Aaron U. Blackham

Variation in susceptibility of human malignant melanomas to oncolytic vesicular stomatitis virus

BACKGROUND Vesicular stomatitis virus (VSV) is a novel, anti-cancer therapy that targets cancer cells selectively with defective antiviral responses; however, not all malignant cells are sensitive to the oncolytic effects of VSV. Herein, we have explored the mechanistic determinants of mutant M protein VSV (M51R-VSV) susceptibility in malignant melanoma cells. METHODS Cell viability after VSV infection was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) viability assay in a panel of melanoma cell lines. VSV infectability, viral protein synthesis, and viral progeny production were quantified by flow cytometry, (35)S-methionine electrophoresis, and viral plaque assays, respectively. Interferon (IFN) responsiveness was determined using MTS assay after β-IFN pretreatment. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV. RESULTS Cell viability after M51R-VSV infection at a multiplicity of infection of 10 pfu/mL, 48 hours postinfection) ranged between 0 ± 1% and 59 ± 9% (mean ± standard deviation). Sensitive cell lines supported VSV infection, viral protein synthesis, and viral progeny production. In addition, when pretreated with β-IFN, sensitive cells became resistant to M51R-VSV, suggesting that IFN-mediated antiviral signaling is defective in these cells. In contrast, resistant melanoma cells do not support VSV infection, viral protein synthesis, or viral replication, indicating that antiviral defenses remain intact. In a murine xenograft model, intratumoral M51R-VSV treatment decreased tumor growth relative to controls after 26 days in SK-Mel 5 (-21 ± 19% vs. 2,100 ± 770%; P < .0001) and in SK-Mel 3 (2,000 ± 810% vs. 7,000 ± 3,000%; P = .008) established tumors. CONCLUSION M51R-VSV is a viable anti-cancer therapy, but susceptibility varies among melanomas. Future work will exploit specific mechanisms of resistance to expand the therapeutic efficacy of M51R-VSV.

Perioperative systemic chemotherapy for appendiceal mucinous carcinoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

The role of systemic chemotherapy (SC) in conjunction with cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in appendiceal mucinous carcinoma peritonei (MCP) is unknown.

A Histomorphologic Grading System That Predicts Overall Survival in Diffuse Malignant Peritoneal Mesothelioma With Epithelioid Subtype.

Diffuse malignant peritoneal mesothelioma (MPeM) is rare and arises from peritoneal serosal surfaces. Although it shares similar histomorphology with its counterpart, malignant pleural mesothelioma, etiologies, clinical courses, and therapies differ. Nuclear grading and level of mitoses have been correlated with prognosis in malignant pleural mesothelioma with epithelioid subtype. Whether nuclear grading and level of mitoses correlate with prognosis in MPeM is still unknown. Our study utilizes a 2 tier system incorporating nuclear features and level of the mitoses to stratify cases of MPeM with epithelioid subtype. Fifty-one cases of MPeM with clinical follow-up underwent retrospective microscopic review. From that subset, 46 cases were of epithelioid subtype, which were then stratified into a low-grade or high-grade tier. Survival times were calculated on the basis of Kaplan-Meier analysis. The low-grade tier had higher overall survival with a median of 11.9 years and 57% at 5 years when compared with the high-grade tier with a median of 3.3 years and 21% at 5 years (P=0.002). Although not statistically significant, the low-grade tier had higher progression-free survival with a median of 4.7 years and 65% at 5 years when compared with the high-grade tier with a median of 1.9 years and 35% at 5 years (P=0.089). Our study is first to specifically evaluate and correlate nuclear features and level of mitoses with overall survival in MPeM with epithelioid subtype.

The prognostic value of residual nodal disease following neoadjuvant chemoradiation for esophageal cancer in patients with complete primary tumor response

The prognostic significance of residual nodal disease in otherwise complete pathologic responders (ypT0N+) to neoadjuvant chemoradiation (nCRT) for esophageal cancer is unknown.

Tumor regression grade in gastric cancer: Predictors and impact on outcome.

The clinical value and prognostic implications of histologic response to neoadjuvant chemotherapy in gastric cancer is unknown.

Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer

Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrence (LRR) is common and factors associated with LRR have not been clearly identified.

Patterns of recurrence and long-term outcomes in patients who underwent pancreatectomy for intraductal papillary mucinous neoplasms with high grade dysplasia: implications for surveillance and future management guidelines

BACKGROUND While intraductal papillary mucinous neoplasms (IPMNs) with high-grade dysplasia (HGD) are thought to represent non-invasive, high-risk lesions, its natural history following resection is unknown. METHODS A retrospective review of HGD-IPMN patients (1999-2015) was performed. Recurrence patterns and clinical outcomes following pancreatectomy were analyzed and the indications for surgery were explored based on current guidelines. RESULTS HGD was diagnosed in 100 of 314 patients (32%) following pancreatectomy for IPMN. IPMNs were classified as main duct, branch duct, or mixed in 15, 58 and 27 patients, respectively. Following resection, 25 patients had low-risk residual disease in the remnant pancreas. With a median follow-up of 35 months (range 1-129), 9 patients developed progressive or recurrent disease, 4 of whom underwent additional pancreatectomy. Three patients developed invasive adenocarcinoma. Median time to recurrence was 15 months (range 7-72). Based on the management algorithm from the international consensus guidelines, resection was indicated in 76 patients (76%). Other indications for surgery included mixed-duct IPMN(13), increased cyst size(7) and other(4). CONCLUSION The prognosis of HGD-IPMN following resection is good; however, HGD may be a marker for developing IPMN recurrence or adenocarcinoma. Current guidelines regarding surgical indications for IPMN can miss a significant number of patients with HGD.

