Contributions of the Microbiome-Derived Metabolome for Risk Assessment and Prognostication of Pancreatic Cancer.

BACKGROUND: Increasing evidence implicates microbiome involvement in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Studies suggest that reflux of gut or oral microbiota can lead to colonization in the pancreas, resulting in dysbiosis that culminates in release of microbial toxins and metabolites that potentiate an inflammatory response and increase susceptibility to PDAC. Moreover, microbe-derived metabolites can exert direct effector functions on precursors and cancer cells, as well as other cell types, to either promote or attenuate tumor development and modulate treatment response. CONTENT: The occurrence of microbial metabolites in biofluids thereby enables risk assessment and prognostication of PDAC, as well as having potential for design of interception strategies. In this review, we first highlight the relevance of the microbiome for progression of precancerous lesions in the pancreas and, using liquid chromatography-mass spectrometry, provide supporting evidence that microbe-derived metabolites manifest in pancreatic cystic fluid and are associated with malignant progression of intraductal papillary mucinous neoplasm(s). We secondly summarize the biomarker potential of microbe-derived metabolite signatures for (a) identifying individuals at high risk of developing or harboring PDAC and (b) predicting response to treatment and disease outcomes. SUMMARY: The microbiome-derived metabolome holds considerable promise for risk assessment and prognostication of PDAC.

Accurate Identification of Mucinous Pancreatic Cystic Lesions Using Small-Volume Analytes.

INTRODUCTION: The accurate identification of mucinous pancreatic cystic lesions (PCLs) is paramount for cancer risk stratification. Cyst fluid carcinoembryonic antigen (CEA), the only routinely used test, requires high volumes and has low sensitivity. We aimed to compare the performance of two investigational small-volume biomarkers, glucose and the protease gastricsin, to CEA for PCL classification. METHODS: We obtained cyst fluid samples from 81 patients with pathologically confirmed PCLs from four institutions between 2003 and 2016. Gastricsin activity was measured using an internally quenched fluorescent substrate. Glucose levels were measured with a standard glucometer. CEA levels were obtained from the medical record. Models using Classification and Regression Trees were created to predict mucinous status. Model performance was evaluated using nested cross-validation. RESULTS: Gastricsin activity, CEA, and glucose levels from patients with mucinous (n = 50) and nonmucinous (n = 31) PCLs were analyzed. Area under the curve (AUC) was similar for individual classifiers (gastricsin volume normalized [GVN] 0.88; gastricsin protein concentration normalized [GPN] 0.95; glucose 0.83; CEA 0.84). The combination of two classifiers did not significantly improve AUC, with CEA + GVN (0.88) performing similarly to CEA + GPN (0.95), GVN + glucose (0.87), GPN + glucose (0.95), and CEA + glucose (0.84). The three-analyte combination performed similarly to single and dual classifiers (GPN + glucose + CEA AUC 0.95; GVN + glucose + CEA AUC 0.87). After multiple comparison corrections, there were no significant differences between the individual, dual, and triple classifiers. CONCLUSIONS: Gastricsin and glucose performed similarly to CEA and required <5% of the volume required for CEA; these classifiers may be useful in patients with limited cyst fluid. Future multicenter prospective studies are needed to validate and compare these novel small-volume biomarkers.

Patients with deleterious germline mutations: A heterogeneous population for pancreatic cancer screening?

BACKGROUND AND OBJECTIVES: Modest data exist on the benefits of screening and surveillance for pancreatic cancer (PC) in high-risk individuals. Intraductal papillary mucinous neoplasms (IPMN) are known precursors to PC. We hypothesized that patients with high-risk deleterious germline mutations have a higher prevalence of IPMN. METHODS: All patients undergoing prospective screening at a single institution from 2013 to 2019 were reviewed. RESULTS: Of 1166 patients screened, 358 (31%) possessed germline mutations and/or family history of PC (mutations n = 201/358, 56%, family history n = 226/358, 63%) (median follow-up 2.7 years). IPMN was found in 127 patients (35.5%). The prevalence of IPMN in mutation carriers (18%) was higher than in the general population (p < 0.01). Germline mutation was an independent predictor of IPMN (odds ratio [OR] = 3.2; p < 0.01), while family history was not (p = 0.22). IPMN prevalence was distributed unevenly between mutation types (67%-Peutz-Jeghers; 43%-HNPCC, 24%-BRCA2; 17%-ATM; 9%-BRCA1; 0%-CDKN2A and PALB2). CONCLUSION: In this series, 18% of mutation carriers harbored IPMN, higher than the general population. Germline mutation, but not a family history of PC, was independently associated with IPMN. This prevalence varied across mutation subtypes, suggesting not all mutation carriers develop precancerous lesions. Genetic testing for patients with a positive family history may improve screening modalities for this high-risk population.

EUS-guided fine needle aspiration-based clues to mistaken or uncertain identity: serous pancreatic cysts.

BACKGROUND/OBJECTIVES: Pancreatic serous cystic neoplasms (SCN) present a diagnostic challenge given their increasing frequency of detection and benign nature yet relatively high rate of misdiagnosis. Here, imaging and analyses associated with EUS-guided fine-needle aspiration (EUS-FNA) are evaluated for their ability to provide a correct preoperative diagnosis of SCN. METHODS: A surgical cohort with confirmed pathological diagnosis of SCN (n = 62) and a surveillance cohort with likely SCN (n = 31) were assessed for imaging (CT/MRI/EUS) and EUS-FNA-based analyses (cytology/DNA analysis for Von Hippel-Lindau [VHL] gene alterations/biomarkers). RESULTS: In the surgical cohort, CT/MRI and EUS respectively predicted SCN in 4 of 58(7%) and 19 of 62(31%). Cyst fluid cytology and VHL alterations predicted SCN in 1 of 51(2%) and 5 of 21(24%), respectively. High specificity cyst fluid biomarkers (vascular endothelial growth factor [VEGF]/glucose/carcinoembryonic antigen [CEA]/amylase) correctly identified SCN in 25 of 27(93%). In the surveillance cohort, cyst fluid biomarkers predicted SCN in 12 of 12(100%) while VHL alterations identified SCN 3 of 10(30%). CONCLUSION: High specificity cyst fluid biomarkers provided the most sensitive means of diagnosing SCN preoperatively. To obtain a preoperative diagnosis of SCN at the highest level of certainty, a multidisciplinary approach should be taken to inform appropriate SCN management.

Biliary Stricture After Necrotizing Pancreatitis: An Underappreciated Challenge.

OBJECTIVE: Biliary stricture in necrotizing pancreatitis (NP) has not been systematically categorized; therefore, we sought to define the incidence and natural history of biliary stricture caused by NP. SUMMARY OF BACKGROUND DATA: Benign biliary stricture occurs secondary to bile duct injury, anastomotic narrowing, or chronic inflammation and fibrosis. The profound locoregional inflammatory response of NP creates challenging biliary strictures. METHODS: NP patients treated between 2005 and 2019 were reviewed. Biliary stricture was identified on cholangiography as narrowing of the extrahepatic biliary tree to <75% of the diameter of the unaffected duct. Biliary stricture risk factors and outcomes were evaluated. RESULTS: Among 743 NP patients, 64 died, 13 were lost to follow-up; therefore, a total of 666 patients were included in the final cohort. Biliary stricture developed in 108 (16%) patients. Mean follow up was 3.5 ±â€Š3.3 years. Median time from NP onset to biliary stricture diagnosis was 4.2 months (interquartile range, 1.8 to 10.9). Presentation was commonly clinical or biochemical jaundice, n = 30 (28%) each. Risk factors for stricture development were splanchnic vein thrombosis and pancreatic head parenchymal necrosis. Median time to stricture resolution was 6.0 months after onset (2.8 to 9.8). A mean of 3.3 ±â€Š2.3 procedures were performed. Surgical intervention was required in 22 (20%) patients. Endoscopic treatment failed in 17% (17/99) of patients and was not associated with stricture length. Operative treatment of biliary stricture was more likely in patients with infected necrosis or NP disease duration ≥6 months. CONCLUSION: Biliary stricture occurs frequently after NP and is associated with splanchnic vein thrombosis and pancreatic head necrosis. Surgical correction was performed in 20%.

