Faculty Bibliography

OBJECTIVE:We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). BACKGROUND:PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. METHODS:Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. RESULTS:Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). CONCLUSIONS:CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.

BACKGROUND:Retroperitoneal sarcomas are rare tumors that can be locally aggressive with high rates of recurrence. Given that data on survival in patients with retroperitoneal sarcomas are conflicting, we sought to use a nationwide cancer database to identify factors associated with survival in patients with retroperitoneal sarcomas. METHODS:The Surveillance, Epidemiology, and End Results database was utilized to identify patients with retroperitoneal sarcomas from 2002 to 2012. Univariable and multivariable survival analysis was performed using a generalized gamma parametric survival function. RESULTS:A total of 2,920 patients were included; overall 5- and 10-year survivals were 58.4% and 45.3%, respectively. On multivariable survival analysis, age, histologic type, grade, size, local extension, lymph node, and distant metastasis were associated with decreased survival (all P < .05). Patients undergoing operative resection survived 2.5 times longer (95% confidence interval: 2.0-3.0, P < .001) and those receiving radiation therapy 1.3 times longer (95% confidence interval: 1.1-1.6, P = .001), respectively. CONCLUSION:During the past decade, retroperitoneal sarcoma patients treated with radiation demonstrate longer survival compared with patients who did not receive radiation. Further study is needed to fully elucidate the mechanisms that underlie the radiation-related survival benefit observed in this study.

BACKGROUND:Although pancreaticoduodenectomy (PD) outcomes have improved, complications including surgical site infection (SSI) remain common. We present a stratification tool to predict risk for SSI after PD. METHODS:Data was retrospectively reviewed on all patients undergoing PD at a tertiary hospital (9/2011-8/2014). Potential SSI risk factors identified by univariate analysis were incorporated into a multivariate logistic regression model. The resulting odds ratios were converted into a point system to create an SSI risk score with internal validation. RESULTS: = 0.99). CONCLUSION:This novel, validated risk score accurately predicts SSI risk after pancreaticoduodenectomy. Identifying the highest risk patients can help target interventions to reduce SSI.

INTRODUCTION:Patients with metastatic pancreatic adenocarcinoma have traditionally been offered palliative chemotherapy alone, and the role of surgery in these patients remains unknown. METHODS:A bi-institutional retrospective review was performed for patients with metastatic pancreatic adenocarcinoma who underwent resection of the primary tumor from 2008 to 2013. The primary outcome measured was postoperative overall survival. Secondary outcomes included postoperative disease-free survival and overall survival from the time of diagnosis. RESULTS:Twenty-three patients were identified who met the study criteria with a median follow-up of 30 months. Metastatic sites included the liver (n = 16), the lung (n = 6), and the peritoneum (n = 2). Chemotherapy included FOLFIRINOX (n = 14) and gemcitabine-based regimens (n = 9), with a median of 9 cycles (range 2-31) prior to surgical treatment. Median time from diagnosis to surgery was 9.7 months (IQR 5.8-12.8). Median overall survival (OS) from surgery, disease-free survival, and OS from diagnosis were 18.2 months (95 % CI 11.8-35.5), 8.6 months (95 % CI 5.2-16.8), and 34.1 months (95 % CI 22.5-46.2), respectively. The 1- and 3-year OS from surgery were 72.7 % (95 % CI 49.1-86.7) and 21.5 % (95 % CI 4.3-47.2), respectively. CONCLUSION:Resection of the primary tumor in patients with metastatic pancreatic adenocarcinoma may be considered in highly selected patients with favorable imaging and CA 19-9 response following chemotherapy at high-volume centers providing multidisciplinary care. These patients should be enrolled in prospective clinical trials or institutional registries to better quantify the potential benefits of such a strategy.

PURPOSE/OBJECTIVE:We previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL). METHODS AND MATERIALS/METHODS:) followed by gemcitabine until progression. European Organization for Research and Treatment of Cancer QoL core cancer (QLQ-C30) and pancreatic cancer-specific (European Organization for Research and Treatment of Cancer QLQ-PAN26) questionnaires were administered to patients pre-SBRT and at 4 to 6 weeks (first follow-up [1FUP]) and 4 months (2FUP) post-SBRT. Changes in QoL scores were deemed clinically relevant if median changes were at least 5 points in magnitude. RESULTS:Forty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (P = .17) or 2FUP (P > .99). Statistical and clinical improvements in pancreatic pain (P = .001) and body image (P = .007) were observed from pre-SBRT to 1FUP. Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (P = .016) by 4 months. Although pancreatic pain initially demonstrated statistical and clinical improvement (P = .020), scores returned to enrollment levels by 2FUP (P = .486). A statistical and clinical decline in role functioning (P = .002) was observed in patients at 2FUP. CONCLUSIONS:Global QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC.

