Germline Testing identifies Pathogenic/Likely Pathogenic Variants in Patients with Pancreatic Neuroendocrine Tumors.

10% of pancreatic neuroendocrine tumors (pNETs) are related to inherited syndromes (MEN1, MEN4, VHL, NF1, TSC). Growing evidence suggests that clinically sporadic pNETs can also harbor germline pathogenic variants. In this study, we report the prevalence of pathological/likely pathological germline variants (P/LP) in a high-risk cohort and an unselected cohort. We collected clinical data of patients with pNETs seen at MD Anderson Cancer Center (MDACC) and Johns Hopkins Hospital (JHH). High-risk cohort included (n=132) patients seen at MDACC who underwent germline testing for high-risk criteria (early onset, personal or family history of cancer and syndromic features) between 2013-2019. Unselected cohort (n=106) patients seen at JHH who underwent germline testing following their diagnosis of pNETs between 2020 to 2022. In the high-risk cohort (n=132), 33% (n=44) had P/LP variants. The majority of the patients had P/LP variants in MEN1 56% (n=25), followed by DNA repair pathways 18% (n=8), and 7 %(n=3) in MSH2 (Lynch Syndrome). Patients with P/LP were younger (45 years vs 50 years; p=0.002). In the unselected cohort (n=106), 21% (n=22) had P/LP. The majority were noted in DNA repair pathways 40% (n=9) and MEN1 36% (n=8). Multifocal tumors correlated with the presence of P/LP (p=0.0035). MEN1 germline P/LP variants correlated with younger age (40 vs 56 years) (p=0.0012). presence of multifocal tumors (p<0.0001), and WHO grade 1 histology (p=0.0078). P/LP variants are prevalent in patients with clinically sporadic pNET irrespective of high-risk features. The findings support upfront universal germline testing in all pNET patients.

Postoperative Global Period Cost Reduction Using 3 Successive Risk-Stratified Pancreatectomy Clinical Pathways.

BACKGROUND: We hypothesized that iterative revisions of our original 2016 risk-stratified pancreatectomy clinical pathways would be associated with decreased 90-day perioperative costs. STUDY DESIGN: From a single-institution retrospective cohort study of consecutive patients with 3 iterations: "version 1" (V1) (October 2016 to January 2019), V2 (February 2019 to October 2020), and V3 (November 2020 to February 2022), institutional data were aggregated using revenue codes and adjusted to constant 2022-dollar value. Grand total perioperative costs (primary endpoint) were the sum of pancreatectomy, inpatient care, readmission, and 90-day global outpatient care. Proprietary hospital-based costs were converted to ratios using the mean cost of all hospital operations as the denominator. RESULTS: Of 814 patients, pathway V1 included 363, V2 229, and V3 222 patients. Accordion Grade 3+ complications decreased with each iteration (V1: 28.4%, V2: 22.7%, and V3: 15.3%). Median length of stay decreased (V1: 6 days, interquartile range [IQR] 5 to 8; V2: 5 [IQR 4 to 6]; and V3: 5 [IQR 4 to 6]) without an increase in readmissions. Ninety-day global perioperative costs decreased by 32% (V1 cost ratio 12.6, V2 10.9, and V3 8.6). Reduction of the index hospitalization cost was associated with the greatest savings (-31%: 9.4, 8.3, and 6.5). Outpatient care costs decreased consistently (1.58, 1.41, and 1.04). When combining readmission and all outpatient costs, total "postdischarge" costs decreased (3.17, 2.59, and 2.13). Component costs of the index hospitalization that were associated with the greatest savings were room or board costs (-55%: 1.74, 1.14, and 0.79) and pharmacy costs (-61%: 2.20, 1.61, and 0.87; all p < 0.001). CONCLUSIONS: Three iterative risk-stratified pancreatectomy clinical pathway refinements were associated with a 32% global period cost savings, driven by reduced index hospitalization costs. This successful learning health system model could be externally validated at other institutions performing abdominal cancer surgery.

