Matthew R. Porembka

Quantitative Weighting of Postoperative Complications Based on the Accordion Severity Grading System: Demonstration of Potential Impact Using the American College of Surgeons National Surgical Quality Improvement Program

BACKGROUND To quantify severity of postoperative complications based on the Accordion Severity Grading System, determine the ability of severity grading to enhance National Surgical Quality Improvement Program (NSQIP) data, and develop an aggregate measure of severity of complications (the postoperative morbidity index). STUDY DESIGN Forty-three surgical experts rated case vignettes containing postoperative complications on a severity scale. Vignettes were based on the Accordion Severity Grading System derived from the Toronto Severity Grading System. The system was adjusted using the expert severity scale results and applied to 1 year of NSQIP outcomes (1,857 patients, 704 complications) at a large tertiary care center. RESULTS Experts initially distinguished the 6 grades of severity in a highly significant manner (t-test probabilities all < 0.005), with 1 exception. They rated reoperation and single-system organ failure without reoperation as similar, rather than distinct, in severity. The Accordion System was adjusted to reflect this. Distinction of grades thereafter was highly significant (t-test probabilities all < 0.005). Application to American College of Surgeons NSQIP data provided important novel insights. For example, complications in 6 American College of Surgeons NSQIP categories spanned 4 or more severity grades. Severity-weighted outcomes revealed that quantitatively the greatest burden of outcomes was due to wound infection, shock, and return to the operating room, which is not revealed by unweighted outcomes. Based on this information, an aggregate measure of severity of complications-the postoperative morbidity index-was proposed. CONCLUSIONS Quantitative severity weighting of complications is feasible. Adjustment of American College of Surgeons NSQIP outcomes using this quantitative severity grading system provides uniquely informative representations of relative burdens of morbidities.

Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth

PurposeMyeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA).Experimental designPeripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15+CD11b+) by flow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b+Gr-1+) and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1+CD11b+), effector T cells, and tumor cytokine levels.ResultsPatients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC infiltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8+ T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-γ and decreased levels of IL-10.ConclusionsMDSC are important mediators of tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer.

Induction of Th17 Cells in the Tumor Microenvironment Improves Survival in a Murine Model of Pancreatic Cancer

An important mechanism by which pancreatic cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, we hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression. Pan02 murine pancreatic tumor cells that secrete TGF-β were transduced with the gene encoding IL-6. C57BL/6 mice were injected s.c. with wild-type (WT), empty vector (EV), or IL-6–transduced Pan02 cells (IL-6 Pan02) to investigate the impact of IL-6 secretion in the tumor microenvironment. Mice bearing IL-6 Pan02 tumors demonstrated significant delay in tumor growth and better overall median survival compared with mice bearing WT or EV Pan02 tumors. Immunohistochemical analysis demonstrated an increase in Th17 cells (CD4+IL-23R+ cells and CD4+IL-17+ cells) in tumors of the IL-6 Pan02 group compared with WT or EV Pan02 tumors. The upregulation of IL-17–secreting CD4+ tumor-infiltrating lymphocytes was substantiated at the cellular level by flow cytometry and ELISPOT assay and mRNA level for retinoic acid-related orphan receptor γt and IL-23R by RT-PCR. Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an antitumor effect.

Myeloid-Derived Suppressor Cells: General Characteristics and Relevance to Clinical Management of Pancreatic Cancer

Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.

Mesh Reinforcement of Pancreatic Transection Decreases Incidence of Pancreatic Occlusion Failure for Left Pancreatectomy: A Single-Blinded, Randomized Controlled Trial

Introduction:Pancreatic leak or fistula is the most frequent complication after left pancreatectomy. We performed a single-blinded, parallel-group, randomized controlled trial comparing stapled left pancreatectomy with stapled left pancreatectomy using mesh reinforcement of the staple line with either Seamguard or Peristrips Dry. Methods:All patients undergoing left pancreatectomy at a large tertiary hospital were eligible for participation. Patients were randomized to either mesh reinforcement or no-mesh reinforcement intraoperatively after being determined a candidate for resection. Patients were blinded to the result of their randomization for 6 weeks. Primary outcome measure was clinically significant leak as defined by the ISGPF (International Study Group on Pancreatic Fistula) pancreatic leak grading system. Results:One hundred patients were randomized to either mesh (54) or no-mesh (46) reinforcement of their pancreatic transection. There was 1 death in each group. ISGPF grade B and C leaks were seen in 1.9% (1/53) of patients undergoing resection with mesh reinforcement and 20% (11/45) of patients without mesh reinforcement (P = .0007). Conclusions:Mesh reinforcement of pancreatic transection line significantly reduces the incidence of significant pancreatic fistula in patients undergoing left pancreatectomy. Trial Registration:Clinicaltrials.gov: NCT01359410

Circulating Mesothelin Protein and Cellular Antimesothelin Immunity in Patients with Pancreatic Cancer

