LRIG1 controls proliferation of adult neural stem cells by facilitating TGFß and BMP signalling pathways.

Adult Neural Stem Cells (aNSCs) in the ventricular-subventricular zone (V-SVZ) are largely quiescent. Here, we characterize the mechanism underlying the functional role of a cell-signalling inhibitory protein, LRIG1, in the control of aNSCs proliferation. Using Lrig1 knockout models, we show that Lrig1 ablation results in increased aNSCs proliferation with no change in neuronal progeny and that this hyperproliferation likely does not result solely from activation of the epidermal growth factor receptor (EGFR). Loss of LRIG1, however, also leads to impaired activation of transforming growth factor beta (TGFß) and bone morphogenic protein (BMP) signalling. Biochemically, we show that LRIG1 binds TGFß/BMP receptors and the TGFß1 ligand. Finally, we show that the consequences of these interactions are to facilitate SMAD phosphorylation. Collectively, these data suggest that unlike in embryonic NSCs where EGFR may be the primary mechanism of action, in aNSCs, LRIG1 and TGFß pathways function together to fulfill their inhibitory roles.

Lead Time and Immortal Time Biases Impact the Calculation of Post-colonoscopy Colorectal Cancer Survival.

The World Endoscopy Organization (WEO) standardized the reporting of post-colonoscopy colorectal cancers (PCCRCs), which account for 7% to 10% of colorectal cancers (CRCs).1 PCCRCs are diagnosed 6 to 36 months after a false negative colonoscopy. Detected CRCs (dCRCs) are diagnosed ≤6 months after an index true positive colonoscopy.2 PCCRC prognosis is unclear, with outcomes reported as comparable,3 superior,4 or inferior5,6 to those of dCRC. Because WEO terminology defines cases relative to the index colonoscopy, conventional survival analyses of PCCRC are susceptible to lead time and immortal time biases. We evaluated the influence of these biases on mortality in a population-based retrospective cohort of 10,938 dCRCs (93.8%) and 717 PCCRCs (6.2%). This study was set within Kaiser Permanente Northern California (KPNC), a large integrated health system, whose members are similar in demographic and socioeconomic characteristics to the Northern California region.7.

Surveillance Colonoscopy Findings in Older Adults With a History of Colorectal Adenomas.

Importance: Postpolypectomy surveillance is a common colonoscopy indication in older adults; however, guidelines provide little direction on when to stop surveillance in this population. Objective: To estimate surveillance colonoscopy yields in older adults. Design, Setting, and Participants: This population-based cross-sectional study included individuals 70 to 85 years of age who received surveillance colonoscopy at a large, community-based US health care system between January 1, 2017, and December 31, 2019; had an adenoma detected 12 or more months previously; and had at least 1 year of health plan enrollment before surveillance. Individuals were excluded due to prior colorectal cancer (CRC), hereditary CRC syndrome, inflammatory bowel disease, or prior colectomy or if the surveillance colonoscopy had an inadequate bowel preparation or was incomplete. Data were analyzed from September 1, 2022, to February 22, 2024. Exposures: Age (70-74, 75-79, or 80-85 years) at surveillance colonoscopy and prior adenoma finding (ie, advanced adenoma vs nonadvanced adenoma). Main Outcomes and Measures: The main outcomes were yields of CRC, advanced adenoma, and advanced neoplasia overall (all ages) by age group and by both age group and prior adenoma finding. Multivariable logistic regression was used to identify factors associated with advanced neoplasia detection at surveillance. Results: Of 9740 surveillance colonoscopies among 9601 patients, 5895 (60.5%) were in men, and 5738 (58.9%), 3225 (33.1%), and 777 (8.0%) were performed in those aged 70-74, 75-79, and 80-85 years, respectively. Overall, CRC yields were found in 28 procedures (0.3%), advanced adenoma in 1141 (11.7%), and advanced neoplasia in 1169 (12.0%); yields did not differ significantly across age groups. Overall, CRC yields were higher for colonoscopies among patients with a prior advanced adenoma vs nonadvanced adenoma (12 of 2305 [0.5%] vs 16 of 7435 [0.2%]; P = .02), and the same was observed for advanced neoplasia (380 of 2305 [16.5%] vs 789 of 7435 [10.6%]; P < .001). Factors associated with advanced neoplasia at surveillance were prior advanced adenoma (adjusted odds ratio [AOR], 1.65; 95% CI, 1.44-1.88), body mass index of 30 or greater vs less than 25 (AOR, 1.21; 95% CI, 1.03-1.44), and having ever smoked tobacco (AOR, 1.14; 95% CI, 1.01-1.30). Asian or Pacific Islander race was inversely associated with advanced neoplasia (AOR, 0.81; 95% CI, 0.67-0.99). Conclusions and Relevance: In this cross-sectional study of surveillance colonoscopy yield in older adults, CRC detection was rare regardless of prior adenoma finding, whereas the advanced neoplasia yield was 12.0% overall. Yields were higher among those with a prior advanced adenoma than among those with prior nonadvanced adenoma and did not increase significantly with age. These findings can help inform whether to continue surveillance colonoscopy in older adults.