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.

BACKGROUND & AIMS: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. METHODS: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. RESULTS: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. CONCLUSION: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

Serial EUS-Guided FNA for the Surveillance of Pancreatic Cysts: A Study of Long-Term Performance of Tumor Markers.

BACKGROUND AND AIM: The natural history of KRAS mutations in mucinous pancreatic cysts (MPCs) over time remains to be fully understood. The aim of this study was to examine the performance of DNA markers and assess changes of KRAS mutations over time. METHODS: Patients who underwent EUS-FNA of pancreatic cysts with at least two separate molecular analysis results were included in the study. We assessed the baseline patient and cyst characteristics, and DNA fluid analysis. The presence of either a KRAS mutation, or a CEA > 192 ng/ml was used as the diagnostic standard for mucinous cysts when surgical pathology was not available. RESULTS: A total of 933 pancreatic cyst fluid samples were collected, including 117 with ≥ 2 FNAs. Examinations were performed over a median of 30 months (range 1-115 months). Forty-three (36%) had a mutant KRAS on the index analysis out of which 26 had a change in their KRAS status to the wild-type. Eighty-one (64%) had a wild-type KRAS on the index analysis out of which 18 had change in their KRAS status to mutant type. There was no significant difference in the index cyst characteristics, presence of symptoms, or main duct involvement based on KRAS status change. Increasing age was associated with a changing KRAS mutation status (p = 0.023). CONCLUSION: KRAS mutations gain and loss in pancreatic cyst fluid appears to occur frequently during long-term surveillance of MPCs. Age appears to be the only predictor for KRAS change over time.

Friend or foe? Feeding tube placement at the time of pancreatoduodenectomy: propensity score case-matched analysis.

BACKGROUND: The role of concomitant gastrostomy or jejunostomy feeding tube (FT) placement during pancreatoduodenectomy (PD) and its impact on patient outcomes remain controversial. METHODS: NSQIP database was surveyed for patients undergoing PD between 2014 and 2017. FT placement was identified using CPT codes. Propensity scores were used to match the two groups (1:1) on baseline characteristics and intraoperative variables including pancreas specific ones (duct size, gland texture, underlying disease, wound class, use of wound protector, drain placement, type of pancreatic reconstruction and vascular reconstruction). Outcomes were compared. Finally, a subset analyses for patients with delayed gastric emptying (DGE) or postoperative pancreatic fistula (POPF) were performed. RESULTS: Out of 15,224 PD, 1,104 (7.5%) had FT. POPF and DGE rates were 17% and 18%, respectively, for the entire cohort. Feeding jejunostomy was the most placed FT (88.2%). Patients with FT placement were more likely to be older (mean, 65.8 vs. 64.6 y), smokers (22.6% vs. 17.8%) who had preoperative weight loss (22.5% vs. 15.3%), ASA class ≥ 3 (80.8% vs. 77.5%), preoperative transfusion (1.5% vs. 0.84%), chemotherapy (22.8% vs. 17.5%), and radiation (14.5% vs. 6.8%, p < 0.05). The matched cohort included 880 patients in each group with completely balanced preoperative and intraoperative characteristics. In the matched cohort, patients with FT placement had higher overall morbidity (52.2% vs. 44.3%, p = 0.001), major morbidity (28.4% vs. 22.5%, p = 0.004), organ/space infection (14.4% vs. 10.9%, p = 0.026), re-operation (8.6% vs. 5.1%, p = 0.003), DGE (26.8% vs. 16.4%, p < 0.001), and longer mean hospital length of stay (12.9 vs. 11.2 days, p = 0.001) than those without FT. There was no difference in mortality (1.7% vs. 2.2%, p = 0.488) or readmission rate (20.2% vs. 17.2%, p = 0.099). In patients with DGE and POPF, FT placement was not associated with morbidity, mortality, length of stay, or readmission rate (p > 0.05). CONCLUSION: Patients with FT placement during PD tend to have higher postoperative morbidity and delayed recovery.

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.

OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. DESIGN: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. RESULTS: Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. CONCLUSION: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.

Outcomes in Endoscopic and Operative Transgastric Pancreatic Debridement.

OBJECTIVES: Select patients with anatomically favorable walled off pancreatic necrosis may be treated by endoscopic (Endo-TGD) or operative (OR-TGD) transgastric debridement (TGD). We compared our experience with these 2 approaches. SUMMARY BACKGROUND DATA: Select necrotizing pancreatitis (NP) patients are suitable for TGD which may be accomplished endoscopically or surgically. Limited experience exists contrasting these techniques exists. METHODS: Patients undergoing Endo-TGD and OR-TGD at a single, high-volume pancreatic center between 2008 and 2019 were identified from a prospective database. Patient characteristics, procedural details, and outcomes of these 2 groups were compared. RESULTS: Among 498 NP patients undergoing necrosis intervention, 160 (32%) had TGD: 59 Endo-TGD and 101 OR-TGD. The groups were statistically similar in age, comorbidity, pancreatitis etiology, necrosis anatomy, pancreatitis severity, and timing of TGD from pancreatitis insult. OR-TGD required 1.1 ±â€Š0.5 and Endo-TGD 3.0 ±â€Š2.0 debridements/patient. Fewer hospital readmissions and repeat necrosis interventions, and shorter total inpatient length of stay were observed in OR-TGD patients. New-onset organ failure [Endo-TGD (13%); OR-TGD (13%); P = 1.0] was similar between groups. Hospital length of stay after TGD was significantly longer in patients undergoing Endo-TGD (13.8 ±â€Š20.8 days) compared to OR-TGD (9.4 ±â€Š6.1 days; P = 0.047). Mortality was 7% in Endo-TGD and 1% in OR-TGD (P = 0.04). CONCLUSIONS: Operative and endoscopic transgastric debridement achieve necrosis resolution with different temporal and procedural profiles. Clear multidisciplinary communication is essential to determine appropriate approach to individual necrotizing pancreatitis patients.

Insurance Type and Marital Status Impact Hospital Length of Stay After Pancreatoduodenectomy.

BACKGROUND: Recognition of the impact of social determinants on health care and surgical outcomes is imperative to improve patient care. This study aims to examine the impact social determinants have on hospital length of stay (LOS) after pancreatoduodenectomy (PD). METHODS: Retrospective review of a prospective American College of Surgeons-National Surgical Quality Improvement Program database identified patients who underwent PD from 2013 to 2018. Patients were categorized by insurance type (public/private/multiple), and electronic medical record review was performed to obtain distance from home, marital status, and race. Public insurance included Medicare and Medicaid; multiple types were defined as public insurance supplemented by a private insurance. Univariable analysis was used to identify potential confounders. Significant differences (P < 0.05) were controlled for using multivariable regression models to examine the effect of variables on LOS. RESULTS: About 813 PDs were included (n = 341 public; n = 238 private; and n = 234 multiple). Patients with public insurance had significantly longer LOS than patients with private on univariate (P < 0.001) and multivariable analyses (P = 0.021) (8 versus 7 d). Patients with multiple insurance types showed significantly increased LOS compared with patients with private on univariable (P < 0.001) and multivariable analyses (P = 0.006) (8 versus 7 d). Single patients had significantly longer LOS compared with married patients on univariable (P = 0.012) and multivariable analyses (P = 0.005) (8 versus 7 d). Distance from home, race, gender, or age did not have a significant impact on LOS. CONCLUSIONS: Single patients and patients with public or multiple insurance types are more likely to have longer hospital LOS after PD. These findings will enable physicians to identify patients at risk and target them for enhanced recovery programming.

Is resident assistance equivalent to fellows during hepatectomy?

OBJECTIVE: Hepatectomy is a complex operative procedure frequently performed at academic institutions with trainee participation. The aim of this study was to determine the effect of assistant's training level on outcomes following hepatectomy. METHODS: A retrospective review of a prospective, single-institution ACS-NSQIP database was performed for patients that underwent hepatectomy (2013-2016). Patients were divided by trainee assistant level: hepatopancreatobiliary (HPB) fellow versus general surgery resident (PGY 4-5). Demographic, perioperative, and 30-day outcome variables were compared using Chi-Square/Fisher's exact, Mann-Whitney U test, and multivariable regression. Cases involving a senior-level general surgery resident or HPB fellow as first assistant were included (n = 352). Those with a second attending, junior-level resident, or no documented assistant were excluded (n = 39). RESULTS: Patients undergoing hepatectomy with an HPB fellow as primary assistant had more frequent preoperative biliary stenting, longer operative time, and more concomitant procedures including biliary reconstruction, resulting in a higher rate of post-hepatectomy liver failure (PHLF) (15% vs. 8%, P = 0.044). However, trainee level did not impact PHLF on multivariable analysis (OR 0.60, 95% CI [0.29-1.25], P = 0.173). Fellows assisted with proportionally more major hepatectomies (45% vs. 31%; P = 0.010) and resections for hepatobiliary cancers (31% vs. 19%, P = 0.014). On stratified analysis of major and minor hepatectomies, outcomes were similar between trainee groups. CONCLUSION: Fellows performed higher complexity cases with longer operative time. Despite these differences, outcomes were similar regardless of assistant training level. Resident and HPB fellow participation in operations requiring liver resection provide comparable quality of care.

Use of primary surgical drains in synchronous resection for colorectal liver metastases: a NSQIP analysis of current practice paradigm.

BACKGROUND: There are no studies examining the use of subhepatic drains after simultaneous resection of synchronous colorectal liver metastases (sCRLM). This study aimed to (1) describe the current practices regarding primary drain placement, (2) evaluate drain efficacy in mitigating postoperative complications, and (3) determine impact of drain maintenance duration on patient outcomes. METHODS: The ACS-NSQIP targeted data from 2014 to 2017 were analyzed. Propensity score of surgical drain versus no drain cohorts was performed. Main study outcomes were mortality, major morbidity, organ/space surgical site infection (SSI), secondary drain/aspiration procedure, and any septic events. Additional univariate/multivariate logistic analyses were performed to identify associations with drain placement and duration. Major hepatectomy was defined as formal right hepatectomy and any trisectionectomy. RESULTS: 584 combined liver and colorectal resection (CRR) cases were identified. Open partial hepatectomy with colectomy was the most common procedure (70%, n = 407). Nearly 40% of patients received surgical drains (n = 226). Major hepatectomy, lower serum albumin, and no intraoperative portal vein occlusion (Pringle maneuver) were significantly associated with drain placement (p < 0.05). In the matched cohort (n = 190 in each arm), patients with surgical drains experienced higher rates of major morbidity (30% vs 12%), organ/space SSI (16% vs 6%), postoperative drain/aspiration procedures (9% vs 3%), and sepsis/septic shock (12% vs 4%) (all p < 0.05). Patients with severely prolonged drain removal, defined as after postoperative day 13 (POD13), had higher risk of postoperative morbidity compared to those with earlier drain removal (p < 0.01). 30-day mortality rate was not significantly different between the two groups. CONCLUSION: Primary surgical drains were placed in a substantial percentage of patients undergoing combined resection for sCRLM. This case-matched analysis suggested that surgical drains are associated with an increase in postoperative morbidity. Postoperative drain maintenance past 13 days is associated with worse outcomes compared to earlier removal.

Disconnected pancreatic duct syndrome predicts failure of percutaneous therapy in necrotizing pancreatitis.

BACKGROUND/OBJECTIVES: Minimally invasive approaches, such as percutaneous drainage (PD), are increasingly utilized as initial treatment in necrotizing pancreatitis (NP) requiring intervention. Predictors of success of PD as definitive treatment are lacking. Our aim was to assess the application, predictors of success, and natural history of PD in NP. We hypothesized that necrosis morphology patterns and disconnected pancreatic duct syndrome (DPDS) may predict the ability of PD to provide definitive therapy. METHODS: 714 NP patients were treated from 2005 to 2018. Patients achieving disease resolution with PD alone (PD) were compared to those requiring an escalation in intervention (Step). Outcomes were compared between groups using independent samples t-test, Fisher's exact test, and Pearson's correlation, as appropriate. P < 0.05 was accepted as statistically significant. RESULTS: 115 patients were initially managed with PD (42 PD, 73 Step). No difference in necrosis morphology was seen between the two groups. The PD group underwent significantly more repeat percutaneous interventions (PD, 3.2; Step, 2.0; P = 0.0006) including additional drain placement and drain upsize/reposition procedures. Patients with DPDS were more likely to require an escalation in intervention (odds ratio, 3.4; 95% confidence interval, 1.5-7.6; P = 0.003). The mean number of months to NP resolution was similar (PD, 5.7; Step, 5.8; P = 0.9). Mortality was similar (PD, 7%; Step 14%, P = 0.3). CONCLUSIONS: Necrosis morphology in and of itself does not reliably predict successful definitive treatment by percutaneous drainage. However, patients with disconnected pancreatic duct syndrome were less likely to have definitive resolution with PD alone.

Pancreatic Adenocarcinoma Causing Necrotizing Pancreatitis: Not as Rare as You Think?

BACKGROUND: Necrotizing pancreatitis (NP) presents a unique clinical challenge because of its complex and lengthy disease course. Pancreatic necrosis occurs in 10%-20% of acute pancreatitis cases and may result from any etiology. Scattered reports describe pancreatic tumors causing NP; however, the relationship between these disease processes is not clear. We have treated patients whose NP was caused by pancreatic ductal adenocarcinoma (PDAC) and therefore sought to clarify the clinical outcomes of these patients. METHODS: Patients treated between 2005 and 2018 for NP caused by PDAC were identified. The relationship between NP and PDAC was examined, and the clinical courses of both disease processes were evaluated. RESULTS: Among 647 patients treated for NP, seven patients (1.1%) had PDAC and NP. The mean age at NP diagnosis was 60.6 y (range, 49-66). Two patients had postprocedural pancreatitis after cancer diagnosis, and the remaining five patients had NP caused by PDAC. Median duration between diagnoses of NP and PDAC was 5.6 mo (range, 3.5-21.8). For PDAC treatment, four patients received chemotherapy alone, one received palliative radiation therapy, and one died without oncologic management. One patient underwent operative resection of PDAC. Median survival was 12.7 mo (range, 0.4-49.9). CONCLUSIONS: PDAC may be a more common cause of NP than previously considered and should be considered in patients with NP of appropriate age in whom etiology is otherwise unclear. Prompt diagnosis facilitates optimal treatment in this challenging clinical situation.

Disconnected Pancreatic Duct Syndrome: Spectrum of Operative Management.

BACKGROUND: Disconnected pancreatic duct syndrome (DPDS) is common after necrotizing pancreatitis (NP). Surgical management may be by internal drainage or left (distal) pancreatectomy. Therapeutic decision-making must consider sinistral portal hypertension, parenchymal volume of disconnected pancreas, and timing relative to definitive management of pancreatic necrosis. The aim of this study is to evaluate outcomes after operative management for DPDS. METHODS: All patients with NP undergoing an operation for DPDS were included in the study (2005-2017). Perioperative outcomes and long-term durability were evaluated. RESULTS: Among 647 patients with NP, 299 (46%) had DPDS. Operative management was required in 202/299 (68%) patients with DPDS. Median follow-up was 30 mo (2-165). Definitive operative therapy included internal drainage (n = 111) or resection (n = 91). Time from NP diagnosis to operation was 126 d (20 d to 81 mo). Overall morbidity was 46%. Postoperative length of stay was 7 d (2-97). Readmission was required in 39 patients (19%). Mortality was 2%. Repeat pancreatic intervention was required in 23 patients (11%) at a median of 15 mo (1-98). Repeat pancreatectomy was performed in nine patients and the remaining 14 patients were managed with endoscopic therapy. CONCLUSIONS: DPDS is a common and challenging consequence of NP. Appropriate operation is durable in nearly 90% of patients.

Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

Visceral artery pseudoaneurysm in necrotizing pancreatitis: incidence and outcomes.

Background: Visceral artery pseudoaneurysms (VA-PSA) occur in necrotizing pancreatitis; however, little is known about their natural history. This study sought to evaluate the incidence and outcomes of VA-PSA in a large cohort of patients with necrotizing pancreatitis. Methods: Data for patients with necrotizing pancreatitis who were treated between 2005 and 2017 at Indiana University Health University Hospital and who developed a VA-PSA were reviewed to assess incidence, presentation, treatment and outcomes. Results: Twenty-eight of 647 patients with necrotizing pancreatitis (4.3%) developed a VA-PSA between 2005 and 2017. The artery most commonly involved was the splenic artery (36%), followed by the gastroduodenal artery (24%). The most common presenting symptom was bloody drain output (32%), followed by incidental computed tomographic findings (21%). The median time from onset of necrotizing pancreatitis to diagnosis of a VA-PSA was 63.5 days (range 1-957 d). Twenty-five of the 28 patients who developed VA-PSA (89%) were successfully treated with percutaneous angioembolization. Three patients (11%) required surgery: 1 patient rebled following embolization and required operative management, and 2 underwent upfront operative management. The mortality rate attributable to hemorrhage from a VA-PSA in the setting of necrotizing pancreatitis was 14% (4 of 28 patients). Conclusion: In this study, VA-PSA occurred in 4.3% of patients with necrotizing pancreatitis. Percutaneous angioembolization effectively treated most cases; however, mortality from VA-PSA was high (14%). A high degree of clinical suspicion remains critical for early diagnosis of this potentially fatal problem.

Contexte: Les faux anévrismes des artères viscérales (FAAV) surviennent en présence d'une pancréatite nécrosante; on en sait cependant peu sur leur histoire naturelle. L'objectif de l'étude était d'évaluer l'incidence et les issues des FAAV dans une grande cohorte de patients atteints de pancréatite nécrosante. Méthodes: Nous avons examiné les données des patients atteints de pancréatite nécrosante traités entre 2005 et 2017 à l'Hôpital universitaire de l'Université de l'Indiana qui ont fait un FAAV afin d'évaluer l'incidence, les premiers signes, le traitement et les issues de cette affection. Résultats: Vingt-huit (4,3 %) des 647 patients atteints de pancréatite nécrosante inclus (2005­2017) ont fait un FAAV. L'artère la plus souvent touchée était l'artère splénique (36 %), suivie de l'artère gastroduodénale (24 %). Les premiers signes les plus courants étaient la présence de sang dans les liquides évacués par drainage (32 %), puis les résultats d'une tomodensitométrie effectuée pour une autre raison (21 %). Le délai médian entre l'apparition de la pancréatite nécrosante et le diagnostic de FAAV était de 63,5 jours (intervalle : 1 à 957 jours). Vingt-cinq des 28 patients ayant fait un FAAV (89 %) ont été traités avec succès par angioembolisation percutanée. Trois patients (11 %) ont dû être opérés : 2 dès le début, et le troisième parce qu'il a recommencé à saigner après l'embolisation. Le taux de mortalité par hémorragie due à un FAAV chez les personnes atteintes d'une pancréatite nécrosante était de 14 % (4 patients sur 28). Conclusion: Dans cette étude, 4,3 % des patients atteints de pancréatite nécrosante ont connu un FAAV. L'angioembolisation percutanée s'est avérée efficace dans la plupart des cas; cependant, la mortalité associée aux FAAV était élevée (14 %). Il est crucial de faire preuve d'une grande suspicion clinique afin de diagnostiquer tôt cette affection potentiellement mortelle.

Cystic pancreatic neuroendocrine tumors: A more favorable lesion?

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are predominantly solid lesions with malignant potential. Cystic PNETs are a small subset in which data are scarce. The aim of this study was to compare clinical and biologic differences between cystic and solid PNETs. METHODS: Patients with PNETs undergoing pancreatectomy between 1988 and 2016 at a high-volume center were reviewed retrospectively. Demographic, clinical, and histopathologic data were collected and analyzed. RESULTS: 347 patients with PNETs were identified; 27% (n = 91) were cystic. Patients with cystic PNETs were generally older (59 vs. 55 years, p = 0.05). Cystic PNETs were more commonly non-functional (95% vs. 82%, p = 0.004), asymptomatic (44% vs. 28%, p = 0.009), and located in the pancreatic body/tail (81% vs. 60%, p < 0.001) than solid PNETs. Although cystic and solid PNETs had similar sizes and pathologic stage at the time of resection, Ki-67 proliferation index (Ki-67 ≤ 9%: 98% vs. 85%; p = 0.007), and histologic grade (grade I: 84% vs. 59%; p = 0.009) had less aggressive features in cystic PNETs. CONCLUSION: In addition to reporting a higher than previously published incidence of cystic PNET (27%), this study found significant differences in multiple clinicopathologic variables between cystic and solid PNETs. Cystic PNET may be a distinct and possibly less aggressive subtype of PNET yet have similar pathologic stage, recurrence, and survival to solid PNETs. Cystic PNETs require further attention to better understand the true natural history.

Sphincter of Oddi Dysfunction After Gastric Bypass: Surgical or Endoscopic Therapy?

BACKGROUND: Management of Sphincter of Oddi Dysfunction (SOD) requires advanced techniques (endoscopic retrograde cholangiopancreatography via gastrostomy [GERCP]) after Roux-en-Y gastric bypass (RYGB) for obesity. Transduodenal sphincteroplasty (TS) is also performed yet carries the risks of surgery. We hypothesized that TS would have increased morbidity and mortality but provide a more durable remission of symptoms. METHODS: All patients between 2005 and 2016 with RYGB for obesity undergoing endoscopic or surgical management for type I or II SOD were included in the study. Patients with type III SOD, or who underwent RYGB for nonobesity indications, were excluded. RESULTS: Thirty-eight patients were identified. GERCP was initially performed in 17 patients, whereas TS was performed in 21. Thirty-day mortality was 0% in our cohort, and 30-d morbidity was similar between GERCP and TS (29% versus 10%; P = 0.207). Resolution of symptoms after initial therapy was seen in 41% of GERCP (7/17) and 67% of TS (14/21) (P = 0.190), respectively, and overall after 35% (8/23) and 64% (16/24) of procedures performed (P = 0.042). Symptom resolution, as defined by the median ratio of days of total remission by total days of observed follow-up, was shorter after initial and all interventions with GERCP compared with TS (0.67 versus 1.00, P = 0.036 and 0.52 versus 1.00, P = 0.028, respectively). CONCLUSIONS: Endoscopic and surgical treatment of SOD had similar morbidity and mortality. However, treatment success and duration of remission was higher in those treated with surgery.