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.

Laparoscopic transverse abdominis plane block: how I do it and a cost efficiency analysis.

PURPOSE: To determine the efficacy and efficiency of laparoscopic transverse abdominis plane block (Lap-TAP) in patients undergoing pancreatoduodenectomy and gastrectomy compared to those of ultrasound-guided TAP (US-TAP). METHODS: We retrospectively analyzed the records of patients who underwent open or minimally invasive (MIS) pancreatoduodenectomy and major gastrectomy with the use of Lap-TAP or US-TAP at our institution between November 1, 2018, and September 30, 2021. We compared the estimated time and cost associated with Lap-TAP and US-TAP. We also compared postoperative opioid use and pain scores between patients who underwent open laparotomy with these TAPs. RESULTS: A total of 194 patients were included. Overall, 114 patients (59%) underwent pancreatectomy, and 80 patients (41%) underwent gastrectomy. Additionally, 138 patients (71%) underwent an open procedure, and 56 patients (29%) underwent MIS. A total of 102 patients (53%) underwent US-TAP, and 92 (47%) underwent Lap-TAP. The median time to skin incision was significantly shorter in the Lap-TAP group (US-TAP, 59 min vs. Lap-TAP, 45 min; P < 0.001), resulting in an estimated reduction in operation cost by $602. Pain scores and postoperative opioid use were similar between Lap-TAP and US-TAP among open surgery patients, indicating equivalent pain control between Lap-TAP and US-TAP. CONCLUSION: Lap-TAP was equally effective in pain control as US-TAP after pancreatectomy and gastrectomy, and Lap-TAP can reduce operation time and cost. Lap-TAP is considered the preferred approach for MIS pancreatectomy and gastrectomy, which occasionally needs conversion to laparotomy.

Evaluation and Recalibration of Risk-Stratified Pancreatoduodenectomy Drain Fluid Amylase Removal Criteria.

BACKGROUND: Risk-stratified drain fluid amylase cutoff values for postoperative day 1 (POD1) (DFA1) and POD3 (DFA3) can guide early drain removal after pancreatoduodenectomy (PD). The aim of this study was to evaluate and recalibrate cutoff values instituted in Feb 2019 using a prospective sequential cohort. METHODS: We performed a single-institution prospective cohort study of consecutive patients who underwent pancreatoduodenectomy following implementation of institution-specific DFA cutoffs in February 2019 through April 2022. DFA values, drain removal, and clinically relevant postoperative pancreatic fistulas (CR-POPF) were analyzed. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values. RESULTS: In total, 267 patients, 173 (65%) low-risk and 94 (35%) high-risk, underwent 228 (85%) open and 39 (15%) robotic pancreatoduodenectomies. Seven (4%) low-risk patients and 21 (22%) high-risk patients developed CR-POPF. Drains were removed in 147 (55%) patients before/on POD3, with 1 (0.7%) CR-POPF. In low-risk patients, CR-POPF was excluded with 100% sensitivity if DFA1 < 286 (area under curve, AUC = 0.893, p = 0.001) or DFA3 < 97 (AUC = 0.856, p = 0.002). DFA1 < 137 (AUC = 0.786, p < 0.001) or DFA3 < 56 (AUC = 0.819, p < 0.001) were 100% sensitive in high-risk patients. Previously established DFA1 cutoffs of 100 (low-risk) and < 26 (high-risk) were 100% sensitive, while DFA3 cutoffs of 300 (low-risk) and 200 (high-risk) had 57% and 91% sensitivity. CONCLUSIONS: Within a learning health system, we recalibrated post-PD drain removal thresholds to DFA1 ≤ 300 and DFA3 ≤ 100 for low-risk and DFA1 ≤ 100 and DFA3 ≤ 50 for high-risk patients. This methodology is generalizable to other centers for developing institution-specific criteria to optimize safe early drain removal.

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.

Elevated CA 19-9 is associated with worse survival in patients with resected ampullary adenocarcinoma.

