Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

New-onset diabetes is a predictive risk factor for pancreatic lesions in high-risk individuals: An observational cohort study.

Background and Objectives: Pancreatic cancer (PC) is the third cause of cancer-related deaths. Early detection and interception of premalignant pancreatic lesions represent a promising strategy to improve outcomes. We evaluated risk factors of focal pancreatic lesions (FPLs) in asymptomatic individuals at hereditary high risk for PC. Methods: This is an observational single-institution cohort study conducted over a period of 5 years. Surveillance was performed through imaging studies (EUS or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and serum biomarkers. We collected demographic characteristics and used univariate and multivariate logistic regression models to evaluate associations between potential risk factors and odd ratios (ORs) for FPL development. Results: A total of 205 patients completed baseline screening. Patients were followed up to 53 months. We detected FPL in 37 patients (18%) at baseline; 2 patients had lesions progression during follow-up period, 1 of them to PC. Furthermore, 13 patients developed new FPLs during the follow-up period. Univariate and multivariate analyses revealed that new-onset diabetes (NOD) is strongly associated with the presence of FPL (OR, 10.94 [95% confidence interval, 3.01-51.79; P < 0.001]; OR, 9.98 [95% confidence interval, 2.15-46.33; P = 0.003]). Follow-up data analysis revealed that NOD is also predictive of lesions progression or development of new lesions during screening (26.7% vs. 2.6%; P = 0.005). Conclusions: In a PC high-risk cohort, NOD is significantly associated with presence of FPL at baseline and predictive of lesions progression or new lesions during surveillance.

Effect of surgical approach on early return to intended oncologic therapy after resection for pancreatic ductal adenocarcinoma.

BACKGROUND: Although robotic pancreatectomy may facilitate an earlier functional recovery, the impact of a robotic pancreatectomy program during its early experience on the timing of return to intended oncologic therapy (RIOT) after surgery is unknown. METHODS: In this retrospective cohort study, we used propensity score matching with a 1:2 ratio to compare patients who underwent robotic or open surgery (distal pancreatectomy or pancreatoduodenectomy) for pancreatic ductal adenocarcinoma (PDAC) during the first 3 years of our robotic pancreatectomy experience (January 2018-December 2021). Generalized estimating equations modeling was used to evaluate the effect of surgical approach on early RIOT, defined as adjuvant chemotherapy initiation within 8 weeks after surgery, and late RIOT, defined as initiation within 12 weeks after surgery. RESULTS: The matched cohort included 26 patients who underwent robotic pancreatectomy and 52 patients who underwent open pancreatectomy. Rates of receipt of adjuvant chemotherapy were 96.2% and 78.9%, respectively. Rate of early RIOT in the robotic group (73.1% was higher than that in the open group (44.2%; P = 0.018). In multivariable analysis, a robotic approach was associated with early RIOT (odds ratio, 3.54; 95% confidence interval 1.08-11.62; P = 0.038). Surgical approach did not impact late RIOT (odds ratio, 3.21; 95% confidence interval 0.71-14.38; P = 0.128). CONCLUSIONS: Compared with open pancreatectomy, robotic pancreatectomy did not delay RIOT. In fact, odds of early RIOT were increased, which supports the oncological safety of our robotic pancreatectomy program during its implementation.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.

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

Ten percent of pancreatic neuroendocrine tumors (pNET) are related to inherited syndromes (MEN1, MEN4, VHL, NF1, and TSC). Growing evidence suggests that clinically sporadic pNETs can also harbor germline pathogenic variants. In this study, we report the prevalence of pathologic/likely pathologic (P/LP) germline variants in a high-risk cohort and an unselected cohort. We collected clinical data of patients with pNETs seen at MD Anderson Cancer Center and Johns Hopkins Hospital. The high-risk cohort included (n = 132) patients seen at MD Anderson Cancer Center who underwent germline testing for high-risk criteria (early onset, personal or family history of cancer, and syndromic features) between 2013 and 2019. The unselected cohort included (n = 106) patients seen at Johns Hopkins Hospital who underwent germline testing following their diagnosis of pNETs between 2020 and 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 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 World Health Organization 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 patients with pNET. Prevention Relevance: Here, we present germline data from the largest reported cohort of patients with pNET (n = 238), comprising both a high-risk cohort and an unselected cohort. In both cohorts, we identify a high number of P/LPs, including those in the DNA repair pathway. Our findings support universal germline testing in patients with pNET.

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.

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.

Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation.

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.

