Faculty Bibliography

BACKGROUND:Despite recent enthusiasm for the use of laparoscopic liver resection, data evaluating costs associated with laparoscopic liver resections are lacking. We sought to examine the use of laparoscopic liver surgery, and investigate variations in cost among hospitals performing these procedures. METHODS:A nationally representative sample of 12,560 patients who underwent a liver resection in 2012 was identified. Multivariable analyses were performed to compare outcomes associated with liver resection. RESULTS:Among the 12,560 patients who underwent liver resection, 685 (5.4%) underwent a laparoscopic liver resection. The proportion of liver resections performed laparoscopically varied among hospitals ranging from 4.6% to 20.0%; the median volume of laparoscopic liver resections was 10 operations/year. Although laparoscopic surgery was associated with lower postoperative morbidity (aOR = 0.60, 95%CI: 0.36-0.99) and shorter lengths of stay [(LOS) aIRR = 0.83, 95%CI: 0.70-0.97], it was not associated with inpatient mortality (p = 0.971) or hospital costs (p = 0.863). Costs associated with laparoscopic liver resection varied ranging from $5,907 (95%CI: $5,140-$6,674) to $67,178 (95%CI: $66,271-$68,083). The observed variations between hospitals were due to differences in morbidity (coefficient: $20,415, 95%CI: $16,000-$24,830) and LOS (coefficient: $24,690, 95%CI: $21,688-$27,692). CONCLUSIONS:Although laparoscopic liver resection was associated with improved short-term perioperative clinical outcomes, utilization of laparoscopic liver resection remains low.

BACKGROUND:Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS:Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS:Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS:Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

BACKGROUND & AIMS:Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS:We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS:We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS:In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

PURPOSE:Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. EXPERIMENTAL DESIGN:A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. RESULTS:effector memory T-cell infiltration, an increase in tumor-specific IFNγ, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target. CONCLUSIONS:This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.

Background Incidental detection of pancreatic cystic neoplasm (PCN) has increased. Since a small percentage of PCNs possess malignant potential, management is challenging. The recently revised American College of Radiology (ACR) recommendations define PCN measurement and growth for different categories based on baseline cyst size. However, no data are available regarding PCN growth rate under the ACR-defined size categories. Purpose To assess growth of incidentally detected PCNs on long-term imaging follow-up using revised ACR recommendations and to evaluate the association between baseline imaging features and growth. Materials and Methods This retrospective study included PCNs with baseline imaging performed between January 2002 and May 2017, with two or more cross-sectional imaging studies performed at least 12 months apart. PCN assessment was based on ACR 2017 recommendations. Cyst features, including location, septations, and mural nodules and multiplicity, were noted. Time to cyst progression (growth by ACR criteria) was examined by using baseline PCN size, among other factors. Results A total of 646 cysts in 390 patients were followed up for a median of 50 months (range, 12-186 months). A total of 184 (28.5%) cysts increased in size, 52 (8.1%) decreased in size, and 410 (63.4%) remained stable. For groups in which baseline PCN size was smaller than 5 mm, 5-14 mm, 15-25 mm, and larger than 25 mm, growth was noted in seven (13.2%), 106 (28.9%), 49 (32.2%), and 22 (29.7%) cysts, respectively. ACR baseline size categories (subhazard ratio: 2.8 [5-14-mm PCN group], 3.4 [15-25-mm PCN group], and 2.7 [>25 mm group], as compared with the <5 mm PCN group; P < .05 for each) demonstrated association with growth. Presence of mural nodules, septations, or lesion multiplicity failed to demonstrate association with growth. Among PCNs smaller than 5 mm at baseline, 100% of PCNs at 3-year follow-up and 94.2% of PCNs at 5-year follow-up were likely to remain stable. Conclusion American College of Radiology baseline size category of 15-25-mm pancreatic cystic neoplasms (PCNs) demonstrated the highest (3.1 times) likelihood of growth, as compared with the category of PCNs smaller than 5 mm. PCNs smaller than 5 mm at baseline did not demonstrate growth at 3-year imaging follow-up. © RSNA, 2019 Online supplemental material is available for this article.

INTRODUCTION/BACKGROUND:The incidence, timing, and implications of recurrence in patients who underwent neoadjuvant treatment and surgical resection of borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer are not well established. MATERIALS AND METHODS/METHODS:Patients with BRPC/LAPC who underwent post-neoadjuvant resection between 2007 and 2015 were included. Associations between clinicopathologic characteristics and specific recurrence locations, recurrence-free survival (RFS), and overall survival from resection (OS) were assessed using Cox regression analyses. RESULTS:For 231 included patients, median survival from diagnosis and resection were 28.0 and 19.8 months, respectively. After a median RFS of 7.9 months, 189 (81.8%) patients had recurred. Multiple-site (n = 87, 46.0%) and liver-only recurrence (n = 28, 14.8%) generally occurred earlier and resulted in significantly worse OS when compared to local-only (n = 52, 27.5%) or lung-only recurrence (n = 18, 9.5%). Microscopic perineural invasion, yN1-yN2 status and elevated pre-surgery CA 19-9 >100 U/mL were associated with both local-only and multiple-site/liver-only recurrence. R1-margin was associated with local-only recurrence (HR 2.03). yN1-yN2 status and microscopic perineural invasion were independent predictors for both poor RFS and OS, while yT3-yT4 tumor stage (HR 1.39) and poor tumor differentiation (HR 1.60) were only predictive of poor OS. Adjuvant therapy was independently associated with both prolonged RFS (HR 0.73; median 7.0 vs. 10.9 months) and OS (HR 0.69; median 15.4 vs. 22.7 months). CONCLUSION/CONCLUSIONS:Despite neoadjuvant therapy leading to resection and relatively favorable pathologic tumor characteristics in BRPC/LAPC patients, more than 80% of patients experienced disease recurrence, 72.5% of which occurred at distant sites.

BACKGROUND & AIMS:Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS:We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker's performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS:The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS:We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.

PURPOSE:ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory. EXPERIMENTAL DESIGN:mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. RESULTS:= 0.011). CONCLUSIONS:ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.

BACKGROUND:The literature suggests favorable survival for patients with isolated pulmonary recurrence after resection of pancreatic ductal adenocarcinoma (PDAC) as compared to other recurrence patterns. Within this cohort, it remains unclear what factors are associated with improved survival. METHODS:Patients who developed pulmonary recurrence after pancreatectomy were selected from a prospective database. Predictors for post-recurrence survival (PRS) were analyzed using a multivariable Cox regression model. RESULTS:Ninety-six patients were included. Median recurrence-free survival (RFS), PRS and overall survival (OS) were 16.3, 18.8 and 39.6 months, respectively. Further systemic treatment and/or metastasectomy (n = 64, 67%) was associated with significantly improved PRS and OS when compared to best supportive care (n = 35, 22%) (26.3 vs. 5.3 and 48.1 vs. 18.4, respectively; both P < 0.001). Patients who were able to undergo metastasectomy (n = 19) achieved a PRS and OS of 35.0 and 68.9 months, respectively. More than 5 pulmonary lesions, symptoms and CA 19-9 ≥100 U/mL at time of recurrence were predictive of decreased PRS. A recurrence-free interval of >16 months and treatment for recurrence were independently associated with improved PRS. CONCLUSIONS:Isolated pulmonary recurrence occurs in 13% of patients with recurrent PDAC and is associated with a median OS of 40 months. Aggressive treatment in highly selected patients was correlated with improved survival.