PARP inhibitor therapy in patients with IDH1 mutated cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. METHODS: We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. RESULTS: Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. CONCLUSION: This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.

Global Prevalence of Pancreatic Cystic Lesions in the General Population on Magnetic Resonance Imaging: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Understanding the burden of pancreatic cystic lesions (PCLs) in the general population is important for clinicians and policymakers. In this systematic review, we sought to estimate the global prevalence of PCLs using magnetic resonance imaging (MRI) and to investigate factors that contribute to its variation. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central, from database inception through February 2023. We included full-text articles that reported the prevalence of PCLs using MRI in the general population. A proportional meta-analysis was performed, and the prevalence of PCLs was pooled using a random-effects model. RESULTS: Fifteen studies with 65,607 subjects were identified. The pooled prevalence of PCLs was 16% (95% confidence interval [CI], 13%-18%; I2 = 99%), most of which were under 10 mm. Age-specific prevalence of PCLs increased from 9% (95% CI, 7%-12%) at 50 to 59 years, to 18% (95% CI, 14%-22%) at 60 to 69 years, 26% (95% CI, 20%-33%) at 70 to 79 years, and 38% at 80 years and above (95% CI, 25%-52%). There was no difference in prevalence between sexes. Subgroup analysis showed higher PCL prevalence when imaging findings were confirmed by independent radiologist(s) (25%; 95% CI, 16%-33%) than when chart review alone was used (5%; 95% CI, 4%-7%; P < .01). There was no independent association of PCL prevalence with geographic location (Europe, North America, or Asia), MRI indication (screening vs evaluation of non-pancreatic pathology), enrollment period, sample size, magnet strength (1.5 vs 3 tesla), and MRI sequence (magnetic resonance cholangiopancreatography vs no magnetic resonance cholangiopancreatography). CONCLUSION: In this systematic review, the global prevalence of PCLs using a highly sensitive noninvasive imaging modality ranged between 13% and 18%.

Efficacy and safety of long-term indwelling plastic stents after resolution of pancreatic fluid collections with endoscopic transmural drainage: a systematic review and meta-analysis.

BACKGROUND: Pancreatic fluid collections (PFCs) may recur after resolution with endoscopic transmural drainage (ETD) and standard stent removal (SSR). Herein, we compared the efficacy and safety of leaving long-term indwelling plastic stents (LTIS) vs. standard stent removal after PFC resolution with ETD. METHODS: We performed a systematic review of MEDLINE, EMBASE, CINAHL, Scopus, and Cochrane databases from inception to September 2022. Full-text articles comparing long-term (> 6 months) outcomes of LTIS and SSR were eligible, as well as single-arm studies with ≥ 10 patients with LTIS. Two independent reviewers selected studies, extracted data, and assessed the risk of bias using the Newcastle-Ottawa Scale. Measured outcomes included the following: (A) PFC recurrence; (B) interventions for PFC recurrence; (C) technical success; and (D) adverse events (AEs). Meta-analysis was carried out using random-effects models. RESULTS: We included 16 studies, encompassing 1285 patients. Compared to SSR after PFC resolution with ETD, LTIS was associated with significantly lower risk of PFC recurrence (3% vs. 23%; OR 0.22 [95%CI 0.09-0.52]; I2 = 45%) and need for interventions (2% vs. 14%; OR 0.35 [95%CI 0.16-0.78]; I2 = 0%). The superiority of LTIS on reducing PFC recurrence was found with walled-off necrosis, with or without disconnected pancreatic duct, and with placement of ≥ 2 LTIS. When using LTIS, the pooled proportion of AEs was 8% (95%CI 4-11%) and technical success was 93% (95%CI 86-99%). CONCLUSIONS: Our results show that LTIS after PFC resolution with ETD is feasible, safe, and superior to SSR in reducing the risk of PFC recurrence and need for interventions.

Practice patterns and adherence to nutrition guidelines in acute pancreatitis: An international physician survey.

BACKGROUND: There is agreement among GI society guidelines for recommending early oral nutrition with non-liquid diet in patients with mild acute pancreatitis (AP). There is less agreement regarding administration of tube feedings (TF) in AP. Data on physicians' adherence to nutrition guidelines and practice variations are limited. AIMS: To report practice patterns in the nutritional management of different severity profiles of AP. METHODS: We conducted an anonymous electronic survey among physician members of the International Association of Pancreatology and the American Pancreatic Association. We assessed nutrition practices based on severity of AP, and asked relevant questions regarding the preferred administration strategies for enteral nutrition. Responses were compared by practice location and subspecialty. RESULTS: A total of 178 physicians, mostly medical pancreatologists (40.4%) and surgeons (34.8%) from Europe (43.4%) and North America (32%) responded. Overall, only 26.7% initiated oral nutrition in mild AP on day 1, 40.9% waited >48 h, and 57.3% initiated nutrition with liquid diets. Physicians reported frequently using TF in patients with moderately-severe (30-75%, depending on the amount and location of necrosis) and severe AP (75-80%). Two-thirds of physicians preferred initiating TF after 48 h, administering it post-pylorically, and using semi-elemental or polymeric formulas. Median TF duration was 11 days (IQR, 7-21). Significant variations were noted based on geographic location and physician subspecialty for several aspects of nutritional practices in both mild and non-mild AP. CONCLUSION: Adherence to oral nutrition guideline recommendations for mild AP is low. There is significant variability in the use of TF in AP. Our study highlights opportunities for improving consistency of nutrition care in AP and identify potential areas for research.

The Role of Magnetic Resonance Imaging (MRI) in the Diagnosis of Pancreatic Cystic Lesions (PCLs).

Pancreatic cystic lesions (PCLs) are a common incidental finding on cross-sectional imaging. Given the high signal to noise and contrast resolution, multi-parametric capability and lack of ionizing radiation, magnetic resonance imaging (MRI) has become the non-invasive method of choice to predict cyst type, risk stratify the presence of neoplasia, and monitor changes during surveillance. In many patients with PCLs, the combination of MRI and the patient's history and demographics will suffice to stratify lesions and guide treatment decisions. In other patients, especially those with worrisome or high-risk features, a multimodal diagnostic approach that includes endoscopic ultrasound (EUS) with fluid analysis, digital pathomics, and/or molecular analysis is often necessary to decide on management options. The application of radiomics and artificial intelligence in MRI may improve the ability to non-invasively stratify PCLs and better guide treatment decisions. This review will summarize the evidence on the evolution of MRI for PCLs, the prevalence of PCLs using MRI, and the MRI features to diagnose specific PCL types and early malignancy. We will also describe topics such as the utility of gadolinium and secretin in MRIs of PCLs, the limitations of MRI for PCLs, and future directions.