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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., Preoperative autophagy inhibition with hydroxychloroquine enhances the therapeutic efficacy of neoadjuvant chemotherapy leading to a sustained and improved survival benefit in high‐risk pancreatic cancer.

BACKGROUND Appendiceal goblet cell adenocarcinomas (GCC) are rare tumors with clinical behavior between classic carcinoids and adenocarcinomas. Current guidelines recommend right hemicolectomy for all GCCs. PATIENTS AND METHODS The National Cancer Database was retrospectively queried for appendiceal GCCs undergoing appendectomy or right hemicolectomy between 2004 and 2016. Demographics, tumor characteristics, and post-operative outcomes were collected. The primary outcome was overall survival, which was examined by surgical type and tumor T stage. Multivariate logistic regression was utilized to identify predictors of survival. RESULTS In total, 1083 GCCs were included, and 81.8% underwent right hemicolectomy. Mean age was 57 years, and 89% were White. Patients undergoing hemicolectomy had higher T-stage tumors (66.6%/14.4% T3/T4 vs. 55.8%/8.1%, p

Objectives The objective of this study was to create a composite measure, optimal oncologic surgery (OOS), for patients undergoing distal pancreatectomy for pancreatic adenocarcinoma and identify factors associated with OOS. Methods Adult patients undergoing distal pancreatectomy were identified from the National Cancer Database between 2010 and 2016. Patients were stratified based on receipt of OOS. Criteria for OOS included 90-day survival, no 30-day readmission, length of stay ≤7 days, negative resection margins, ≥12 lymph nodes harvested, and receipt of chemotherapy. Multivariate logistic regression was performed to identify predictors of OOS. Survival curves and a Cox proportional hazards model were created to compare survival and identify risk factors for mortality. Results Three thousand five hundred forty-six patients were identified. The rate of OOS was 22.3%. Diagnosis after 2012, treatment at an academic medical center, and a minimally invasive surgical approach (MIS) were associated with OOS. Survival was superior for patients undergoing OOS. Decreasing age at diagnosis, fewer comorbidities, surgery at an academic medical center, MIS, and lower pathologic stage were also associated with improved survival on multivariate analysis. Conclusions Rates of OOS for distal pancreatectomy are low. Time trends show increasing rates of OOS that may be related to increasing MIS, adjuvant chemotherapy, and referrals to academic medical centers.

To compare the rate of postoperative 30-day complications between laparoscopic and robotic pancreaticoduodenectomy.Previous studies suggest that minimally invasive pancreaticoduodenectomy (MI-PD) - either laparoscopic (LPD) or robotic (RPD) - is non-inferior to open PD in terms of operative outcomes. However, a direct comparison of the two minimally invasive approaches has not been rigorously performed.Patients who underwent MI-PD were abstracted from the 2014-2019 pancreas-targeted ACS NSQIP dataset. Optimal outcome was defined as absence of postoperative mortality, serious complication, percutaneous drainage, reoperation, and prolonged length of stay (75th percentile, 11▒d) with no readmission. Multivariable logistic regression models were used to compare optimal outcome of RPD and LPD.1,540 MI-PDs were identified between 2014-2019, of which 885 (57%) were RPD and 655 (43%) were LPD. The rate of RPD cases/year significantly increased from 2.4% to 8.4% (P=0.008) from 2014-2019, while LPD remained unchanged. Similarly, the rate of optimal outcome for RPD increased during the study period from 48.2% to 57.8% (P0.001) but significantly decreased for LPD (53.5% to 44.9%, P0.001). During 2018-2019, RPD outcomes surpassed LPD for any complication (OR 0.58, P=0.004), serious complications (OR 0.61, P=0.011), and optimal outcome (OR 1.78, P=0.001).RPD adoption increased compared to LPD and was associated with decreased overall complications, serious complications, and increased optimal outcome compared to LPD in 2018-2019.