PURPOSE/OBJECTIVE:Pancreatic cysts frequently pose clinical dilemmas. On one hand, cysts with high-grade dysplasia offer opportunities for cure, on the other hand, those with low-grade dysplasia are easily over treated. Cyst fluid markers have the potential to improve the evaluation of these cysts. Because telomerase activity is commonly activated in malignant cells, we evaluated the diagnostic performance of cyst fluid telomerase activity measurements for predicting histologic grade. EXPERIMENTAL DESIGN/METHODS:Telomerase activity was measured using telomerase repeat amplification with digital-droplet PCR in surgically aspirated cyst fluid samples from 219 patients who underwent pancreatic resection for a cystic lesion (184 discovery, 35 validation) and 36 patients who underwent endoscopic ultrasound fine-needle aspiration. Methodologic and clinical factors associated with telomerase activity were examined. RESULTS:Telomerase activity was reduced in samples that had undergone prior thawing. Among 119 samples not previously thawed, surgical cyst fluids from cystic neoplasms with high-grade dysplasia ± associated invasive cancer had higher telomerase activity [median (interquartile range), 1,158 (295.9-13,033)] copies/μL of cyst fluid than those without [19.74 (2.58-233.6) copies/μL; P < 0.001)]. Elevated cyst fluid telomerase activity had a diagnostic accuracy for invasive cancer/high-grade dysplasia of 88.1% (discovery), 88.6% (validation), and 88.2% (merged). Among cysts classified preoperatively as having "worrisome features," cyst fluid telomerase activity had high diagnostic performance (sensitivity 73.7%, specificity 90.6%, accuracy, 86.1%). In multivariate analysis, telomerase activity independently predicted the presence of invasive cancer/high-grade dysplasia. CONCLUSIONS:Cyst fluid telomerase activity can be a useful predictor of the neoplastic grade of pancreatic cysts. Clin Cancer Res; 22(20); 5141-51. ©2016 AACRSee related commentary by Allen et al., p. 4966.

OBJECTIVE:Total pancreatectomy (TP) may be considered for diffuse disease of the pancreas. However, the quality of life (QOL) implications of TP have not been well studied in the contemporary era. We report the QOL and cause of death after TP. METHODS:186 patients underwent TP between 2000 and 2013. The 100 who were still alive at last follow-up were sent a questionnaire including the Short Form-36 (SF-36), the Audit of Diabetes Dependent QoL (ADD QoL), and the European Organization for Research and Treatment in Cancer Pancreas 26 (EORTC-PAN-26). The cause of death was determined for the 86 patients who were dead at last follow-up. RESULTS:While the majority of deaths of the 86 patients were cancer related (n = 65), only one patient died of diabetes complications. Among the 100 surviving patients, the median follow-up was 5.9 years. Among the 36 patients who responded to the survey, every patient required pancreatic enzymes and insulin; four patients required seven total hospitalizations for hypoglycemia. The SF-36 survey indicated a worse QOL in six domains compared with a national population matched with age and gender. However, only physical and emotional domains were decreased compared with self-matched preoperative state (p < 0.01 and p < 0.05, respectively). The ADD QoL survey showed an overall decrease in diabetes-related QoL (p < 0.01). When compared to other types of insulin-dependent diabetes, no significant difference in QoL were found in 14 of 19 domains. The EORTC-PAN-26 survey demonstrated that more than 50 % of patients had moderate to severe changes in three of seven domains. CONCLUSIONS:Mortality from diabetic complications following TP is uncommon. The decreasing QoL after TP is comparable to self-matched preoperative assessment or insulin-dependent diabetes from other causes. Accounting for the overall health changes, TP should be considered in carefully selected patients.

BACKGROUND:With improved neoadjuvant regimens, more aggressive surgical resections may be warranted for patients with locally advanced pancreatic cancer (LAPC) with focal encasement of the celiac axis (CA) and proximal common hepatic artery (HA). We sought to investigate the clinicopathological features and outcomes of the modified Appleby procedure (DP-CAR) in light of improved neoadjuvant therapies. METHODS:A prospectively maintained database of all pancreatectomies performed at Johns Hopkins Hospital, Baltimore, MD, USA, was reviewed to identify all patients who underwent DP-CAR for pancreatic ductal adenocarcinoma (PDAC) between 2004 and 2016. A 3:1 match for patients undergoing distal pancreatectomy (DP) versus DP-CAR was performed on the basis of their clinicopathological features. RESULTS:Seventeen patients who underwent DP-CAR were matched to 51 patients who underwent DP for resection of PDAC. Prior to DP-CAR, 15 (88.2 %) patients received neoadjuvant therapy, and the most frequently used regimen was FOLFIRINOX (80.0 %). DP-CAR was associated with longer operative time (404 vs. 309 min; p = 0.003) and elevated postoperative liver transaminases compared with DP. No difference was observed in estimated blood loss and length of hospitalization. R0 resection was achieved in 82.4 % of DP-CAR patients versus 92.2 % of DP patients (p = 0.355). No difference was observed in postoperative outcomes, including overall complications, pancreatic fistula, readmission, and mortality. Median survival for DP-CAR was 20 versus 19 months in the DP group (p = 0.757). CONCLUSION:In light of improved neoadjuvant therapeutic regimens, the modified Appleby procedure is a feasible and safe treatment option for patients with LAPC involving the CA, with morbidity and mortality similar to patients undergoing classic DP.

Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1. In contrast, SOCS1 gene methylation and downregulation in CAF activated STAT3 and induced insulin-like growth factor-1 expression to support PDAC cell growth. Moreover, CAF facilitated methylation-dependent growth of PDAC tumor xenografts in mice. The ability of patient-derived CAF with SOCS1 methylation to promote PDAC growth was more robust than CAF without SOCS1 methylation. Overall, our results reveal how PDAC cells can reprogram CAF to modify tumor-stromal interactions in the TME, which promote malignant growth and progression. Cancer Res; 76(18); 5395-404. ©2016 AACR.

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.