Paul Toomey

Survival After Pancreaticoduodenectomy is not Improved by Extending Resections to Achieve Negative Margins

Objective:This study was undertaken to determine the survival benefit of extending resections to obtain microscopically negative margins after positive intraoperative frozen sections. Summary Background Data:The impact of residual microscopic disease after pancreaticoduodenectomy is currently a point of controversy. It is, however, generally believed that microscopically positive margins negatively impact survival and this may be improved by ultimately achieving negative margins. Methods:Since 1995, patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma have been prospectively followed. Margin status has been codified as macro/microscopically negative (R0) or macroscopically negative/microscopically positive (R1). The impact of margin status on survival was evaluated utilizing survival curve analysis. Data are presented as median, mean ± SD where appropriate. Results:For pancreatic adenocarcinoma, 202 patients underwent pancreaticoduodenectomy. R0 resections were achieved in 158 patients, 17 of whom required extended resections to achieve complete tumor extirpation after an initially positive intraoperative frozen section (R1 → R0). R1 resections were undertaken in 44 patients. Median survival for patients undergoing R0 resections was 21 months, 26 ± 23.4 months versus 13 months, 17 ± 21.0 months for patients undergoing R1 resections (P = 0.02). Median survival for patients undergoing R1 → R0 resections was 11 months, 16 ± 17.3, (P = 0.001). Margin status had a significant correlation with “N” stage and AJCC stage but not “T” stage. Conclusion:Survival after pancreaticoduodenectomy is not improved by extending pancreatic resections to achieve negative margins after initially positive intraoperative frozen sections. Tumor-specific factors beyond the presence of disease at a surgical margin are responsible for the abbreviated survival seen in patients undergoing R1 resections.

Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer

Intralesional (IL) injection of PV-10 has shown to induce regression of both injected and non-injected lesions in patients with melanoma. To determine an underlying immune mechanism, the murine B16 melanoma model and the MT-901 breast cancer model were utilized. In BALB/c mice bearing MT-901 breast cancer, injection of PV-10 led to regression of injected and untreated contralateral subcutaneous lesions. In a murine model of melanoma, B16 cells were injected into C57BL/6 mice to establish one subcutaneous tumor and multiple lung lesions. Treatment of the subcutaneous lesion with a single injection of IL PV-10 led to regression of the injected lesion as well as the distant B16 melanoma lung metastases. Anti-tumor immune responses were measured in splenocytes collected from mice treated with IL PBS or PV-10. Splenocytes isolated from tumor bearing mice treated with IL PV-10 demonstrated enhanced tumor-specific IFN-gamma production compared to splenocytes from PBS-treated mice in both models. In addition, a significant increase in lysis of B16 cells by T cells isolated after PV-10 treatment was observed. Transfer of T cells isolated from tumor-bearing mice treated with IL PV-10 led to tumor regression in mice bearing B16 melanoma. These studies establish that IL PV-10 therapy induces tumor-specific T cell-mediated immunity in multiple histologic subtypes and support the concept of combining IL PV10 with immunotherapy for advanced malignancies.

Immunotherapy for Gastrointestinal Malignancies

BACKGROUND Gastrointestinal (GI) cancers are the most common human tumors encountered worldwide. The majority of GI cancers are unresectable at the time of diagnosis, and in the subset of patients undergoing resection, few are cured. There is only a modest improvement in survival with the addition of modalities such as chemotherapy and radiation therapy. Due to an increasing global cancer burden, it is imperative to integrate alternative strategies to improve outcomes. It is well known that cancers possess diverse strategies to evade immune detection and destruction. This has led to the incorporation of various immunotherapeutic strategies, which enable reprogramming of the immune system to allow effective recognition and killing of GI tumors. METHODS A review was conducted of the results of published clinical trials employing immunotherapy for esophageal, gastroesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers. RESULTS Monoclonal antibody therapy has come to the forefront in the past decade for the treatment of colorectal cancer. Immunotherapeutic successes in solid cancers such as melanoma and prostate cancer have led to the active investigation of immunotherapy for GI malignancies, with some promising results. CONCLUSIONS To date, monoclonal antibody therapy is the only immunotherapy approved by the US Food and Drug Administration for GI cancers. Initial trials validating new immunotherapeutic approaches, including vaccination-based and adoptive cell therapy strategies, for GI malignancies have demonstrated safety and the induction of antitumor immune responses. Therefore, immunotherapy is at the forefront of neoadjuvant as well as adjuvant therapies for the treatment and eradication of GI malignancies.

Surgery residency training programmes have greater impact on outcomes after pancreaticoduodenectomy than hospital volume or surgeon frequency

BACKGROUND Hospital volume of pancreaticoduodenectomy (PD) and surgeon frequency of PD have been shown to impact outcomes. The impact of surgery residency training programmes after PD is unknown. This study was undertaken to determine the impact of surgery training programmes on outcomes after PD, as well as their importance relative to hospital volume and surgeon frequency of PD. METHODS The State of Florida Agency for Healthcare Administration Database was queried for patients undergoing PD during 2002-2007. Measures of outcome were compared for patients undergoing PD at centres with vs. without surgery residency training programmes. RESULTS A total of 2345 PDs were identified, of which 1478 (63%) were undertaken at training centres and 867 (37%) were performed at non-training centres. Patients undergoing PD at training centres had shorter lengths of stay, lower hospital charges and lower in-hospital mortality. Relative to surgeon frequency of PD, training centres had a greater favourable impact on hospital length of stay, hospital charges and in-hospital mortality (P < 0.001 for each, ancova). Relative to hospital volume of PDs undertaken, training centres had a greater impact on hospital charges (P < 0.001, ancova). CONCLUSIONS Surgery residency training programmes have a favourable effect on outcomes following PD and their impact on outcome is greater than the impact of hospital volume or surgeon frequency of PD.

Survival after pancreatectomy for pancreatic adenocarcinoma is not impacted by performance status

BACKGROUND Patients with the best performance status have the best prognosis after resection for pancreatic adenocarcinoma. This study was undertaken to determine the impact of performance status on survival after pancreatectomy for adenocarcinoma. METHODS Patients with a Karnofsky Performance Score (KPS) status (KPS) ≥60 after pancreatectomy for adenocarcinoma were evaluated, and the impact of the KPS at 6 weeks after pancreatectomy on survival was determined using survival curve analysis. RESULTS Recurrence was experienced by 84% of patients and negatively impacted patient survival. The median overall survival was 12 months, and the 2-year overall survival was 35%. The KPS after pancreatectomy did not impact survival when using survival curve analysis (P = .5740). CONCLUSIONS Performance status for patients with a KPS ≥60 after pancreatectomy does not impact survival. Patients with pancreatic adenocarcinoma without adjuvant therapy have poor overall survival, and KPS after pancreatectomy for adenocarcinoma should not be used to withhold therapy for these patients.

Increasing the relevance of laparoendoscopic single‐site surgery

Early in its infancy, the practice of laparoscopy was undertaken with some trepidation because of fear that it was risky. Clearly that has changed. We are now in the midst of an era where laparoscopy is commonly used in surgery. For some operations, such as cholecystectomy and anti-reflux surgery, laparoscopy is nearly uniformly applied (1–3). For other areas of surgery, such as colectomy, use of laparoscopy is on the rise. Laparoscopy has moved beyond simple operations into application with complex procedures. Now, laparoendoscopic single-site surgery (LESS) surgery offers advancements beyond laparoscopy, and it may herald a paradigm shift in surgery. However, questions about the relevance of LESS remain. Relevance implies many things: significance, importance, weight, meaningfulness, application, and consequences, to mention a few. To achieve relevance, LESS surgery must be significantly different and better than conventional laparoscopy, and the public and medical communities must be aware of it so that it is requested, learned, and applied. How will all of this happen? Achieving relevance in the medical world has no distinct algorithm. Traditional laparoscopy has gained in popularity and relevance within the surgical realm over the past two decades, while LESS operations are novel and on the brink of implementation within ‘‘advanced’’ surgical practices. To be truly relevant, LESS surgery needs to be within the practice and repertoire of all general surgeons across the United States and beyond. Relevance of LESS surgery will increase by raising the awareness and application of LESS surgery within the surgical community. Catalyzing this awareness starts with clearly defining LESS surgery.