Activities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients METHOD: A single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis.742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56-0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53-0.86],p = 0.002) for overall survival.In this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

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. 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. 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. 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.

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.

Background Open extended cholecystectomy (O-EC) has long been the recommended treatment for resectable gallbladder cancer (GBC), while the minimally-invasive approach for EC (MIS-EC) remains controversial. Our aim was to analyze overall survival of GBC patients treated with MIS-EC vs O-EC at the national level. Methods A retrospective review of the National Cancer Database of patients with resectable GBC (2010-2016) and treated with either MIS-EC or O-EC was performed. Overall survival (OS) was compared by the surgical approach. Results A total of 680 patients were identified, of whom 235 (34.6%) underwent MIS-EC. There were no differences in the rates of positive margins between MIS-EC and O-EC (14% vs 19%, respectively; P = .278), and in the mean lymph node yield (6.54 vs 6.66, respectively; P = .914). The median survival following MIS-EC was significantly higher than that of O-EC (39 vs 26 months; P = .048). After stratification by pathological stage and after adjustment, there was no significant difference in OS between the groups (HR = 0.9, 95% CI, 0.6-1.5). Conclusion In this large national cohort, MIS-EC oncologic outcomes were noninferior to the O-EC. Proficiency with MIS techniques, proper patient selection, and referral to specialized centers may allow a greater benefit from this treatment modality.

The robotic platform is increasingly being utilized in pancreatic surgery, yet its overall merits and putative advantages remain to be adjudicated. We hypothesize that the benefits of minimally invasive pancreatic surgery are maximized in pancreatic benign and premalignant disease, in the setting of friable pancreatic tissue and small pancreatic duct.Retrospective analysis of our prospectively maintained pancreatic database of all consecutive patients who underwent pancreaticoduodenectomy (PD) for benign or premalignant conditions between 2010 and 2020. Peri-operative outcomes and long-term complications were compared between robotic pancreaticoduodenectomy (RPD) and open pancreaticoduodenectomy (OPD).One hundred and eighty eight (n = 188) patients met our inclusion criteria, of which 68 were OPD and 120 RPD. Malignant histologies were excluded. There were only minor differences in baseline characteristics between the two groups. Post-operative merits of the RPD included lower clinically relevant post-operative pancreatic fistula 10 (8.3%) vs 24 (35.3%), p 0.001, fewer surgical site infections; 9 (7.5%) vs 11 (16.2%), p = 0.024, shorter operative time, greater lymph node yield; 29 (IQR 21, 38) vs 21 (IQR 13, 34), p = 0.001, and lower 90 days mortality; 1 (0.8%) vs 4 (5.9%), p = 0.039. Rates of long-term complications were similar, exception made for a higher occurrence of small bowel obstruction (SBO) 2 (1.7%) vs 4 (5.9%), p = 0.031 and need for surgical intervention for SBO 0 (0.0%) vs 2 (2.9%), p = 0.019 in the OPD group.Our study suggests that RPD benefits include lower 90-day mortality, shorter LOS, and lower rates of selected complications compared to open pancreaticoduodenectomy.