Purpose: Mesothelin is a glycoprotein expressed on normal mesothelial cells and is overexpressed in several histologic types of tumors including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has prognostic value. Mesothelin has also been considered as a target for immune-based therapies. We conducted a study on the potential clinical utility of mesothelin as a biomarker for pancreatic disease and therapeutic target pancreatic cancer. Experimental Design: Tumor cell–bound and soluble mesothelin in patients was evaluated by immunohistochemistry and ELISA, respectively. The in vitro cellular immune response to mesothelin was evaluated by INFγ ELISA and intracellular cytokine staining for IFNγ in CD4+ and CD8+ T cells. The level of circulating antibodies to mesothelin was measured by ELISA. Results: All tumor tissue from patients with pancreatic adenocarcinoma expressed mesothelin (n = 10). Circulating mesothelin protein was detected in patients with pancreatic adenocarcinoma (73 of 74 patients) and benign pancreatic disease (5 of 5) but not in healthy individuals. Mesothelin-specific CD4+ and CD8+ T cells were generated from peripheral blood lymphocytes of patients with pancreatic cancer in 50% of patients compared with only 20% of healthy individuals. Antibodies reactive to mesothelin were detected in <3% of either patients or healthy individuals. Conclusions: Circulating mesothelin is a useful biomarker for pancreatic disease. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer. (Clin Cancer Res 2009;15(21):6511–8)

A STING-activating nanovaccine for cancer immunotherapy

Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis

Purpose To compare overall survival between patients who received neoadjuvant therapy (NAT) followed by resection and those who received upfront resection (UR)-as well as a subgroup of UR patients who also received adjuvant therapy-for early-stage resectable pancreatic adenocarcinoma. Patients and Methods Adult patients with resected, clinical stage I or II adenocarcinoma of the head of the pancreas were identified in the National Cancer Database from 2006 to 2012. Patients who underwent NAT followed by curative-intent resection were matched by propensity score with patients whose tumors were resected upfront. Overall survival was compared by using a Cox proportional hazards regression model. Early postoperative and oncologic outcomes were evaluated. Results We identified 15,237 patients with clinical stage I or II resected pancreatic head adenocarcinoma. From the NAT group, 2,005 patients (95%) were matched with 6,015 patients who underwent UR. The NAT group was associated with improved survival compared with UR (median survival, 26 months v 21 months, respectively; stratified log-rank P < .01; hazard ratio, 0.72; 95% CI, 0.68 to 0.78). Patients in the UR group had higher pathologic T stage (pT3 and T4: 86% v 73%; P < .01), higher positive lymph nodes (73% v 48%; P < .01), and higher positive resection margin (24% v 17%; P < .01). Compared with a subset of UR patients who received adjuvant therapy, NAT patients had a better survival (adjusted hazard ratio, 0.83; 95% CI, 0.73 to 0.89). Conclusion NAT followed by resection has a significant survival benefit compared with UR in early-stage, resected pancreatic head adenocarcinoma. These findings support the use of NAT, particularly as a patient selection tool, in the management of resectable pancreatic adenocarcinoma.

The effect of mesh reinforcement of a stapled transection line on the rate of pancreatic occlusion failure after distal pancreatectomy: review of a single institution's experience

BACKGROUND Pancreatic occlusion failure (POF) after distal pancreatectomy remains a common source of morbidity. Here, we review our experience with distal pancreatectomy and attempt to identify factors which influence POF rates. PATIENTS AND METHODS One hundred sixty-nine distal pancreatectomies were performed between 2002 and 2007. Review of the computerized medical records and physician office records was performed for all patients. Univariate and multivariate analyses were performed to determine factors which might influence the incidence of POF. The data set was analysed for factors which might influence the pancreatic occlusion rate. Analysis included patient and disease characteristics including: age, gender, body mass index (BMI), diagnosis, consistency of the pancreas and history of pancreatitis, as well as intra-operative variables including: surgeon, absorbable mesh reinforcement and operative approach. RESULTS POF was the most common peri-operative complication. POF was identified in 32 out of 169 patients (19%). Transection technique (hand sewn, stapled, stapled with mesh) and procedure complexity were factors associated with differences in POF rates by both univariate and multivariate analyses. POF was identified in 7 out of 70 patients (10%) when an absorbable mesh was utilized, and 25 of 99 patients (25%) when mesh was not utilized (P < 0.02). DISCUSSION These data suggest that a randomized controlled trial will be required to determine if mesh reinforcement reduces the rate and severity of POF after distal pancreatectomy.

Radiologic and intraoperative detection of need for mesenteric vein resection in patients with adenocarcinoma of the head of the pancreas

OBJECTIVE The need for mesenteric venous resection (MVR) is determined by a combination of preoperative radiologic and intraoperative surgical assessments. A single-centre review was performed to determine how efficient these processes are in evaluating the need for MVR. METHODS A retrospective study was performed of 343 patients who received resection for adenocarcinoma of the head of the pancreas, 100 of whom underwent MVR. Three radiologic signs (abutment, fat plane obliteration, focal narrowing) were evaluated for their ability to predict the need for MVR. Pathologic assessment was performed to determine if MVR had been necessary to achieve negative-margin (R0) resection. Microscopic tumour in the vein wall, or within 1 mm of the vein wall, was considered to indicate that MVR had been necessary to achieve an R0 resection. RESULTS Radiologic evaluation (showing any of the three signs) had sensitivity of only 60%. Overall, 40% of the patients who required MVR showed none of the signs. Specificity was 77%. A total of 80% of patients who underwent MVR had either microscopic invasion or abutment. R0 resection at the vein margin was achieved in 98% of patients in both the MVR and non-MVR groups. CONCLUSIONS Preoperative radiologic evaluation is not highly reliable in predicting the need for MVR. Therefore, surgical teams performing resections of cancers of the head of the pancreas must be skilled in MVR as the need for this procedure may arise unexpectedly. Surgical assessment of the need for MVR has an accuracy of about 80% and is nearly 100% accurate in determining when MVR is not required.