Joshua A. Waters

Intraductal papillary mucinous neoplasms: Predictors of malignant and invasive pathology

Objective:Determine whether size and other preoperative parameters predict malignant or invasive intraductal papillary mucinous neoplasia (IPMN). Summary Background Data:From 1991 to 2006, 150 patients underwent 156 operations for IPMN. Methods:Prospectively collected, retrospective review of a single academic institutions experience. All preoperative parameters including a detailed radiologic-based classification of IPMN type, location, distribution, size, number, cytology, and mural nodularity were correlated with IPMN pathology. Results:Malignant IPMN was present in 32% of cases, whereas 19% of cases were invasive. IPMN type and main pancreatic duct diameter were significant predictors of malignant IPMN (P < 0.001). Side-branch lesion number was negatively associated with invasive IPMN (P = 0.03). Side-branch size, location, and distribution did not predict IPMN pathology. The presence of mural nodules was associated with malignant and invasive IPMN (P < 0.001; P < 0.02). Atypical cytopathology was significantly associated with malignant and invasive IPMN (P < 0.001; P < 0.001). Multivariate analysis demonstrated mural nodularity and atypical cytopathology were predictive of malignancy and/or invasion in branch-type IPMN. Conclusions:To lower the rate of invasive pathology, surgery should be recommended for fit patients with main-duct IPMN and for branch-duct IPMN with mural nodularity or positive cytology irrespective of location, distribution, or size.

CT vs MRCP: optimal classification of IPMN type and extent.

IntroductionIntraductal papillary mucinous neoplasms (IPMNs) of the pancreas are being diagnosed with increased frequency. CT scanning commonly serves as the primary imaging modality before surgery. We hypothesized MRCP provides better characterization of IPMN type/extent, which more closely matches actual pathology.MethodsOf 214 patients treated with IPMN (1991–2006), 30 had both preoperative CT and MRCP. Of these, 18 met imaging study criteria. Independent readers performed retrospective, blinded analyses using standardized criteria for IPMN type and extent.ResultsA ductal connection was detected on 73% of MRCP scans and only 18% of CT. IPMN type was classified differently in seven (39%); four (22%) of which were read on CT as having main duct involvement where this was not appreciated on MRCP or found on surgical pathology. MRCP showed multifocal disease in 13(72%) versus only 9(50%) on CT. A different disease distribution was seen in 9(50%). Finally, 101 branch lesions were identified on MRCP compared to 46 on CT.ConclusionsCT falls short of MRCP in detecting a ductal connection, estimating main duct involvement, and identification of small branch duct cysts. These factors influence diagnostic accuracy, cancer risk stratification and operative strategy. MRCP should be employed for optimal management of patients with IPMN.

Does the interval from imaging to operation affect the rate of unanticipated metastasis encountered during operation for pancreatic adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a propensity for early metastasis that is often encountered unexpectedly at operation. Our objective was to examine the effect of the time interval between preoperative imaging and attempted resection and the venue in which imaging was performed on the frequency of unanticipated metastasis (UM) encountered at operation. We hypothesize that imaging obtained locally at our hospital and within 4 weeks of operation will result in a lesser frequency of UM encountered at operation. METHODS Between January 2004 and December 2009, records of patients undergoing planned pancreatic resection for PDAC at a high volume pancreatic surgery center were compiled. Exclusion criteria included neoadjuvant therapy, prior pancreatic resection, or evidence of metastasis on imaging. Review and analysis of clinical, radiographic, operative, and pathologic data were undertaken. Frequency of UM and outcome of resection was compared with the interval between most recent cross-sectional imaging (dual-phase contrast-enhanced CT or MRI) and operation defined as imaging-to-operation interval (IOI). RESULTS Four-hundred eighty-seven patients met eligibility requirements for the study: 431 (88%) proximal and 56 (12%) distal PDAC. 202 (41%) patients had their most recent imaging performed at an outside institution, and no difference in the rates of UM was observed whether imaging was conducted at our institution or at an outside institution (P > .05). Of 329 with complete imaging information for analysis, UM were discovered in 60 (18%): 52 (18%) of 293 proximal PDAC and 8 (22%) of 36 distal PDAC. In proximal PDAC, there was a linear relationship in the frequency of UM as a function of the weekly IOI (R(2) = .99; P = .006). For distal PDAC, no significant difference in the frequency of UM as a function of IOI was observed. CONCLUSION For proximally located PDAC, the frequency of UM increases with greater imaging-to-operation interval. Performing imaging at a high volume, pancreatic surgery center compared with elsewhere was not associated with a decrease in the rate of UM. Obtaining timely diagnostic imaging for proximal PDAC may improve the accuracy of preoperative staging, and thereby reduce the number of operations not producing oncologic benefit.

