Citations

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.

Abstract Isatuximab is an immunoglobulin G1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multicenter, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered IV weekly during the first 28-day cycle, and then every other week during cycles 2 to 24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a very good partial response (VGPR) or better. The median time to partial response (PR) or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement, and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing N-terminal pro b-type natriuretic peptide (NT-proBNP) with cardiac involvement. The most common treatment-related grade ≥3 adverse events included lymphopenia (n = 3, 8.5%) and infection (n = 2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis, and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as #NCT03499808.

Abstract Rationale Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (>3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1–3. Conclusions Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.

Objectives: A framework of high-reliability principles was used to identify, investigate, and mitigate infusion pump safety concerns at a large, multisite health care system. We developed a systematic approach to address challenges associated with overinfusions, underinfusions, and the inability to clear upstream occlusion alarms. We identified 112,875 upstream occlusion events for 389,604 infusion starts (failure rate, 29%) within 6 months. Methods: Five high-reliability principles were applied to infusion pump management. Preoccupation with failure emphasized reporting safety concerns and performing appropriate clinical and bench tests. Deference to expertise prompted the development of a multidisciplinary team with internal and external partners. Sensitivity to operations prompted assessment of human factors design, with simulations and analysis of medication-specific factors (e.g., viscosity; infusion rates). Reluctance to simplify prompted assessment of tubing characteristics (e.g., concentricity; wall thickness) with micro–computed tomography and process development for removing faulty equipment. Practice of resilience ensured ongoing engagement and commitment to a culture of safety and patient advocacy. Results: The multidisciplinary oversight team prompted a national recall, removal of malfunctioning pumps, and development of system-wide training and mitigation protocols. Despite ongoing pump challenges, our team optimized internal patient safety systems and processes. The cause of these malfunctions remains under investigation, but serious patient harm has been prevented. Conclusions: Key strategies for enhancing patient safety were continuous vigilance, interdisciplinary collaboration, and embracing complexity in a large health care organization. Future directions involve deeply integrating these high-reliability principles across all aspects of health care delivery to continue improving safety and quality outcomes.

Abstract Objectives Determine differences in quantitative stenosis severity measurements for ultra-high-resolution (UHR) photon-counting detector (PCD) coronary CT angiography (cCTA) relative to energy-integrating detector (EID) cCTA in a large patient cohort. Methods Adult participants seen between November 2022 and March 2023 underwent a clinical dual-source EID-CT cCTA and a research dual-source PCD-CT cCTA on the same day. Percent diameter stenosis (PDS) was measured, and stenosis severity was assigned based on the PDS of the most severe lesion per patient to determine a coronary artery disease reporting and data system (CAD-RADS) score. Agreement between EID-CT and PCD-CT for PDS and CAD-RADS was determined. Results A total of 112 participants were enrolled, yielding 82 subjects with at least 1 stenosis at PCD-CT (mean age, 68.0 ± 10.8 years; 69.5% [57/82] males). A total of 177 paired stenoses were quantified. The percent decrease in mean PDS from PCD-CT (24.3%) to EID-CT (29.4%) was 17.3% (median difference in PDS: −5.0%, 95% CI: −5.7% to −4.0%). The assigned CAD-RADS score changed in 31/82 subjects. In 11/31 subjects, the most severe stenosis was missed at EID-CT due to partial volume averaging of a small calcification, yet PCD clearly identified stenosis at those locations. In 20/31 subjects, the CAD-RADS score decreased at PCD-CT due to the decreased calcium blooming resulting from the improved spatial resolution. Conclusions UHR PCD cCTA decreases quantitative measures of stenosis severity when a stenosis is identified at EID, leading to decreases in CAD-RADS assignments. Advances in knowledge With its improved spatial resolution, PCD-CT identifies stenoses missed on EID-CT.

