Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. PATIENTS AND METHODS: This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. RESULTS: Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. CONCLUSIONS: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

Epsilon aminocaproic acid is associated with acute kidney injury after life-threatening hemorrhage in children.

BACKGROUND: Antifibrinolytic medications have been associated with reduced mortality in pediatric hemorrhage but may contribute to adverse events such as acute kidney injury (AKI). STUDY DESIGN AND METHODS: We conducted a secondary analysis of the MAssive Transfusion in Children (MATIC), a prospectively collected database of children with life-threatening hemorrhage (LTH), and evaluated for risk of adverse events with either antifibrinolytic treatment, epsilon aminocaproic acid (EACA) or tranexamic acid (TXA). The primary outcome was AKI and secondary outcomes were acute respiratory distress syndrome (ARDS) and sepsis. RESULTS: Of 448 children included, median (interquartile range) age was 7 (2-15) years, 55% were male, and LTH etiology was 46% trauma, 34% operative, and 20% medical. Three hundred and ninety-three patients did not receive an antifibrinolytic (88%); 37 (8%) received TXA and 18 (4%) received EACA. Sixty-seven (17.1%) patients in the no antifibrinolytic group developed AKI, 6 (16.2%) patients in the TXA group, and 9 (50%) patients in the EACA group (p = .002). After adjusting for cardiothoracic surgery, cyanotic heart disease, preexisting renal disease, lowest hemoglobin pre-LTH, and total weight-adjusted transfusion volume during the LTH, the EACA group had increased risk of AKI (adjusted odds ratio 3.3 [95% CI: 1.0-10.3]) compared to no antifibrinolytic. TXA was not associated with AKI. Neither antifibrinolytic treatment was associated with ARDS or sepsis. CONCLUSION: Administration of EACA during LTH may increase the risk of AKI. Additional studies are needed to compare the risk of AKI between EACA and TXA in pediatric patients.

Does CT scanning after pancreatoduodenectomy reduce readmission rates: an analysis of 900 resections at a high-volume center.

BACKGROUND: Pancreatoduodenectomy (PD) remains associated with significant complication and readmission rates. Infection constitutes a significant proportion of morbidity. We aim to evaluate whether CT scans performed prior to discharge for suspected infection prevents readmission. METHODS: A retrospective review of patients undergoing PD at a tertiary referral center from 2010 to 2018. RESULTS: A total of 982 patients underwent PD: 74% had no clinical infection at the index admission. Of the non-infected patients, 59% exhibited leukocytosis, 27% underwent a CT scan, and 33.6% were readmitted. Of the non-infected patients, 148 (20.3%) experienced major complications, and this was the strongest predictor of readmission (OR: 10.5, [95% CI: 6.5-17], p = 0.0001). In the non-infected patients who had major complications, CT scanning was predictive of lower risk of readmission (OR: 0.38, [95% CI: 0.17-0.83], p = 0.015). Leukocytosis was also found to be predictive of lower risk of readmission (OR: 0.42, [95% CI: 0.18-0.98], p = 0.044). These findings did not hold true for those who had yet to experience major complications on their index admission. CONCLUSION: CT scanning without evidence of infection was associated with reduction of readmission in the cohort with major complications and showed a trend towards preventing readmission in the overall cohort. Development of clinical algorithms to maximize the utility of this test is warranted.

Association of robotic approach with patient-reported outcomes after pancreatectomy: a prospective cohort study.

BACKGROUND: Robotic-assisted pancreatectomy continues to proliferate despite limited evidence supporting its benefits from the patient's perspective. We compared patient-reported outcomes (PROs) between patients undergoing robotic and open pancreatectomies. METHODS: PROs, measured with the FACT-Hep, FACT-G, and HCS, were assessed in the immediate postoperative (i.e., preoperative to discharge) and recovery (i.e., discharge to three months postoperative) periods. Linear mixed models estimated the association of operative approach on PROs. Minimally important differences (MIDs) were also considered. RESULTS: Among 139 patients, 105 (75.5%) underwent robotic pancreatectomies. Compared to those who underwent open operations, those who underwent robotic operations experienced worse FACT-Hep scores that were both statistically and clinically significant (mean difference [MD] 8.6 points, 95% CI 1.0-16.3). Declines in FACT-G (MD 4.3, 95% CI -1.0 to 9.6) and HCS (MD 4.3, 95% CI 0.8-7.9) scores appeared to contribute equally in both operative approaches to the decline in total FACT-Hep score. Patients who underwent robotic versus open operations both statistically and clinically significantly improved due to improvements in HCS (MD 6.1, 95% CI 2.3-9.9) but not in FACT-G (MD 1.2, 95% CI - 5.1-7.4). CONCLUSION: The robotic approach to pancreas surgery might offer, from the patient's perspective, greater improvement in symptoms over the open approach by three months postoperatively.

Significance of Uncinate Duct Dilatation in IPMNs: A New High-risk Criterion?

OBJECTIVE: To evaluate the significance of UDD in IPMNs. BACKGROUND: The uncinate process of the pancreas has an independent ductal drainage system. International consensus guidelines of IPMNs still consider it as a branch-duct, even though it is the main drainage system for the uncinate process. METHODS: A retrospective review of all surgically treated IPMNs at our institution after 2008 was performed. Preoperative radiological studies were reviewed by an abdominal radiologist who was blinded to the pathological results. In addition to the Fukuoka criteria, presence of UDD was recorded. Using multivariate analysis, the pathological significance of UDD in predicting advanced neoplasia [high grade dysplasia or invasive carcinoma (HGD/ IC)] was determined. RESULTS: Two hundred sixty patients were identified (mean age at diagnosis was 68 years and 49% were females): 122 (47%) had HGD/IC. UDD was noted in 59 (23%), of which 36 (61%) had HGD/IC (P < 0.003). On multivariate analysis, UDD was an independent predictor of HGD/IC (odds ratio = 2.99, P < 0.04). Subgroup analysis on patients with IPMNs confined to the dorsal portion of the gland (n = 161), also demonstrated UDD to be a significant predictor of HGD/IC in those remote lesions (odds ratio: 4.41, P = 0.039). CONCLUSIONS: This is the largest study to evaluate the significance of UDD in IPMNs and shows it to be a high-risk feature. This association persisted for remote IPMNs limited to the dorsal pancreas, suggesting UDD may be associated with an aggressive phenotype even in remote IPMN lesions.

Laparoscopic-assisted ERCP following RYGB: a 12-year assessment of outcomes and learning curve at a high-volume pancreatobiliary center.

INTRODUCTION: Treatment of pancreaticobiliary pathology following Roux-en-Y gastric bypass (RYGB) poses significant technical challenges. Laparoscopic-assisted endoscopic retrograde cholangiopancreatography (LA-ERCP) can overcome those anatomical hurdles, allowing access to the papilla. Our aims were to analyze our 12-year institutional outcomes and determine the learning curve for LA-ERCP. METHODS: A retrospective review of cases between 2007 and 2019 at a high-volume pancreatobiliary unit was performed. Logistic regression was used to identify predictors of specific outcomes. To identify the learning curve, CUSUM analyses and innovative methods for standardizing the surgeon's timelines were performed. RESULTS: 131 patients underwent LA-ERCP (median age 60, 81% females) by 17 surgeons and 10 gastroenterologists. Cannulation of the papilla was achieved in all cases. Indications were choledocholithiasis (78%), Sphincter of Oddi dysfunction/Papillary stenosis (18%), management of bile leak (2%) and stenting/biopsy of malignant strictures (2%). Median total, surgical and ERCP times were 180, 128 and 48 min, respectively, and 47% underwent concomitant cholecystectomy. Surgical site infection developed in 9.2% and post-ERCP pancreatitis in 3.8%. Logistic regression revealed multiple abdominal operations and magnitude of BMI decrease (between RYGB and LA-ERCP) to be predictive of conversion to open approach. CUSUM analysis of operative time demonstrated a learning curve at case 27 for the surgical team and case 9 for the gastroenterology team. On binary cut analysis, 3-5 cases per surgeon were needed to optimize operative metrics. CONCLUSION: LA-ERCP is associated with high success rates and low adverse events. We identify outcome benchmarks and a learning curve for new adopters of this increasingly performed procedure.

Encouraging long-term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high-risk patients with resectable pancreatic carcinoma.

