Matthew P. Holtzman

Induction of CD8+ T-Cell Responses Against Novel Glioma–Associated Antigen Peptides and Clinical Activity by Vaccinations With α-Type 1 Polarized Dendritic Cells and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Patients With Recurrent Malignant Glioma

PURPOSE A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. PATIENTS AND METHODS Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 10(7)/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays. RESULTS The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression. CONCLUSION These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.

Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis

Survival benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion was demonstrated by a prospective randomized trial for colorectal peritoneal carcinomatosis. Because of a recent substantial improvement in chemotherapy, the authors analyzed treatment options of colorectal carcinomatosis in the current era.

Immune Monitoring of the Circulation and the Tumor Microenvironment in Patients with Regionally Advanced Melanoma Receiving Neoadjuvant Ipilimumab

We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2–19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1−/HLA-DR−/CD33+/CD11b+ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4+CD25hi+Foxp3+) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8+ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69+) CD3+/CD4+ and CD3+/CD8+ T cells with evidence of induction/potentiation of memory T cells (CD45RO+). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1−/HLA-DR−/CD33+/CD11b+ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy.

Treatment factors associated with long-term survival after cytoreductive surgery and regional chemotherapy for patients with malignant peritoneal mesothelioma.

OBJECTIVES Malignant peritoneal mesothelioma (MPM) is a primary cancer that arises diffusely from the mesothelial cells lining the peritoneum. Morbidity and mortality are almost invariably owing to locoregional progression. Cytoreduction surgery (CRS) with intraoperative or perioperative high-dose regional chemotherapy has been established as the preferred approach in selected patients. This study was performed to identify factors associated with long-term outcome. METHODS Between January 1992 and 2010, 211 patients with MPM treated at 3 major referral centers with operative CRS and hyperthermic intraoperative peritoneal chemotherapy (HIPEC) were analyzed. RESULTS The median, actuarial overall survival was 38.4 months; the actuarial 5- and 10-year survivals were 41% and 26%, respectively. On multivariate analysis, factors independently associated with favorable outcome were younger age <60 years (P < .01), complete or near complete (R0-1) versus incomplete (R2-3) resection (P < .02), low versus high histologic grade (P < .01), and the use of cisplatin versus mitomycin-C during HIPEC (P < .01). There was a trend toward female sex and improved survival (male hazard ratio, 1.46; 95% confidence interval, 0.89-2.41; P = .13). CONCLUSION Operative CRS with HIPEC is associated with prolonged survival in patients with MPM. Factors associated with survival include age, complete or near complete gross tumor resection, histologic tumor grade, and HIPEC with cisplatin. Cisplatin (versus mitomycin-C) was independently associated with improved survival and demonstrates a salutary effect for HIPEC with cisplatin in the management of patients with MPM.

Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2–6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7–14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

Safety in Numbers: Progressive Implementation of a Robotics Program in an Academic Surgical Oncology Practice.

Background. Robotic-assisted surgery has potential benefits over laparoscopy yet little has been published on the integration of this platform into complex surgical oncology. We describe the outcomes associated with integration of robotics into a large surgical oncology program, focusing on metrics of safety and efficiency. Methods. A retrospective review of a prospectively maintained database of robotic procedures from July 2009 to October 2014 identifying trends in volume, operative time, complications, conversion to open, and 90-day mortality. Results. Fourteen surgeons performed 1236 cases during the study period: thyroid (246), pancreas/duodenum (458), liver (157), stomach (56), colorectal (129), adrenal (38), cholecystectomy (102), and other (48). There were 38 conversions to open (3.1%), 230 complications (18.6%), and 13 mortalities (1.1%). From 2009 to 2014, operative volume increased (7 cases/month vs 24 cases/month; P < .001) and procedure time decreased (471 ± 166 vs 211 ± 140 minutes; P < .001) with statistically significant decreases for all years except 2014 when volume and time plateaued. Conversion to open decreased (12.1% vs 1.7%; P = .009) and complications decreased (48.5% vs 12.3%; P < .001) despite increasing complexity of cases performed. There were 13 deaths within 90 days (5/13 30-day mortality) and 2 (15.4%) were from palliative surgeries. Conclusions. Implementation of a diverse robotic surgical oncology program utilizing multiple surgeons is safe and feasible. As operative volume increased, operative time, complications, and conversions to open decreased and plateaued at approximately 3 years. No unanticipated adverse events attributable to the introduction of this platform were observed.

