Fabian M. Johnston

Left-sided pancreatectomy: a multicenter comparison of laparoscopic and open approaches.

Objectives:To compare perioperative outcomes of laparoscopic left-sided pancreatectomy (LLP) with traditional open left-sided pancreatectomy (OLP) in a multicenter experience. Summary and Background Data:LLP is being performed more commonly with limited data comparing results with outcomes from OLP. Methods:Data from 8 centers were combined for all cases performed between 2002–2006. OLP and LLP cohorts were matched by age, American Society of Anesthesiologists, resected pancreas length, tumor size, and diagnosis. Multivariate analysis was performed using binary logistic regression. Results:Six hundred sixty-seven LPs were performed, with 159 (24%) attempted laparoscopically. Indications were solid lesion in 307 (46%), cystic in 295 (44%), and pancreatitis in 65 (10%) cases. Positive margins occurred in 51 (8%) cases, 335 (50%) had complications, and significant leaks occurred in 108 (16%). Conversion to OLP occurred in 20 (13%) of the LLPs. In the matched comparison, 200 OLPs were compared with 142 LLPs. There were no differences in positive margin rates (8% vs. 7%, P = 0.8), operative times (216 vs. 230 minutes, P = 0.3), or leak rates (18% vs. 11%, P = 0.1). LLP patients had lower average blood loss (357 vs. 588 mL, P < 0.01), fewer complications (40% vs. 57%, P < 0.01), and shorter hospital stays (5.9 vs. 9.0 days, P < 0.01). By MVA, LLP was an independent factor for shorter hospital stay (P < 0.01, odds ratio 0.33, 95% confidence interval 0.19–0.56). Conclusions:In selected patients, LLP is associated with less morbidity and shorter LOS than OLP. Pancreatic fistula rates are similar for OLP and LLP. LLP is appropriate for selected patients with left-sided pancreatic pathology.

Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site

The sigma-2 receptor, whose gene remains to be cloned, has been validated as a biomarker for tumor cell proliferation. Here we report the use of a novel photoaffinity probe, WC-21, to identify the sigma-2 receptor binding site. WC-21, a sigma-2 ligand containing both a photoactive moiety azide and a fluorescein isothiocyanate group, irreversibly labels sigma-2 receptors in rat liver; the membrane-bound protein was then identified as PGRMC1 (progesterone receptor membrane component-1). Immunocytochemistry reveals that both PGRMC1 and SW120, a fluorescent sigma-2 receptor ligand, colocalizes with molecular markers of the endoplasmic reticulum and mitochondria in HeLa cells. Overexpression and knockdown of the PGRMC1 protein results in an increase and a decrease in binding of a sigma-2 selective radioligand, respectively. The identification of the putative sigma-2 receptor binding site as PGRMC1 should stimulate the development of unique imaging agents and cancer therapeutics that target the sigma-2 receptor/PGRMC1 complex.

Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy

BackgroundResistance to modern adjuvant treatment is in part due to the failure of programmed cell death. Therefore the molecules that execute the apoptotic program are potential targets for the development of anti-cancer therapeutics. The sigma-2 receptor has been found to be over-expressed in some types of malignant tumors, and, recently, small molecule ligands to the sigma-2 receptor were found to induce cancer cell apoptosis.ResultsThe sigma-2 receptor was expressed at high levels in both human and murine pancreas cancer cell lines, with minimal or limited expression in normal tissues, including: brain, kidney, liver, lung, pancreas and spleen. Micro-PET imaging was used to demonstrate that the sigma-2 receptor was preferentially expressed in tumor as opposed to normal tissues in pancreas tumor allograft-bearing mice. Two structurally distinct sigma-2 receptor ligands, SV119 and WC26, were found to induce apoptosis to mice and human pancreatic cancer cells in vitro and in vivo. Sigma-2 receptor ligands induced apoptosis in a dose dependent fashion in all pancreatic cell lines tested. At the highest dose tested (10 μM), all sigma-2 receptor ligands induced 10–20% apoptosis in all pancreatic cancer cell lines tested (p < 0.05). In pancreas tumor allograft-bearing mice, a single bolus dose of WC26 caused approximately 50% apoptosis in the tumor compared to no appreciable apoptosis in tumor-bearing, vehicle-injected control animals (p < 0.0001). WC26 significantly slowed tumor growth after a 5 day treatment compared to vehicle-injected control animals (p < 0.0001) and blood chemistry panels suggested that there is minimal peripheral toxicity.ConclusionWe demonstrate a novel therapeutic strategy that induces a significant increase in pancreas cancer cell death. This strategy highlights a new potential target for the treatment of pancreas cancer, which has little in the way of effective treatments.