INTRODUCTION: Preoperative autophagy inhibition with hydroxychloroquine (HCQ) in combination with gemcitabine in pancreatic adenocarcinoma (PDAC) has been shown to be safe and effective in inducing a serum biomarker response and increase resection rates in a previous phase I/II clinical trial. We aimed to analyze the long-term outcomes of preoperative HCQ with gemcitabine for this cohort. METHODS: A review of patients enrolled between July 2010 and February 2013 in the completed phase I/II single arm (two doses of fixed-dose gemcitabine (1500 mg/m2 ) in combination with oral hydroxychloroquine administered for 31 consecutive days until the day of surgery for high-risk pancreatic cancer) was undertaken. Progression-free survival (PFS) and overall survival analysis (OS) using Kaplan-Meier estimates were performed. RESULTS: Of 35 patients initially enrolled, 29 patients underwent surgical resection (median age at diagnosis: 62 years, 45% females). Median duration of follow-up was 7.5 years. There was a median 15% decrease in the serum CA19-9 levels following completion of neoadjuvant therapy and 83% of the cohort underwent a pancreaticoduodenectomy, 7 (24%) patients had a concomitant venous resection. On histopathology, 14 (48%) patients had at least a partial treatment response. The median PFS and OS were 11 months (95% Confidence interval [CI]: 7-28) and 31 months (95% CI: 13-47), respectively, while 9 (31%) patients survived beyond 5 years from diagnosis; a rate that compares very favorably with contemporaneous series. CONCLUSION: Compared to historical data, neoadjuvant autophagy inhibition with HCQ plus gemcitabine is associated with encouraging long-term survival for patients with PDAC.

Protective/reparative cytokines are suppressed at high injury severity in human trauma.

BACKGROUND: Trauma elicits a complex inflammatory response that, among multiple presenting factors, is greatly impacted by the magnitude of injury severity. Herein, we compared the changes in circulating levels of mediators with known proinflammatory roles to those with known protective/reparative actions as a function of injury severity in injured humans. METHODS: Clinical and biobank data were obtained from 472 (trauma database-1 (TD-1), University of Pittsburgh) and 89 (trauma database-2 (TD-2), Indiana University) trauma patients admitted to the intensive care unit (ICU) and who survived to discharge. Injury severity was estimated based on the Injury Severity Score (ISS), and this was used as both a continuous variable and for the purpose of grouping patients into severity-based cohorts. Samples within the first 24 hours were obtained from all patients and then daily up to day 7 postinjury in TD-1. Sixteen cytokines were assayed using Luminex and were analyzed using two-way analysis of variance (p<0.05). RESULTS: Patients with higher ISSs had longer ICU and hospital stays, days on mechanical ventilation and higher rates of nosocomial infection when compared with the mild and moderate groups. Time course analysis and correlations with ISS showed that 11 inflammatory mediators correlated positively with injury severity, consistent with previous reports. However, five mediators (interleukin (IL)-9, IL-21, IL-22, IL-23 and IL-17E/25) were suppressed in patients with high ISS and inversely correlated with ISS. DISCUSSION: These findings suggest that severe injury is associated with a suppression of a subset of cytokines known to be involved in tissue protection and regeneration (IL-9, IL-22 and IL-17E/25) and lymphocyte differentiation (IL-21 and IL-23), which in turn correlates with adverse clinical outcomes. Thus, patterns of proinflammatory versus protective/reparative mediators diverge with increasing ISS.

Impact of postoperative pancreatic fistula on long-term oncologic outcomes after pancreatic resection.

BACKGROUND: The short-term morbidity associated with post-operative pancreatic fistula (POPF) is well established, however data regarding the long-term impact are lacking. We aim to characterize long-term oncologic outcomes of POPF after pancreatic resection through a single institution, retrospective study of pancreatic resections performed for adenocarcinoma from 2009 to 2016. METHODS: Kaplan-Meier survival analysis, logistic regression, and multivariate analysis (MVA) were used to evaluate impact of POPF on overall survival (OS), disease free survival (DFS), and receipt of adjuvant chemotherapy (AC). RESULTS: 767 patients were included. 82 (10.6%) developed grade B (n = 67) or C (n = 15) POPF. Grade C POPF resulted in decreased OS when compared to no POPF (20.22 vs 26.33 months, p = 0.027) and to grade B POPF (20.22 vs. 26.87 months, p = 0.049). POPF patients were less likely to receive AC than those without POPF (59.5% vs 74.9%, p = 0.003) and grade C POPF were less likely to receive AC than all others (26.7% vs 74.2%, p = 0.0001). CONCLUSION: POPF patients are less likely to receive AC and more likely to have delay in time to AC. These factors are exacerbated in grade C POPF and likely contribute to decreased OS. These findings validate the clinical significance of the ISGPF definition of POPF.

Oncologic Outcomes After Robotic Pancreatic Resections Are Not Inferior to Open Surgery.

