Joal D. Beane

Tumor-Infiltrating Lymphocytes Genetically Engineered with an Inducible Gene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma

Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose–escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 109 NFAT.IL12–transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients. Clin Cancer Res; 21(10); 2278–88. ©2015 AACR.

Impact of Maximal Cytoreductive Surgery Plus Regional Heated Intraperitoneal Chemotherapy (HIPEC) on Outcome of Patients With Peritoneal Carcinomatosis of Gastric Origin: Results of the GYMSSA Trial

A prospective randomized trial was conducted to compare the impact of systemic chemotherapy versus multi‐modality therapy (complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy) on overall survival (OS) in patients with gastric carcinomatosis.

Splenic preserving distal pancreatectomy: does vessel preservation matter?

BACKGROUND Splenic preserving distal pancreatectomy (SPDP) can be accomplished with splenic artery and vein preservation or ligation. However, no data are available on the relative merits of these techniques. The aim of this analysis was to compare the outcomes of splenic preserving distal pancreatectomy with and without splenic vessel preservation. STUDY DESIGN From 2002 through 2009, 434 patients underwent distal pancreatectomy and 86 (20%) had splenic preservation. Vessel preservation (VP) was accomplished in 45 and ligation (VL) was performed in 41. These patients were similar with respect to age, American Society of Anesthesiologists class, pathology, surgeons, and minimally invasive approach (79%). For comparison, a matched group of 86 patients undergoing distal pancreatectomy with splenectomy (DP+S) was analyzed. RESULTS The VP-SPDP procedure was associated with less blood loss than VL-SPDP or DP+S (224 vs 508 vs 646 mL, respectively; p < 0.05). The VP-SPDP procedure also resulted in fewer grade B or C pancreatic fistulas (2% vs 12% vs 14%; p = NS) and splenic infarctions (5% vs 39%; p < 0.01), less overall morbidity (18% vs 39% vs 38%, respectively; p < 0.05) and need for drainage procedure (2% vs 15% vs 16%; p < 0.05), and shorter post-operative length of stay (4.5 vs 6.2 vs 6.6 days; p < 0.05). CONCLUSIONS This analysis suggests that outcomes are (1) best for VP-SPDP and (2) VL-SPDP provides no short-term advantage over distal pancreatectomy with splenectomy. We conclude that splenic VP is preferred when SPDP is performed.

Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma

Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9-84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFα, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500-2,000-fold in vitro. Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted.

Risk-adjusted Outcomes of Clinically Relevant Pancreatic Fistula Following Pancreatoduodenectomy: A Model for Performance Evaluation.

Objective: To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator. Background: Accurate assessment of surgeon and institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk. Methods: This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance. Results: There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (≥15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment. Conclusions: This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes.

Incorporation of Procedure-specific Risk Into the ACS-NSQIP Surgical Risk Calculator Improves the Prediction of Morbidity and Mortality After Pancreatoduodenectomy.

Objective: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Programs (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity. Background: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD – clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD. Methods: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score. Results: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001). Conclusions: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

Outcomes after preoperative endoscopic ultrasonography and biopsy in patients undergoing distal pancreatectomy

BACKGROUND This retrospective cohort study analyzes the potential risks associated with preoperative fine needle aspiration (FNA) biopsy guided by endoscopic ultrasonography (EUS) in patients undergoing distal pancreatectomy. METHODS Excluding 204 patients with acute or chronic pancreatitis and those with previous pancreatic resections, 230 consecutive patients with primary pancreatic neoplasms underwent elective distal pancreatectomy between 2002 and 2009. The most common indications were adenocarcinoma (28%), intraductal papillary mucinous neoplasm (IPMN; 20%), and endocrine neoplasms (17%). Two-way statistical comparisons were performed between patients who did (EUS(+)) or did not (EUS(-)) undergo preoperative EUS-FNA. RESULTS Distal pancreatectomy was performed open in 118 patients (56%) and laparoscopically in 102 patients (44%). No differences were observed in age, sex, American Society of Anesthesiologists class, operative time, or blood loss between the EUS(+) (n = 179) and EUS(-) (n = 51) groups. Splenectomy was performed in 162 patients (70%) and was more common in the EUS(+) group. With the exception of adenocarcinoma (n = 57 [32%] EUS(+) vs n = 6 [12%] EUS(-); P < .01), the final pathologic diagnosis did not differ significantly between the EUS groups. Postoperative complications were more common in the EUS(+) patients with cystic neoplasms (43% vs 16% EUS(-); P = .04). EUS-FNA caused pancreatitis in 2 patients preoperatively. No differences in overall or recurrence-free survival were noted between cancer patients in the EUS groups. Patterns of tumor recurrence were not associated with EUS-FNA. CONCLUSION Preoperative EUS-FNA is not associated with adverse perioperative or long-term outcomes in patients undergoing distal pancreatectomy for solid neoplasms of the pancreas. The potentially detrimental long-term impact of preoperative EUS-FNA in patients with resectable pancreatic adenocarcinoma was not observed, but will require additional study.