In contrast to pancreatic ductal adenocarcinoma (PDAC), neoadjuvant therapy (NAT) for periampullary adenocarcinomas is not well studied, with data limited to single-institution retrospective reviews with small cohorts. We sought to compare outcomes of NAT versus upfront resection (UR) for non-PDAC periampullary adenocarcinomas.Using the National Cancer Database (NCDB), we identified patients who underwent surgery for extrahepatic cholangiocarcinoma, ampullary adenocarcinoma, or duodenal adenocarcinoma from 2006 to 2016. We compared outcomes between NAT versus UR groups for each tumor subtype with 1:3 propensity score matching. Cox regression was used to identify predictors of survival.Among 7656 patients who underwent resection for non-PDAC periampullary adenocarcinoma, the proportion of patients who received NAT increased from 6 to 11% for cholangiocarcinoma (p0.01), 1 to 4% for ampullary adenocarcinoma (p = 0.01), and 5 to 8% for duodenal adenocarcinoma (p = 0.08). Length of stay, readmission, and 30-day mortality were comparable between NAT and UR. All tumor subtypes were downstaged following NAT (p0.01). The R0 resection rate was significantly higher in patients with extrahepatic cholangiocarcinoma who received NAT, and these patients had improved median overall survival (38 vs 26 months, p0.001). After adjustment for clinicopathologic factors and adjuvant chemotherapy, use of NAT was associated with improved survival in patients with cholangiocarcinoma [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.54-0.89, p = 0.004] but not duodenal or ampullary adenocarcinoma. The survival advantage for cholangiocarcinoma persisted after propensity matching.This national cohort analysis suggests, for the first time, that neoadjuvant therapy is associated with improved survival in patients with extrahepatic cholangiocarcinoma.

ImportanceNeoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT).ObjectivesTo examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS).Design, Setting, and ParticipantsA retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology.ExposuresPatients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT.Main Outcomes and MeasuresThe association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis.ResultsIn this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04).Conclusions and RelevanceThe findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.

Drain management algorithms are based on studies that predict clinically relevant postoperative pancreatic fistula (CR-POPF) using drain fluid amylase level on POD1 (DFA1). These studies are focused on pancreaticoduodenectomy which is inherently different than distal pancreatectomy. Moreover, the change of DFA between POD1 and POD3 (ΔDFA) is underutilized despite its importance in predicting CR-POPF. We sought to generate a calculator that estimates the risk of CR-POPF following distal pancreatectomy.The 2014-2018 pancreas-targeted ACS-NSQIP database was used to identify patients who underwent elective distal pancreatectomy. Models to predict CR-POPF were constructed using DFA1 with/without ΔDFA. The fittest model was used to construct a calculator.Out of 12,042 distal pancreatectomies, 692 patients met the study's inclusion criteria. The risk of CR-POPF was 15.9% in the included cohort versus 14.8% in the excluded one (P = 0.421). The predictors of the CR-POPF were age, operative time, DFA1, and ΔDFA. Adding ΔDFA decreased the Akaike's information criterion of the model (507.7 vs 544.7)-indicating a significantly better model fit-and improved the cross-validated area under the curve from 0.731 to 0.791. An easy-to-use calculator was created for surgeons to estimate the risk of CR-POPF based on the abovementioned variables. A sensitivity/specificity table was created at various cutoffs to direct clinical decision-making with respect to early drain removal.This study highlights the importance of ΔDFA, in addition to DFA1, in predicting CR-POPF. The provided calculator will facilitate predicting CR-POPF and postoperative drain management following distal pancreatectomy.

Right hemicolectomy is recommended for appendiceal adenocarcinoma but may not be needed for early stage disease.This study aimed to determine whether appendectomy offers adequate oncologic outcomes for T1 appendiceal adenocarcinoma from a national cohort of patients.Patients with T1 appendiceal adenocarcinoma (mucinous and nonmucinous histology) treated with either a right hemicolectomy or appendectomy between 2004 and 2016 were retrieved. Multivariate Cox regression analysis was used to identify predictors of overall survival.The study was conducted using a national cancer database.A total of 320 patients (median age, 62 y; 47% women) were identified: 69 (22%) underwent an appendectomy and 251 (78%) underwent a right hemicolectomy.Overall survival was measured.Nonmucinous adenocarcinoma was identified in 194 (61%), whereas 126 (39%) had mucinous adenocarcinoma. Of the overall cohort, 43% had well-differentiated histology, 39% had moderately differentiated disease, and 4% had poorly differentiated tumors. The rate of lymph node metastasis was lower in well-differentiated tumors (3%) compared with moderately (10%) or poorly differentiated tumors (25%). On univariate survival analysis, right hemicolectomy was associated with improved 1-, 3-, and 5-year overall survival in patients with moderately/poorly differentiated disease ( p0.001) but not for well-differentiated disease ( p = 1.000). After adjustment, right hemicolectomy was associated with overall survival improvement for moderately/poorly differentiated T1 adenocarcinoma (HR = 0.26 [95% CI, 0.08-0.82]; p = 0.02) but not for well-differentiated disease.This study was limited by its retrospective nature.The current analysis from the National Cancer Database demonstrates that appendectomy is associated with equivalent survival to right hemicolectomy for well-differentiated T1 adenocarcinoma, whereas for moderately and poorly differentiated disease, right hemicolectomy is oncologically superior to appendectomy. See Video Abstract at http://links.lww.com/DCR/B689 .ANTECEDENTES:La hemicolectomía derecha se recomienda para el adenocarcinoma apendicular, pero puede no ser necesaria para la enfermedad en estadio temprano.OBJETIVO:Este estudio tuvo como objetivo determinar si la apendicectomía ofrece resultados oncológicos adecuados para el adenocarcinoma apendicular T1 de una cohorte nacional de pacientes.DISEÑO:Se recuperaron pacientes con adenocarcinoma apendicular T1 (histología mucinoso y no mucinoso) tratados con hemicolectomía derecha o apendicectomía entre 2004-2016. Se utilizó un análisis de regresión de Cox multivariante para identificar los predictores de la supervivencia global.ENTORNO CLÍNICO:Base de datos nacional sobre cáncer.PACIENTES:Se identificaron un total de 320 pacientes (mediana de edad 62 años, 47% mujeres): 69 (22%) se sometieron a una apendicectomía y 251 (78%) se sometieron a una hemicolectomía derecha.PRINCIPAL MEDIDA DE RESULTADO:Sobrevida global.RESULTADOS:Se identificó adenocarcinoma no mucinoso en 194 (61%) mientras que 126 (39%) tenían adenocarcinoma mucinoso. De la cohorte general, el 43% tenía una histología bien diferenciada, el 39% tenía una enfermedad moderadamente diferenciada y el 4% tenía tumores poco diferenciados. La tasa de metástasis en los ganglios linfáticos fue menor en los tumores bien diferenciados (3%) en comparación con los tumores moderadamente (10%) o pobremente diferenciados (25%). En el análisis de sobrevida univariante, la hemicolectomía derecha se asoció con una mejor sobrevida general a 1, 3, y 5 años en pacientes con enfermedad moderada / pobremente diferenciada ( p0,001) pero no para la enfermedad bien diferenciada ( p = 1,000). Después del ajuste, la hemicolectomía derecha se asoció con una mejora de la sobrevida general para el adenocarcinoma T1 moderadamente / poco diferenciado (HR = 0,26, IC del 95%: 0,08-0,82, p = 0,02) pero no para la enfermedad bien diferenciada.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva.CONCLUSIONES:El análisis actual de la base de datos nacional de cáncer demuestra que la apendicectomía se asocia con una sobrevida similar a la hemicolectomía derecha para el adenocarcinoma T1 bien diferenciado, mientras que para la enfermedad moderada y pobremente diferenciada, la hemicolectomía derecha es oncológicamente superior a la apendicectomía. Consulte Video Resumen en http://links.lww.com/DCR/B689 . (Traducción-Dr. Yazmin Berrones-Medina ).

BACKGROUND AND OBJECTIVES Neoadjuvant chemotherapy (NAT) for pancreatic adenocarcinoma (PDAC) is increasingly being utilized. However, a significant number of patients will experience early recurrence, possibly negating the benefit of surgery. We aimed to identify factors implicated in early disease recurrence. METHODS A retrospective review of pancreaticoduodenectomies performed between 2005 and 2017 at our institution for PDAC following NAT was performed. A 6-month cut-off was used to stratify patients into early/late recurrence groups. Multivariate analysis was performed to identify predictors of recurrence. RESULTS Of 273 patients, 64 (23%) developed early recurrence or died within 90 days of surgery. The median time to recurrence was 4 months (95% confidence interval [CI]: 2.2-4.3) in the early group versus 16 months (95% CI: 13.7-19.9) in the late group. The former had higher baseline and post-NAT Ca19-9 levels than the latter (472 vs. 153 IU/ml, p = 0.001 and 71 vs. 39 IU/ml, p = 0.005, respectively). A higher positive lymph node ratio significantly increased the risk of early recurrence (hazard ratio [HR]: 15.9, p

Neoadjuvant therapy is increasingly used in localized pancreatic carcinoma, and survival is correlated with carbohydrate antigen 19-9 (CA19-9) levels and histopathologic response following neoadjuvant therapy. With several regimens now available, the choice of chemotherapy could be best dictated by response to neoadjuvant therapy (as measured by CA19-9 levels and/or pathologic response), a strategy defined herein as adaptive dynamic therapy.To evaluate the association of adaptive dynamic therapy with oncologic outcomes in patients with surgically resected pancreatic cancer.This retrospective cohort study included patients with localized pancreatic cancer who were treated with either gemcitabine/nab-paclitaxel or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) preoperatively between 2010 and 2019 at a high-volume tertiary care academic center. Participants were identified from a prospectively maintained database and had a median follow-up of 49 months. Data were analyzed from October 17 to November 24, 2020.The adaptive dynamic therapy group included 219 patients who remained on or switched to an alternative regimen as dictated by CA19-9 response and for whom the adjuvant regimen was selected based on CA19-9 and/or pathologic response. The nonadaptive dynamic therapy group included 103 patients who had their chemotherapeutic regimen selected independent of CA19-9 and/or tumoral response.Prognostic implications of dynamic perioperative therapy assessed through Kaplan-Meier analysis, Cox regression, and inverse probability weighted estimators.A total of 322 consecutive patients (mean [SD] age, 65.1 [9] years; 162 [50%] women) were identified. The adaptive dynamic therapy group, compared with the nonadaptive dynamic therapy group, had a more pronounced median (IQR) decrease in CA19-9 levels (-80% [-92% to -56%] vs -45% [-81% to -13%]; P .001), higher incidence of complete or near-complete tumoral response (25 [12%] vs 2 [2%]; P = .007), and lower median (IQR) number of lymph node metastasis (1 [0 to 4] vs 2 [0 to 4]; P = .046). Overall survival was significantly improved in the dynamic group compared with the nondynamic group (38.7 months [95% CI, 34.0 to 46.7 months] vs 26.5 months [95% CI, 23.5 to 32.9 months]; P = .03), and on adjusted analysis, dynamic therapy was independently associated with improved survival (hazard ratio, 0.73; 95% CI, 0.53 to 0.99; P = .04). On inverse probability weighted analysis of 320 matched patients, the average treatment effect of dynamic therapy was to increase overall survival by 11.1 months (95% CI, 1.5 to 20.7 months; P = .02).In this cohort study that sought to evaluate the role of adaptive dynamic therapy in localized pancreatic cancer, selecting a chemotherapeutic regimen based on response to preoperative therapy was associated with improved survival. These findings support an individualized and in vivo assessment of response to perioperative therapy in pancreatic cancer.