Factors predictive of tumor recurrence and overall survival in patients with esophageal cancer who have pathologic complete response after neo-adjuvant therapy.

170 Background: Pathologic complete response (pCR) to neoadjuvant therapy is presumably associated with favorable outcomes in patients (pts) with esophageal cancer, but reported survival rates vary. This study evaluates patterns of recurrence after curative esophagectomy and identifies factors predictive of recurrent disease and overall survival (OS) in patients with pCR. Methods: An IRB-approved, retrospective review of a prospective esophageal cancer database was conducted. Patient demographics, perioperative data, and outcomes were examined. Recurrences were classified as locoregional (LR) or systemic. Cox regression model and Kaplan–Meier (KM) plots were used for survival analysis. Results: 837 pts with invasive esophageal cancer treated at a single institution from 1994 to 2013 were identified. 176 pts underwent neoadjuvant therapy followed by surgery and had pCR. Of these, 93.7% had adenocarcinoma and 6.3% had squamous cell cancer. Mean age was 56.6 and most pts were white (96.6%) males (79.5%). Med...

Is linitis plastica a contraindication for surgical resection? A 7-institution study of the U.S. Gastric Cancer Collaborative.

118 Background: Linitis plastica (LP) describes a diffusively infiltrative gastric adenocarcinoma that portends poor prognosis. Current treatment guidelines do not differentiate between LP and non-LP cancers and it is not known if the same staging system should be applied to both situations. Methods: Using the multi-institutional U.S. Gastric Cancer Collaborative database, 869 patients with gastric adenocarcinoma who underwent resection between 2000-2012 were identified. Clinicopathologic, perioperative and survival outcomes of the 58 patients with LP were compared to the 811 patients without LP. Results: Advanced disease (stage III/IV) at presentation was more common in patients with LP compared to non-LP patients (90 vs 44%, p<0.01). Despite the fact that most LP patients underwent total gastrectomy (88% vs 57%, p<0.01), positive margins were more common in LP patients (33 vs 7%, p<0.01). There was no difference in perioperative complications (48 vs 43%, p=0.45) or mortality (7 vs 3%, p=0.12) between LP...

986 Ratio of Intraoperative Fluid to Anesthesia Time and Its Impact on Short Term Perioperative Outcomes Following Gastrectomy for Cancer

INTRODUCTION: High hospital volume has a protective effect on surgical outcomes, however, it is not known whether the effect is different depending on the patient population studied. We sought to analyze the treatment effect with regard to in-hospital mortality in different patient populations who undergo gastric resection for cancer, based on hospital volume.METHODSAND PROCEDURES: The Nationwide Inpatient Sample (NIS) database was used and data was extracted using ICD-9 codes. Adults were included if they had a diagnosis of gastric cancer and underwent a potentially curative partial or total gastrectomy. Multivariate logistic regression analyses were used with in-hospital mortality as the dependent variable to evaluate the effect of low, intermediate, and high hospital volume (average of ≤5, 6-20, and >20 gastric resections for cancer per year, respectively). Multivariate analyses were repeated in different subsets of patients to determine if hospital volume had variable effects on mortality depending on the subset evaluated. RESULTS: From 1998-2011, a total of 24,538 patients were included. The overall perioperative mortality rate was 5.5%, and multivariate analysis demonstrated that patients who received an operation in a center that performed a high-volume of gastric resections was protective (OR 0.64, 95% CI 0.500.81) when compared to patients who underwent surgery in a low-volume hospital. Other independent risk factors included male gender, age ≥65 years, Caucasian race, and Charlson Comorbidity Index (CCI) ≥3. Upon subset analyses, there were no cohorts of patients that had a significantly lower risk of mortality if they received their operation in a low or intermediate-volume center when compared to a high-volume center. The risk of mortality for those undergoing surgery in low-volume hospitals was statistically significantly elevated in certain subsets (age ≥75, male, Caucasian, Asian, CCI ≥6) when compared to high-volume hospitals. Similarly, in intermediate-volume hospitals, mortality risk was significantly elevated in males, Caucasians, and those with CCI 0-2 and CCI ≥6. There were no significant differences in mortality between subgroups as evidenced by overlapping confidence intervals. (Figures 1A,B). CONCLUSION(S): There was no heterogeneity of treatment effect observed in gastric cancer patients undergoing surgery at low, intermediate, or high volume centers. These data support the current recommendation that all patients with gastric cancer should receive treatment at high-volume centers. This recommendation is particularly important for high-risk subgroups such as elderly patients and those with medical comorbidities.