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 single-institution review of 157 patients presenting with benign and malignant tumors of the ampulla of Vater: Management and outcomes

BACKGROUND Although benign ampullary tumors are removed endoscopically, due to their potential to progress to malignant disease, the favored treatment for adenocarcinoma is pancreaticoduodenectomy. We reviewed our institutions experience in order to identify which patients were at highest risk of disease progression following surgical resection, as well as evaluate whether localized T1 tumors are best treated by pancreaticoduodenectomy. METHODS We retrospectively reviewed 157 patients who presented with an ampullary mass, from 2001 to 2010, and identified 51 with benign adenoma and 106 with adenocarcinoma. RESULTS Patients with malignant tumors most often presented with larger tumors and jaundice, which alone was predictive of survival (OR = 67). Forty-five percent of patients with pathologically confirmed T1 tumors had positive lymph nodes and median survival was modest at 60 months. Lymph node involvement was predictive of recurrence and decreased survival. CONCLUSION Patients with malignant tumors often present with jaundice and larger tumors. These findings should warrant suspicion for cancer and expedited preoperative workup. Based on our finding that nearly half the patients with T1 tumors had positive lymph nodes, we recommend pancreaticoduodenectomy for any patient with biopsy proven adenocarcinoma who is a suitable candidate for surgery.

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.

The prognostic implications of primary colorectal tumor location on recurrence and overall survival in patients undergoing resection for colorectal liver metastasis

The prognostic impact of primary colorectal cancer (CRC) location following resection of colorectal liver metastasis (CRLM) remains largely unknown. We sought to characterize the prognostic implications of primary tumor location among patients who underwent curative‐intent hepatectomy for CRLM.

Gastric and small intestine gastrointestinal stromal tumors: Do outcomes differ?

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous literature has suggested that small intestine GISTs are more aggressive than gastric GISTs. Our primary objective was to compare the outcomes of gastric and small intestine GISTs in the decade after approval of imatinib for treatment.

Effect of surgeon “experience” with laparoscopy on postoperative outcomes after colorectal surgery

Background. Although the relationship between laparoscopic surgery and improved clinical outcomes has been well established across a variety of procedures, the effect of operative experience with laparoscopic surgery remains less defined. The present study sought to assess the comparative benefit of laparoscopic colorectal surgery relative to surgeon volume. Methods. Commercially insured patients aged 18 to 64 years undergoing a colorectal resection were identified using the MarketScan Database from 2010–2014. Multivariable logistic regression analysis was used to calculate and compare postoperative mortality/morbidity by operative approach relative to surgeon volume. Results. A total of 21,827 patients were identified who met inclusion criteria. The median age among patients was 53 years (interquartile range: 46–59) with a slight majority of patients being female (n = 11,248, 51.5%). Laparoscopic operations were performed in 49.2% of patients (n = 10,756), whereas 50.7% (n = 11,071) underwent an open colorectal resection. On multivariable analysis, laparoscopic surgery was associated with 64% decreased odds of developing a postoperative complication or mortality (odds ratio = 0.36, 95% confidence interval, 0.32–0.41, P < .001). Patients who underwent colectomy performed by a higher operative volume surgeon (high versus low: odds ratio = 0.68, 95% confidence interval, 0.61–0.77, P < .001) demonstrated decreased odds of developing a postoperative complication/mortality. Interestingly the potential decrease in risk‐adjusted morbidity/mortality between laparoscopic and open surgery was somewhat greater among high‐operative‐volume surgeons (odds ratio = 0.29, 95% confidence interval, 0.25–0.34, P < .001) and intermediate‐operative‐volume surgeons (odds ratio = 0.30, 95% confidence interval, 0.25–0.36, P < .001) compared with low‐operative‐volume surgeons (odds ratio = 0.36, 95% confidence interval, 0.32–0.41, P < .001). Conclusion. Although laparoscopic surgery was associated with improved postoperative clinical outcomes, the effect of laparoscopic surgery varied somewhat according to surgeon volume.