Survival after resection for invasive intraductal papillary mucinous neoplasm and for pancreatic adenocarcinoma: a multi-institutional comparison according to American Joint Committee on Cancer Stage.

BACKGROUND Survival after resection for invasive intraductal papillary mucinous neoplasm (inv-IPMN) is superior to pancreatic ductal adenocarcinoma (PDAC). This difference may be explained by earlier presentation of inv-IPMN. We hypothesized that inv-IPMN has survival comparable with PDAC after resection when matched by stage. STUDY DESIGN From 1999 to 2009, 113 patients underwent resection for inv-IPMN at 2 large academic institutions. These data were compared with 845 patients during the same period undergoing resection for PDAC. Demographics, pathology, and overall survival (OS) were compared according to current American Joint Committee on Cancer stage. RESULTS Mean age with inv-IPMN and PDAC was 68 and 65 years, respectively. Follow-up was 33 and 24 months for inv-IPMN and PDAC, respectively. Median OS was 32 months for inv-IPMN and 17 months in PDAC (p < 0.001). Median OS in lymph node-negative inv-IPMN was 41 months and 24 months in PDAC (p = 0.003), with the greatest absolute difference in stage Ia patients with OS of 80 and 50 months in inv-IPMN and PDAC, respectively (p = 0.03). In node-positive patients, OS was 20 months in inv-IPMN and 15 months in PDAC (p = 0.06). Of inv-IPMN, 24% was colloid versus 75% of tubular subtype; 37(85%) of node-positive inv-IPMN were tubular subtype. Median OS was 23 and 127 months for tubular and colloid subtypes, respectively (p < 0.001). CONCLUSIONS When matched by stage, inv-IPMN has superior survival after resection compared with PDAC. This disparity is greatest in node-negative and least in node-positive disease. These findings suggest the behaviors of inv-IPMN and PDAC, although different, converge with advancing American Joint Committee on Cancer stage because of a greater proportion of tubular subtype.

Laparoscopic colectomy: does the learning curve extend beyond colorectal surgery fellowship?

Colorectal fellowship training adequately surpasses the learning curve with regard to safety and outcome; however, the surgeon continues to increase operative efficiency during the first year of practice.

Natural language processing for the development of a clinical registry: a validation study in intraductal papillary mucinous neoplasms

BACKGROUND Medical natural language processing (NLP) systems have been developed to identify, extract and encode information within clinical narrative text. However, the role of NLP in clinical research and patient care remains limited. Pancreatic cysts are common. Some pancreatic cysts, such as intraductal papillary mucinous neoplasms (IPMNs), have malignant potential and require extended periods of surveillance. We seek to develop a novel NLP system that could be applied in our clinical network to develop a functional registry of IPMN patients. OBJECTIVES This study aims to validate the accuracy of our novel NLP system in the identification of surgical patients with pathologically confirmed IPMN in comparison with our pre-existing manually created surgical database (standard reference). METHODS The Regenstrief EXtraction Tool (REX) was used to extract pancreatic cyst patient data from medical text files from Indiana University Health. The system was assessed periodically by direct sampling and review of medical records. Results were compared with the standard reference. RESULTS Natural language processing detected 5694 unique patients with pancreas cysts, in 215 of whom surgical pathology had confirmed IPMN. The NLP software identified all but seven patients present in the surgical database and identified an additional 37 IPMN patients not previously included in the surgical database. Using the standard reference, the sensitivity of the NLP program was 97.5% (95% confidence interval [CI] 94.8-98.9%) and its positive predictive value was 95.5% (95% CI 92.3-97.5%). CONCLUSIONS Natural language processing is a reliable and accurate method for identifying selected patient cohorts and may facilitate the identification and follow-up of patients with IPMN.

