Amer H. Zureikat

250 Robotic Pancreatic Resections: Safety and Feasibility

Background and Objectives: Computer-assisted robotic surgery allows complex resections and anastomotic reconstructions to be performed with nearly identical standards to open surgery. We applied this technology to a variety of pancreatic resections to assess the safety, feasibility, versatility, and reliability of this technology. Methods: A retrospective review of a prospective database of robotic pancreatic resections at a single institution between August 2008 and November 2012 was performed. Perioperative outcomes were analyzed. Results: A total of 250 consecutive robotic pancreatic resections were analyzed; pancreaticoduodenectomy (132), distal pancreatectomy (83), central pancreatectomy (13), pancreatic enucleation (10), total pancreatectomy (5), Appleby resection (4), and Frey procedure (3). Thirty-day and 90-day mortality was 0.8% and 2.0%. Rate of Clavien 3 and 4 complications was 14% and 6%. The International Study Group on Pancreatic Fistula grade C fistula rate was 4%. Mean operative time for the 2 most common procedures was 529 ± 103 minutes for pancreaticoduodenectomy and 257 ± 93 minutes for distal pancreatectomy. Continuous improvement in operative times was observed over the course of the experience. Conversion to open procedure was required in 16 patients (6%) (11 with pancreaticoduodenectomy, 2 with distal pancreatectomy, 2 with central pancreatectomy, 1 with total pancreatectomy) for failure to progress (14) and bleeding (2). Conclusions: This represents to our knowledge the largest series of robotic pancreatic resections. Safety and feasibility metrics including the low incidence of conversion support the robustness of this platform and suggest no unanticipated risks inherent to this new technology. By defining these early outcome metrics, this report begins to establish a framework for comparative effectiveness studies of this platform.

Outcomes with FOLFIRINOX for Borderline Resectable and Locally Unresectable Pancreatic Cancer

Trials examining FOLFIRINOX in metastatic pancreatic cancer demonstrate higher response rates compared to gemcitabine‐based regimens. There is currently limited experience with neoadjuvant FOLFIRINOX in pancreatic cancer.

Assessment of Quality Outcomes for Robotic Pancreaticoduodenectomy: Identification of the Learning Curve

IMPORTANCE Quality assessment is an important instrument to ensure optimal surgical outcomes, particularly during the adoption of new surgical technology. The use of the robotic platform for complex pancreatic resections, such as the pancreaticoduodenectomy, requires close monitoring of outcomes during its implementation phase to ensure patient safety is maintained and the learning curve identified. OBJECTIVE To report the results of a quality analysis and learning curve during the implementation of robotic pancreaticoduodenectomy (RPD). DESIGN, SETTING, AND PARTICIPANTS A retrospective review of a prospectively maintained database of 200 consecutive patients who underwent RPD in a large academic center from October 3, 2008, through March 1, 2014, was evaluated for important metrics of quality. Patients were analyzed in groups of 20 to minimize demographic differences and optimize the ability to detect statistically meaningful changes in performance. EXPOSURES Robotic pancreaticoduodenectomy. MAIN OUTCOMES AND MEASURES Optimization of perioperative outcome parameters. RESULTS No statistical differences in mortality rates or major morbidity were noted during the study. Statistical improvements in estimated blood loss and conversions to open surgery occurred after 20 cases (600 mL vs 250 mL [P = .002] and 35.0% vs 3.3% [P < .001], respectively), incidence of pancreatic fistula after 40 cases (27.5% vs 14.4%; P = .04), and operative time after 80 cases (581 minutes vs 417 minutes [P < .001]). Complication rates, lengths of stay, and readmission rates showed continuous improvement that did not reach statistical significance. Outcomes for the last 120 cases (representing optimized metrics beyond the learning curve) included a mean operative time of 417 minutes, median estimated blood loss of 250 mL, a conversion rate of 3.3%, 90-day mortality of 3.3%, a clinically significant (grade B/C) pancreatic fistula rate of 6.9%, and a median length of stay of 9 days. CONCLUSIONS AND RELEVANCE Continuous assessment of quality metrics allows for safe implementation of RPD. We identified several inflexion points corresponding to optimization of performance metrics for RPD that can be used as benchmarks for surgeons who are adopting this technology.