GNAS is frequently mutated in both low-grade and high-grade disseminated appendiceal mucinous neoplasms but does not affect survival

We analyzed a series of 55 disseminated appendiceal mucinous neoplasms treated at our institution for GNAS and KRAS mutations in an attempt to correlate mutation status with clinicopathological findings and patient survival. GNAS mutations (p.R201H, c.602G>A and p.R201C, and c.602C>T) were identified in 17 (31%) of 55 of disseminated mucinous neoplasms and were found in 8 (35%) of 23 low-grade mucinous neoplasms, 7 (37%) of 19 high-grade mucinous adenocarcinomas lacking a signet ring cell component, and 2 (15%) of 13 high-grade mucinous adenocarcinomas with a signet ring cell component. All 7 mucinous adenocarcinomas composed of pure (>95%) signet ring cells harbored wild-type GNAS. There was no significant association between GNAS mutations and sex and age (both with P > .05) or between GNAS mutations and individual adverse histologic features including cytologic grade, destructive invasion, tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cells (all with P > .05). KRAS mutations were identified in 22 (40%) of 55 disseminated mucinous neoplasms. GNAS-mutated disseminated appendiceal mucinous neoplasms more frequently harbored concurrent KRAS mutations compared with GNAS wild-type tumors (65% versus 29%, P = .018). GNAS mutations were not significantly associated with overall survival (both with P > .05). Only overall tumor grade was an independent predictor of overall survival in the multivariate analysis (P = .01). Our results indicate that GNAS mutations are frequently identified in both low-grade and high-grade disseminated appendiceal mucinous neoplasms indicating that GNAS mutation status cannot be used to distinguish between low-grade from high-grade appendiceal mucinous neoplasms.

Aggressive locoregional management of recurrent peritoneal sarcomatosis.

and Objectives Peritoneal sarcomatosis responds poorly to systemic chemotherapy and demonstrates high rates of recurrence after resection. We sought to determine perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for recurrent sarcomatosis.

Gastric Adenocarcinoma in patients with Roux-en-Y Gastric bypass: A case series

/10.10 15 A mmo ence: . gedr@ The incidence of gastric cancer is approximately 24,000 cases per year with a mortality of 14,000 cases per year. There has been an increasing incidence of proximal gastric cancer and gastroesophageal junction cancer in the United States over the past 5–10 years [1]. Gastric cancer in patients who had previously undergone gastric restrictive surgery and gastric bypass has been reported but is rare. Seventeen case reports and series have been performed describing patients with gastric cancer after undergoing gastric bypass surgery [2]. In the majority of patients who had undergone previous Roux-en-Y gastric bypass surgery, gastric cancer developed in the excluded stomach, leading to delayed diagnosis. Unfortunately, management for these patients is difficult, given their often late diagnoses, which results in the advanced nature of their cancers when symptoms eventually develop [2]. Two cases of gastric adenocarcinoma in patients after Roux-en-Y gastric bypass will be described.

Depressive Symptoms in Patients Scheduled for Hyperthermic Intraperitoneal Chemotherapy With Cytoreductive Surgery: Prospective Associations With Morbidity and Mortality.

PURPOSE The current study examined prospective relationships between preoperative depressive symptoms and short-term (30-day morbidity and readmission) and long-term (overall survival) outcomes after hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (HIPEC + CS). METHODS Ninety-eight patients scheduled for HIPEC + CS completed the Center for Epidemiologic Studies-Depression (CES-D) scale before surgery. Demographic and disease-specific factors and information about morbidity and readmission within 30 days after discharge were gathered from medical records. Survival was measured from date of surgery to death. RESULTS Twenty-eight percent of patients had CES-D scores indicative of clinically significant depressive symptoms. Thirty-day morbidity occurred in 31.9% of patients and readmission in 22.2%. At the time of analysis (median follow-up of 49 months), 71.6% of patients were deceased, with median survival time of 11 months for those who died. After adjusting for relevant preoperative demographic and disease-specific factors, depressive symptoms were associated with greater odds of 30-day morbidity (n = 68; odds ratio, 5.50; 95% CI, 1.23 to 24.73; P = .03) and greater likelihood of 30-day readmission (n = 72; odds ratio, 5.92; 95% CI, 1.27 to 27.64; P = .02). Depressive symptoms were associated with shorter survival after adjustment for preoperative demographic and disease-specific factors (n = 87; hazard ratio, 1.88; 95% CI, 1.07 to 3.31; P = .03). This association was no longer significant when intraoperative/postoperative prognostic variables were added to the statistical model (n = 87; hazard ratio, 1.31; 95% CI, 0.72 to 2.37; P = .37). CONCLUSION Patients with clinically significant levels of preoperative depressive symptoms are at risk for poor clinical outcomes after HIPEC + CS, including greater risk of 30-day morbidity and readmission. Further research is warranted to determine biobehavioral mechanisms and examine whether effective interventions targeting preoperative depressive symptoms can reduce postoperative risk in this patient population.