Faculty Bibliography

Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.

BACKGROUND:Although the prognostic role of surgical margin status after resection of colorectal liver metastasis (CRLM) has been previously examined, controversy still surrounds the importance of surgical margin status in patients with multiple tumors. METHODS:Patients who underwent curative-intent surgery for CRLM from 2000 to 2015 and who presented with multiple tumors were identified. Patients with R1 resection status determined by the closest resection margin of the non-largest tumor were classified as R1-Type 1; patients with R1 status determined by the resection margin of the largest tumor were defined as R1-Type 2. Data regarding surgical margin status, size of tumors, and overall survival (OS) were collected and assessed. RESULTS:A total of 251 patients met inclusion criteria; 156 patients (62.2%) had a negative margin (R0), 50 had an R1-type 1 (19.9%), and 45 had an R1-type 2 (17.9%) margin. Median and 5-year OS in the entire cohort was 56.4 months and 48.0%, respectively. When all R1 (Type 1 + Type 2) patients were compared with R0 patients, an R1 was not associated with worse prognosis (P = 0.05). In contrast, when R1-type 2 patients were compared with R0 patients, an R1 was strongly associated with worse OS (P = 0.009). On multivariate analysis, although the prognostic impact of all R1 was not associated with OS (hazard ratio [HR] 1.56; P = 0.08), R1-Type 2 margin status independently predicted a poor outcome (HR 1.93; P = 0.03). CONCLUSIONS:The impact of margin status varied according to the size of the tumor assessed. While R1 margin status defined according to the non-largest tumor was not associated with OS, R1 margin status relative to the largest index lesion was associated with prognosis.

OBJECTIVES:Circulating epithelial cells (CECs) are identified in the blood of patients with intraductal papillary mucinous neoplasms (IPMNs) despite the absence of malignancy. We assessed the blood of patients undergoing resection for IPMN or other benign pancreatic lesions for CECs. METHODS:Peripheral blood was collected from 26 patients prior to pancreatic resection and filtered by the ISET (Isolation by Size of Epithelial Tumor Cells) method. Circulating epithelial cells were identified with antibodies to cytokeratin and Pdx1 (pancreas and duodenal homeobox protein 1), a pancreas marker. RESULTS:Nineteen patients underwent resection of an IPMN without associated malignancy. Eleven patients (58%) had cytokeratin-positive CECs. Circulating epithelial cells were significantly more likely to be found in patients with IPMNs with high-grade dysplasia (P = 0.04). In addition, 10 of the 11 patients with cytokeratin-positive CECs also had separate populations of cytokeratin-positive, Pdx1-positive CECs, suggesting a pancreatic source. Dual-staining CECs were more frequently found in patients with high-grade dysplasia (P = 0.04). Patients with IPMNs were significantly more likely to have pan-cytokeratin CECs in the blood compared with those without IPMNs (P = 0.01). CONCLUSIONS:Circulating epithelial cells staining with potential pancreas-specific markers have been found in patients with IPMNs, even without malignancy. Circulating epithelial cells may help to differentiate patients with high-grade IPMN from lower grades of dysplasia and other pancreatic cysts.

The management of intraductal papillary mucinous neoplasm (IPMN) continues to evolve. In particular, the indications for resection of branch duct IPMN have changed from early resection to more deliberate observation as proposed by the international consensus guidelines of 2006 and 2012. Another guideline proposed by the American Gastroenterological Association in 2015 restricted indications for surgery more stringently and recommended physicians to stop surveillance if no significant change had occurred in a pancreatic cyst after five years of surveillance, or if a patient underwent resection and a non-malignant IPMN was found. Whether or not it is safe to do so, as well as the method and interval of surveillance, has generated substantial debate. Based on a consensus symposium held during the meeting of the International Association of Pancreatology in Sendai, Japan, in 2016, the working group has revised the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. As the working group did not recognize the need for major revisions of the guidelines, we made only minor revisions and added most recent articles where appropriate. The present guidelines include updated information and recommendations based on our current understanding, and highlight issues that remain controversial or where further research is required.

BACKGROUND:Distal pancreatectomy (DP) is performed to treat tumors of the pancreatic body and tail. Traditionally, splenectomy is performed with a DP, however, laparoscopic spleen-preserving DP (SPDP) using Warshaw's (splenic vessels ligation) or Kimura's (splenic vessels preservation) techniques have been reported. The clinical benefits of using either technique remain unclear. In this study, we conducted a meta-analysis to compare the clinical outcomes of patients undergoing Warshaw's and Kimura SPDP. This is the first study to evaluate the geographical variation in outcomes of Warshaw's and Kimura SPDP. METHODS:Databases of PubMed, Embase, and Cochrane library were used to identify studies reporting Warshaw's and Kimura SPDP. Clinical outcomes were compared. Pooled odds risk and weighted mean difference with 95% confidence interval were calculated using random effect models. RESULTS:Fourteen non-randomized controlled studies involving 945 patients met our selection criteria. 301 (31.9%) patients underwent Warshaw's SPDP; 644 (68.1%) underwent Kimura SPDP. Compared to Warshaw's SPDP, patients undergoing Kimura SPDP had a lower incidence of post-operative complications including spleen infarction (OR = 9.64, 95% CI = 5.79 to 16.05, P < 0.001) and gastric varices (OR = 11.88, 95% CI = 5.11 to 27.66, P < 0.001). The length of surgery was significantly shorter for Warshaw's SPDP (WMD = -18.12, 95%CI = -26.52 to -9.72, p < 0.001). Decreased blood loss was reported for patients undergoing Warshaw's SPDP (WMD = -59.72, 95%CI = -102.01 to -17.43, p = 0.006). There were no differences between the two groups' rates of conversion to an open procedure (P = 0.35), postoperative pancreatic fistula (P = 0.71), need for reoperation (P = 0.25), and length of hospital stay (P = 0.38). CONCLUSION/CONCLUSIONS:Both Warshaw's and Kimura are safe SPDP techniques. These data suggest Kimura SPDP is the preferred technique due to less risk of splenic infarct and gastric varices. Despite evidence of regional variation in volume performed (between Kimura and Warshaw's), there are no statistically significant differences in outcomes between these techniques.