Deficiency in PHD2-mediated hydroxylation of HIF2α underlies Pacak-Zhuang syndrome.

Pacak-Zhuang syndrome is caused by mutations in the EPAS1 gene, which encodes for one of the three hypoxia-inducible factor alpha (HIFα) paralogs HIF2α and is associated with defined but varied phenotypic presentations including neuroendocrine tumors and polycythemia. However, the mechanisms underlying the complex genotype-phenotype correlations remain incompletely understood. Here, we devised a quantitative method for determining the dissociation constant (Kd) of the HIF2α peptides containing disease-associated mutations and the catalytic domain of prolyl-hydroxylase (PHD2) using microscale thermophoresis (MST) and showed that neuroendocrine-associated Class 1 HIF2α mutants have distinctly higher Kd than the exclusively polycythemia-associated Class 2 HIF2α mutants. Based on the co-crystal structure of PHD2/HIF2α peptide complex at 1.8 Å resolution, we showed that the Class 1 mutated residues are localized to the critical interface between HIF2α and PHD2, adjacent to the PHD2 active catalytic site, while Class 2 mutated residues are localized to the more flexible region of HIF2α that makes less contact with PHD2. Concordantly, Class 1 mutations were found to significantly increase HIF2α-mediated transcriptional activation in cellulo compared to Class 2 counterparts. These results reveal a structural mechanism in which the strength of the interaction between HIF2α and PHD2 is at the root of the general genotype-phenotype correlations observed in Pacak-Zhuang syndrome.

Predicting Risk of Colorectal Cancer After Adenoma Removal in a Large Community-Based Setting.

INTRODUCTION: Colonoscopy surveillance guidelines categorize individuals as high or low risk for future colorectal cancer (CRC) based primarily on their prior polyp characteristics, but this approach is imprecise, and consideration of other risk factors may improve postpolypectomy risk stratification. METHODS: Among patients who underwent a baseline colonoscopy with removal of a conventional adenoma in 2004-2016, we compared the performance for postpolypectomy CRC risk prediction (through 2020) of a comprehensive model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and prior polyp findings (i.e., adenoma with advanced histology, polyp size ≥10 mm, and sessile serrated adenoma or traditional serrated adenoma) with a polyp model featuring only polyp findings. Models were developed using Cox regression. Performance was assessed using area under the receiver operating characteristic curve (AUC) and calibration by the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Among 95,001 patients randomly divided 70:30 into model development (n = 66,500) and internal validation cohorts (n = 28,501), 495 CRC were subsequently diagnosed; 354 in the development cohort and 141 in the validation cohort. Models demonstrated adequate calibration, and the comprehensive model demonstrated superior predictive performance to the polyp model in the development cohort (AUC 0.71, 95% confidence interval [CI] 0.68-0.74 vs AUC 0.61, 95% CI 0.58-0.64, respectively) and validation cohort (AUC 0.70, 95% CI 0.65-0.75 vs AUC 0.62, 95% CI 0.57-0.67, respectively). DISCUSSION: A comprehensive CRC risk prediction model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and polyp findings was more accurate at predicting postpolypectomy CRC diagnosis than a model based on polyp findings alone.

Maximizing scarce colonoscopy resources: the crucial role of stool-based tests.

During the COVID-19 pandemic, health systems, including federally qualified health centers, experienced disruptions in colorectal cancer (CRC) screening. National organizations called for greater use of at-home stool-based testing followed by colonoscopy for those with abnormal test results to limit (in-person) colonoscopy exams to people with acute symptoms or who were high risk. This stool-test-first strategy may also be useful for adults with low-risk adenomas who are due for surveillance colonoscopy. We argue that colonoscopy is overused as a first-line screening method in low- and average-risk adults and as a surveillance tool among adults with small adenomas. Yet, simultaneously, many people do not receive much-needed colonoscopies. Delivering the right screening tests at intervals that reduce the risk of CRC, while minimizing patient inconvenience and procedural risks, can strengthen health-care systems. Risk stratification could improve efficiency of CRC screening, but because models that adequately predict risk are years away from clinical use, we need to optimize use of currently available technology-that is, low-cost fecal testing followed by colonoscopy for those with abnormal test results. The COVID-19 pandemic highlighted the urgent need to adapt to resource constraints around colonoscopies and showed that increased use of stool-based testing was possible. Learning how to adapt to such constraints without sacrificing patients' health, particularly for patients who receive care at federally qualified health centers, should be a priority for CRC prevention research.

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.

Randomized Trial of Patient Outreach Approaches to De-implement Outdated Colonoscopy Surveillance Intervals.

BACKGROUND AND AIMS: Guidelines now recommend patients with low-risk adenomas receive colonoscopy surveillance in 7-10 years and those with the previously recommended 5-year interval be re-evaluated. We tested 3 outreach approaches for transitioning patients to the 10-year interval recommendation. METHODS: This was a 3-arm pragmatic randomized trial comparing telephone, secure messaging, and mailed letter outreach. The setting was Kaiser Permanente Northern California, a large integrated healthcare system. Participants were patients 54-70 years of age with 1-2 small (<10 mm) tubular adenomas at baseline colonoscopy, due for 5-year surveillance in 2022, without high-risk conditions, and with access to all 3 outreach modalities. Patients were randomly assigned to the outreach arm (telephone [n = 200], secure message [n = 203], and mailed letter [n = 201]) stratified by age, sex, and race/ethnicity. Outreach in each arm was performed by trained medical assistants (unblinded) communicating in English with 1 reminder attempt at 2-4 weeks. Participants could change their assigned interval to 10 years or continue their planned 5-year interval. RESULTS: Sixty-day response rates were higher for telephone (64.5%) and secure messaging outreach (51.7%) vs mailed letter (31.3%). Also, more patients adopted the 10-year surveillance interval in the telephone (37.0%) and secure messaging arms (32.0%) compared with mailed letter (18.9%) and rate differences were significant for telephone (18.1%; 97.5% confidence interval: 8.3%-27.9%) and secure message outreach (13.1%; 97.5% confidence interval: 3.5%-22.7%) vs mailed letter outreach. CONCLUSIONS: Telephone and secure messaging were more effective than mailed letter outreach for de-implementing outdated colonoscopy surveillance recommendations among individuals with a history of low-risk adenomas in an integrated healthcare setting. (ClinicalTrials.gov, Number: NCT05389397).

Revisiting the Malignant Masquerade at the Liver Hilum: Have We Made Progress?

BACKGROUND: Distinguishing malignant from benign causes of obstruction at the liver hilum can pose a diagnostic dilemma. This study aimed to determine factors that predict benign causes of hilar obstruction and long-term outcomes after resection. METHODS: Consecutive patients who underwent surgery for hilar obstruction at a single institution between 1997 and 2022 were retrospectively analyzed. Median follow-up was 26 months (range 0-281 months). RESULTS: Among 182 patients who underwent surgery for hilar obstruction, 25 (14%) patients were found to have benign disease. Median CA19-9 level after normalization of serum bilirubin was 80 U/mL (range 1-5779) and 21 U/mL (range 1-681) among patients with malignant and benign strictures, respectively (p = 0.001). Cross-sectional imaging features associated with malignancy were lobar atrophy, soft tissue mass/infiltration, and vascular involvement (all p < 0.05). Factors not correlated with malignancy were jaundice upon presentation, peak serum bilirubin, sex, and race. Preoperative bile duct brushing or biopsy had sensitivity and specificity rates of 82% and 55%, respectively. Among patients who underwent resection with curative intent, grade 3-4 complications occurred in 55% and 29% of patients with malignant and benign strictures, respectively (p = 0.028). Postoperative long-term complications of chronic portal hypertension and recurrent cholangitis occurred in ≥ 10% of patients with both benign and malignant disease (p = non-significant). CONCLUSIONS: Strictures at the liver hilum continue to present diagnostic and management challenges. Postoperative complications and long-term sequelae of portal hypertension and recurrent cholangitis develop in a significant number of patients after resection of both benign and malignant strictures.