OBJECTIVE: Compare oncologic outcomes after open and robotic pancreatic resections for pancreatic adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: Receipt of adjuvant chemotherapy improves survival after resected PDAC. Complications after pancreatectomy have been shown to prohibit the administration of adjuvant chemotherapy and survival. We examined the effect of surgical approach on receipt of adjuvant chemotherapy, complications, and overall survival after pancreatectomy. METHODS: A single-institution retrospective review of all patients with PDAC who underwent robotic or open pancreatectomy from 2011 to 2016 with 24-month follow-up. RESULTS: Four hundred fifty-six patients underwent resection: 226 robotic and 230 open. No significant difference was identified in major complications or receipt of adjuvant chemotherapy between robotic and open pancreatectomy, nor was approach an independent predictor of these outcomes. Robotic pancreatectomy patients had a shorter length of stay than patients who underwent open pancreatectomy (7 days vs 9 days; P < 0.001). Additionally, wound infection rate (32.3% vs 12.4%, P < 0.0001) and transfusion (39.6% vs 12.4%, P < 0.0001) was improved in robotic pancreatectomy group with no differences in perioperative mortality. Improved median overall survival approached statistical significance for the robotic cohort (25.6 months vs 23.9 months; P = 0.055); however, on multivariable analysis the robotic approach predicted overall survival, (hazard ratio 0.77, P = 0.041). Robotic approach was an independent predictor of decreased blood loss and less transfusions than the open approach. CONCLUSIONS: Robotic pancreatectomy was not inferior compared to open pancreatectomy in a high-volume experienced center for oncologic outcomes and due to decreased blood loss and transfusion may have improved survival.

500 Minimally Invasive Robotic Pancreatoduodenectomies: One Decade of Optimizing Performance.

OBJECTIVES: This study aims to present the outcomes of our decade-long experience of robotic pancreatoduodenectomy and provide insights into successful program implementation. BACKGROUND: Despite significant improvement in mortality over the past 30 years, morbidity following open pancreatoduodenectomy remains high. We implemented a minimally invasive pancreatic surgery program based on the robotic platform as one potential method of improving outcomes for this operation. METHODS: A retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent robotic pancreatoduodenectomy (RPD) between 2008 and 2017 at the University of Pittsburgh. RESULTS: In total, 500 consecutive RPDs were included. Operative time, conversion to open, blood loss, and clinically relevant postoperative pancreatic fistula improved early in the experience and have remained low despite increasing complexity of case selection as reflected by increasing number of patients with pancreatic cancer, vascular resections, and higher Charlson Comorbidity scores (all P<0.05). Operating room time plateaued after 240 cases at a median time of 391 minutes (interquartile rang 340-477). Major complications (Clavien >2) occurred in less than 24%, clinically relevant postoperative pancreatic fistula in 7.8%, 30- and 90-day mortality were 1.4% and 3.1% respectively, and median length of stay was 8 days. Outcomes were not impacted by integration of trainees or expansion of selection criteria. CONCLUSIONS: Structured implementation of robotic pancreatoduodenectomy can be associated with excellent outcomes. In the largest series of RPD, we establish benchmarks for the surgical community to consider when adopting this approach.

Video review reveals technical factors predictive of biliary stricture and cholangitis after robotic pancreaticoduodenectomy.

BACKGROUND: Cholangitis due to anastomotic stricture of the hepaticojejunostomy (HJ) following pancreaticoduodenectomy (PD), while uncommon, adversely affects postoperative quality-of-life. While prior studies have identified patient-related risk factors for these biliary complications, technical risk factors have not been systematically examined. Video review of surgical procedures has helped define technical details predictive of postoperative complications in bariatric and hepato-pancreato-biliary (HPB) surgery. Similarly, the present study utilized video review to identify technical factors associated with cholangitis and anastomotic biliary stricture following robotic PD. METHODS: This was an observational study. A blinded experienced HPB surgeon reviewed videos of post-learning-curve HJs performed during robotic PD and extracted 20 technical variables. Other demographic and clinical variables were collected from a prospectively maintained database. RESULTS: 241 robotic PD videos were reviewed. 29 (12.0%) developed cholangitis and/or biliary stricture, with a median time-to-event of 189 (IQR 78-365) days. Several clinical and technical factors were independently predictive of cholangitis and/or biliary stricture: preoperative radiotherapy, small duct size (<10 mm diameter), increased distance of the HJ (>10 mm) from the hilar plate, and continuous suturing technique. CONCLUSION: Post-hoc video review of HJ is a powerful method to predict biliary complications. Moreover, altering specific technical factors might enable surgeons to improve postoperative outcomes.

Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial.

IMPORTANCE: In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE: To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS: Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. RESULTS: In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, -1.8%; 95% CI, -5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, -3.0%; 95% CI, -5.7% to -0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003). CONCLUSIONS AND RELEVANCE: In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02086500.

Long-Term Surgical Complications After Pancreatoduodenectomy: Incidence, Outcomes, and Risk Factors.

BACKGROUND: Long-term complications following pancreatoduodenectomy (PD) can significantly impact quality of life and healthcare utilization. Most reports focus on short-term (within 90 days) PD outcomes; however, the incidence and risk factors for long-term complications (> 90 days) remain to be evaluated. We sought to identify the incidence, outcomes, and risk factors for long-term complications post-PD. METHODS: All PD survivors between 2010 and 2017 were identified from a single-institutional database. Long-term complications (> 90 days post-PD and not resulting from cancer recurrence), including biliary stricture, cholangitis, pancreatitis, peptic ulcer, small bowel obstruction, and incisional hernia, were identified. Logistic regression was used to identify perioperative predictors of long-term complications. RESULTS: Of 906 PDs, 628 long-term survivors met criteria for analysis (mean age of 65.3 years, 47% female). Median follow-up and overall survival were 51.1 months (95% CI 47.6, 55.7) and 68.5 months (95% CI 57.9, 81.4), respectively. A total of 198 (31.5%) experienced at least one long-term complication. Complications included incisional hernia (17.7%), biliary stricture or cholangitis (8.0%), pancreatitis (5.7%), small bowel obstruction (4.3%), and peptic ulcer (3.2%). In total, 108 (17.2%) of the complications required an intervention, nearly half of which were surgical. On multivariable analysis, several predictors of long-term complications were identified: obesity (BMI ≥ 30 kg/m2), postoperative wound infection, prolonged index length of stay, readmission (< 90 days), operative approach (open vs. robotic), and pylorus-preservation. CONCLUSION: Long-term complications occur in nearly a third of PDs and nearly one-fifth of all PDs require re-intervention. Several modifiable predictors of long-term complications were identified.

CA19-9 Change During Neoadjuvant Therapy May Guide the Need for Additional Adjuvant Therapy Following Resected Pancreatic Cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly utilized for pancreatic cancer, however the added benefit of adjuvant therapy (AT) in this setting is unknown. We hypothesized that the magnitude of CA19-9 response to NAT can guide the need for further AT in resected pancreatic cancer. METHODS: CA19-9 secretors who received NAT for pancreatic cancer during 2008-2016 at a single institution were analyzed and CA19-9 response (difference between pre- and post-NAT values) was measured. Kaplan-Meier estimators and Cox proportional hazard ratio models were used to determine the optimal CA19-9 response at which AT ceases to confer any additional survival benefit after NAT. RESULTS: A total of 241 patients (mean age 65.4 years, 50% female) with complete CA19-9 data who underwent NAT followed by resection were analyzed. In a cohort of patients (n = 78) in whom CA19-9 normalized with a decrease > 50% after NAT (optimal responders), AT was not associated with additional survival benefit (40.6 vs. 39.0 months, p = 0.815). Conversely, in the cohort of patients (n = 163) in whom NAT was not associated with normalization and a decrease of ≤ 50% in CA19-9 (suboptimal responders), receipt of AT was associated with a survival benefit (34.5 vs. 19.1 months, p < 0.001) following NAT. A Cox proportional hazards model confirmed CA19-9 normalization and decrease > 50% during NAT to predict no additional survival benefit from AT. CONCLUSIONS: The magnitude of CA19-9 response to NAT may predict the need for further AT in resected pancreatic cancer. Prospective studies are needed to elucidate the optimal interplay of NAT and AT in pancreatic cancer.

Association Between Preoperative Metformin Exposure and Postoperative Outcomes in Adults With Type 2 Diabetes.

Importance: Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention. Objective: To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin. Design, Setting, and Participants: This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018. Exposures: Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure. Main Outcomes and Measures: All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort. Results: Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding. Conclusions and Relevance: This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

Predictors of Disease Progression or Performance Status Decline in Patients Undergoing Neoadjuvant Therapy for Localized Pancreatic Head Adenocarcinoma.

INTRODUCTION: Neoadjuvant therapy (NT) is a growing strategy in localized head pancreatic adenocarcinoma (PDC). However, a significant portion of NT patients do not reach resection due to disease progression or performance status decline. We sought to identify predictors of disease progression or performance status decline during NT. METHODS: Retrospective cohort analysis of consecutive patients with localized head-PDC who received NT at a tertiary referral center between 2005 and 2017. Univariate and multivariate (MVA) analysis were performed to identify factors associated with disease progression or performance status decline during NT preventing surgical resection. RESULTS: A total of 479 patients with PDC underwent NT; 71.2% proceeded to surgery, 20.5% had disease progression, and 8.3% experienced performance status decline. Median OS was 28 [95% confidence interval (CI) 23.8-32.3], 12.8 (CI 11.2-14.3), and 6.9 (CI 5.2-9.4) months, respectively (p < 0.05). MVA predictors of disease progression were larger clinical CT tumor size [odds ratio (OR) 1.03, CI 1.0-1.1], unplanned change in NT regimen (OR 2.6, CI 1.0-6.9), hospital admission during NT (OR 2.2, CI 1.2-3.9), and lack of CA19-9 response (OR 4.4, CI 4.0-8.4). MVA predictors of performance status decline were increasing age (OR 1.1, CI 1.0-1.2), presence of pre-NT diabetes (OR 3.8, CI 1.3-11.3), hospital admission during NT (OR 14.0, CI 3.9-49.8), and lack of CA19-9 response (OR 4.7, CI 1.4-15.5). CONCLUSIONS: This analysis identifies several predictors of disease progression and performance status decline during NT for PDC. Knowledge of these factors informs the physician on the risks and limitations of NT and provides insight to guide patient selection and counseling.

Robotic Pancreaticoduodenectomy Is Associated with Decreased Clinically Relevant Pancreatic Fistulas: a Propensity-Matched Analysis.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD) is a major complication that adversely affects recovery. The robotic approach may decrease the incidence of this complication. This propensity-matched analysis evaluates the impact of robotic PD (RPD) on CR-POPF. METHODS: Patients undergoing PD after the learning curve at a high-volume academic medical center were reviewed. CR-POPF outcomes after open PD (OPD) and RPD were compared. Logistic regression and propensity score matching (PSM) were used to define the independent effect of RPD on CR-POPF. RESULTS: Of 865 PDs performed over the study period, 405 (46.8%) were OPD and 460 (53.2%) were RPD. RPD was associated with a similar overall POPF rate, but a lower incidence of CR-POPF (6.7% vs. 15.8%, p < 0.001). On multivariate analysis, RPD was an independent predictor of lower CR-POPF (OR 0.278, p < 0.001). Following propensity matching, RPD continued to be protective against the occurrence of CR-POPF (coefficient = - 0.113, p = 0.001). CONCLUSIONS: This is the largest single-center PSM analysis to evaluate the impact of robotic approach on pancreatoduodenectomy and suggests that RPD can minimize the clinical impact of pancreatic leaks after PD.

Prognostic Value of the Systemic Immune-Inflammation Index (SII) After Neoadjuvant Therapy for Patients with Resected Pancreatic Cancer.

BACKGROUND: The systemic immune-inflammation index (SII), calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently emerged as a predictor of survival for patients with pancreatic ductal adenocarcinoma (PDAC) when assessed at diagnosis. Neoadjuvant therapy (NAT) is increasingly used in the treatment of PDAC. However, biomarkers of response are lacking. This study aimed to determine the prognostic significance of SII before and after NAT and its association with the pancreatic tumor biomarker carbohydrate-antigen 19-9 (CA 19-9). METHODS: This study retrospectively analyzed all PDAC patients treated with NAT before pancreatic resection at a single institution between 2007 and 2017. Pre- and post-NAT lab values were collected to calculate SII. Absolute pre-NAT, post-NAT, and change in SII after NAT were evaluated for their association with clinical outcomes. RESULTS: The study analyzed 419 patients and found no significant correlation between pre-NAT SII and clinical outcomes. Elevated post-NAT SII was an independent, negative predictor of overall survival (OS) when assessed as a continuous variable (hazard ratio [HR], 1.0001; 95% confidence interval [CI] 1.00003-1.00014; p = 0.006). Patients with a post-NAT SII greater than 900 had a shorter median OS (31.9 vs 26.1 months; p = 0.050), and a post-NAT SII greater than 900 also was an independent negative predictor of OS (HR, 1.369; 95% CI 1.019-1.838; p = 0.037). An 80% reduction in SII independently predicted a CA 19-9 response after NAT (HR, 4.22; 95% CI 1.209-14.750; p = 0.024). CONCLUSION: Post-treatment SII may be a useful prognostic marker in PDAC patients receiving NAT.