BACKGROUND: The prognostic utility of Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) in ampullary adenocarcinoma is unclear. We sought to evaluate the association between initial tumor marker levels and survival in patients with resected ampullary adenocarcinoma. METHODS: This was a single-institution, retrospective cohort study of consecutive patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma from 1999 to 2021. CA 19-9 was assessed after biliary decompression. Contal and O'Quigley method determined optimal biomarker cutoff levels which were correlated with overall survival (OS) using the Kaplan-Meier method and Cox Proportional Hazards Regression. RESULTS: A total of 180 patients underwent pancreatoduodenectomy. Patients with CA 19-9 >100 U/mL had a shorter median OS (28 vs. 132 months, p < 0.001) compared to patients with CA 19-9 ≤ 100 U/mL at diagnosis. Survival was similar between pancreaticobiliary and intestinal tumor subtypes when CA 19-9 was >100 U/mL (OS:25 vs. 33 months, p = 0.415). By Cox regression analysis, CA 19-9 >100 U/mL was independently associated with worse OS (HR 2.8, p = 0.001). CONCLUSIONS: Preoperative CA 19-9 >100 U/mL was associated with shorter OS in patients with resected ampullary adenocarcinoma. CA 19-9 may be useful when counseling patients about prognosis or when considering the role of perioperative systemic therapy.

Opioid-Free Discharge After Pancreatic Resection Through a Learning Health System Paradigm.

Importance: Postoperative opioid overprescribing leads to persistent opioid use and excess pills at risk for misuse and diversion. A learning health system paradigm using risk-stratified pancreatectomy clinical pathways (RSPCPs) may lead to reduction in inpatient and discharge opioid volume. Objective: To analyze the outcomes of 2 iterative RSPCP updates on inpatient and discharge opioid volumes. Design, Setting, and Participants: This cohort study included 832 consecutive adult patients at an urban comprehensive cancer center who underwent pancreatic resection between October 2016 and April 2022, comprising 3 sequential pathway cohorts (version [V] 1, October 1, 2016, to January 31, 2019 [n = 363]; V2, February 1, 2019, to October 31, 2020 [n = 229]; V3, November 1, 2020, to April 30, 2022 [n = 240]). Exposures: After V1 of the pathway established a baseline and reduced length of stay (n = 363), V2 (n = 229) updated patient and surgeon education handouts, limited intravenous opioids, suggested a 3-drug (acetaminophen, celecoxib, methocarbamol) nonopioid bundle, and implemented the 5×-multiplier (last 24-hour oral morphine equivalents [OME] multiplied by 5) to calculate discharge volume. Pathway version 3 (n = 240) required the nonopioid bundle as default in the recovery room and scheduled conversion to oral medications on postoperative day 1. Main Outcomes and Measures: Inpatient and discharge opioid volume in OME across the 3 RSPCPs were compared using nonparametric testing and trend analyses. Results: A total of 832 consecutive patients (median [IQR] age, 65 [56-72] years; 410 female [49.3%] and 422 male [50.7%]) underwent 541 pancreatoduodenectomies, 285 distal pancreatectomies, and 6 other pancreatectomies. Early nonopioid bundle administration increased from V1 (acetaminophen, 320 patients [88.2%]; celecoxib or anti-inflammatory, 98 patients [27.0%]; methocarbamol, 267 patients [73.6%]) to V3 (236 patients [98.3%], 163 patients [67.9%], and 238 patients [99.2%], respectively; P < .001). Total inpatient OME decreased from a median 290 mg (IQR, 157-468 mg) in V1 to 184 mg (IQR, 103-311 mg) in V2 to 129 mg (IQR, 75-206 mg) in V3 (P < .001). Discharge OME decreased from a median 150 mg (IQR, 100-225 mg) in V1 to 25 mg (IQR, 0-100 mg) in V2 to 0 mg (IQR, 0-50 mg) in V3 (P < .001). The percentage of patients discharged opioid free increased from 7.2% (26 of 363) in V1 to 52.5% (126 of 240) in V3 (P < .001), with 187 of 240 (77.9%) in V3 discharged with 50 mg OME or less. Median pain scores remained 3 or lower in all cohorts, with no differences in postdischarge refill requests. A subgroup analysis separating open and minimally invasive surgical cases showed similar results in both groups. Conclusions and Relevance: In this cohort study, the median total inpatient OME was halved and median discharge OME reduced to zero in association with a learning health system model of iterative opioid reduction that is freely adaptable by other hospitals. These findings suggest that opioid-free discharge after pancreatectomy and other major cancer operations is realistic and feasible with this no-cost blueprint.