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.

Beyond the three P's: adrenal involvement in MEN1.

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.

Endoscopic Evaluation of PET/CT Abnormalities in the Gastrointestinal Tract: Yield and Approach.

BACKGROUND: Unexpected hypermetabolic activity is often encountered in the gastrointestinal tract when PET/CT is performed for various indications, prompting endoscopic evaluation. Our aim was to characterize the types of lesions seen in segments of the gastrointestinal tract with unexpected PET/CT abnormalities as well as clinically significant lesions seen on endoscopy which did not produce a PET/CT abnormality to guide the endoscopist tasked with evaluating these imaging findings. METHODS: We retrospectively reviewed a database of endoscopies performed at City of Hope Comprehensive Cancer Center between January 1, 2016 and September 30, 2021 for an indication of "abnormal PET." We divided the gastrointestinal tract into segments and defined categories of endoscopic/histologic findings for each segment. We counted the number of segments with an abnormal PET/CT finding and corresponding endoscopic/histologic abnormality as well as the number of segments with an endoscopic/histologic abnormality but normal PET/CT. RESULTS: PET/CT identified 209 segments with hypermetabolic activity, 109 of which had corresponding endoscopic/histologic abnormalities. In the jejunum and ileum, all corresponding lesions were malignant. Seventy-three percent of corresponding lesions in the stomach were H. pylori positive. PET/CT failed to detect 34.7% of clinically significant lesions diagnosed endoscopically, including 1 malignancy in the transverse colon and many inflammatory or low-risk premalignant lesions. CONCLUSION: PET/CT abnormalities seen in the small bowel should be evaluated urgently as nearly all correlates were malignant, while abnormalities in the stomach should prompt workup for H. pylori. Most lesions missed by PET/CT were inflammatory or low-risk premalignant yet clinically significant, confirming the need to inspect the entirety of the upper or lower gastrointestinal tract during endoscopy.

Biliary Drainage in Hilar and Perihilar Cholangiocarcinoma; 25-Year Experience at a Tertiary Cancer Center.

INTRODUCTION: This study analyzes the optimal biliary stenting strategy for palliation in cholangiocarcinoma (CCA). METHODS: This is a retrospective study of patients with CCA who underwent biliary drainage from 1997-2023. A per-patient analysis of percutaneous biliary drainage (PTBD) rates, the median number of ERCPs, overall survival (OS), and a per-procedure analysis of clinical success (CS), stent-specific Adverse Events (AEs), and mean time to reintervention by stent type and laterality (unilateral(u) & bilateral(b)) is presented. RESULTS: A total of 333 patients underwent 1,050 ERCPs; 85% with plastic stents (PS). PTBD was eventually done in 23% of PS patients, 35% of whom had PS removed prior to PTBD. ERCPs with SEMS/uniSEMS use had higher CS (89%/91%) vs PS/uPS (85% both) and PS within SEMS (PS-SEMS)/uPS-SEMS (71%/74%;p=0.013/p=0.054). Compared to PS, SEMS and PS-SEMS were associated with higher stent-specific AEs (OR SEMS 4.85; 3.23-7.27; PS-SEMS 9.99; 5.33-18.71;p<0.001). Straight PS were associated with more stent-specific AEs compared to double-pigtail stents (OR 6.74; 3.95-11.45;p<0.001). More 7 Fr stents were used in cases with balloon dilation (BD, 109 vs. 88 with no BD; p<0.001). BD had 79% CS rate vs 87% without BD (p<0.001). Cases with pus on ERCP and those with BD had a shorter mean time to reintervention. On regression analyses, higher Bismuth class, PS use, and PS-SEMS use were associated with a shorter mean time to repeat ERCP. 52% of patients in the bSEMS arm died from cholangitis (p=0.005). CONCLUSION: The relatively higher clinical success of SEMS is countered by the higher stent-specific complication rate. PS can be removed and may better facilitate PTBD. Within PS types, DPTs may have fewer stent-specific AEs. Cases requiring balloon dilation and with endoscopic evidence of pus may benefit from earlier reintervention.

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.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

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.