Faculty Bibliography

OBJECTIVE:To describe accurately the pattern, timing, and predictors of disease recurrence after a potentially curative resection for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA:After surgery for PDAC, most patients will develop disease recurrence. Understanding the patterns and timing of disease failure can help guide improvements in therapy. METHODS:Patients who underwent pancreatectomy for PDAC at the Johns Hopkins Hospital between 2000 and 2010 were included. Exclusion criteria were incomplete follow-up records, follow-up <24 months, and neoadjuvant therapy. The first recurrence site was recorded and recurrence-free survival (RFS) was estimated using Kaplan-Meier curves. Predictive factors for specific recurrence patterns were assessed by univariate and multivariate analyses using Cox-proportional hazard regression models. RESULTS:From the identified cohort of 1103 patients, 692 patients had comprehensive and detailed follow-up data available. At a median follow-up of 25.3 months, 531 (76.7%) of the 692 had recurred after a median RFS of 11.7 months. Most patients recurred at isolated distant sites (n = 307, 57.8%), while isolated local recurrence was seen in 126 patients (23.7%). Liver-only recurrence (n = 134, 25.2%) tended to occur early (median 6.9 mo), while lung-only recurrence (n = 78, 14.7%) occurred later (median 18.6 mo). A positive lymph node ratio >0.2 was a strong predictor for all distant disease recurrence. Patients receiving adjuvant chemotherapy or chemoradiotherapy had fewer recurrences and a longer RFS of 18.0 and 17.2 months, respectively. CONCLUSIONS:Specific recurrence locations have different predictive factors and possess distinct RFS curves, supporting the hypothesis that unique biological differences exist among tumors leading to distinct patterns of recurrence.

OBJECTIVE:The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy. BACKGROUND:The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored. METHODS:This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching. RESULTS:A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25-0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30-0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an "optimal" mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001). CONCLUSIONS:The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.

OBJECTIVE:To examine the impact of surgical margin width on survival following R0 hepatic resection for colorectal metastases (CRLM). SUMMARY OF BACKGROUND DATA:Although negative resection margin is considered of paramount importance for the prognosis of patients with colorectal liver metastases, optimal resection margin width remains controversial. METHODS:Eligible studies examining the association between margin status after R0 hepatic resection for CRLM and survival, including overall survival (OS) and disease-free survival (DFS) were sought using the Medline, Cochrane, and EMBASE databases. Random-effects models were used for the calculation of pooled relative risks (RRs) with their 95% confidence intervals (95% CIs). RESULTS:Thirty-four studies were deemed eligible for inclusion representing a cohort of 11,147 hepatic resections. Wider resection margin (>1 vs <1 cm) was significantly associated with improved OS at 3 years (pooled RR = 0.86, 95% CI: 0.79-0.95), 5 years (pooled RR = 0.91, 95% CI: 0.85-0.97), and 10 years (pooled RR = 0.94, 95% CI: 0.88-1.00). Similarly, DFS was positively associated with >1 cm resection margin at 3, 5, and 10 years. Interestingly, >1 mm (vs <1 mm) resection margin was significantly associated with improved OS at all-time points. Meta-regression analyses did not reveal any significant modifying role of the study features under investigation, such as the administration of neoadjuvant/adjuvant therapy. CONCLUSIONS:Importantly, our findings suggest that while a >1 mm margin is associated with better prognosis than a submillimeter margin, achieving a margin >1 cm may result in even better oncologic outcomes and should be considered if possible.

PURPOSE:Introduction of effective neoadjuvant therapy for pancreas cancer has resulted in complex and aggressive operations involving vasculature resection. This results in complicated postoperative CT appearance of vasculature, which in addition to high rate of recurrence makes interpretation of imaging difficult. The aim of this study was to identify patterns of postoperative appearance of portal vein-superior mesenteric vein complex (PV-SMV). METHODS:A retrospective study was conducted on patients undergoing pancreaticoduodenectomy with PV-SMV resection and reconstruction (PVR) between 2004 and 2014. Clinicopathological data were collected from a prospectively maintained database. Postoperative CT scans were reviewed to identify patterns of venous and perivenous features. RESULTS:The mean age, of 70 patients included in the study, was 63.0 ± 12.2 years and 37 (52.9%) were males. The median time between surgery and postoperative scan was 10 days (IQR 7-25). Tangential resection with PVR via primary closure or use of a patch was performed in 37 (52.9%) patients while the rest underwent segmental resection with PVR via end-to-end anastomosis or use of a graft. Postoperative patterns of PV-SMV included concentric narrowing (N = 40, 57.1%), eccentric narrowing (N = 19, 27.1%) or partial venous thrombosis (N = 7, 10.0%). Perivenous features included perivenous fluid collection and induration (N = 57, 81.4%) and mass-like soft tissue thickening (N = 13, 18.6%). Long-term follow-up was available on 44 (62.9%) patients of which 28 (63.6%) demonstrated no recurrence of disease. CONCLUSION:This is a novel study that identifies and categorizes postoperative features of PV-SMV after PVR. These features overlap with those of disease recurrence and their better understanding can results in an accurate interpretation of postoperative imaging.

Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer.

This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19-9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.

INTRODUCTION:, Inc., Seattle, WA) and second, the ISET system (Rarecells Diagnostics, France), a CTC detection method based on cell size-exclusion. METHODS:system), and pancytokeratin, vimentin (Vim) and CD45 (ISET system). RESULTS:system was moderately correlated with the PanCK+/Vim- CTCs, and strongly correlated with the PanCK+/Vim+ CTCs (r = 0.700, P = 0.004 and r = 0.810, P < 0.001, respectively). CONCLUSION:Our results highlight significant disparities in the enumeration and phenotype of CTCs detected by both techniques. Although the median amount of CTCs/7.5 mL differed significantly, total CTC counts of both methods were strongly correlated. For future studies, a more uniform approach to the isolation and definition of CTCs based on immunofluorescent stains is needed to provide reproducible results that can be correlated with clinical outcomes.