Prophylactic Antibiotic Duration and Infectious Complications in Pancreatoduodenectomy Patients With Biliary Stents: Opportunity for De-escalation.

OBJECTIVE: The aim of this study was to compare infectious complications in pancreatoduodenectomy (PD) patients with biliary stents treated with short, medium, or long durations of prophylactic antibiotics. BACKGROUND: Pre-existing biliary stents have historically been associated with higher infection risk after PD. Patients are administered prophylactic antibiotics, but the optimal duration remains unknown. METHODS: This single-institution retrospective cohort study included consecutive PD patients from October 2016 to April 2022. Antibiotics were continued past the operative dose per surgeon discretion. Infection rates were compared by short (≤24 h), medium (>24 but ≤96 h), and long (>96 h) duration antibiotics. Multivariable regression analysis was performed to evaluate associations with a primary composite outcome of wound infection, organ-space infection, sepsis, or cholangitis. RESULTS: Among 542 PD patients, 310 patients (57%) had biliary stents. The composite outcome occurred in 28% (34/122) short, 25% (27/108) medium, and 29% (23/80) long-duration ( P =0.824) antibiotic patients. There were no differences in other infection rates or mortality. On multivariable analysis, antibiotic duration was not associated with infection rate. Only postoperative pancreatic fistula (odds ratio 33.1, P <0.001) and male sex (odds ratio 1.9, P =0.028) were associated with the composite outcome. CONCLUSIONS: Among 310 PD patients with biliary stents, long-duration prophylactic antibiotics were associated with similar composite infection rates to short and medium durations but were used almost twice as often in high-risk patients. These findings may represent an opportunity to de-escalate antibiotic coverage and promote risk-stratified antibiotic stewardship in stented patients by aligning antibiotic duration with risk-stratified pancreatectomy clinical pathways.

Trends Over Time in Recurrence Patterns and Survival Outcomes after Neoadjuvant Therapy and Surgery for Pancreatic Cancer.

OBJECTIVE: We aimed to determine if advances in neoadjuvant therapy affected recurrence patterns and survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Data are limited on how modern multimodality therapy affects PDAC recurrence and post-recurrence survival. METHODS: Patients who received neoadjuvant therapy followed by curative-intent pancreatectomy for PDAC during 1998-2018 were identified. Treatments, recurrence sites and timing, and survival were compared between patients who completed neoadjuvant therapy and pancreatectomy in 1998-2004, 2005-2011, and 2012-2018. RESULTS: The study included 727 patients (203, 251, and 273 in the 1998-2004, 2005-2011, and 2012-2018 cohorts, respectively). Use of neoadjuvant induction chemotherapy increased over time, and regimens changed over time, with >80% of patients treated in 2012-2018 receiving FOLFIRINOX or gemcitabine with nab-paclitaxel. Overall, recurrence sites and incidence (67.5%, 66.1%, and 65.9%) remained stable, and 85% of recurrences occurred within 2 years of surgery. However, compared to earlier cohorts, the 2012-2018 cohort had lower conditional risk of recurrence in postoperative year 1 and higher risk in postoperative year 2. Overall survival increased over time (median, 30.6, 33.6, and 48.7 mo, P < 0.005), driven by improved post-recurrence overall survival (median, 7.8, 12.5, and 12.6 mo; 3-year rate, 7%, 10%, and 20%; P < 0.005). CONCLUSIONS: We observed changes in neoadjuvant therapy regimens over time and an associated shift in the conditional risk of recurrence from postoperative year 1 to postoperative year 2, although recurrence remained common. Overall survival and post-recurrence survival remarkably improved over time, reflecting improved multimodality regimens for recurrent disease.

Serum CEA as a Prognostic Marker for Overall Survival in Patients with Localized Pancreatic Adenocarcinoma and Non-Elevated CA19-9 Levels Treated with FOLFIRINOX as Initial Treatment: A TAPS Consortium Study.