Benefits of the Enhanced Recovery After Surgery (ERAS) Pathway With Quadratus Lumborum Blocks for Minimally Invasive Gynecologic Surgery Patients: A Retrospective Cohort Study.

STUDY OBJECTIVE: This study aimed to determine the effect of the implementation of the Enhanced Recovery After Surgery (ERAS) protocol among patients receiving minimally invasive gynecologic surgery. DESIGN AND SETTING: This retrospective cohort study was performed in a tertiary care hospital. PATIENTS: A total of 328 females who underwent minimally invasive gynecologic surgeries requiring at least one overnight stay at Keck Hospital of University of Southern California (USC), California, USA, from 2016 to 2020 were included in this study. INTERVENTIONS: The institutional ERAS protocol was implemented in late 2018. A total of 186 patients from 2016 to 2018 prior to the implementation were compared to 142 patients from 2018 to 2020 after the implementation. Intraoperatively, the ERAS group received a multimodal analgesic regimen (including bilateral quadratus lumborum (QL) blocks) and postoperative care geared toward a satisfactory, safe, and expeditious discharge. MEASUREMENTS AND MAIN RESULTS: The two groups were similar in demographics, except for the shorter surgical time noted in the ERAS group. The median opioid use was significantly less among the ERAS patients compared with the non-ERAS patients on postoperative day 1 (7.5 vs. 14.3 mg; p<0.001) and throughout the hospital stay (17.4 vs. 36.2 mg; p<0.001). The ERAS group also had a shorter median hospital length of stay compared to the non-ERAS group (p<0.01). Among patients with a malignant diagnosis, patients in the ERAS group had significantly less postoperative day 1 and total opioid use and a shorter hospital stay (p<0.01). Within the ERAS group, 20% of the patients did not end up receiving a QL block. Opioid use and length of stay were similar between patients who did and did not receive the QL block. CONCLUSIONS: The ERAS pathway was associated with a reduction in opioid use postoperatively and a shorter length of hospital stay after minimally invasive gynecologic surgery. There was a more significant decrease in opioid use and hospital length of stay for patients with malignant diagnoses compared to patients with benign diagnoses. Further research can be done to fully delineate the effect of QL blocks in ERAS protocols.

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.

Bacterial and fungal characterization of pancreatic adenocarcinoma from Endoscopic Ultrasound-guided biopsies.

Introduction: The tumor microbiome (TM) has been linked to pancreatic cancer prognosis. Specific microbes can confer tumor resistance to therapies. Early knowledge of the TM at time of diagnosis would be clinically relevant for precision therapy based on microbial composition. However, it is difficult to define the TM prior to surgical resection. Methods: In this pilot feasibility study, patients underwent Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) biopsy of pancreatic adenocarcinoma. These samples were analyzed using 16S rRNA and internal transcribed spacer (ITS) sequencing for characterization of the tumor bacteria and fungi. Result: After in silico decontamination and comparison to non-matched tumor, we were able to characterize the TM in biopsies, which was comparable to the TM from surgical specimens. Discussion: EUS-FNA biopsy may represent a feasible modality to characterize the pancreatic TM prior to surgical resection with proper decontamination strategies and improvements in matched controls.

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.

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.

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.

KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells.

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.

Integrated spatial transcriptomics and lipidomics of precursor lesions of pancreatic cancer identifies enrichment of long chain sulfatide biosynthesis as an early metabolic alteration.

Background: The development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted the first integrated cross-species assessment of spatial transcriptomics and spatial metabolomics alterations associated with progression of intraductal papillary mucinous neoplasms (IPMN), bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC). Methods: Matrix Assisted Laster Desorption/Ionization (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) (10X Genomics) was performed on human resected IPMN tissues (N= 23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN. Findings were further compared with lipidomic analyses of cystic fluid from 89 patients with histologically confirmed IPMNs, as well as single-cell and bulk transcriptomic data of PDAC and normal tissues. Results: MALDI-MS analyses of IPMN tissues revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Integrated ST analyses confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1 , and FA2H , were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid identified several sulfatide species, including the C24:0(OH) and C24:1(OH) species, to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Targeting of sulfatide metabolism via the selective galactosylceramide synthase inhibitor, UGT8-IN-1, resulted in ceramide-induced lethal mitophagy and subsequent cancer cell death in vitro , and attenuated tumor growth of mutant Kras;Gnas allografts. Transcript levels of UGT8 and FA2H were also selectively enriched in PDAC transcriptomic datasets compared to non-cancerous areas, and elevated tumoral UGT8 was prognostic for poor overall survival. Conclusion: Enhanced sulfatide metabolism is an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception.

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.