Distal pancreatectomy with celiac axis resection: what are the added risks?

BACKGROUND Reported series of a distal pancreatectomy with celiac axis resection (DP-CAR) are either small or not adequately controlled. The aim of this analysis was to report a multicentre series of modified Appleby procedures with a comparison group to determine the relative operative risk. METHODS Data were gathered through the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) Pancreatectomy Demonstration Project. Over 14 months, 822 patients underwent a distal pancreatectomy at 43 institutions. Twenty of these patients (2.4%) also underwent a celiac axis resection. DP-CAR patients were matched by age, gender, BMI, serum albumin, ASA class, gland texture, duct size and pathology to 172 patients undergoing DP alone. RESULTS The majority of DP and DP-CAR patients had adenocarcinomas (61% and 60%). The median operative time for a DP alone was shorter than for a DP-CAR (207 versus 276 min, P < 0.01). Post-operative acute kidney injury (1% versus 10%, P < 0.03) and 30-day mortality were higher after a DP-CAR (1% versus 10%, P < 0.03). CONCLUSION A distal pancreatectomy with celiac axis resection is associated with increased operative time, post-operative acute kidney injury and a 10% operative mortality. The decision to offer a modified Appleby procedure for a body of pancreas tumour should be made with full disclosure of the increased risks.

Dimethylamino parthenolide enhances the inhibitory effects of gemcitabine in human pancreatic cancer cells.

IntroductionGemcitabine is standard treatment for pancreatic cancer but has limited clinical benefit due to chemoresistance. Nuclear factor-kappaB (NF-κB) can promote chemoresistance and is therefore an attractive therapeutic target. We hypothesize that NF-κB suppression with the novel, orally bioavailable inhibitor dimethylamino parthenolide (DMAPT) will sensitize pancreatic cancer cells to gemcitabine.MethodsBxPC-3, PANC-1, and MIA PaCa-2 human pancreatic cancer cell lines were treated with gemcitabine and/or DMAPT. Effects on the NF-κB pathway were determined by electrophoretic mobility shift assay, ELISA, or Western blot. Proliferation and apoptosis were measured by cell counts and ELISA, respectively. The effect of gemcitabine in vivo was determined using a MIA PaCa-2 heterotopic xenograft model.ResultsGemcitabine induced NF-κB activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-κB inhibitor IκBα in BxPC-3 and PANC-1 cells. DMAPT prevented the gemcitabine-induced activation of NF-κB. The combination of DMAPT/gemcitabine inhibited pancreatic cancer cell growth more than either agent alone. Gemcitabine also induced intratumoral NF-κB activity in vivo.ConclusionsDMAPT enhanced the anti-proliferative effects of gemcitabine in association with NF-κB suppression in pancreatic cancer cells in vitro. Furthermore, gemcitabine induced NF-κB activity in vivo, thus supporting the evaluation of NF-κB-targeted agents to complement gemcitabine-based therapies.

Defining the post-operative morbidity index for distal pancreatectomy

BACKGROUND Accurate assessment of complications is critical in analysing surgical outcomes. The post-operative morbidity index (PMI), derived from the Modified Accordion Severity Grading System and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), is a quantitative measure of post-operative morbidity. This study utilizes PMI to establish the complication burden for a distal pancreatectomy (DP). METHODS From 2005-2011, nine centres contributed ACS-NSQIP complication data for 655 DPs. Each complication was assigned an Accordion severity weight ranging from 0.11 for grade 1 to 1.00 for grade 6 (death). The PMI is the sum of complication severity weights divided by the total number of patients. RESULTS ACS-NSQIP complications occurred in 177 patients (27.0%). The non risk-adjusted PMI for DP is 0.087. Bleeding/Transfusion and Organ Space Infection were the most common complications. Frequency and burden differed across Accordion grades. While grade 4-6 complications represented only 15.4% of complication occurrences, they accounted for 30.4% of the burden. Subgroup analysis demonstrates that the PMI did not vary based on laparoscopic versus open approach or the performance of a splenectomy. DISCUSSION This study uses two validated systems to quantitatively establish the morbidity of a DP. The PMI allows estimation of both the frequency and severity of complications and thus provides a more comprehensive assessment of risk.