Comparative Effectiveness of Minimally Invasive and Open Distal Pancreatectomy for Ductal Adenocarcinoma

IMPORTANCE Multicenter studies indicate that outcomes of open (ODP) and minimally invasive distal pancreatectomy (MIDP) are equivalent for benign lesions. However, data for pancreatic carcinoma are limited. OBJECTIVE To compare outcomes of ODP and MIDP for early-stage pancreatic ductal carcinoma to determine relative safety and oncologic efficacy. DESIGN Retrospective analysis of 62 consecutive patients undergoing ODP or MIDP for pancreatic ductal carcinoma by intention to treat with propensity scoring to correct for selection bias. SETTING A high-volume university center for pancreatic surgery. PARTICIPANTS Sixty-two patients at a single institution. INTERVENTIONS Patients underwent ODP or MIDP. MAIN OUTCOME MEASURES Perioperative mortality, morbidity, readmission, postoperative complications, disease progression, and overall survival. RESULTS Thirty-four patients underwent ODP, and 28 underwent MIDP with 5 conversions to ODP. No significant differences in age, body mass index, performance status, tumor size, or radiographic stage were identified. High rates of margin-negative resection (ODP, 88%; MIDP, 86%) and median lymph node clearance (ODP, 12; MIDP, 11) were achieved in both groups with equal rates and severity of postoperative complications (ODP, 50%; MIDP, 39%) and pancreatic fistula (ODP, 29%; MIDP, 21%). Despite conversions, intended MIDP was associated with reduced blood loss (P = .006) and length of stay (P = .04). Conversion was associated with a poor histologic grade and positive nodes. Median overall survival for the entire cohort was 19 (95% CI, 14-47) months. Minimally invasive distal pancreatectomy was performed increasingly in later study years and for patients with a higher Charlson-Age Comorbidity Index. Overall survival after ODP or intended MIDP was equivalent after adjusting for comorbidity and year of surgery (relative hazard, 1.11 [95% CI, 0.47-2.62]). CONCLUSIONS AND RELEVANCE We detected no evidence that MIDP was inferior to ODP based on postoperative outcomes or overall survival. This conclusion was verified by propensity score analysis with adjustment for factors affecting selection of operative technique.

American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data

BACKGROUND AND AIMS The American Gastroenterological Association (AGA) recently reported evidence-based guidelines for the management of asymptomatic neoplastic pancreatic cysts. These guidelines advocate a higher threshold for surgical resection than prior guidelines and imaging surveillance for a considerable number of patients with pancreatic cysts. The aims of this study were to assess the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts. METHODS The study population consisted of 225 patients who underwent EUS-guided FNA for pancreatic cysts between January 2014 and May 2015. For each patient, clinical findings, EUS features, cytopathology results, carcinoembryonic antigen analysis, and molecular testing of pancreatic cyst fluid were reviewed. Molecular testing included the assessment of hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN. RESULTS Diagnostic pathology results were available for 41 patients (18%), with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of intraductal papillary mucinous neoplasms with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 patients (15%) with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue magnetic resonance imaging (MRI) surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasias with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value. CONCLUSIONS The AGA guidelines were inaccurate in detecting pancreatic cysts with advanced neoplasia. Furthermore, because the AGA guidelines manage all neoplastic cysts similarly, patients with SCAs will continue to undergo unnecessary MRI surveillance. The results of an alternative approach with integrative molecular testing are encouraging but require further validation.

Preoperative GNAS and KRAS Testing in the Diagnosis of Pancreatic Mucinous Cysts

Purpose: Management guidelines for pancreatic intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound–fine-needle aspiration (EUS–FNA) remains unclear. Experimental Design: GNAS and KRAS testing was performed on EUS–FNA pancreatic cyst fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNET), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts, and 1 lymphoepithelial cyst. Results: Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts, and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity [95% confidence interval (CI), 0.83–1.00] but 65% sensitivity (95% CI, 0.52–0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had 98% specificity (95% CI, 0.86–1.00) and 84% sensitivity (95% CI, 0.70–0.92). Conclusions: The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms. Clin Cancer Res; 20(16); 4381–9. ©2014 AACR.