INTRODUCTION: About 25% of patients with localized pancreatic adenocarcinoma have non-elevated serum carbohydrate antigen (CA) 19-9 levels at baseline, hampering evaluation of response to preoperative treatment. Serum carcinoembryonic antigen (CEA) is a potential alternative. METHODS: This retrospective cohort study from five referral centers included consecutive patients with localized pancreatic adenocarcinoma (2012-2019), treated with one or more cycles of (m)FOLFIRINOX, and non-elevated CA19-9 levels (i.e., < 37 U/mL) at baseline. Cox regression analyses were performed to assess prognostic factors for overall survival (OS), including CEA level at baseline, restaging, and dynamics. RESULTS: Overall, 277 patients were included in this study. CEA at baseline was elevated (≥5 ng/mL) in 53 patients (33%) and normalized following preoperative therapy in 14 patients (26%). In patients with elevated CEA at baseline, median OS in patients with CEA normalization following preoperative therapy was 33 months versus 19 months in patients without CEA normalization (p = 0.088). At time of baseline, only elevated CEA was independently associated with (worse) OS (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.04-1.98). At time of restaging, elevated CEA at baseline was still the only independent predictor for (worse) OS (HR 1.44, 95% CI 1.04-1.98), whereas elevated CEA at restaging (HR 1.16, 95% CI 0.77-1.77) was not. CONCLUSIONS: Serum CEA was elevated in one-third of patients with localized pancreatic adenocarcinoma having non-elevated CA19-9 at baseline. At both time of baseline and time of restaging, elevated serum CEA measured at baseline was the only predictor for (worse) OS. Therefore, serum CEA may be a useful tool for decision making at both initial staging and time of restaging in patients with non-elevated CA19-9.

Impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX: Trans-Atlantic Pancreatic Surgery (TAPS) Consortium study.

BACKGROUND: Surgery in selected patients with locally advanced pancreatic cancer after induction chemotherapy may have drawbacks related to surgical risks and breaks or delays in oncological treatment, in particular when curative intent resection is not possible (that is non-therapeutic laparotomy). The aim of this study was to assess the incidence and oncological impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX chemotherapy. METHODS: This was a retrospective international multicentre study including patients diagnosed with pathology-proven locally advanced pancreatic cancer treated with at least one cycle of (m)FOLFIRINOX (2012-2019). Patients undergoing a non-therapeutic laparotomy (group A) were compared with those not undergoing surgery (group B) and those undergoing resection (group C). RESULTS: Overall, 663 patients with locally advanced pancreatic cancer were included (67 patients (10.1%) in group A, 425 patients (64.1%) in group B, and 171 patients (25.8%) in group C). A non-therapeutic laparotomy occurred in 28.2% of all explorations (67 of 238), with occult metastases in 30 patients (30 of 67, 44.8%) and a 90-day mortality rate of 3.0% (2 of 67). Administration of palliative therapy (65.9% versus 73.1%; P = 0.307) and median overall survival (20.4 [95% c.i. 15.9 to 27.3] versus 20.2 [95% c.i. 19.1 to 22.7] months; P = 0.752) did not differ between group A and group B respectively. The median overall survival in group C was 36.1 (95% c.i. 30.5 to 41.2) months. The 5-year overall survival rates were 11.4%, 8.7%, and 24.7% in group A, group B, and group C, respectively. Compared with group B, non-therapeutic laparotomy (group A) was not associated with reduced overall survival (HR = 0.88 [95% c.i. 0.61 to 1.27]). CONCLUSION: More than a quarter of surgically explored patients with locally advanced pancreatic cancer after induction (m)FOLFIRINOX did not undergo a resection. Such non-therapeutic laparotomy does not appear to substantially impact oncological outcomes.

Prognosis Associated With CA19-9 Response Dynamics and Normalization During Neoadjuvant Therapy in Resected Pancreatic Adenocarcinoma.