Appendiceal goblet cell adenocarcinomas (GCC) are rare tumors with clinical behavior between classic carcinoids and adenocarcinomas. Current guidelines recommend right hemicolectomy for all GCCs.The National Cancer Database was retrospectively queried for appendiceal GCCs undergoing appendectomy or right hemicolectomy between 2004 and 2016. Demographics, tumor characteristics, and post-operative outcomes were collected. The primary outcome was overall survival, which was examined by surgical type and tumor T stage. Multivariate logistic regression was utilized to identify predictors of survival.In total, 1083 GCCs were included, and 81.8% underwent right hemicolectomy. Mean age was 57 years, and 89% were White. Patients undergoing hemicolectomy had higher T-stage tumors (66.6%/14.4% T3/T4 vs. 55.8%/8.1%, p 0.001). Lymph node positivity increased with T stage (1.1%, 2.1%, 9.9%, and 29.1% for T1-T4). GCCs undergoing colectomy were more frequently moderately or poorly differentiated (16.7%/9.0% vs. 12.2%/6.6%, p = 0.011). Appendectomy surgical margins were positive in 17.3% (3.4% hemicolectomy, p 0.001). In T3/T4 tumors, a significant survival benefit at 5 years was observed in patients undergoing colectomy as compared with appendectomy (85.4% vs. 82.0%, p = 0.028). On multivariate analysis, lymph node positivity markedly decreased survival overall for the entire cohort (HR 7.58, p 0.001) and for T3/T4 tumors (HR 7.63, p 0.001). In patients with T3/T4 tumors, there was a trend towards improved survival with right hemicolectomy (HR 0.42, p = 0.068).Omitting right hemicolectomy can be considered for select T1/T2 appendiceal GCCs with negative appendectomy margins, given low rates of lymph node metastases and lack of survival benefit with right hemicolectomy.

Although laparoscopic cholecystectomy is the gold standard treatment for benign gallbladder disease, a number of conditions have been repetitively shown to be associated with an increased risk of conversion to the open approach. These include several disease-related and patient-related factors such as advanced age, severe acute cholecystitis, a history of multiple abdominal operations, and comorbidities. Although preoperative identification is crucial for proper patient selection and treatment algorithm, the verdict to convert is primarily deemed on the intraoperative surgeon decision as a safe “bailout” technique. This chapter aims to review the conditions that have been shown to consistently increase the risk of conversion, as well as highlight the importance of conversion as wise approach in the difficult cholecystectomy case where the risks of continuing with the laparoscopic cholecystectomy clearly outweigh the morbidity that comes with conversion to open.

Robotic pancreaticoduodenectomy (RPD) is performed for resectable periampullary lesions with comparable outcomes to the open approach.1 Surgical therapy for borderline-resectable (BR) pancreatic tumors is technically challenging and poses a significant risk of bleeding and positive margins.2 As experience with RPD grows at high-volume centers, case selection can be carefully expanded to include complex vascular resections.3 We demonstrate a RPD performed for BR pancreatic adenocarcinoma with portal vein (PV) involvement and presence of anomalous hepatic arterial anatomy. A 75-year-old female presented with abdominal pain and obstructive jaundice. She was previously healthy and had a relatively normal body mass index (25.7 kg/m2). Endoscopic ultrasound and computed tomography imaging identified a pancreatic head mass measuring 2.3 cm with evidence of concomitant abutment of the PV (90–180 degree) and abutment of a replaced right hepatic artery (rRHA) originating from the superior mesenteric artery (SMA). Following four cycles of neoadjuvant gemcitabine/nab-paclitaxel, restaging imaging demonstrated partial radiographic response, represented by a lesser degree of PV abutment and resolution of rRHA abutment. RPD was performed with side-bite resection of the PV and preservation of rRHA. The video demonstrates the key steps followed in a robotic pancreaticoduodenectomy performed for a technically challenging pancreatic head cancer and highlights robotic control of bleeding from the PV and SMA obviating the need for conversion. Histopathology revealed a residual moderately differentiated ductal adenocarcinoma with 4-of-40 positive lymph nodes and negative surgical margins. The tumor was staged as ypT1cN2 (AJCC 8th edition). The patient had an uneventful postoperative course and was discharged on hospital day 8. In high-volume centers, the robotic approach can be safely used in selected cases of technically challenging BR pancreatic head cancers.

Goblet cell carcinoids (GCC) are an aggressive, albeit rare, subtype of appendiceal tumors that exhibit distinct histologic features and lack clear treatment guidelines. We aimed to ascertain the impact of adjuvant chemotherapy (AC) for GCC in a national cohort of patients.Patients who underwent a right hemicolectomy for stage I-III GCC of the appendix between 2006 and 2016 were selected from the National Cancer Database (NCDB). Stratification based on AC receipt was performed. Kaplan-Meier survival estimates and Cox proportional hazard regression were used to identify predictors of overall survival (OS).A total of 867 patients were identified, of whom 124 (14%) received AC. Patients in the AC group were significantly younger (54 vs. 57 years; p = 0.006) and were predominantly of male sex (60 vs. 48%; p = 0.012). On histopathology, patients in the AC group had a higher proportion of poorly/undifferentiated grade (27 vs. 5%; p 0.001), T4 disease (35 vs. 11%; p 0.001), and lymph node-positive disease (45 vs. 7%; p 0.001) than patients who did not receive AC. After excluding patients diagnosed in 2016 due to a lack of follow-up data (n = 162), a survival advantage for the AC group was detected only after stratification for lymph node-positive disease (p = 0.007). On Cox proportional hazard regression, AC demonstrated an independent association with improved OS (hazard ratio 0.24, 95% confidence interval 0.084-0.683; p = 0.007).The current analysis from the NCDB supports the role of AC for GCC of the appendix, chiefly for patients with lymph node metastatic disease.

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.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.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.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.

PURPOSE/OBJECTIVE(S) Loss of the tumor suppressor gene SMAD4 is a critical genetic alteration in pancreatic carcinoma (PC). We hypothesized that SMAD4 status in PC is associated with outcomes in patients who received neoadjuvant (NARx) or adjuvant (ARx) radiotherapy. MATERIALS/METHODS PC patients who underwent surgical resection at two high-volume centers following NARx-or those treated with ARx-between 2008-2019 were identified. SMAD4 status was determined based on immunohistochemical staining and classified as preserved (SMAD4+) or lost (SMAD4-). Kaplan-Meier survival estimates and multivariate analysis were used to analyze correlations between SMAD4 status, radiation therapy, and clinical outcome measures. RESULTS A total of 290 patients (mean age at diagnosis 66 years, 51% female) were identified; 131 (45%) were SMAD4+ and 159 (55%) SMAD4-. Resectable disease was diagnosed in 95 (33%) and borderline-resectable disease in 166 (57%); 29 patients (10%) had locally-advanced disease. NARx was administered in 147 (51%) in combination with chemotherapy while 143 (49%) received ARx; 26 (18%) of which received ARx solely. NARx in SMAD4- PC was associated with a significantly increased incidence of near-complete/complete histopathologic response and reduced incidence of none/poor response compared to SMAD4- PC not treated with NARx (12% vs 2% and 44% vs 19% respectively, P = 0.001). On adjusted analysis, NARx was a significant predictor of histopathologic response in SMAD4- patients (HR: 3.5, 95% CI 1.6-7.6, P < 0.001) while no association was seen for SMAD4+ PC. Neither radiation therapy receipt nor SMAD4 status were associated with overall survival (OS). Yet, SMAD4- PC had a worsened disease-free survival (DFS) compared to SMAD4+ PC (19 vs 16 months, P = 0.03). This difference persisted even among patients who had received NARx (21 vs 16 months, P = 0.04) and those with histopathologic treatment response (24 vs 16 months, P = 0.031). No difference in DFS between SMAD4- and SMAD4+ PC was identified in the ARx group. Lastly, NARx, significantly improved local-recurrence free survival in SMAD4+ PC but not in SMAD4- PC (33 vs 21 months, P = 0.047). CONCLUSION `Outcomes following surgical resection for PC remain primarily driven by SMAD4 status irrespective of radiation therapy timing (NARx vs ARx). However, this analysis suggests that SMAD4 status may help identify a subset of patients who are most likely to benefit from NARx.

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.