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts.

With improvements in abdominal imaging, detection of incidental pancreatic cysts are becoming increasingly common. Analysis of pancreatic cyst fluid from fine-needle aspiration is particularly important in identifying intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which have significant implications in clinical intervention and follow-up. Previous controlled studies have shown that KRAS mutations in cyst fluid are highly specific for mucinous differentiation in pancreatic cysts; however, this has not been examined in the clinical setting. Over a 6-year study period, 618 pancreatic cyst fluids obtained by fine-needle aspiration at the time of endoscopic ultrasound were tested for KRAS mutations as part of routine evaluation for a cystic neoplasm. Of the 618 specimens, 603 (98%) from 546 patients were satisfactory for molecular analysis. Patients ranged in age from 17 to 90 years (mean, 63.9 years) and were predominantly female (68%). Pancreatic cysts were relatively evenly distributed throughout the pancreas and ranged in size from 0.6 to 11.0 cm (mean, 2.3 cm). Mutations in KRAS were detected in 232 of 603 (38%) aspirates. Although sufficient for molecular analysis, 320 of 603 (53%) specimens were either less than optimal (38%) or unsatisfactory (15%) for cytopathologic diagnosis. Surgical follow-up information was available for 142 (26%) patients and consisted of 53 KRAS-mutated and 89 KRAS-wild-type cysts. Overall, KRAS mutations had a specificity of 100%, but a sensitivity of 54% for mucinous differentiation. When stratified by cyst type, KRAS had a sensitivity of 67% and 14% for IPMNs and MCNs, respectively. In summary, KRAS mutations were highly specific for mucinous differentiation, but were inadequate in identifying MCNs. Future molecular studies and the combination of other fluid markers are required to improve the detection and classification of pancreatic mucinous neoplasms by endoscopic ultrasound fine-needle aspiration.

The learning curve for robotic distal pancreatectomy: an analysis of outcomes of the first 100 consecutive cases at a high‐volume pancreatic centre

BACKGROUND Robotic distal pancreatectomy (RDP) is performed increasingly, but knowledge of the number of cases required to attain procedural proficiency is lacking. The aim of this study was to identify the learning curve associated with RDP at a high-volume pancreatic centre. METHODS Metrics of perioperative safety and efficiency for all consecutive RDPs were evaluated. Outcomes were followed to 90 days. Cumulative sum (CUSUM) analysis was used to identify inflexion points corresponding to the learning curve. RESULTS Between 2008 and 2013, 100 patients underwent RDP. There was no 90-day mortality. In two patients (2.0%), surgery was converted to laparotomy. Thirty procedures were performed for pancreatic adenocarcinoma. Precipitous operative time reductions from an initial operative time of 331 min were observed after the first 20 and 40 cases to 266 min and 210 min, respectively (P < 0.0001). The likelihood of readmission was significantly lower after the first 40 cases (P = 0.04), and non-significant reductions were observed in incidences of major (Clavien-Dindo Grade II or higher) morbidity and Grade B and C leaks, and length of stay. CONCLUSIONS In this experience, RDP outcomes were optimized after 40 cases. Familiarity with the platform and dedicated training are likely to contribute to significantly shorter learning curves in future adopters.

Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2–6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7–14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

The current state of robotic-assisted pancreatic surgery.

Pancreatic surgery is challenging for both surgeon and patient. With the advent of minimally invasive surgical techniques, patient morbidity could be reduced. However, these techniques must conform to established principles of open pancreatic surgery with regards to meticulous dissection, haemostasis and oncologic results. The robotic platform is utilized in all facets of surgery, and is being increasingly applied in pancreatic surgery. As with the introduction of any new technology, this approach must undergo rigorous examination before widespread adoption of the technique. In this article, we review the techniques and outcomes of robotic-assisted pancreatic resections, focusing on robotic-assisted pancreaticoduodenectomy, robotic-assisted distal pancreatectomy and robotic-assisted central pancreatectomy. As the outcomes of robotic-assisted surgery have yet to be rigorously evaluated against the gold standard of open surgery, this Review also highlights major laparoscopic pancreatic series in an effort to summarize the available literature on minimally invasive pancreatic surgery.