OBJECTIVE: To characterize associations between carbohydrate antigen 19-9 (CA19-9) dynamics during neoadjuvant therapy (NT) and survival for patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Although normalization of CA19-9 during NT is associated with improved outcomes following PDAC resection, we hypothesize that CA19-9 dynamics during NT can improve prognostication. METHODS: Characteristics for patients with PDAC undergoing NT (July 2011-October 2018) with ≥3 CA19-9 results (bilirubin<2mg/dL) were collected and grouped by CA19-9 dynamics. Nonproducers (<1 U/ml) were excluded, and normal was ≤35 U/ml. Postresection survival was compared among groups. RESULTS: Of 431 patients, 166 had eligible CA19-9 values. Median baseline CA19-9 was 98 U/ml. Overall 2-year postresection recurrence-free survival (RFS) and overall survival (OS) were 37% and 63%, respectively. Patients with normalization (53%) had improved 2-year RFS (47% vs. 28%, P = 0.01) and OS (75% vs. 49%, P = 0.01). CA19-9 dynamics during NT were analyzed by shape, direction, and normalization creating response types ("A-B-C-D-E"). Type A was "Always" decreasing to normalization, B "Bidirectional" with eventual normalization, C "Consistently" normal, D any "Decrease" without normalization, and E "Elevating" without normalization. Types A and B responses were associated with the longest postresection 2-year RFS (51% and 56%) and OS (75% and 92%, respectively) whereas Types D and E had the worst outcomes. After adjusting for node-positivity, perineural invasion, and margin-positivity, CA19-9 response types were independently associated with both RFS and OS, and predicted outcomes are better than CA19-9 normalization alone (likelihood ratio test RFS P < 0.001, OS P = 0.01). CONCLUSIONS: This novel A-B-C-D-E classification of CA19-9 dynamics during NT was associated with postresection outcomes more precisely than CA19-9 normalization alone.

Classification of Post-Pancreatectomy Readmissions and Opportunities for Targeted Mitigation Strategies.

OBJECTIVE: Within a learning health system paradigm, this study sought to evaluate reasons for readmission to identify opportunities for improvement. SUMMARY BACKGROUND DATA: Post-pancreatectomy readmission rates have remained constant despite improved index hospitalization metrics. METHODS: We performed a single-institution case-control study of consecutive pancreatectomy patients (October 2016 - April 2022). Complications were prospectively graded in biweekly faculty and advanced practice provider meetings. We analyzed risk factors during index hospitalization and categorized indications for 90-day readmissions. RESULTS: A total of 835 patients, median age 65 years and 51% (427/835) males, underwent 64% (534/835) pancreatoduodenectomies, 34% (280/835) distal pancreatectomies, and 3% (21/835) other resections. 24% (204/835) of patients were readmitted. Primary indication for readmission was technical in 51% (105/204), infectious in 17% (35/204), and medical/metabolic in 31% (64/204) of patients. Procedures were required in 77% (81/105) and 60% (21/35) of technical and infectious readmissions, respectively, while 66% (42/64) of medical/metabolic readmissions were managed non-invasively. During the index hospitalization, benign pathology (OR 1.8, P=0.049), biochemical pancreatic leak (OR 2.3, P=0.001), bile/gastric/chyle leak (OR 6.4, P=0.001), organ-space infection (OR 3.4, P=0.007), undrained fluid on imaging (OR 2.4, P=0.045), and increasing white blood cell count (OR 1.7, P=0.045) were independently associated with odds of readmission. CONCLUSIONS: Most readmissions following pancreatectomy were technical in origin. Patients with complications during index hospitalization, increasing white blood cell count, or undrained fluid before discharge were at highest risk for readmission. Pre-discharge risk-stratification of readmission risk factors and augmentation of in-clinic resources may be strategies to reduce readmission rates.

Effects of a Pragmatic Home-based Exercise Program Concurrent With Neoadjuvant Therapy on Physical Function of Patients With Pancreatic Cancer: The PancFit Randomized Clinical Trial.

OBJECTIVE: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer. BACKGROUND: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer. METHODS: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was a 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included additional physical function tests, health-related quality of life, and clinical outcomes. RESULTS: One hundred fifty-one patients were randomized. Objectively measured weekly activity (153.2±135.6 and 159.8±122.8 min in Arm A and B, respectively, P =0.62) and self-reported weekly moderate-to-strenuous physical activity (107.4±160.4 and 129.6±161.6 min in Arm A and Arm B, respectively, P =0.49) were similar, but weekly strength training sessions increased more in Arm B (by 1.8±1.8 vs 0.1±2.4 sessions, P <0.001). 6MWD improved in both Arm A (mean change 18.6±56.8 m, P =0.01) and Arm B (27.3±68.1 m, P =0.002). Quality of life and clinical outcomes did not significantly differ between arms. Pooling patients in both study groups, exercise, and physical activity was favorably associated with physical performance and clinical outcomes. CONCLUSIONS: In this randomized trial of prescribed exercise versus enhanced usual care during neoadjuvant therapy for pancreatic cancer, a high volume of physical activity and increased exercise capacity were observed in both arms, highlighting the importance of activity among patients preparing for surgery.

