We performed single-blind re-evaluations of radiological images by independent radiologists on a retrospectively assembled cohort of patients with advanced melanoma (n=254, median follow-up 31 months) receiving anti-PD-1 monotherapy at Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial time points were analyzed and correlated with each other and with survival. Primary and secondary resistance was defined as per the SITC Immunotherapy Resistance Taskforce definitions.Results The most significant target lesion measurement change took place within the first 3 months after anti-PD-1 initiation. Patients with stable disease with versus without tumor shrinkage at the initial evaluation exhibited distinct disease trajectory, as the rate of further upgrade to a partial or complete remission (CR/PR) was 44% and 0%, respectively. Eleven per cent of PR patients ultimately achieved a CR. In multivariate analyses, deeper response depth was independently associated with a more limited progression pattern, fewer involved organs, lower tumor burden, slower growth rate at disease progression (PD) (all p≤0.001), and longer post-progression survival (PPS) (bivariate analysis, p=0.005). Compared with primary resistance, secondary resistance was associated with less widespread PD pattern, lower tumor burden and slower tumor growth (all p≤0.001). Patients with secondary resistance were less likely to receive further systemic therapy (28% vs 57%, p&lt;0.001) yet had significantly better PPS (HR 0.503, 95% CI 0.288 to 0.879, p=0.02).Conclusions Radiological dynamics were variable, yet significantly correlated with survival outcomes. SITC-defined primary and secondary resistance are distinct clinical manifestations in patients with melanoma, suggesting the possibility of resistance-type-based therapeutic decision-making and clinical trial design, once further validated by future prospective studies

Disparities in access to care among patients with appendiceal or colorectal cancer and peritoneal metastases: A medicare insurance-based study in the United States

BackgroundPrior studies attempting to identify disparities in the care of patients with appendiceal (AC) or colorectal cancer (CRC) with peritoneal metastasis (PM) are limited to single-institution, highly selected patient populations. This observational cohort study sought to identify factors associated with specialty care for Medicare beneficiaries with AC/CRC-PM.Materials and methodsPatients &gt;65 years old in the United States diagnosed with AC/CRC and isolated PM were identified within the Medicare Standard Analytic File (2013-2017). Mixed-effects analyses assessed patient factors associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and outpatient consultation with a peritoneal surface malignancy (PSM) surgeon, and Cox proportional-hazards analysis compared 3-year overall survival (OS) between patients receiving CRS/HIPEC versus systemic therapy alone.ResultsAmong 7,653 patients, only 250 (3.3%) underwent CRS/HIPEC. Among those individuals who did not undergo CRS/HIPEC (N=7,403), only 475 (6.4%) had outpatient consultation with a PSM surgeon. Patient factors independently associated with lower odds of CRS/HIPEC and PSM surgery consultation included older age, greater comorbidity burden, higher social vulnerability index, and further distance from a PSM center (p&lt;0.05). CRS/HIPEC was independently associated with better 3-year OS compared with systemic therapy alone (HR=0.29, 95%CI=0.21-0.38).ConclusionAn exceedingly small proportion of Medicare beneficiaries with AC/CRC-PM undergo CRS/HIPEC or even have an outpatient consultation with a PSM surgeon. Significant disparities in treatment and access to care exist for patients with higher levels of social vulnerability and those that live further away from a PSM center. Future research and interventions should focus on improving access to care for these at-risk patient populations

Plasma-derived extracellular vesicle analysis and deconvolution enable prediction and tracking of melanoma checkpoint blockade outcome

Immune checkpoint inhibitors (ICIs) show promise, but most patients do not respond. We identify and validate biomarkers from extracellular vesicles (EVs), allowing non-invasive monitoring of tumor- intrinsic and host immune status, as well as a prediction of ICI response. We undertook transcriptomic profiling of plasma-derived EVs and tumors from 50 patients with metastatic melanoma receiving ICI, and validated with an independent EV-only cohort of 30 patients. Plasma-derived EV and tumor transcriptomes correlate. EV profiles reveal drivers of ICI resistance and melanoma progression, exhibit differentially expressed genes/pathways, and correlate with clinical response to ICI. We created a Bayesian probabilistic deconvolution model to estimate contributions from tumor and non-tumor sources, enabling interpretation of differentially expressed genes/pathways. EV RNA-seq mutations also segregated ICI response. EVs serve as a non-invasive biomarker to jointly probe tumor-intrinsic and immune changes to ICI, function as predictive markers of ICI responsiveness, and monitor tumor persistence and immune activation

International Validation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) TNM Staging System in Patients With Resected Pancreatic Cancer

Importance: The recently released eighth edition of the American Joint Committee on Cancer TNM staging system for pancreatic cancer seeks to improve prognostic accuracy but lacks international validation. Objective: To validate the eighth edition of the American Joint Committee on Cancer TNM staging system in an international cohort of patients with resected pancreatic ductal adenocarcinoma. Design, Setting, and Participants: This international multicenter cohort study took place in 5 tertiary centers in Europe and the United States from 2000 to 2015. Patients who underwent pancreatoduodenectomy for nonmetastatic pancreatic ductal adenocarcinoma were eligible. Data analysis took place from December 2017 to April 2018. Exposures: Patients were retrospectively staged according to the seventh and eighth editions of the TNM staging system. Main Outcomes and Measures: Prognostic accuracy on survival rates, assessed by Kaplan-Meier and multivariate Cox proportional hazards analyses and concordance statistics. Results: A total of 1525 consecutive patients were included (median [IQR] age, 66 (58-72) years; 802 (52.6%) male). Distribution among stages via the seventh edition was stage IA in 41 patients (2.7%), stage IB in 42 (2.8%), stage IIA in 200 (13.1%), stage IIB in 1229 (80.6%), and stage III in 12 (0.8%); this changed with use of the eighth edition to stage IA in 118 patients (7.7%), stage IB in 144 (9.4%), stage IIA in 22 (1.4%), stage IIB in 643 (42.2%), and stage III in 598 (39.2%). With the eighth edition, 774 patients (50.8%) migrated to a different stage; 183 (12.0%) were reclassified to a lower stage and 591 (38.8%) to a higher stage. Median overall survival for the entire cohort was 24.4 months (95% CI, 23.4-26.2 months). On Kaplan-Meier analysis, 5-year survival rates changed from 38.2% for patients in stage IA, 34.7% in IB, 35.3% in IIA, 16.5% in IIB, and 0% in stage III (log-rank P\u2009&lt;\u2009.001) via classification with the seventh edition to 39.2% for patients in stage IA, 33.9% in IB, 27.6% in IIA, 21.0% in IIB, and 10.8% in stage III (log-rank P\u2009&lt;\u2009.001) with the eighth edition. For patients who were node negative, the T stage was not associated with prognostication of survival in either edition. In the eighth edition, the N stage was associated with 5-year survival rates of 35.6% in N0, 20.8% in N1, and 10.9% in N2 (log-rank P\u2009&lt;\u2009.001). The C statistic improved from 0.55 (95% CI, 0.53-0.57) for the seventh edition to 0.57 (95% CI, 0.55-0.60) for the eighth edition. Conclusions and Relevance: The eighth edition of the TNM staging system demonstrated a more equal distribution among stages and a modestly increased prognostic accuracy in patients with resected pancreatic ductal adenocarcinoma compared with the seventh edition. The revised T stage remains poorly associated with survival, whereas the revised N stage is highly prognostic

Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy.

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers