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Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) lacking worrisome features (WF) and high-risk stigmata (HRS) warrant surveillance. However, their optimal duration, especially among cysts with initial 5 years of size stability, warrants further investigation. We systematically reviewed the surveillance of low-risk BD-IPMNs and investigated the incidence of WF/HRS and advanced neoplasia, high-grade dysplasia, and pancreatic cancer during the initial (5 years) and extended surveillance period (5-years).A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among the Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included the incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as percentage per patient-years). The meta-analysis relied on time-to-event plots and used a random-effects model.Forty-one eligible studies underwent systematic review, and 18 studies were meta-analyzed. The pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance was 2.2% (95% CI, 1.0%-3.7%) and 2.9% (95% CI, 1.0%-5.7%) patient-years, respectively, whereas the incidence of advanced neoplasia was 0.6% (95% CI, 0.2%-1.00%) and 1.0% (95% CI, 0.6%-1.5%) patient-years, respectively. The pooled incidence of disease-specific mortality during initial and extended surveillance was 0.3% (95% CI, 0.1%-0.6%) and 0.6% (95% CI, 0.0%-1.6%) patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had a WF/HRS and advanced neoplasia incidence of 1.9% (95% CI, 1.2%-2.8%) and 0.2% (95% CI, 0.1%-0.5%) patient-years, respectively.A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs was a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.

BackgroundThe COVID-19 pandemic yielded rapid telehealth deployment to improve healthcare access, including for surgical patients.MethodsWe conducted a secret shopper study to assess telehealth availability for new patient and follow-up colorectal cancer care visits in a random national sample of Commission on Cancer accredited hospitals and investigated predictive facility-level factors.ResultsOf 397 hospitals, 302 (76%) offered telehealth for colorectal cancer patients (75% for follow-up, 42% for new patients). For new patients, NCI-designated Cancer Programs offered telehealth more frequently than Integrated Network (OR: 0.20, p=0.01), Academic Comprehensive (OR: 0.18, p=0.001), Comprehensive Community (OR: 0.10, p&nbsp

Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesized that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF.The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach.A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P.001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone.In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes.

Background: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored. Methods: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with a = 0.05 and b = 0.2. Results: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.4 4; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P 1/4 .156). Conclusion: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal. (c) 2021 Elsevier Inc. All rights reserved.

Background Neutrophil-to-lymphocyte ratio (NLR) has been reported as prognostic in pancreatic ductal adenocarcinoma (PDAC). Data about NLR changes during neoadjuvant therapy (NAT) and its relationship with pathological tumor response and survival are lacking. Methods Pancreatic ductal adenocarcinoma patients with NAT followed by resection between 2009 and 2015 were identified from a prospective database. Neutrophil-to-lymphocyte ratio was collected prior to NAT (baseline), on chemotherapy (prior to cycle 3), and prior to surgery. Baseline NLR, and changes in NLR between baseline and on chemotherapy (delta 1) and between baseline and surgery (delta 2) were compared with pathologic response (Results Of 93 patients, 17% had good pathological response. Median (interquartile range) NLR at baseline, third cycle, and surgery were 2.7 (2.0-3.7), 2.5 (1.9-4.1), and 3.1 (2.1-5.3), respectively. Median change in NLR from baseline to third cycle was .06 ( P = .72), and .6 from baseline to surgery ( P < .01). Baseline NLR, delta 1, and delta 2 were not associated with pathological response, OS, or DFS. Discussion Neutrophil-to-lymphocyte ratio increased after NAT, but a significant association between NLR and pathological response, OS, and DFS in resected PDAC patients was not observed.

OBJECTIVES The potential of DNA methylation alterations in early pancreatic cancer (PC) detection among pancreatic tissue cell-free DNA seems promising. This study investigates the diagnostic capacity of the 4-gene methylation biomarker panel, which included ADAMTS1, BNC1, LRFN5, and PXDN genes, in a case-control study. METHODS A genome-wide pharmacoepigenetic approach identified ADAMTS1, BNC1, LRFN5, and PXDN genes as putative targets. Tissue samples including stage I-IV PC (n = 44), pancreatic intraepithelial neoplasia (n = 15), intraductal papillary mucinous neoplasms (n = 24), and normal pancreas (n = 8), and cell-free DNA, which was acquired through methylation on beads technology from PC (n = 22) and control patients (n = 10), were included. The 2-∆ct was the outcome of interest and underwent receiver operating characteristic analysis to determine the diagnostic accuracy of the panel. RESULTS Receiver operating characteristic analysis revealed an area under the curve of 0.93 among ADAMTS1, 0.76 among BNC1, 0.75 among PXDN, and 0.69 among LRFN5 gene. The combination gene methylation panel (ADAMTS1, BNC1, LRFN5, and PXDN) had an area under the curve of 0.94, with a sensitivity of 100% and specificity of 90%. CONCLUSIONS This methylation-based biomarker panel had promising accuracy for PC detection and warranted further validation in prospective PC surveillance trials.

Reports of higher rates of medical errors in the month of July have generated concern regarding major surgery at academic institutions early in the yearly promotion cycle. This study was designed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy (PD) at different times of the year. Outcomes were retrospectively evaluated for patients treated in July versus the rest of the year and in the first quarter (July–September) versus the remaining quarters. The primary outcome was operative morbidity as measured by Clavien-Dindo grade, a classification system of surgical complications. Secondary outcomes included mortality, operative blood loss, pancreatic fistula formation, delayed gastric emptying, intraabdominal abscess, anastomotic leak, reoperation, and other variables of interest. From January 2003 to September 2015, 472 patients underwent PD by a single academic surgeon. Overall, 77.1% of PDs were performed for malignancy. The number of patients did not significantly vary by month or by quarter. The incidence of major morbidity (Clavien-Dindo grade ≥ III) in patients who had a PD was 12.2% in July and 17.5% in all other months (P = 0.79). The rate of pancreatic fistula, intraabdominal abscess, reoperation, readmission, and mortality did not differ significantly by month or by quarter (P > 0.05 for all). The current study does not find any correlation between time of year and operative morbidity or mortality, suggesting that PD can be safely performed irrespective of timing.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Background: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood.Methods: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models.Results: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (>400 pancreatoduodenectomies performed or >21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruc-tion and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experi-ence. Moreover, minimizing blood loss (

The Charlson Comorbidity Index (CACI) has been suggested as a tool to determine comorbidity burden and guide management for patients with mucinous pancreatic cysts (Intrapapillary Mucinous Neoplasms and Mucinous Cystic Neoplasms), but has not been studied well among "low-risk" mucinous pancreatic cysts i.e. without worrisome features (WF) and high-risk stigmata (HRS). This study sought to determine the comorbidity burden among surveillance population of low-risk pancreatic cysts and provide their follow-up mortality outcomes.A single center study retrospectively reviewed a prospective pancreatic cyst database and included individuals with low-risk cysts undergoing serial imaging during 2016. Electronic medical records were reviewed to determine their baseline age-adjusted CACI (age-CACI). After 4 years, their progression to WF, disease specific (pancreatic malignancy-related, DSM), extra-pancreatic (EPM), and overall mortalities (OM) were determined using Kaplan-Meir Survival Analysis.502 individuals underwent prospective surveillance. The study included 440 individuals with low-risk suspected or presumed mucinous cysts and excluded 50 and 12 individuals with WF and HRS respectively. Over a median follow-up of 56 months, 12 WF progressions, 2 DSMs, 42 EPMs, and 44 OMs were observed. Baseline age-CACI had good predictive capacity for 4-year EPM (Area-Under Curve: 0.87; p.0001). The median age-CACI of 4 enabled cohort stratification into Low (age-CACI4) and High CACI (age-CACI ≥4) groups. A significantly higher OM (p.001) was observed among the High CACI group as compared to the Low CACI group.Through real-time application of CACI to patient outcomes, our analysis supports incorporation of this comorbidity assessment tool in making shared surveillance decisions among low-risk pancreatic cyst population.

Foci of papillary or follicular thyroid carcinoma are frequently noted in thyroidectomy specimens of anaplastic thyroid carcinoma (ATC). However, whether ATCs evolve from these co-existing well-differentiated thyroid carcinomas (WDTCs) has not been well-understood. To investigate the progression of ATC in patients with co-existing WDTCs, five ATC tumors with co-existing WDTCs and matching normal tissues were whole-exome sequenced. After mapping the somatic alteration landscape, evolutionary lineages were constructed by sub-clone analysis. Though each tumor harbored at least some unique private mutations, all five ATCs demonstrated numerous overlapping mutations with matched WDTCs. Clonal analysis further demonstrated that each ATC/WDTC pair shared a common ancestor, with some pairs diverging early in their evolution and others in which the ATC seems to arise directly from a sub-clone of the WDTC. Though the precise lineal relationship remains ambiguous, based on the genetic relationship, our study clearly suggests a shared origin of ATC and WDTC.

Dysregulated expression of the secretory protein renalase can promote pancreatic ductal adenocarcinoma (PDAC) growth in animal models. We characterized renalase expression in premalignant and malignant PDAC tissue and investigated whether plasma renalase levels corresponded to clinical PDAC characteristics. Renalase immunohistochemistry was used to determine the presence and distribution of renalase in normal pancreas, chronic pancreatitis, PDAC precursor lesions, and PDAC tissues. Associations between pretreatment plasma renalase and PDAC clinical status were assessed in patients with varied clinical stages of PDAC and included tumor characteristics, surgical resection in locally advanced/borderline resectable PDAC, and overall survival. Data were retrospectively obtained and correlated using non-parametric analysis. Little to no renalase was detected by histochemistry in the normal pancreatic head in the absence of abdominal trauma. In chronic pancreatitis, renalase immunoreactivity localized to peri-acinar spindle-shaped cells in some samples. It was also widely present in PDAC precursor lesions and PDAC tissue. Among 240 patients with PDAC, elevated plasma renalase levels were associated with worse tumor characteristics, including greater angiolymphatic invasion (80.0% vs. 58.1%, p = 0.012) and greater node positive disease (76.5% vs. 56.5%, p = 0.024). Overall survival was worse in patients with high plasma renalase levels with median follow-up of 27.70 months vs. 65.03 months (p < 0.001). Renalase levels also predicted whether patients with locally advanced/borderline resectable PDAC underwent resection (AUC 0.674; 95%CI 0.42–0.82, p = 0.04). Overall tissue renalase was increased in both premalignant and malignant PDAC tissues compared to normal pancreas. Elevated plasma renalase levels were associated with advanced tumor characteristics, decreased overall survival, and reduced resectability in patients with locally advanced/borderline resectable PDAC. These studies show that renalase levels are increased in premalignant pancreatic tissues and that its levels in plasma correspond to the clinical behavior of PDAC.

Use of drain remains frequent following pancreaticoduodenectomy (PD) due to concern for postoperative pancreatic fistula (POPF) and anastomotic leak development. Despite controversy, a recent randomized trial suggested omitting drainage would result in a large increase in operative mortality. This study sought to comprehensively examine the effects of forgoing drainage in the large cohort of patients undergoing PD. A prospective cohort study of two consecutive groups undergoing PD was constructed. The initial group had operative drains placed in cases subjectively concerning for POPF development; the second cohort did not undergo operative drainage. Outcomes including POPF incidence, need for reintervention, and overall morbidity were examined. A total of 106 patients were evaluated in two consecutive cohorts of 53; in the first group, 30 per cent had operative drains placed; 22.6 per cent developed POPF versus 7.5 per cent of patients in the no drainage group (P = 0.06). Despite this, no significant difference in major morbidity (Clavien ≥3, 20.8% versus 17.0%) or need for procedural reintervention (18.9% versus 15.1%) was observed. A subsequent validation cohort of 237 additional patients where drains were used only in exceptional circumstances was examined. Operative drains were placed in only 3 per cent of patients (n = 7) and 90-day mortality was 1.3 per cent (n = 3). Incidence of POPF was 8.0 per cent and the overall major complication rate was 14.8 per cent. Given such findings, it appears that drainage after PD can be avoided resulting in acceptable operative morbidity and mortality in most cases.

Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown.To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity.This cohort study used data on 278 936 patients with PDAC with database-defined race from the National Cancer Database from January 1, 2004, to December 31, 2015. The median follow-up for censored patients was 24 months. The National Cancer Database, comprising academic and community facilities, includes about 70% of new cancer diagnoses in the United States. Race-stratified receipt of therapy was the primary variable of interest. Multivariable analyses included additional demographic and clinical parameters. Data analysis was initially completed on November 30, 2018, and revised data analysis was completed on June 27, 2019.Overall survival was the primary outcome, analyzed with Kaplan-Meier and multivariable Cox proportional hazards regression modeling.The cohort included 278 936 patients (137 121 women and 141 815 men; mean [SD] age, 68.72 [11.57] years); after excluding patients from other racial categories, 243 820 of the 278 936 patients (87.4%) were white and 35 116 of the 278 936 patients (12.6%) were black. Unadjusted median overall survival was longer for white patients than for black patients (6.6 vs 6.0 months; P .001). Black patients presented at younger ages than white patients (15 819 of 35 116 [45.0%] vs 83 846 of 243 820 [34.4%] younger than 65 years; P .001) and with more advanced disease (20 853 of 31 600 [66.0%] vs 135 317 of 220 224 [61.4%] with stage III or IV disease; P .001). Black patients received fewer surgical procedures than white patients for potentially resectable stage II disease (4226 of 8097 [52.2%] vs 39 214 of 65 124 [60.2%]; P .001) and slightly less chemotherapy for advanced disease (2756 of 4067 [67.8%] vs 17 296 of 25 227 [68.6%] for stage III disease [P = .001]; 8208 of 16 104 [51.0%] vs 58 603 of 105 616 [55.5%] for stage IV disease [P .001]). Decreased survival for black patients persisted in multivariable modeling controlled for sociodemographic parameters (hazard ratio, 1.04 [95% CI, 1.02-1.05]). Conversely, modeling that controlled specifically for clinical parameters such as disease stage and treatment revealed a modest survival advantage (hazard ratio, 0.94 [95% CI, 0.93-0.96]) among black patients. Resection was the factor most strongly associated with overall survival (hazard ratio, 0.39 [95% CI, 0.38-0.39]).Black patients with PDAC present at younger ages and with more advanced disease than white patients, suggesting that differences in tumor biology may exist. Black patients receive less treatment stage for stage and fewer surgical procedures for resectable cancers than white patients; these findings may be only partly associated with socioeconomic differences. When disease stage and treatment were controlled for, black patients had no decrease in survival.

Reports of higher rates of medical errors in the month of July have generated concern regarding major surgery at academic institutions early in the yearly promotion cycle. This study was designed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy (PD) at different times of the year.Outcomes were retrospectively evaluated for patients treated in July versus the rest of the year and in the first quarter (July-September) versus the remaining quarters. The primary outcome was operative morbidity as measured by Clavien-Dindo grade, a classification system of surgical complications. Secondary outcomes included mortality, operative blood loss, pancreatic fistula formation, delayed gastric emptying, intraabdominal abscess, anastomotic leak, reoperation, and other variables of interest.From January 2003 to September 2015, 472 patients underwent PD by a single academic surgeon. Overall, 77.1% of PDs were performed for malignancy. The number of patients did not significantly vary by month or by quarter. The incidence of major morbidity (Clavien-Dindo grade ≥ III) in patients who had a PD was 12.2% in July and 17.5% in all other months (P = 0.79). The rate of pancreatic fistula, intraabdominal abscess, reoperation, readmission, and mortality did not differ significantly by month or by quarter (P 0.05 for all).The current study does not find any correlation between time of year and operative morbidity or mortality, suggesting that PD can be safely performed irrespective of timing.

Background Outcome improvement is a major goal of pancreatic surgery. Such efforts include decreasing perioperative narcotic use to optimize care and reduce potential contributions to the opioid crisis. Ketorolac, a frequent component of opioid-minimizing recovery pathways, has not been universally adopted over concerns regarding adverse events including anastomotic fidelity, hemorrhage, and renal failure. We examined ketorolac’s effects on pancreatic fistula (PF) formation and related morbidity after pancreaticoduodenectomy (PD). Study Design A retrospective review of consecutive patients undergoing PD from December 2008 to September 2018 was conducted and stratified by receipt of ketorolac during the initial 5 postoperative days. The primary outcome was clinically relevant PF (CR-PF) per international consensus definitions. Secondary outcomes included fistula risk score (FRS)-adjusted CR-PF and cumulative morbidity. Results Of 429 patients, CR-PF occurred in 9.3% (n = 40), and 249 patients received ketorolac before postoperative day 6 (58.0%), with a mean dose of 36.1 ± 22.3 mg/day. CR-PF occurred in 11.2% (n = 28) of patients receiving ketorolac vs 6.7% (n = 12) who did not ( p = 0.12); CR-PF incidence was unrelated to dose. Overall CR-PF incidence did not differ statistically by ketorolac use in the first 5 days postoperatively across FRS categories. Results from multivariable logistic regression models, adjusted for known PF risk factors suggested that ketorolac was not significantly associated with risk of CR-PF (odds ratio [OR] 1.99 [range 0.93 to 4.26], p = 0.08). Operative mortality and major (Clavien ≥ 3) morbidity, including hemorrhage and renal failure, did not differ statistically between groups. Conclusions Ketorolac administration was associated with an acceptable risk of CR-PF and no increase in major morbidity after PD. These data suggest ketorolac can be used in strategies to optimize analgesia and minimize opioid usage.

Objective: The aim of this study was to elucidate the impact of intraoperative blood loss on outcomes following pancreatoduodenectomy (PD). Background: The negative impact of intraoperative blood loss on outcomes in PD has long been suspected but not well characterized, particularly those factors that may be within surgeons’ control. Methods: From 2001 to 2015, 5323 PDs were performed by 62 surgeons from 17 institutions. Estimated blood loss (EBL) was discretized (0 to 300, 301 to 750, 751 to 1300, and >1300 mL) using optimal scaling methodology. Multivariable regression, adjusted for patient, surgeon, and institutional variables, was used to identify associations between EBL and perioperative outcomes. Factors associated with both increased and decreased EBL were elucidated. The relative impact of surgeon-modifiable contributors was estimated through beta coefficient standardization. Results: The median EBL of the series was 400 mL [interquartile range (IQR) 250 to 600]. Intra-, post-, and perioperative transfusion rates were 15.8%, 24.8%, and 37.2%, respectively. Progressive EBL zones correlated with intra- but not postoperative transfusion in a dose-dependent fashion (P < 0.001), with a key threshold of 750 mL EBL (8.14% vs 40.9%; P < 0.001). Increasing blood loss significantly correlated with poor perioperative outcomes. Factors associated with increased EBL were trans-anastomotic stent placement, neoadjuvant chemotherapy, pancreaticogastrostomy reconstruction, multiorgan or vascular resection, and elevated operative time, of which 38.7% of the relative impact was “potentially modifiable” by the surgeon. Conversely, female sex, small duct, soft gland, minimally invasive approach, pylorus-preservation, biological sealant use, and institutional volume (≥67/year) were associated with decreased EBL, of which 13.6% was potentially under the surgeon's influence. Conclusion: Minimizing blood loss contributes to fewer intraoperative transfusions and better perioperative outcomes for PD. Improvements might be achieved by targeting modifiable factors that influence EBL.

Context Follicular thyroid carcinoma (FTC) is classified into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes, according to the 2017 World Health Organization guidelines. The genetic signatures of these subtypes may be crucial for diagnosis, prognosis, and treatment but have not been described. Objective Identify and describe the genetic underpinnings of subtypes of FTC. Methods Thirty-nine tumors, comprising 12 miFTCs, 17 eaFTCs, and 10 wiFTCs, were whole-exome sequenced and analyzed. Somatic mutations, constitutional sequence variants, somatic copy number alterations, and mutational signatures were described. Clinicopathologic parameters and mutational profiles were assessed for associations with patient outcomes. Results Total mutation burden was consistent across FTC subtypes, with a median of 10 (range 1 to 44) nonsynonymous somatic mutations per tumor. Overall, 20.5% of specimens had a mutation in the RAS subfamily (HRAS, KRAS, or NRAS), with no notable difference between subtypes. Mutations in TSHR, DICER1, EIF1AX, KDM5C, NF1, PTEN, and TP53 were also noted to be recurrent across the cohort. Clonality analysis demonstrated more subclones in wiFTC. Survival analysis demonstrated worse disease-specific survival in the eaFTC and wiFTC cohorts, with no recurrences or deaths for patients with miFTC. Mutation burden was associated with worse prognosis, independent of histopathological classification. Conclusions Though the number and variety of somatic variants are similar in the different histopathological subtypes of FTC in our study, mutational burden was an independent predictor of mortality and recurrence.

Electronic supplementary material The online version of this article ( https://doi.org/10.1007/s11605-017-3547-2 ) contains supplementary material, which is available to authorized users.

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 circ

Background Diabetes mellitus is postulated to be both a risk factor and manifestation of pancreatic adenocarcinoma. This study evaluated the effects of preoperative glycemic control as determined by hemoglobin A1c (HbA1c) on outcomes following pancreaticoduodenectomy (PD). Methods A prospective cohort study whereby HbA1c was assessed preoperatively in 243 patients undergoing PD was performed. The primary outcome measure was operative morbidity. Secondary outcomes included individual adverse events, time to dietary resumption, and length of stay. Results Preoperative HbA1c ranged from 4.0% to 13.5%. Overall morbidity and incidence of specific adverse events were similar regardless of preoperative HbA1c. No correlation between HbA1c and length of stay, dietary resumption, or readmission was observed. Pancreatic fistula formation had a decreased incidence in patients with elevated versus normal HbA1c (2.2% vs 9.6%, P = .083). Conclusions PD can be safely performed in patients with HbA1c levels suggestive of poor long-term preoperative glycemic control. Medical efforts to optimize HbA1c should not delay resection.

Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.

This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity.The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD - clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD.This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score.The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume450 were less likely to have serious complications (P0.001) or perform reoperations (P0.001).Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

BackgroundPost-operative pancreatic fistula (POPF) formation occurs frequently after a pancreaticoduodenectomy (PD). Recently, a 10-point Fistula Risk Score (FRS) evaluating the likelihood of clinically relevant POPF (CR-POPF) development has been described and validated. This scheme has yet to be evaluated in PD patients managed without intra-operative drain placement.MethodsAmong patients undergoing PD at an academic centre since 2003, a retrospective analysis calculating FRS and its correlation with CR-POPF development was evaluated by logistic regression. Secondary analysis examined presentation and management of CR-POPF in undrained PD patients.ResultsFRS was calculated for 265 patients; 97.7% were managed without operative drains. The overall incidence of CR-POPF was 7.9%. Logistic regression revealed a 1.6-fold increase in CR-POPF risk per 1-point increase in FRS [95% confidence interval (CI) 1.2–2.0]. The negative predictive value in patients with FRS 6 was 16.7%. The median time to CR-POPF diagnosis was 18 days [interquartile range (IQR) 13–23]; 70.0% required readmission and 10.0% required a laparotomy.ConclusionsAmong patients without operative drainage, CR-POPF often has delayed presentations but most are managed non-operatively. The predictive value of high-risk FRS appears limited; conversely, a low-risk FRS accurately predicts the absence of CR-POPF and seems an appropriate metric for guiding care.

Owing to its diagnostic challenges, subclinical Cushing syndrome (SCS) is likely to be highly underdiagnosed and undertreated, and the overall incidence may be as high as 5% to 20% in patients with adrenal incidentalomas. The diagnosis can be established by a systematic and thorough biochemical evaluation. SCS has been associated with significant morbidity, which at least partly may be reversed by surgery. Given the low rates of complications and the possibility to reverse the detrimental effects of elevated cortisol secretion, minimally invasive adrenalectomy is recommended for patients with biochemically proven or suspected SCS who are appropriate surgical candidates.

Richard Lifton and colleagues identify a recurrent activating mutation in PRKACA, which encodes the catalytic subunit of protein kinase A, in cortisol-producing adrenal tumors. They further show that the mutation results in loss of binding by the regulatory subunit PRKAR1A, leading to increased phosphorylation of downstream targets.