Sulfonylureas (not metformin) improve survival of patients with diabetes and resectable pancreatic adenocarcinoma

Introduction: Patients with pancreatic adenocarcinoma have an increased propensity for diabetes. Recent studies suggest patients with diabetes and pancreatic adenocarcinoma treated with metformin have increased survival. This study was undertaken to determine whether metformin use is associated with increased survival in patients with pancreatic adenocarcinoma. Methods: Patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma from 1991 to 2013 were included in this study. Survival was evaluated by Kaplan-Meier analysis. Median data are reported. Significance was accepted with 95% probability. Results: Of 414 patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, 132 (32%) were diabetic. Of patients with diabetes, 35 (27%) were diet-controlled, 34 (26%) were treated with insulin alone, 18 (14%) were treated with metformin alone, 14 (10%) were treated with sulfonylureas alone, 7 (5%) were taking sulfonylureas with insulin, and 24 (18%) patients were taking metformin with sulfonylureas and/or insulin. Patients with/without diabetes not taking sulfonylureas had survival of 16.4 months compared with patients taking sulfonylureas who achieved survival of 27.5 months after undergoing pancreaticoduodenectomy (P<0.05). Conclusions: Patients taking sulfonylureas with or without other therapy had improved survival compared with patients not taking sulfonylureas after pancreaticoduodenectomy. Metformin does not seem to be beneficial for patients with resectable disease, but may be beneficial for patients with unresectable and/or metastatic disease as shown in prior studies. The use of sulfonylureas is associated with a survival benefit for patients undergoing resection for pancreatic adenocarcinoma. Tumor staging and margin status continue to be the overriding predictors of survival in patients with resectable pancreatic adenocarcinoma, not metformin therapy.

Sulfonylureas (Not Metformin) Improve Survival for Patients with Diabetes andResectable Pancreatic Adenocarcinoma

Objective: Patients with pancreatic adenocarcinoma have an increased propensity for diabetes. Recent studies suggest patients with diabetes and pancreatic adenocarcinoma treated with metformin have increased survival. This study was undertaken to determine if metformin use is associated with increased survival for patients with pancreatic adenocarcinoma. Methods: Patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma from 1991-2013 were included in this study. Survival was evaluated by Kaplan-Meier analysis. Median data are reported. Significance was accepted with 95% probability. Results: Out of 414 patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, 132 (32%) was diabetic. Of diabetic patients, 35 (27%) were diet-controlled, 34 (26%) were treated with insulin alone, 18 (14%) were treated with metformin alone, 14 (10%) were treated with sulfonylureas alone, 7 (5%) were taking sulfonylureas with insulin, and 24 (18%) patients were taking metformin with sulfonylureas and/or insulin. Patients with or without diabetes not taking sulfonylureas had survival of 16.4 months compared to patients taking sulfonylureas who achieved survival of 27.5 months after undergoing pancreaticoduodenectomy (p<0.05). Conclusion: Patients taking sulfonylureas with or without other therapy had improved survival compared to patients not taking sulfonylureas after pancreaticoduodenectomy. Metformin does not appear to be beneficial for patients with resectable disease, but may have a benefit for patients with unresectable and/or metastatic disease as shown in prior studies. The use of sulfonylureas is associated with a survival benefit for patients undergoing resection for pancreatic adenocarcinoma. Tumor staging and margin status continue to be the overriding predictors of survival for patients with resectable pancreatic adenocarcinoma, not metformin therapy.

Tu1576 Surgical Apgar Score Does Not Predict Morbidity and Mortality for Patients Undergoing Pancreaticoduodenectomy for Pancreatic Adenocarcinoma

S A T A b st ra ct s 51.9%, electrocautery 34.6%, ultrasonic scalpel 8.4%, saline coupled radio frequency ablation (RFA) 3.17% and scalpel 1.8%. The visible pancreatic duct and/or parenchymawere oversewn in 73%. In 21.6%, pancreatic stump was treated with the RFA device. Clinically significant leak was seen in 3.4% of patients whose pancreas was transected with a stapler and oversewn versus 15.3% of patients in whose pancreas was stapled. Patients whose pancreas was transected using the scalpel or an energy device and treated with RFA had a 13.3% CSL rate. Pancreas transected using a stapler and the stump treated with RFA had a 19.2% CSL rate, whereas oversewing a pancreatic margin that had been treated with the RFA device had a 28.6% clinically significant leak rate. A patient with transected margin treated with oversewn relative to a patient whose pancreas transected with stapler and oversewn was at highest risk for CSL [p = ,0.001, OR 11.5 (CI 3.1 42.4)]. In univariate models, the use of the RFA device and oversewing of the pancreatic duct were predictors of a CSL (p ,0.05). On evaluating various modes of transection, there was interaction of RFA with oversewing and stapling with oversewing of the pancreatic stump (p ,0.001)]. Conclusion: Among various methods available for pancreatic transection during DP, many of them recent technologies, none have a clinical superiority. Using the stapler to transect the pancreas has a higher rate of clinically significant leak as compared to treating the transected stump with RFA. Using the RFA device in addition to a stapler or oversewing the transected margin has a higher rate of clinically significant leak and should not be attempted. Randomized trials of newer technologies to help solve this age old dilemma are necessary.

Abstract 1248: Intralesional injection with PV-10 induces a systemic anti-tumor immune response in murine models of breast cancer and melanoma.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC PV-10 is a 10% solution of Rose Bengal that is currently being examined as a novel cancer therapeutic. In melanoma patients, intralesional injection (IL) of PV-10 has led to regression of injected lesions as well as distant metastases. In this study, we examined the efficacy and potential immune mechanism of PV-10 treatment in murine models of breast cancer and melanoma. In BALB/c mice bearing MT-901 breast cancer, injection of PV-10 led to regression of injected and untreated contralateral subcutaneous lesions (p<0.05 compared to IL-PBS-treated mice). A significant increase in survival was observed in mice treated with PV-10. To examine immune response, MT901-specific IFN-gamma production and cytotoxicity were measured in splenocytes collected from mice treated with IL-PBS or IL-PV-10. MT901-bearing mice treated with IL-PV-10 demonstrated enhanced IFN-gamma production (992 ± 453 pg/ml) compared to splenocytes from PBS-treated mice (174 ± 105, p<0.05). In addition, a significant increase in lysis of MT-901 cells by T cells after PV-10 treatment was observed (p<0.01 compared to PBS-treated mice). No lysis of irrelevant CT-26 cells was detected. In a murine model of melanoma, B16-F10 cells were injected into C57BL/6 mice to establish one subcutaneous tumor and multiple lung lesions. Treatment of the subcutaneous lesion with a single injection of IL-PV-10 led to regression of the injected lesion as well as distant B16 melanoma lung metastases. In B16-bearing mice, treatment with IL-PV-10 led to the induction of T cells that produced IFN-gamma in response to B16 tumors but not irrelevant tumor (p<0.05) and demonstrated specific lysis of B16 (p<0.01 compared to T cells isolated from PBS-treated mice). In total, these studies support the induction of tumor-specific T cell-mediated immunity after single treatment with IL-PV-10 in multiple histologic subtypes. The immune mechanism of PV-10 ablation in cutaneous melanoma patients is currently under investigation at our institution. Citation Format: Shari A. Pilon-Thomas, Amy Weber, Krithika Kodumudi, Lisa Kuhn, Paul Toomey, Amod Sarnaik. Intralesional injection with PV-10 induces a systemic anti-tumor immune response in murine models of breast cancer and melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1248. doi:10.1158/1538-7445.AM2013-1248