Analysis of Opioid Use in Patients Undergoing Open Versus Robotic Gastrectomy.

BACKGROUND: Minimally invasive, robotic gastrectomy is associated with better short-term outcomes and quicker functional recovery. However, the degree to which the robotic approach influences postoperative pain and opioid use after gastrectomy is unknown. Our primary aim was to determine whether the robotic approach to gastrectomy reduces postoperative opioid use compared with the open approach. METHODS: Patients who underwent gastrectomy (November 2018 to September 2021) were identified retrospectively. Clinical characteristics, short-term surgical outcomes, oral morphine equivalent (OME) use, and pain scores were collected. Both groups were managed through an enhanced recovery program in the perioperative period. RESULTS: Of 81 patients, 50 underwent open and 31 underwent robotic gastrectomy. Compared with open gastrectomy patients, robotic gastrectomy patients had longer surgery time (360 vs. 288 min), less blood loss (50 vs. 138 mL), and shorter hospital stay (4 vs. 6 days) (all medians, P < 0.001). Robotic gastrectomy patients used lower OMEs on postoperative days 0-4 (all P < 0.05) and in total for days 0-4 (total mean dose 65.0 vs. 169.5 mg; P < 0.001) than did open gastrectomy patients. The robotic gastrectomy patients were prescribed a lower mean OME dose than the open gastrectomy patients (19.0 vs. 29.0 mg, respectively; P = 0.001). Multivariable analysis showed that robotic approach was associated with lower opioid use (odds ratio 3.70; 95% CI 1.01-14.3; P = 0.049). CONCLUSIONS: Compared with open gastrectomy, robotic gastrectomy reduces opioid use in the early postoperative period and is associated with fewer OME discharge prescriptions and shorter hospital stay.

Radiographic and Serologic Response to First-Line Chemotherapy in Unresected Localized Pancreatic Cancer.

BACKGROUND: This study aimed to determine the clinical relevance of putative radiographic and serologic metrics of chemotherapy response in patients with localized pancreatic cancer (LPC) who do not undergo pancreatectomy. Studies evaluating the response of LPC to systemic chemotherapy have focused on histopathologic analyses of resected specimens, but such specimens are not available for patients who do not undergo resection. We previously showed that changes in tumor volume and CA 19-9 levels provide a clinical readout of histopathologic response to preoperative therapy. METHODS: Our institutional database was searched for patients with LPC who were treated with first-line chemotherapy between January 2010 and December 2017 and did not undergo pancreatectomy. Radiographic response was measured using RECIST 1.1 and tumor volume. The volume of the primary tumor was compared between pretreatment and posttreatment images. The percentage change in tumor volume (%Δvol) was calculated as a percentage of the pretreatment volume. Serologic response was measured by comparing pretreatment and posttreatment CA 19-9 levels. We established 3 response groups by combining these metrics: (1) best responders with a decline in %Δvol in the top quartile and in CA 19-9, (2) nonresponders with an increase in %Δvol and in CA 19-9, and (3) other patients. RESULTS: This study included 329 patients. Individually, %Δvol and change in CA 19-9 were associated with overall survival (OS) (P≤.1), but RECIST 1.1 was not. In all, 73 patients (22%) were best responders, 42 (13%) were nonresponders, and there were 214 (65%) others. Best responders lived significantly longer than nonresponders and others (median OS, 24 vs 12 vs 17 months, respectively; P<.01). A multivariable model adjusting for type of chemotherapy regimen, number of chemotherapy doses, and receipt of radiotherapy showed that best responders had longer OS than did the other cohorts (hazard ratio [HR], 0.35; 95% CI, 0.21-0.58 for best responders, and HR, 0.55; 95% CI, 0.37-0.83 for others). CONCLUSIONS: Changes in tumor volume and serum levels of CA 19-9-but not RECIST 1.1-represent reliable metrics of response to systemic chemotherapy. They can be used to counsel patients and families on survival expectations even if pancreatectomy is not performed.

Neoadjuvant Radiotherapy After (m)FOLFIRINOX for Borderline Resectable Pancreatic Adenocarcinoma: A TAPS Consortium Study.

BACKGROUND: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. METHODS: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. RESULTS: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). CONCLUSIONS: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Association of Patient Controlled Analgesia and Total Inpatient Opioid Use After Pancreatectomy.

INTRODUCTION: The initial settings on an intravenous patient-controlled analgesia (IV-PCA) pump can represent a significant source of postoperative opioid exposure. The primary aim of this study was to evaluate the impact of first day IV-PCA use on total inpatient opioid use after open pancreatectomy, before and after standardization of initial dosing. METHODS: Inpatient oral morphine equivalents (OMEs) were reviewed for pancreatectomy patients treated with IV-PCA at a single institution before and after (3/2016-8/2017 versus 3/2019-11/2020) implementation of a standardized initial IV-PCA dosing regimen (initial limit 0.1 mg hydromorphone, or 1 mg OME, every 10 min as needed). IV-PCA OME in the first 24 h and the total inpatient OME were compared between cohorts. RESULTS: Of 220 total patients, 132 were in the prestandardization (PRE) historical cohort. A first-24-h IV-PCA use was different (PRE median 95 mg versus poststandardization [POST] 15 mg, P < 0.001). The median total inpatient OME was different (P < 0.001) between PRE (525 mg, interquartile range [IQR] 239-951 mg) and POST patients (129 mg, IQR 65-204 mg) with 77% (median 373 mg) of total inpatient OMEs contributed by IV-PCA in the PRE and 56% (median 64 mg) in the POST cohorts. There were similar patient-reported pain scores between groups. CONCLUSIONS: Standardizing initial IV-PCA settings was associated with a reduced first-24-h opioid exposure, proportional and absolute total IV-PCA use, and total inpatient OMEs. Because of the contribution of an IV-PCA to the total inpatient opioid exposure, purposeful reduction or omission of an IV-PCA is critical to perioperative opioid reduction strategies.

Prognostic significance of preoperative and postoperative CA 19-9 normalization in pancreatic adenocarcinoma treated with neoadjuvant therapy or surgery first.

BACKGROUND: Normal(ization) of serum carbohydrate 19-9 (CA19-9) before/after surgery has not been compared in patients with pancreatic adenocarcinoma (PDAC) treated with neoadjuvant therapy (NT) versus surgery-first (SF). METHODS: Characteristics for patients with PDAC who underwent resection from July 2011 to October 2018 were collected. Patients with pre-/postoperative CA19-9, bilirubin <2 mg/dL, and initial CA19-9 > 1 U/ml were included. Overall survival (OS) and recurrence-free survival (RFS) were compared by pre-/postoperative CA19-9. RESULTS: In patients receiving NT, normal pre/postoperative CA19-9 ("NTnl/nl ") was associated with median RFS and OS (26 and 77mo), followed by those who normalized after surgery ("NTabnl/nl " 16 and 44mo). For SF patients, normal pre-/postoperative CA19-9 ("SFnl/nl ") was associated with median RFS and OS (115 and not estimable mo), followed by those who normalized after resection ("SFabnl/nl " 18 and 49mo). Groups "NTabnl/abnl " and "SFabnl/abnl " with elevated CA19-9 both before and after resection had the worst median RFS and OS durations. CONCLUSIONS: While a normal(ized) postoperative CA19-9 may result in similar survival as preoperative normal(ization), postoperative normalization failed to occur in nearly 30% of SF patients. NT should be considered in patients presenting with elevated CA19-9. If considering SF, ideal patients may include those with normal CA19-9 at presentation.

Impact of Intraoperative Dexamethasone on Surgical and Oncologic Outcomes for Patients with Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Administration of dexamethasone to mitigate postoperative nausea and vomiting has been suggested to improve short- and long-term outcomes after pancreatic ductal adenocarcinoma (PDAC) resection. This study aimed primarily to evaluate these hypotheses in a contemporary patient cohort treated with multimodality therapy. METHODS: The clinicopathologic and perioperative characteristics of consecutive resected PDAC patients (July 2011 to October 2018) were analyzed from a prospectively maintained database. Intraoperative administration of dexamethasone (4-10 mg) was retrospectively abstracted from the electronic medical record. RESULTS: The majority of 373 patients (59.8%) received intraoperative dexamethasone. Most of these patients underwent neoadjuvant therapy (75.3%), were potentially resectable at presentation (69.7%), and underwent pancreaticoduodenectomy (79.9%). Women were more likely to receive dexamethasone than men (69.9 vs 30.1%; p < 0.001). The cohorts were otherwise clinically similar. Intraoperative dexamethasone was not associated with differences in postoperative major complications (PMCs) (21.1 vs 19.3%; p = 0.68), postoperative pancreatic fistulas (6.3 vs 6.7%; p = 0.88), or composite infectious complications (28.7 vs 24.7%; p = 0.39). Dexamethasone was not associated with any improvement in median recurrence-free survival (RFS) (17 vs 17 months; p = 0.99) or overall survival (OS) (46 vs 43 months; p = 0.90). After adjustment for clinical factors including margin status, clinical classification, tumor size, and dexamethasone, the only factors independently associated with OS were pathologic node-positivity (hazard ratio [HR], 1.80, 95% confidence interval [CI], 1.32-2.47), perineural invasion (HR, 2.02; 95% CI, 1.23-3.31), multimodality therapy (HR, 0.30; 95% CI, 0.13-0.70), and PMCs (HR, 1.64; 95% CI, 1.17-2.29) (all p < 0.006). CONCLUSIONS: Dexamethasone failed to demonstrate any protective advantage in terms of mitigating short-term PMCs or infectious complications, or to confer any long-term survival benefit. Tumor biology, multimodality therapy, and PMCs remain the main prognostic factors after PDAC resection.

GRP78 expression and prognostic significance in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant therapy versus surgery first.

BACKGROUND: Glucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported. METHODS: This retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival. RESULTS: GRP78 expression was higher in SF patients compared to NAT patients (P < 0.001). In SF cohort, the median disease-free survival (DFS) and overall survival (OS) for patients with GRP78-positive tumors were 11.2 months and 25.0 months, respectively, compared to DFS of 52.1 months (P = 0.008) and OS of 69.5 months (P = 0.02) for those with GRP78-negative tumors. GRP78 expression correlated with higher frequency of recurrent/metastasis (P = 0.045). In NAT cohort, GRP78 expression correlated with shorter OS (P = 0.03), but not DFS (P = 0.08). GRP78 expression was an independent prognosticator for both DFS (P = 0.02) and OS (P = 0.049) in SF cohort and was an independent prognosticator for OS (P = 0.03), but not for DFS (P = 0.06) in NAT cohort by multivariate analysis. CONCLUSIONS: Our study showed that GRP78 expression in NAT cohort is lower than that in SF cohort. GRP78 expression correlated with shorter survival in both SF and NAT patients. Our findings suggest that targeting GRP78 may help to improve the prognosis in PDAC patients.

Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival.

BACKGROUND: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear. METHODS: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4+, CD8+, CD21+ and CD45RO + tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs. RESULTS: CD73 overexpression correlated with poor differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.02) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4+ TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort. CONCLUSIONS: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4+, CD8+ and CD21+ TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.

Clinicopathological correlation of radiologic measurement of post-therapy tumor size and tumor volume for pancreatic ductal adenocarcinoma.

OBJECTIVES: Tumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival. MATERIALS AND METHODS: Retrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant. RESULTS: As a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P < 0.001) and RadV (δ: 0.63, p < 0.0001). However, there was no correlation between RadL and pathologic tumor size in patients with ypT0 and those with pathologic tumor size of ≤1.0 cm. Post-therapy RTS and RadV group correlated with ypT stage, tumor response grades using either CAP or MDA grading system, distance of superior mesenteric artery margin and tumor recurrence/metastasis. CONCLUSION: Although RadL tends to understage ypT in PDAC patients who had no radiologically detectable tumor or small tumors (RTS0 or RTS1), radiologic measurement of post-therapy tumor size may be used as a marker for the pathologic tumor staging and tumor response to neoadjuvant therapy.

Perioperative blood transfusions and survival in resected pancreatic adenocarcinoma patients given multimodality therapy.

BACKGROUND AND OBJECTIVES: The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection. METHODS: Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT). RESULTS: Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p < 0.001), perineural invasion (HR: 1.64, p = 0.050), postoperative pancreatic fistula (HR: 1.94, p = 0.018), and 24HR-BT (HR: 1.75, p = 0.001). CONCLUSIONS: Transfusions given within 24 h are associated with dose-dependent decreases in survival after pancreatectomy for PDAC.

Pancreatic neuroendocrine tumors.

PURPOSE OF REVIEW: Pancreatic neuroendocrine tumors (pNETs) are a rare, heterogeneous group of pancreatic neoplasms with a wide range of malignant potential. They may manifest as noninfiltrative, slow-growing tumors, locally invasive masses, or even swiftly metastasizing cancers. RECENT FINDINGS: In recent years, because of the increasing amount of scientific literature available for pNETs, the classification, prognostic stratification criteria, and available consensus guidelines for diagnosis and therapy have been revised and updated. SUMMARY: The vast majority of new pNET diagnoses consist of incidentally discovered lesions on cross-sectional imaging. The biologic behavior of pNETs is defined by the grade and stage of the tumor. Surgery is the only curative treatment and it, therefore, represents the first therapeutic choice for any localized pNET; however, recent evidence suggests that patients with small (<2 cm), nonfunctioning G1 tumors can be safely observed.An aggressive surgical approach towards liver metastases is recommended in selected cases, as well as liver-directed therapies for disease control. In the presence of unresectable progressive disease, somatostatin analogs, targeted therapies such as everolimus, peptide receptor radionuclide therapy, and systemic chemotherapy are all useful tools for prolonging survival.

Perioperative blood transfusions for vein resection during pancreaticoduodenectomy for pancreatic adenocarcinoma: Identification of clinical targets for optimization.

BACKGROUND: Perioperative blood transfusion (PBT) during resection of pancreatic adenocarcinoma (PDAC) has been linked to worse short-term and oncologic outcomes. However, little is known about contemporary rates of transfusion utilization among patients requiring pancreaticoduodenectomy with vein resection (PDVR). The primary aims of this study were to evaluate rates of PBT and to identify modifiable factors associated with PBT during PDVR. METHODS: Patients with PDAC treated with preoperative therapy and PDVR (2008-15) were analyzed from a prospective, single-institution database. RESULTS: Among 120 total patients, approximately half (52.5%) of all patients received PBT; rates decreased significantly in the most recent years [70.7%, 2008-10 vs. 36.8%, 2014-15 (p = 0.013)]. Lower preoperative hemoglobin, greater intraoperative percent drop in hemoglobin, increased EBL, and advanced age were all associated with PBT (p < 0.01). The only factors independently associated with PBT by multivariable analysis were age [OR-1.08 per year (95% CI 1.02-1.14)] and EBL [OR-1.30 per 100 mL, (95% CI 1.13-1.50)]. CONCLUSION: PBT for PDVR for PDAC have decreased, with only 1/3 of contemporary patients requiring PBT. As preoperative therapy and PDVR become more ubiquitous, addressing anemia during preoperative therapy and limiting EBL may reduce blood utilization. Re-evaluation of clinical thresholds for transfusions may further reduce transfusion rates.

Vein resection during pancreaticoduodenectomy for pancreatic adenocarcinoma: Patency rates and outcomes associated with thrombosis.

BACKGROUND AND OBJECTIVES: Venous patency rates after pancreaticoduodenectomy (PD) with portal vein (PV) resection are not well established, and the oncologic impact of portal vein thrombosis (PVT) is unknown. The primary aim of this study was to determine rates and predictors of PVT after PD with PV resection for pancreatic adenocarcinoma (PDAC). METHODS: A retrospective cohort study was performed on PDAC patients treated with preoperative therapy and PD with PV resection at a high-volume institution (2008-15). Primary outcomes were early and late PVT (≤ or >90 days of surgery). Secondary outcomes included major complications and OS. RESULTS: Patients undergoing vein resection (N = 120) included 41.7% (N = 50) primary repair or patch venoplasty, 29.2% (N = 35) primary anastomosis, and 29.2% (N = 35) interposition graft. Thirty-four (28.3%) patients developed PVT (early 7.5% [N = 9]; late 20.8% [N = 25]). Late PVT was often detected concurrently with local recurrence (76.0%; N = 19). There was no association of PVT with vascular resection extent or complications (P > 0.05). On multivariable analysis, PVT was associated with worse OS (HR 2.2 [95% CI 1.34-3.5], P < 0.001). CONCLUSIONS: Overall postoperative patency rates following PV resection PDAC were high. PVT is associated with worse OS, which appears less likely related to technical issues, but rather representative of disease biology.