Morbidity after pancreatectomy is commonly due to leakage of exocrine secretions resulting in abscess or pancreatic fistula (PF). Previously, we authored a double-blind randomized controlled trial demonstrating that perioperative pasireotide administration lowers abscess or PF formation by50%. Accordingly, we adopted pasireotide use as standard practice after pancreatectomy in October 2014 and hypothesized a similar PF/abscess rate reduction would be observed.A prospectively maintained database was queried for all patients who underwent pancreatectomy between October 2014 and July 2017. Pasireotide was administered preoperatively and twice daily for 7 days postoperatively or until discharge. The primary end point was clinically relevant PF/abscess requiring procedural intervention, identical to the earlier trial outcomes. Logistic regression was used to compare outcomes with the placebo arm of the earlier randomized trial and to control known PF risk factors.During the 34-month study period, 652 patients underwent pancreatectomy (211 distal pancreatectomy, 441 pancreaticoduodenectomy). Compared with the historical placebo group (n = 148), the observational group had an increased prevalence of higher American Society of Anesthesiologists scores (69% vs 54%; p0.001) and high-risk cases (small duct and soft gland, 47% vs 36%; p = 0.030). The primary end point occurred in 13.3% of patients receiving pasireotide vs 20.9% in the placebo arm of the earlier trial trial (odds ratio 0.58; 95% CI 0.37 to 0.92; p = 0.020). Biliary leakage was lower in those receiving pasireotide (0.6% vs 3.4%; p = 0.014), and other morbidity was unchanged. No subpopulation was identified more likely to benefit from pasireotide.At our center, adoption of pasireotide has allowed us to achieve a clinically significant abscess or pancreatic leak rate of 13.3%, approximating the effect observed in the randomized trial of pasireotide during routine surgical practice.

Epigenetic alterations such as DNA methylation are widespread cancer, contributing to tumorigenesis and acting as markers for prognostication. Papillary thyroid cancer (PTC) demonstrates tumor-specific methylation of numerous genes, including RASSF1A. Although the function of RASSF1A in PTC tumorigenesis is still being defined, quantitative evaluation of RASSF1A methylation and its correlation with tumor characteristics has not been performed.Analysis of RASSF1A methylation was performed using quantitative polymerase chain reaction after methylation-dependent and -sensitive restriction enzyme digestion in PTC (n = 41) and normal (n = 18) thyroid tissue. Methylation was then evaluated for correlation with tumor size, stage, and multiple histopathologic characteristics.RASSF1A promoter hypermethylation was observed in nearly all PTC cases versus normal thyroid tissue, with mean hypermethylation 4.2 times greater in PTC (P.05). Hypermethylation was greater in multifocal than unifocal PTC (P.05). Furthermore, tumor methylation was inversely correlated with extracapsular invasion (P.05).RASSF1A methylation differs in PTC compared with normal thyroid, is associated with multifocality, and is inversely correlated with extracapsular invasion. The ease of evaluating methylation status with minute amounts of DNA suggests a potential role for RASSF1A as a molecular marker for characterization of PTC histopathology.

Clinical Context: The prevalence of hyperparathyroidism, especially primary hyperparathyroidism, has increased in recent decades due to improvements in diagnostic techniques with a corresponding surge in parathyroid surgery, leading to the development of focused, minimally invasive surgical approaches. Focused parathyroidectomy is predicated on preoperative localization of suspected parathyroid pathology. As a result, there has been a proliferation of parathyroid imaging modalities and protocols, resulting in confusion about their indications and applications. Evidence Acquisition: Bibliographies from clinical trials and review articles published since 2000 were reviewed and supplemented with targeted searches using biomedical databases. We also employed our extensive clinical experience. Evidence Synthesis: The best-studied modalities for parathyroid localization are nuclear scintigraphy and sonography and are widely applied as initial studies. Multiple variations exist, and several additional noninvasiv...

Background Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis. Methods Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues’ common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples. Results Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden. Conclusions The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote’s germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2665-7) contains supplementary material, which is available to authorized users.