Surgical Considerations for Neoadjuvant Therapy for Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease process with a 5-year survival rate of only 11%. Neoadjuvant therapy in patients with localized pancreatic cancer has multiple theoretical benefits, including improved patient selection for surgery, early delivery of systemic therapy, and assessment of response to therapy. Herein, we review key surgical considerations when selecting patients for neoadjuvant therapy and curative-intent resection. Accurate determination of resectability at diagnosis is critical and should be based on not only anatomic criteria but also biologic and clinical criteria to determine optimal treatment sequencing. Borderline resectable or locally advanced pancreatic cancer is best treated with neoadjuvant therapy and resection, including vascular resection and reconstruction when appropriate. Lastly, providing nutritional, prehabilitation, and supportive care interventions to improve patient fitness prior to surgical intervention and adequately address the adverse effects of therapy is critical.

Postoperative Opioid Use Is Associated with Increased Rates of Grade B/C Pancreatic Fistula After Distal Pancreatectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a major source of morbidity after distal pancreatectomy. This study examined the association between postoperative opioid use and CR-POPF in the context of opioid-sparing postoperative care. METHODS: A case-control study was performed on consecutive patients who underwent distal pancreatectomy between October 2016 and April 2022 at a single institution. Patients who developed CR-POPF were compared to controls. Multivariable regression modeling was used to identify factors associated with CR-POPF. RESULTS: A total of 281 patients underwent 187 open, 20 laparoscopic, and 74 robotic-assisted operations. The rate of CR-POPF was 21% (n = 58). CR-POPF rate declined from 32 to 8% over the study period (p < 0.001). Median oral morphine equivalents (OME) administered on POD 0-1 and 0-3 were 94 and 129 mg, respectively, in patients who did not develop a fistula versus 130 and 180 mg in those who did (both p ≤ 0.001). POD 0-3 OME (OR 1.11, p = 0.044) was independently associated with increased odds of CR-POPF, with each additional 50 mg (equivalent to 10 tramadol pills) increasing the relative risk by 11% and absolute risk by 2%. CONCLUSION: Early postoperative opioid use after distal pancreatectomy was associated with increased odds of CR-POPF. Decreasing perioperative opioid use through enhanced postoperative management is a low-cost and generalizable approach that may reduce rates of CR-POPF after distal pancreatectomy.

Differential Gains in Surgical Outcomes for High-Risk vs Low-Risk Pancreaticoduodenectomy with Successive Refinements of Risk-Stratified Care Pathways.

BACKGROUND: The use of risk-stratified pancreatectomy care pathways (RSPCPs) is associated with reduced length of stay (LOS). This study sought to evaluate the impact of successive pathway revisions with the hypothesis that high-risk patients require iterative pathway revisions to optimize outcomes. STUDY DESIGN: A prospectively maintained database (October 2016 to December 2021) was evaluated for pancreaticoduodenectomy patients managed with RSPCPs preoperatively assigned based on postoperative pancreatic fistula (POPF) risk. Launched in October 2016 (version [V] 1), RSPCPs were optimized in February 2019 (V2) and November 2020 (V3). Targeted pathway components included earlier nasogastric tube removal, diet advancement, reduced intravenous fluids and opioids, institution-specific drain fluid amylase cutoffs for early day 3 removal, and patient education. Primary outcome was LOS. Secondary outcomes included major complication (Accordion grade 3+), POPF (International Study Group for Pancreatic Surgery Grade B/C), and delayed gastric emptying (DGE). RESULTS: Of 481 patients, 234 were managed by V1 (83 high-risk), 141 by V2 (43 high-risk), and 106 by V3 (43 high-risk). Median LOS reduction was greatest in high-risk patients with a 7-day reduction (pre-RSPCP, 12 days; V1, 9 days; V2, 7 days; V3, 5 days), compared with low-risk patients (pre-pathway, 10 days; V1, 6 days; V2, 5 days; V3, 4 days). Complications decreased significantly among high-risk patients (V1, 45%; V2, 33%; V3, 19%; p < 0.001), approaching rates in low-risk patients (V1, 21%; V2, 20%; V3, 14%). POPF (V1, 33%; V2, 23%; V3, 16%; p < 0.001) and DGE (V1, 23%; V2, 22%; V3, 14%; p < 0.001) improved among high-risk patients. CONCLUSIONS: Risk-stratified pancreatectomy care pathways are associated with reduced LOS, major complication, Grade B/C fistula, and DGE. The easiest gains in surgical outcomes are generated from the immediate improvement in the patients most likely to be fast-tracked, but high-risk patients benefit from successive application of the learning health system model.

Incidence of Postoperative Complications Following Pancreatectomy for Pancreatic Cystic Lesions or Pancreatic Cancer.

BACKGROUND: In contrast to pancreatic ductal adenocarcinoma (PDAC), the risks of pancreatectomy for mucinous pancreatic cysts (MCs) are balanced against the putative goal of removing potentially malignant tumors. Despite undergoing similar operations, different rates of perioperative complications and morbidity between MC and PDAC patient populations may affect recommendations for resection. We therefore sought to compare the rates of postoperative complications between patients undergoing pancreatectomies for MCs or PDAC. METHODS: A prospectively maintained institutional database was used to identify patients who underwent surgical resection for MCs or PDAC from July 2011 to August 2019. Patient demographics, complications, and perioperative data were compared between groups. RESULTS: A total of 103 patients underwent surgical resection for MCs and 428 patients underwent resection for PDAC. Combined major 90-day postoperative complications were similar between MC and PDAC patients undergoing pancreaticoduodenectomy (PD, 32.5% vs. 20.0%, p = 0.068) or distal pancreatectomy (DP, 30.2% vs. 20.5%, p = 0.172). The most frequent complications were postoperative pancreatic fistula (POPF), abscess, and postoperative bleeding. The incidence of 90-day ISGPS Grade B/C POPF was higher in cyst patients undergoing PD (17.5% vs. 4.1%, p = 0.003) but not DP (25.4% vs. 20.5%, p = 0.473). No significant differences in operative time or length of stay between MCs and PDAC cohorts were observed. CONCLUSIONS: POPFs occur more frequently and at higher grades in patients undergoing PD for MCs than for PDAC and should inform patient selection. Accordingly, the perioperative management of MC patients undergoing PD should emphasize POPF risk mitigation.

Quality of superior mesenteric and hepatic artery dissection in robotic pancreatoduodenectomy for pancreatic cancer.

This video manuscript by Ikoma and colleagues demonstrates their approach to the superior mesenteric artery and hepatic artery periadventitial dissection. The quality of superior mesenteric artery and hepatic artery dissections should be maintained in robotic pancreatoduodenectomy when performed for pancreatic cancer, to provide the best possible oncological outcomes.

Comparative analysis of opioid use between robotic and open pancreatoduodenectomy.

BACKGROUND/PURPOSE: Risk-stratified pancreatectomy clinical pathways using regional anesthesia and multimodality analgesia have decreased overall opioid use, but the additional benefits of robotic surgery in opioid reduction for pancreatoduodenectomy (PD) are unknown. We compared the inpatient opioid use between robotic PD and open PD. METHODS: Patients undergoing open PD within a protocol evaluating preincisional regional anesthetic block bundles were compared to consecutively-treated patients undergoing robotic PD identified from a prospectively maintained single-institutional database. Clinical characteristics, operative outcomes, pain scores and inpatient oral morphine equivalent (OME) use were compared between patients treated with robotic or open PD. Patients with a history of continuous-release opioid dependence were excluded. RESULTS: Of 114 total patients, 25 underwent robotic PD and 89 underwent open PD. Intraoperative opioid use was not different (P = .87), nor were cumulative pain scores. Robotic PD patients used significantly fewer OMEs per day on postoperative days 1-4 (P = .039), used fewer total OMEs during hospitalization (robotic: median = 79, IQR 42.5-141; open: median = 126, IQR 61.3-203.8; P = .0036) and were discharged with fewer OMEs (robotic: median = 0, IQR 0-43.8; open: median = 25, IQR 0-75; P = .009) despite a shorter length of stay (robotic: median = 4, open: median = 5, P = .002). CONCLUSIONS: Robotic PD patients required fewer inpatient OMEs than open PD while maintaining similar pain scores. A higher percentage of robotic PD patients tapered off of opioids prior to discharge than open surgery patients treated with a standardized opioid reduction protocol despite a shorter length of stay. These results provide a rationale for choosing robotic PD when feasible to minimize opioid use.

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.

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.

Neuroendocrine hepatic metastatic disease: the surgeon's perspective.

Neuroendocrine tumors are a rare subset of tumors that are increasing in incidence over the last 4 decades. These tumors occur along the gastrointestinal tract and bronchopulmonary tree and frequently metastasize. Up to 90% of patients with gastroenteropancreatic neuroendocrine tumors develop liver metastases (NeLM) during their clinical course. The development of NeLM and their appropriate management has a profound impact on patient morbidity and mortality. Workup of NeLM involves biopsy to define tumor grade, cross-sectional imaging to delineate the distribution and number of metastases, and hormonal studies to determine tumor functionality. Depending on these three factors, a combination of cytoreductive surgery, liver-directed therapies, and medical management-with cytostatic and cytotoxic chemotherapies, is utilized. The multidisciplinary management of patients with NeLM should carefully consider all these factors.

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.

Shifting Paradigms in the Pathophysiology and Treatment of Carcinoid Crisis.

Carcinoid crisis is a potentially fatal condition characterized by various symptoms, including hemodynamic instability, flushing, and diarrhea. The incidence of carcinoid crisis is unknown, in part due to inconsistency in definitions across studies. Triggers of carcinoid crisis include general anesthesia and surgical procedures, but drug-induced and spontaneous cases have also been reported. Patients with neuroendocrine tumors (NETs) and carcinoid syndrome are at risk for carcinoid crisis. The pathophysiology of carcinoid crisis has been attributed to secretion of bioactive substances, such as serotonin, histamine, bradykinin, and kallikrein by NETs. The somatostatin analog octreotide has been considered the standard of care for carcinoid crisis due to its inhibitory effect on hormone release and relatively fast resolution of carcinoid crisis symptoms in several case studies. However, octreotide's efficacy in the treatment of carcinoid crisis has been questioned. This is due to a lack of a common definition for carcinoid crisis, the heterogeneity in clinical presentation, the paucity of prospective studies assessing octreotide efficacy in carcinoid crisis, and the lack of understanding of the pathophysiology of carcinoid crisis. These issues challenge the classical physiologic model of carcinoid crisis and its common etiology with carcinoid syndrome and raise questions regarding the utility of somatostatin analogs in its treatment. As surgical procedures and invasive liver-directed therapies remain important treatment modalities in patients with NETs, the pathophysiology of carcinoid crisis, potential benefits of octreotide, and efficacy of alternative treatment modalities must be studied prospectively to develop an effective evidence-based treatment strategy for carcinoid crisis.