BACKGROUND AND OBJECTIVES/OBJECTIVE:While preoperative treatment is frequently administered to CRLM patients, the impact of chemotherapy, with or without bevacizumab, on liver regeneration remains controversial. METHODS:The early and late regeneration indexes were defined as the relative increase in liver volume (RLV) within 2 and 9 months from surgery. Regeneration rates of the preoperative treatment groups were compared. RESULTS:Preoperative chemotherapy details and volumetric data were available for 185 patients; 78 (42.2%) received preoperative chemotherapy with bevacizumab (Bev+), 46 (24.8%) received chemotherapy only (Bev-), and 61 (33%) received no chemotherapy. Patients in the Bev+ and Bev- groups received similar chemotherapy cycles (4 [3-6] vs 4 [4-6]; P = 0.499). Despite the comparable clinicopathological characteristics and Resected Volume/Total Liver Volume (TLV) at surgery (P = 0.944) of both groups, Bev+ group had higher early and late regeneration (17.2% vs 4.3%; P = 0.035 and 14.0% vs 9.4%; P = 0.091, respectively). Of note, early and late regeneration rates (3.7% and 10.9% vs 6.6% and 5.5%, respectively) were comparable between the no chemotherapy and Bev- groups (all P > 0.05). In multivariable analysis -adjusted for gender, age, portal vein embolization, preoperative chemotherapy, resected liver volume, tumor number, postoperative chemotherapy, fibrosis, steatosis- bevacizumab independently predicted early liver regeneration (P = 0.019). CONCLUSION/CONCLUSIONS:Our findings suggest that preoperative bevacizumab administered along with chemotherapy was associated with enhanced volumetric restoration. Interestingly, this effect was more pronounced among patients who received oxaliplatin-based regimens and bevacizumab compared to those treated with irinotecan-based regimens and bevacizumab.

BACKGROUND:Although laparoscopic distal pancreatectomy is considered a standard approach, 10% to 40% of these are converted. The preoperative risk factors for conversion are not well described. The aim of this study was to identify risk factors associated with conversion. METHODS:Clinicopathological variables of 211 consecutive patients who underwent laparoscopic distal pancreatectomy between January 2007 and December 2015 at Johns Hopkins were analyzed to identify factors associated with conversion. Furthermore, the learning curve for laparoscopic distal pancreatectomy was studied. RESULTS:On univariate analysis of diabetes mellitus, preoperative diagnosis of malignant disease, multiorgan resection, surgeons' years and case experience were significantly associated with conversion (all P < .05). Risk factors independently associated with conversion included diagnosis of malignant disease (odds ratio = 5.40; 95% confidence interval, 1.93-15.12, P = .001), multiorgan resection (odds ratio = 7.10; 95% confidence interval, 1.60-31.53, P = .01), and surgeons' case experience (odds ratio = 0.32; 95% confidence interval, 0.12-0.85, P = .023). Intraoperative reasons for conversion included presence of excessive intraabdominal and retroperitoneal fat (N = 10, 32.3%), adhesions (N = 10, 32.3%), extent of tumor invasion (N = 8, 25.8%), anatomy of vessels (N = 6, 19.4%), and intraoperative bleeding (N = 2, 6.5%). CONCLUSION:Patients undergoing laparoscopic distal pancreatectomy with a preoperative diagnosis of malignant disease or possible multiorgan resection are at a higher risk of conversion. Surgeon experience of performing >15 procedures significantly reduces the risk of conversion.

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (CEL) gene and the nearby CEL pseudogene (CELP) and was recently identified as a risk factor for chronic pancreatitis. Since chronic pancreatitis is a risk factor for the development of pancreatic cancer, we compared the prevalence of the CEL-HYB allele in patients with pancreatic ductal adenocarcinoma to spousal controls and disease controls. The CEL-HYB allele was detected using Sanger and next generation sequencing. There was no significant difference in the prevalence of the CEL-HYB allele between cases with pancreatic ductal adenocarcinoma compared to controls; 2.6% (22/850) vs. 1.8% (18/976) (p=0.35). CEL-HYB carriers were not more likely to report a history of pancreatitis. Patients with pancreatic cancer are not more likely than controls to be carriers of the CEL-HYB allele.