Citations

Background: Self-expanding metal stents (SEMS) are recommended for the endoscopic palliation of distal malignant biliary obstruction (DMBO). Placement of SEMS during endoscopic retrograde cholangiopancreatography (ERCP) has been associated with an increased risk of post-ERCP pancreatitis (PEP). Objectives: The aim of this study is to evaluate rates of PEP in patients who underwent SEMS placement for pancreatic versus non-pancreatic malignancy. Design: Retrospective Cohort Study. Methods: Patients who underwent SEMS placement for DMBO between June 2017 and May 2021 were identified retrospectively from a procedural billing database. PEP incidence was compared between pancreatic and non-pancreatic DMBO groups and multivariate logistic regression was performed to identify risk factors for PEP. Results: A total of 488 individuals were identified, with 395 (80.9%) cases of DMBO due to pancreatic and 93 (19.1%) due to non-pancreatic malignancy. Stent types included 124 (25.4%) fully covered (FCSEMS) and 364 (74.6%) uncovered metal stents (UCSEMS). The overall rate of PEP in the cohort was 6.3% with no significant difference between pancreatic and non-pancreatic etiologies (6.1% vs 7.5%, p = 0.606). When adjusted for age <50 years old, female sex, and pancreatic stent placement, a non-pancreatic malignancy was not associated with an increased risk of PEP (OR 0.83, 95% CI 0.36–2.15). Conclusion: No statistically significant difference in PEP rates was seen after biliary sphincterotomy and SEMS placement for palliation of DMBO in patients with pancreatic versus non-pancreatic malignancies.

Abstract Workplace stress is one of the main sources of stress for adults, although physiological and cognitive factors may impact each person's stress response. Numerous studies have shown heart rate, heart rate variability, neural activity, and cognitive performance are affected by stress. Additionally, visual and auditory stimuli in one's environment have been shown to affect individuals' reaction to stressful events. To our knowledge, few studies have examined how each of these physiological and cognitive measures relate to one's perception of stress, the ability to recover from stress, and what environmental factors may help with stress recovery. Here, 80 healthy adults performed a laboratory-controlled stress induction task where they experienced and recovered from an acute psychological stressor (Trier Social Stress Test, TSST, using verbal math skills and a public presentation that was videotaped). Throughout the assessment, heart rate, heart rate variability, and neural activity were measured using wearable devices to assess changes before, during, and after the stressor. Additionally, participants were assessed their perceived stress levels at specific times throughout the assessment. After the psychological stressor, participants were randomly assigned to one of four recovery conditions within a multisensory relaxation room: Control (C), Auditory Only (A), Visual Only (V), or Combined Auditory and Visual (AV). During the stressor, anxiety, heart rate, and beta EEG power increased and high-frequency power and heart rate variability decreased, confirming participants reactivity to the stressor ( P < 0.01 for all vs. baseline). Only the V and AV conditions led to notable reductions in anxiety (15 and 17%, respectively) vs. the C condition, but these did not reach statistical significance. There was no difference between V and AV, suggesting a stronger impact of V. We observed no differences between conditions during recovery for HR and HRV. Overall, these findings suggest the visual features of the relaxation room impacted self-reported anxiety, however physiological and neurological effects did not demonstrate a statistically meaningful response.

Anesthesiologists are sometimes slow to adopt new technologies despite proven benefits. The authors undertook to understand community anesthesiologists’ perspectives and practices regarding neuromuscular monitoring and reversal. Specifically, they sought to generate evidence for why some guidance-congruent practices— i.e. , quantitative train-of-four monitoring, ulnar nerve stimulation, and evidence-based reversal—remain inconsistently adopted despite robust evidence of patient harm from residual neuromuscular blockade and decades of effort to improve adoption. Thirty-six U.S. community anesthesiologists underwent a detailed qualitative cognitive interview. Analysis revealed four clinician archetypes whose neuromuscular monitoring and reversal practices are shaped by identifiable individual and practice-related biases and device- and system-level barriers. Perceived confidence in sugammadex efficacy was frequently cited as a rationale for omitting quantitative neuromuscular monitoring. The authors propose a research and implementation action agenda to close the evidence-to-practice gap in neuromuscular monitoring and reversal.

Hypoxia is a prevalent characteristic of neurological diseases, including ischemic injury, neurodegeneration and infectious disease complications. Concurrently, hypoxia shapes both protective and pathological responses within the central nervous system (CNS). Central to this process is hypoxia-inducible factor 1α (HIF1α), a transcription factor that regulates cellular adaptation to reduced oxygen availability through coordinated glycolytic, inflammatory and cell survival pathways. Under hypoxic conditions, HIF1α transcriptional activity influences microglial activation, mitochondrial quality control, and cytokine production, thereby modulating neuroinflammation and neuroprotection. Preclinical evidence points toward hypoxia preconditioning being neuroprotective through HIF1α-dependent mechanisms in a context-dependent matter. This review synthesizes the current understanding of the role of HIF1α across neurological disease contexts, highlighting the intersection of hypoxia, neuroinflammation and neuronal survival. Ultimately, defining the cell-specific and context-dependent involvement of HIF1α will be critical for targeted therapeutic approaches to alleviate neuronal death and slow disease progression.

Abstract Background TOPAZ-1 demonstrated durvalumab + gemcitabine and cisplatin (GemCis) superiority over GemCis in first-line treatment of advanced biliary tract cancers. Real-world data from US patients and patients excluded from TOPAZ-1 (patients with autoimmune conditions [AICs] who did not receive immunotherapy) are lacking. We report real-world data for patients with cholangiocarcinoma treated with durvalumab + GemCis. Methods This retrospective, observational study enrolled adult patients diagnosed with cholangiocarcinoma in the US from the International Cholangiocarcinoma Patient Registry (ICPR) treated with first-line durvalumab + GemCis between 2021–2023. De-identified medical records from ICPR were obtained directly from consenting patients/caregivers. Patient demographics and tumor characteristics (primary objective; assessed at initial diagnosis), comorbidities, second-line treatment modalities, median real-world overall survival (mrwOS), and median real-world time to next treatment (mrwTTNT; initiation of first-line treatment and last activity in the database or death) are reported. Results Seventy patients received first-line durvalumab + GemCis: 13 (18.6%) had AIC(s) and 57 (81.4%) did not. Patient demographics, clinical characteristics, and comorbidities are shown (Table). Median (quartile 1–3) time from diagnosis to start of first-line treatment was 1.0 (0.7–1.7) months; median follow-up from first dose of first-line treatment was 7.0 (3.7–12.1) months. The mrwOS (95% CI) was 15.5 (15.1–not evaluable [NE]) months. mrwTTNT (95% CI) was 10.8 (10.4–15.7) months overall and was 20.8 (10.4–NE) months in patients who died without receiving subsequent treatment (censored at date of last activity). Among patients with AIC(s), &lt;5 received second-line therapy (all received chemotherapy alone). Among patients with no AICs, 15 received second-line treatment; 11 (73.3%) received targeted therapy alone and &lt;5 received chemotherapy alone. Conclusions This dataset demonstrates patients with AIC(s) are treated with durvalumab + GemCis in clinical practice. The mrwOS for durvalumab + GemCis in this patient population is consistent with TOPAZ-1 and global real-world studies.

Abstract Background and Aims Primary sclerosing cholangitis (PSC) increases the risk of developing cholangiocarcinoma (CCA), which is the leading cause of premature death in these patients. Current diagnostic methods for early detection of either condition remain largely suboptimal. This study investigates serum metabolites as potential non-invasive diagnostic biomarkers. Methods This multicenter international study analyzed 459 serum samples from 13 international centers, including patients with PSC (n = 216), PSC who developed CCA during follow-up (PSC to CCA; n = 24), PSC with concomitant CCA (PSC-CCA; n = 88), ulcerative colitis (UC; n = 14), and healthy individuals (n = 79). Serum metabolomics was evaluated by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and the accuracy of the single candidate metabolite biomarkers was further assessed. Machine learning was used to generate the best diagnostic and predictive algorithms. Results Fifty-two serum metabolites were identified as markers of PSC, independent of age, biological sex, cirrhosis, UC, or ursodeoxycholic acid (UDCA) treatment. A diagnostic model based on only six lipids distinguished PSC patients from healthy controls with high accuracy (AUC 0.952 discovery, 0.918 validation), independently of the levels of transaminases or cholestasis markers (i.e., GGT, AP, bilirubin) in blood. Subgroup analyses were performed in PSC patients with and without inflammatory bowel disease (IBD), confirming the model’s consistent performance across both subgroups when compared with their respective control groups – UC and healthy controls (AUC 0.959 and 0.939, respectively). The PSC model also confirmed its diagnostic performance in patients with established PSC-CCA or progression to CCA within 2 years, when compared to UC and healthy controls, showing AUC values ranging from 0.911 to 0.976. Additionally, 20 metabolites were significantly altered in PSC patients with CCA (PSC-CCA), regardless of demographics, cirrhosis, UDCA treatment, IBD status, or CCA subtype, and independently of serum transaminases and cholestatic markers levels. A model incorporating six lipids accurately identified PSC-CCA cases compared to PSC patients (AUC = 0.912 discovery; 0.896 validation), showing excellent performance in early-stage tumor detection (AUC 0.921) and outperforming CA19-9 (AUC 0.708). Importantly, the model retained high accuracy even in CCA patients with low CA19-9 levels (AUC 0.905) and in PSC patients who developed CCA within a year of clinical diagnosis (AUC 0.792). Conclusion The PSC and PSC-CCA blood tests provide a non-invasive approach for diagnosing PSC and PSC-CCA, addressing an important need in this population. Their integration into clinical practice could enhance risk stratification, early detection, personalized surveillance, and treatment decision-making in PSC patients.

Abstract Background and Objectives Cholangiocarcinoma (CCA) is an aggressive, highly lethal cancer of the biliary tract epithelium for which tumor resection is the only curative treatment. However, approximately half of patients present with nonresectable disease and median survival of these patients is just 8-12 months. A significant need exists for tumor-targeted therapeutics for patients with advanced disease who currently have limited treatment options. We aimed to address this need by developing an aptamer-targeted therapy for delivery of siRNAs inhibiting undruggable components of the Hippo pathway, a key driver of cholangiocarcinoma. Method We applied cell-SELEX against human CCA model cell line HuCCTl with negative selection against normal hepatocytes and cholangiocytes to identify an aptamer that selectively bound tumor cells. This aptamer, termed MC7122, was chemically modified to include fluorescent labels that enabled whole-animal biodistribution studies to assess in vivo selectivity. MC7122 was then deployed onto the surface of siRNA-loaded nanovesicles to drive tumor-targeted nucleic acid delivery. Tumor-bearing mice were treated with siRNAs three times per week for two weeks alone or in combination with standard of care chemotherapy. Results Combined treatment with siRNAs and standard of care chemotherapy reduced tumor burden in mice versus vehicle controls and slowed the spread of metastasis. Importantly, we found tumor-specific target gene knockdown without corresponding off-target knockdown in healthy surrounding liver tissue. Further, we demonstrated that sites in the lung, the primary location of metastasis in this model, were reduced not because of global target knockdown in lung but due to tumor-specific knockdown at the site of liver implantation. Conclusions Aptamer-guided vesicles represent a promising platform for targeted therapy delivery for previously undruggable targets. With this platform, tumor-selective therapies can be designed to exhibit exceptionally potent cytotoxicity, as healthy tissues remain unaffected by off-target effects. Future work will focus on refinement of therapeutic siRNA target selection and modification of nanovesicle components for enhanced levels of tumor specificity.

Abstract Background & Objectives Based on the TOPAZ-I study, durvalumab combined with gemcitabine and cisplatin (GemCis) is now supported as a standard of care treatment for cholangiocarcinoma. Patients with extrahepatic cholangiocarcinoma (eCCA) often have underlying autoimmune conditions (AICs) which could restrict immunotherapy use. Treatment patterns in patients with eCCA with AICs and non-autoimmune conditions (NAICs) are reported. Method This retrospective observational analysis of adult patients diagnosed with eCCA in the United States enrolled in the International Cholangiocarcinoma Patient Registry between 2019 and 2023, focused on those treated with durvalumab. The registry contains de-identified data from medical records obtained directly from consenting patients and caregivers. Patients were followed from index date (date of eCCA diagnosis) until the last activity in the database or death. Demographics, clinical characteristics, biomarkers, treatment patterns, and adverse events (AEs) are reported. Results Overall, 135 patients with eCCA were enrolled: 24 (17.8%) had 2:1 AICs and 111 (82.2%) had NAICs. Baseline demographics were comparable between groups: the median (quartile [Q]l-Q3) age at diagnosis was 63.0 (55.0-70.0) years, the mean number of comorbidities in the overall population was 10.1, and 50.4% of patients were female. PD-Ll positivity was noted in 12.6% of patients and HER2 positivity in 10.4%. Of 91 patients with eCCA who received first-line therapy, 34 (37.4%) received GemCis alone, 27 (29.7%) chemotherapy alone (non-GemCis +/- nab-paclitaxel), 9 (9.9%) GemCis plus nab-paclitaxel, 7 (7.7%) durvalumab plus GemCis, 7 (7.7%) durvalumab monotherapy or in combination, and 7 (7.7%) other regimens. Treatment patterns by autoimmune comorbidity status are also reported (Table). Overall, 129 patients (95.6%) had ≥1 AE; fatigue was the most common (71.1%). Conclusion More patients with eCCA received a first-line durvalumab-based regimen post-March 2022 vs the full study period. The use of durvalumab as first-line treatment in this subgroup may suggest that AICs do not restrict its use.

Abstract Background Cholangiocarcinoma (CCA) is an aggressive primary liver cancer with remarkable molecular heterogeneity. Mutations in SWI/SNF chromatin remodeling components occur in &gt; 20% of CCA cases, with ARID1A and PBRM1 being significantly co-mutated. However, how the dual loss of these subunits reshapes chromatin architecture and drives oncogenic programs remains unclear that we aimed to address by profiling SWI/SNF redistribution, chromatin accessibility, 3D chromatin structure, and transcriptome in a dual Arid1a/Pbrm1 knockout mouse model. Methods CCA was induced in Cas9 knock-in mice via biliary instillation of myr-AKT along with sgRNAs targeting Arid1a and Pbrm1, generating APAC cell line. AC cell line was derived from mice receiving myr-AKT alone. Isogenic dual knockout (AC-sgAP) and control (AC-NT) lines were then generated from AC cells. Multi-omics profiling included ChIP-seq for SMARCA4/BRG1 and DPF2, ATAC-seq, RNA-seq, and Hi-C. Results ChIP-seq revealed that AC-sgAP cells showed decreased BRG1 binding (9,217 vs. 20,769 peaks) but increased DPF2 binding (7,527 vs. 2,068 peaks) and co-occupancy (5,037 vs. 1,888 peaks) compared to AC-NT. In contrast, APAC cells exhibited depletion of both BRG1 (12,994 peaks) and particularly DPF2 (146 peaks) with minimal overlap (68 shared peaks). Genome-wide accessibility profiling demonstrated that APAC cells had 78,582 differentially accessible regions compared to AC-NT, the majority (&gt;70%) representing loss of accessibility, whereas AC-sgAP cells showed only 6,587 differentially accessible regions. Transcriptional profiling identified both unique and common significantly differentially expressed genes in APAC and AC-sgAP relative to AC-NT controls. Interestingly, topologically associating domains (TADs) calling revealed that AC-sgAP cells displayed approximately three-fold more differential TADs compared to AC-NT than APAC cells relative to controls. Conclusions Concurrent Arid1a/Pbrm1 loss drives extensive chromatin and transcriptional reprogramming through SWI/SNF redistribution. APAC cells achieving greater transcriptional dysregulation with fewer TAD disruptions might suggest that intra-TAD regulatory changes are critical events in SWI/SNF-mutant cholangiocarcinoma.

Abstract Background and Aims Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, characterized by a poor prognosis and limited treatment options. Potentially curative interventions include surgical resection with negative margins (R0) and liver transplantation. However, despite these treatments, the likelihood of post-surgical recurrence remains high, with 50–70% of patients experiencing disease recurrence within five years. This highlights the urgent need for reliable prognostic biomarkers to guide clinical decision-making and personalize postoperative care. Numerous prognostic biomarkers identified in tumor tissue for CCA have been proposed, but many studies suffer from limitations such as single-center designs, small patient cohorts, and semi-quantitative techniques such as immunohistochemistry. These methods often rely on observer interpretation and antibody specificity, which can compromise objectivity and reproducibility. To overcome these limitations, we aimed to identify and validate robust quantitative prognostic biomarkers for CCA by analyzing tumor mRNA expression, integrating them using machine learning (ML), and developing a web-based tool to predict tumor recurrence and overall survival (OS). Method A systematic literature review was conducted to identify candidate prognostic tissue biomarkers for CCA, which were further validated using Cox proportional hazards (PH) OS analyses in five independent transcriptomic cohorts. An international multicenter cohort of 221 patients undergoing tumor resection was assembled, and tumor mRNA expression was analyzed using high-throughput TaqMan OpenArray RT-qPCR. Associations between clinical and molecular features and recurrence-free survival (RFS) and OS were assessed using Cox PH analyses. Six ML survival models were trained and evaluated using nested cross-validation, followed by feature reduction. Shapley Additive exPlanations (SHAP) values were applied to assess feature importance and enhance model interpretability. Results Among 496 candidate CCA prognostic biomarkers identified from the literature, 52 showed prognostic value in Cox PH analyses across transcriptomic cohorts. In the multicenter validation cohort, integrative Cox PH analyses incorporating clinical variables and gene expression identified 11 genes significantly associated with RFS and 25 with OS. The 11 RFS-associated genes, combined with five clinical variables, were used to train six ML survival models, among which the random survival forest (RSF) model demonstrated the highest predictive accuracy. Following training of RSF models across all combinations of four genes and five clinical variables, and subsequent feature importance–based selection, a final model incorporating three genes (FSCN1, LDHA, and SLC2A1) and four clinical variables (CCA subtype, resection margin status, biological sex, and age at surgery) achieved a testing time-dependent AUC of 0.82. This model significantly stratified patients into high- and low recurrence-risk groups, with a median RFS (mRFS) of 8 months and 70 months, respectively. In addition, an OS prediction model using the same feature set achieved a testing AUC of 0.775 and significantly stratified patients according to 5-year OS risk, with a median OS (mOS) of 23 months in the high-risk group and 77 months in the low-risk group. Conclusion We identified and validated a robust panel of prognostic tissue biomarkers in patients with resected CCA. Integration of these biomarkers with clinical variables into ML-based prognostic models enabled accurate prediction of RFS and OS. The resulting web-based tool allows clinicians to input RT-qPCR results for the validated biomarkers and obtain precise, individualized prognostic predictions for postoperative recurrence and survival.