Dimethylamino parthenolide enhances the inhibitory effects of gemcitabine in human pancreatic cancer cells.

IntroductionGemcitabine is standard treatment for pancreatic cancer but has limited clinical benefit due to chemoresistance. Nuclear factor-kappaB (NF-κB) can promote chemoresistance and is therefore an attractive therapeutic target. We hypothesize that NF-κB suppression with the novel, orally bioavailable inhibitor dimethylamino parthenolide (DMAPT) will sensitize pancreatic cancer cells to gemcitabine.MethodsBxPC-3, PANC-1, and MIA PaCa-2 human pancreatic cancer cell lines were treated with gemcitabine and/or DMAPT. Effects on the NF-κB pathway were determined by electrophoretic mobility shift assay, ELISA, or Western blot. Proliferation and apoptosis were measured by cell counts and ELISA, respectively. The effect of gemcitabine in vivo was determined using a MIA PaCa-2 heterotopic xenograft model.ResultsGemcitabine induced NF-κB activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-κB inhibitor IκBα in BxPC-3 and PANC-1 cells. DMAPT prevented the gemcitabine-induced activation of NF-κB. The combination of DMAPT/gemcitabine inhibited pancreatic cancer cell growth more than either agent alone. Gemcitabine also induced intratumoral NF-κB activity in vivo.ConclusionsDMAPT enhanced the anti-proliferative effects of gemcitabine in association with NF-κB suppression in pancreatic cancer cells in vitro. Furthermore, gemcitabine induced NF-κB activity in vivo, thus supporting the evaluation of NF-κB-targeted agents to complement gemcitabine-based therapies.

Quality Improvement Initiatives in Colorectal Surgery: Value of Physician Feedback

BACKGROUND: The impact of process improvement through surgeon feedback on outcomes is unclear. OBJECTIVE: We sought to evaluate the effect of biannual surgeon-specific feedback on outcomes and adherence to departmental and Surgical Care Improvement Project process measures on colorectal surgery outcomes. DESIGN: This was a retrospective analysis of prospectively collected 100% capture surgical quality improvement data. SETTING: This study was conducted at the department of colorectal surgery at a tertiary care teaching hospital from January 2008 through December 2013. MAIN OUTCOME MEASURES: Each surgeon was provided with biannual feedback on process adherence and surgeon-specific outcomes of urinary tract infection, deep vein thrombosis, surgical site infection, anastomotic leak, 30-day readmission, reoperation, and mortality. We recorded adherence to Surgical Care Improvement Project process measures and departmentally implemented measures (ie, anastomotic leak testing) as well as surgeon-specific outcomes. RESULTS: We abstracted 7975 operations. There was no difference in demographics, laparoscopy, or blood loss. Adherence to catheter removal increased from 73% to 100% (p < 0.0001), whereas urinary tract infection decreased 52% (p < 0.01). Adherence to thromboprophylaxis administration remained unchanged as did the deep vein thrombosis rate (p = not significant). Adherence to preoperative antibiotic administration increased from 72% to 100% (p < 0.0001), whereas surgical site infection did not change (7.6%–6.6%; p = 0.3). There were 2589 operative encounters with anastomoses. For right-sided anastomoses, the proportion of handsewn anastomoses declined from 19% to 1.5% (p < 0.001). For left-sided anastomoses, without diversion, anastomotic leak testing adherence increased from 88% to 95% (p < 0.01). Overall leak rate decreased from 5.2% to 2.9% (p < 0.05). LIMITATIONS: Concurrent process changes make isolation of the impact from individual process improvement changes challenging. CONCLUSIONS: Nearly complete adherence to process measures for deep vein thrombosis and surgical site infection did not lead to measureable outcomes improvement. Process measure adherence was associated with decreased rate of anastomotic leak and urinary tract infection. Biannual surgeon-specific feedback of outcomes was associated with improved process measure adherence and improvement in surgical quality.

Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model. METHODS To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks. RESULTS The mean increase in tumor volume was 47 mm(3) (89%) and 196 mm(3) (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm(3) (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9). CONCLUSION Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB-targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC.