EBV-Associated Smooth Muscle Neoplasms: Solid Tumors Arising in the Presence of Immunosuppression and Autoimmune Diseases

Background. Epstein-Barr virus (EBV)-related smooth muscle neoplasms (SMNs) have been associated with immune dysregulation, most notably in patients who have undergone solid organ transplantation or in patients with HIV/AIDS. Objective. to report our experience with EBV-related neoplasms as well as describing the first EBV-related SMN in the setting of administration of glucocorticoids and the tumor necrosis factor inhibitor etanercept. Design. We have case reports, of minimum 3-year follow-up, 2002–2005. Setting. It was held in an academic and tertiary referral cancer center. Patients. Patients are with dysregulated immunity after solid organ transplantation, HIV/AIDS, or with psoriasis after treatment with etanercept. Interventions. There were discontinuation of etanercept, right hepatic trisegmentectomy, and chemotherapy. Measurements. We use survival as a measurement here. Results. Patients who were able to withstand reduction in immunosuppression survived. Surgical resection or chemotherapy was successful in delaying progression of disease. Limitations. There was a relatively short follow-up for these slow-growing neoplasms. Conclusion. EBV-related SMNs have variable aggressiveness. While chemotherapy may slow disease progression, resection and improving the host immune status provide the best opportunity for primary tumor control

Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis

The high rate of mortality in patients with sepsis results from an inappropriately amplified systemic inflammatory response to infection. Toll-like receptors (TLRs) are important for the activation of innate immunity against microbial pathogens. We demonstrate a critical role of TLR9 in the dysregulated immune response and death associated with sepsis. Compared with wild-type (WT) mice, TLR9−/− mice exhibited lower serum inflammatory cytokine levels, higher bacterial clearance, and greater survival after experimental peritonitis induced by cecal ligation and puncture (CLP). Protection of TLR9−/− mice after CLP was associated with a greater number of peritoneal dendritic cells (DCs) and granulocytes than in WT controls. Adoptive transfer of TLR9−/− DCs was sufficient to protect WT mice from CLP and increased the influx of peritoneal granulocytes. Subsequent experiments with a depleting antibody revealed that granulocytes were required for survival in TLR9−/− mice. Remarkably, a single injection of an inhibitory CpG sequence that blocks TLR9 protected WT mice, even when administered as late as 12 h after CLP. Our findings demonstrate that the detrimental immune response to bacterial sepsis occurs via TLR9 stimulation. TLR9 blockade is a potential strategy for the treatment of human sepsis

Prognostic significance of early recurrence: a conditional survival analysis in patients with resected colorectal liver metastasis

AbstractBackgroundFor patients undergoing liver resection for colorectal metastases, specific clinico‐pathological variables have been shown to be prognostic at baseline. This study analyses how the prognostic capability of these variables changes in a conditional survival model.MethodsRetrospective review of a prospectively maintained database of patients who underwent an R0 resection of colorectal liver metastases from 1994 to 2004 at a single institution.ResultsIn total, 807 patients were identified, with an 87‐month median follow‐up for survivors. Five‐ and 10‐year disease‐specific survivals (DSS) were 68% and 55%, respectively. The probability of further survival increased as the survival time increased. For 3‐year survivors (n = 504), DSS were no longer significantly different between patients with a low (0–2) or high (3–5) clinical risk score (CRS, P = 0.19). On multivariate analysis, independent predictors of DSS for 3‐year survivors were recurrence within the first 3 years after a liver resection, a pre‐operative carcinoembryonic antigen (CEA) >200 ng/ml and disease‐free interval <12 months prior to the diagnosis of liver metastasis. However, for those patients who were recurrence free at 1 year, no clinico‐pathological variables retained prognostic significance.DiscussionAfter 3 years of DSS and 1 year of recurrence‐free survival, baseline clinico‐pathological variables have a limited ability to predict future survival. Early post‐operative recurrence appears to be the most useful single clinical feature in estimating conditional DSS

Mutation location on the RAS oncogene affects pathologic features and survival after resection of colorectal liver metastases

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136316/1/cncr30351_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136316/2/cncr30351.pd

Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression.

OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA). BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection. METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (\u3c12 \u3emonths) or long-term (\u3e30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes (eg, recurrence pattern and early cancer-specific mortality) were determined. RESULTS: Loss of SMAD4 expression in pancreatic adenocarcinoma was identified in 40 of 127 patients (32%). SMAD4 loss occurred in 27% of patients who experienced isolated local recurrence, 33% of patients with a distant recurrence, 33% of patients who experienced local and distant site recurrences, and 25% of patients who were without evidence of recurrence (Fisher exact, P = 0.9). In a multivariate analysis, the presence of regional lymph node metastases was the only factor associated with the development of distant metastases (odds ratio = 4.7, P = 0.02). SMAD4 was neither associated with recurrence pattern (odds ratio = 0.9, P = 0.9) nor associated with early death (odds ratio = 0.5, P = 0.15). CONCLUSIONS: Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected PDA

Risk Factors for Gastrointestinal Stromal Tumor Recurrence in Patients Treated With Adjuvant Imatinib

Peer reviewe

Percutaneous Preoperative Biliary Drainage for Resectable Perihilar Cholangiocarcinoma: No Association with Survival and No Increase in Seeding Metastases

Background: Endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) are both used to resolve jaundice before surgery for perihilar cholangiocarcinoma (PHC). PTBD has been associated with seeding metastases. The aim of this study was to compare overall survival (OS) and the incidence of initial seeding metastases that potentially influence survival in patients with preoperative PTBD versus EBD. Methods: Between 1991 and 2012, a total of 278 patients underwent preoperative biliary drainage and resection of PHC at 2 institutions in the Netherlands and the United States. Of these, 33 patients were excluded for postoperative mortality. Among the 245 included patients, 88 patients who underwent preoperative PTBD (with or without previous EBD) were compared to 157 patients who underwent EBD only. Survival analysis was done with Kaplan–Meier and Cox regression with propensity score adjustment. Results: Unadjusted median OS was comparable between the PTBD group (35 months) and EBD-only group (41 months; P = 0.26). After adjustment for propensity score, OS between the PTBD group and EBD-only group was similar (hazard ratio, 1.05; 95 % confidence interval, 0.74–1.49; P = 0.80). Seeding metastases in the laparotomy scar occurred as initial recurrence in 7 patients, including 3 patients (3.4 %) in the PTBD group and 4 patients (2.7 %) in the EBD-only group (P = 0.71). No patient had an initial recurrence in percutaneous catheter tracts. Conclusions: The present study found no effect of PTBD on survival compared to patients with EBD and no increase in seeding metastases that developed as initial recurrence. These data suggest that PTBD can safely be used in preoperative management of PHC

FOLFIRINOX Induction Therapy for Stage 3 Pancreatic Adenocarcinoma

ABSTRACT Background. Reports show that FOLFIRINOX therapy for pancreatic ductal adenocarcinoma (PDAC) results in objective response rates two to threefold higher than those of other regimens. This study aimed to assess response and resection rates for locally unresectable (stage 3) patients initially treated with induction FOLFIRINOX. Methods. The institutional cancer database was queried for patients treated with induction FOLFIRINOX therapy between 2010 and 2013. Patients were included in the study if they were treated at the authors&apos; institution for stage 3 PDAC (locally unresectable) that had been adjudicated at a weekly multidisciplinary tumor board. Results. The study identified 101 patients. The median age was 64 years (range 37-81 years), and the median followup period was 12 months (range 3-37 months). The patients received a median of six cycles (range 1-20 cycles) of induction FOLFIRINOX. No grade 4 or 5 toxicity was recorded. At the initial restaging (median of 3 months after diagnosis), 23 patients (23 %) had developed distant metastases, 15 patients (15 %) had undergone resection, and 63 patients (63 %) had proceeded to chemoradiation. In the group of 63 patients who had proceeded to chemoradiation (median of 9 months after diagnosis), an additional 16 patients (16 %) had undergone resection, and 5 patients (5 %) had developed metastases. A partial radiographic response was observed in 29 % of all the patients, which was associated with ability to perform resection (p = 0.004). The median overall survival time was 11 months for the group that progressed with FOLFIRINOX and 26 months for the group that did not progress. Conclusion. Nearly one third of the patients who had been initially identified as having stage 3 pancreatic carcinoma and had been treated with FOLFIRINOX responded radiographically and underwent tumor resection. A recently completed phase 3 randomized trial for stage 4 pancreatic ductal adenocarcinoma (PDAC) identified FOL-FIRINOX as superior to gemcitabine in terms of radiographic response together with improved progression-free and overall survival. 1 Patients who received FOLFIRINOX experienced a 32 % objective response rate (ORR) compared with 9 % in the gemcitabine arm of the study, which correlated with survival benefit (median overall and progression-free survival, 11 and 6 versus 7 and 3 months, respectively). Retrospective studies of patients with both borderline resectable PDAC (stages 1 and 2) and stage 3 disease (locally unresectable) also have suggested an ORR of approximately 30 % with FOLFIRINOX. 2,3 The reported ORR from non-FOLFIRINOX regimens has generally been in the range of 10 %, including the results of a phase

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies