Citations

Background and Aims: Cholangiocarcinoma (CCA) is one of the most lethal cancers, characterized by molecular heterogeneity and treatment resistance. To uncover new biological signals and therapeutic opportunities, we employed multiomic characterization combined with machine learning. Approach and Results: We profiled all anatomical CCA subtypes using whole exome sequencing, mRNA sequencing, and proteome/phosphoproteome analysis. Integrative dimensional reduction revealed RNA, protein, and phosphoprotein features driving tumor heterogeneity, enabling clustering. Machine learning algorithms identified molecular features for each cluster and mapped external datasets and patient-derived xenograft (PDX) models onto these clusters. Kinase enrichment analysis highlighted targetable kinases active in each cluster. In vivo validation was performed in cluster-specific PDX models using the selective TNK1 inhibitor, TP-5801. We identified 3 molecular clusters with distinct pathway characterization: immunomodulatory (cluster 1), metabolic (cluster 2), and gene regulation/cellular fate (cluster 3). Cluster assignment was independent of anatomic subtype but correlated with overall survival following curative-intent resection. We also identified multiomic features and pathways linked to overall survival and lymph node metastases, crucial for patient treatment selection. Kinase enrichment analysis pinpointed TNK1 as a highly active kinase in the metabolic cluster. Treatment with TP-5801 significantly reduced tumor growth in a metabolic PDX model, but not in models representing the other clusters. Combining internal data with publicly available datasets, we identified the immunomodulatory cluster as most responsive to gemcitabine/cisplatin therapy, confirmed in vivo using cluster-specific PDX models. Conclusions: Integrated multiomic characterization provides translational insights by defining unique molecular subtypes associated both with therapeutic response and overall clinical outcomes. This approach identified TNK1 as a previously unrecognized therapeutic target in a defined subset of CCA tumors.

Abstract Invariant Natural Killer T (iNKT) cells recognize glycolipid antigens presented on CD1d and rapidily respond to direct immune responses. iNKT cells develop in the thymus and migrate to peripheral tissues in what has been presumed to be differentiated/committed states. Accordingly, colonic iNKT cells are established in early life, considered to remain ‘fixed’ post-weaning, and determine life-long colitis susceptibility. Using single cell RNA sequencing (scRNA-seq), we demonstrate that humans and mice contain colonic iNKT populations transcriptionally resembling immature and intermediate thymic iNKT precursors. Contrary to prevailing paradigms, we demonstrate colonic iNKT cell populations expand in adult mice when CD1d expressing colonic goblet cells form goblet cell-associated antigen passages. Expansion preferentially affected intermediate iNKT cells, was durable, and protective in a colitis model. These studies reveal that the adult colon harbors iNKT cells with retained plasticity and uncover a novel role for goblet cells as unconventional antigen presenting cells regulating this axis.

PURPOSE Given the extended survivorship of young adults with breast cancer, characterizing health care utilization and adherence to surveillance guidelines can inform gaps in care. PATIENTS AND METHODS Patients age 40 years and younger at diagnosis of stage 0-III breast cancer enrolled in a prospective cohort study completed a survey 7 years after diagnosis assessing receipt of care and surveillance. We evaluated factors associated with transition to a primary care provider (PCP) for cancer-related follow-up and adherence to mammography and bone density scans. RESULTS Among 660 women, 92% reported having a PCP, although for cancer-related follow-up, 57% saw only an oncology provider, 29% saw both a PCP and oncology provider. In the past 2 years, 68% reported getting a flu shot, 76% a pap test/pelvic examination, 56% cholesterol screening, and 42% (n = 232 endocrine therapy [ET] users) a bone density scan. Among women who had a unilateral mastectomy or lumpectomy (n = 356), 82% reported a mammogram in the past year. In multivariate analyses, those with stage 0 ( v I disease) were more likely to see a PCP for follow-up ( v PCP + oncology provider); ET users and those more concerned about recurrence were less likely. Patients with human epidermal growth factor receptor 2-positive (HER2) disease were more likely to adhere to mammography; those with a BRCA mutation and those with a unilateral mastectomy were less likely. Patients with a BRCA mutation and who had chemotherapy were more likely to report a bone density scan. CONCLUSION Although most have a PCP, over half of young survivors continue to see an oncology provider for follow-up in long-term survivorship. Mammography uptake was high; uptake of other health maintenance practices was lower. Identification of barriers/facilitators to receipt of guideline-concordant care may inform strategies to optimize survivorship.

Abstract Background Opioid stewardship policies could adversely affect pain management for patients with cancer. Yet patients with cancer are also at risk for opioid‐related harms. This study sought to determine trends in opioid prescribing by clinical stratum and pain for patients with cancer from 2016 to 2020. Methods A retrospective study was conducted of opioid‐naive adults with newly diagnosed cancer from 2016 to 2020 ( N = 10,232) in a large Connecticut health system. Logistic regression was used to calculate changes in the predicted probability of opioid prescribing from 2016 to 2020. Two subpopulations were examined: patients treated surgically ( n = 4405) and patients with metastatic cancer ( n = 2158). Flowsheet pain scores for patients with metastatic cancer were used to stratify by no pain (all scores, 0) versus any pain. The main outcomes were new (≥1 prescription in the 0–6 months after diagnosis) and additional (0–6 and 7–9 months) opioid prescriptions. Results A decline was observed in the predicted probability of new (71.1% to 64.6%; p < .001) and additional prescribing (27.2% to 24.2%; p = .07 [not significant]) declined. Among surgical patients, the predicted probability of new opioid prescribing fell (96.0% to 88.6%; p < .001), whereas additional prescribing was stable (13%). For patients with metastatic cancer with pain, new opioid prescribing was stable (56%). For those reporting no pain, the predicted probability of new opioid prescribing declined from 61.6% to 36.1% ( p < .001). Conclusions In the context of widespread policy changes, this study showed a modest decline in new and additional opioid prescribing for patients with cancer. In metastatic cancer, prescribing remained stable for patients reporting pain and declined steeply for those reporting no pain.

Abstract Background Breast cancer (BC) survivors frequently experience sleep disturbances, which may persist for many years after treatment. This study aimed to describe trends in sleep-related symptoms over time and identify factors that may be associated with sleep disturbances in BC survivors. Patients and Methods Adult patients from the Mayo Clinic Breast Disease Registry were surveyed annually for up to 7 years post-diagnosis. Sleep disturbance severity was assessed using numeric rating scales for difficulty falling and staying asleep. Data from 3354 unique patients were analyzed, excluding those with metastatic disease or recurrence. Univariable and multivariable analyses were performed at the 1-year survey timepoint to evaluate disease and patient-related factors that were associated with increased sleep-related symptoms, and these factors were also assessed in relationship to sleep-related symptoms over time. Results In multivariable analyses, more trouble falling asleep was associated with financial insecurity, higher clinical stage, more cigarettes smoked per day, and less weekly exercise. More trouble staying asleep was associated with older age, race, advanced education, financial insecurity, and higher clinical stage. Over time, there was a nonsignificant trend toward increased trouble falling asleep and fluctuations in trouble staying asleep. Higher clinical stage and receipt of radiotherapy were associated with decreased severity in trouble falling asleep over time, while more cigarettes smoked per day was linked to increased severity in trouble staying asleep. Conclusions These findings highlight the complex interplay of clinical, lifestyle, and demographic factors in sleep disturbances among BC survivors, underscoring the need for tailored sleep management strategies.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P &lt; 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Background/Objectives: This study aims to evaluate the quality of life (QoL) and oncological outcomes in premenopausal women diagnosed with hormone receptor-positive breast cancer who are receiving either bilateral oophorectomy (BO) or gonadotropin-releasing hormone agonist (GnRH) therapy. Both methods serve to inhibit ovarian function, which is essential for the management of estrogen-dependent tumors; however, their effects on QoL have yet to be fully clarified. Methods: Data were analyzed from the Mayo Clinic Breast Disease Registry, focusing on women under 55 diagnosed with estrogen receptor-positive breast cancer who received either BO or GnRH within one year of diagnosis. QoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10) at baseline and annually for five years. Results: A total of 181 patients were enrolled in the study; 40 into the BO group and 141 to the GnRH group. Both groups exhibited similar levels of sexual dysfunction after a one-year period; however, the BO group stated a higher frequency of hot flashes. PROMIS-10 scores improved in both mental and physical health over time, with no significant differences between the groups. Within the BO group, one recurrence was observed, in contrast to the GnRH group, which had six events. Nonetheless, the difference in recurrence rates did not reach statistical significance. Conclusions: The long-term QoL and oncologic outcomes for premenopausal women with hormone receptor-positive breast cancer were similar for BO and GnRH therapy. These findings emphasize the need for individualized treatment decisions, considering patient preferences and side effects.

Background/importance Spinal cord stimulation (SCS) is an established therapy for chronic pain conditions when conventional treatments fail. However, global research implementation varies significantly due to patient demographics, healthcare infrastructure, and economic factors, creating disparities in access that directly impact patient care and public health outcomes. Objective To evaluate the global landscape of SCS research by analyzing patient demographics, geographic distribution, funding sources, and pain conditions treated across chronic pain populations aged 18 years and older, with primary focus on associations between geographic regions and patient age demographics. Evidence review We conducted a systematic literature review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, searching five major databases through October 2024. Studies from 2000 onward reporting SCS in adults with chronic pain lasting 3 months or longer were included. We included randomized trials, comparative studies, and case series with at least 10 patients, excluding commentaries, reviews, and insurance databases. Findings Analysis of 187 studies revealed heterogeneity in age distributions across geographic regions, with Asian studies showing higher mean ages compared to North America, while European showed lower mean ages. Research concentration was predominantly in high-income regions, with 57% of studies receiving industry funding and significant associations between funding source and geographic origin. Post-surgical pain syndrome-thoracolumbar emerged as the most prevalent condition globally, representing 44.9% of cases. Conclusions Significant associations exist between geographic regions and patient demographics in SCS research, with notable disparities in research concentration highlighting the need for broader investigation in underrepresented areas to optimize global application of this chronic pain management therapy. PROSPERO registration number CRD42025635147.