Ronnekleiv-Kelly, Sean M

SUMMARY Intraductal oncocytic papillary neoplasms (IOPNs) are rare tumors that develop from biliary and pancreatic ductal epithelium and progress to lethal cancers. Human IOPNs and IOPN-associated carcinomas are known to harbor the DNAJB1-PRKACA gene fusion, however the role of the oncogenic fusion in carcinogenesis is poorly understood. We developed a Cre-inducible mouse model of human DNAJB1-PRKACA expression and substantiated that the DNAJB1-PRKACA fusion gene is a bona fide driver of IOPN-associated biliary and pancreatic carcinoma. By analyzing the unique histopathologic and transcriptional changes that occur at each stage of tumor development, we found that these murine tumors closely mimic human DNAJB1-PRKACA driven tumors. Furthermore, we identified that many of the salient features of invasive carcinoma are established at the pre-invasive stage, including evidence of tumor cell metabolic dysregulation, immunosuppressive tumor stroma and expression of genes strongly associated with invasive DNAJB1-PRKACA driven cancer in humans. Finally, we found that Slc16a14 , a characteristic DNAJB1-PRKACA regulated super-enhancer associated gene, serves as a robust biomarker of malignant transformation from IOPN to invasive carcinoma.

The NCCN Guidelines for Biliary Tract Cancers (BTCs) provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts is convened at least once annually to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. This manuscript focuses on the adjuvant chemotherapy and chemoradiation treatment options for BTCs as well as the systemic treatment recommendations for patients with advanced BTCs.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

AbstractBackgroundVariations in care have been demonstrated both within and among institutions in many clinical settings. By standardizing perioperative practices, Enhanced Recovery After Surgery (ERAS) pathways reduce variation in perioperative care. We sought to characterize the variation in cytoreductive surgery (CRS)/heated intraperitoneal chemotherapy (HIPEC) perioperative practices among experienced US medical centers.MethodsData from the US HIPEC Collaborative represents a retrospective multi‐institutional cohort study of CRS and CRS/HIPEC procedures performed from 12 major academic institutions. Patient characteristics and perioperative practices were reported and compared. Institutional variation was analyzed using hierarchical mixed‐effects linear (continuous outcomes) or logistic (binary outcomes) regression models.ResultsA total of 2372 operations were included. CRS/HIPEC was performed most commonly for appendiceal histologies (64.2%). The rate of complications (overall 56.3%, range: 31.8‐70.9) and readmissions (overall 20.6%, range: 8.9‐33.3) varied by institution (P < .001). Institution‐level variation in perioperative practice patterns existed among measured ERAS pathway process/outcomes (P < .001). The percentages of variation with each process/outcome measure attributable solely to institutional practices ranged from 0.6% to 66.6%.ConclusionsSignificant variation exists in the perioperative care of patients undergoing CRS/HIPEC at major US academic institutions. These findings provide a strong rationale for the investigation of best practices in CRS/HIPEC patients.

184 Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into < 65 or >65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were >65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients >65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p < 0.01) compared to those < 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age >65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age >65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients >65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age >65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.