Abstract Objectives Family caregivers (FCGs) may experience numerous psychosocial and practical challenges with interpersonal relationships, mental health, and finances both before and after their care recipient (CR) dies. The specific challenges affecting rural FCGs who often have limited access to palliative care services, transitional care, and other community resources are not well understood. The purpose of this paper is to quantify the challenges rural FCGs experienced immediately before the death of a CR and continuing into the bereavement period. Methods A secondary analysis of data from a randomized controlled trial was conducted. The 8-week intervention included video visits between a palliative care research nurse and FCGs caring for someone with a life-limiting illness. Data were from structured interviews during nurse visits with FCGs in the intervention arm whose CR died during the intervention period. Results Ninety (41.8%) of the 215 FCGs experienced the death of their CR. The majority of FCGs were female (58.9%), White (97.5%), spouses or partners (55.6%) and lived with the CR (66.7%). Most FCGs (84%) continued with intervention visits by the study nurse after the CR’s death. Visits resumed on average 7.2 days post-death. The majority of FCGs experienced challenges with grief/coping skills (56%) and interpersonal relationships/support systems (52%) both pre- and post-death of the CR. FCGs also experienced practical challenges with income/finance, housing, and communication with community resources both pre-and post-death. Significance of results Bereavement support should extend beyond a focus on grief to include practical challenges experienced by FCGs. Because challenges experienced in the bereavement period often begin before a CR’s death, there is benefit in continuity of FCG support provided by a known clinician from pre- to post-death. When given an option, many rural FCGs are open to bereavement support as early as a week after the death of a CR.

Abstract Background Disruption of the blood–brain barrier (BBB) in high-grade brain tumors is characterized by contrast accumulation on diagnostic imaging. This window of opportunity study correlates contrast imaging features with the tumor distribution of BBB-permeable (levetiracetam) and -impermeable (cefazolin) drugs. Methods Patients with a clinical diagnosis of a high-grade brain tumor underwent MRI for surgical planning. Cefazolin and levetiracetam were administered prior to skin incision, and serial plasma and image-registered tumor samples were collected during the operation. Drug levels were measured by LC-MS/MS, tissue drug levels were corrected for residual blood, and tumor-to-plasma concentration ratios were calculated. Intraoperative microdialysis was performed in a subset of patients to measure the same two drugs. Results Tumor (n = 125) and plasma (n = 261) samples were available for analysis from 42 operative cases. Across all samples, the tumor-to-plasma ratio was significantly lower for cefazolin (marginal mean [MM]: 0.15, 95% CI: 0.11–0.19) as compared to levetiracetam (MM: 0.70, 95% CI: 0.64–0.75; P < .001). When compared between contrast-enhancing and non-enhancing regions, tumor-to-plasma ratios for cefazolin varied by 4.4-fold (0.27, 95% CI: 0.20–0.35 vs. 0.06, 95% CI: 0.04–0.08, respectively; P < .001), and varied for levetiracetam by 1.4-fold (0.88, 95% CI: 0.78–0.97 vs. 0.61, 95% CI: 0.55–0.66, respectively; P < .001). These results were confirmed with the intra-operative microdialysis and a population pharmacokinetic analysis. Conclusions This study demonstrates significant inter- and intra-tumoral heterogeneity in drug delivery for both levetiracetam and cefazolin within high-grade brain tumors that is not necessarily predicted by clinical MR imaging and may reflect tumor-induced changes in both perfusion and BBB integrity.

Abstract Uterine fibroids (leiomyomas) and adenomyosis are among the most common benign gynecological conditions affecting women of reproductive age. These disorders are frequently associated with abnormal uterine bleeding, pelvic pain, pressure symptoms on adjacent pelvic organs, and potential infertility. The incidence of fibroids increases as women enter their third and fourth decades of life. In parallel, recent trends in delayed childbearing have further emphasized the need for fertility‐preserving treatment options. Notably, fibroids have a higher prevalence in African‐American women, highlighting a significant disparity in health needs compared to white women. Historically, hysterectomy and myomectomy were considered definitive treatments. However, these procedures carry inherent surgical risks, longer recovery periods, and, in the case of hysterectomy, a complete loss of reproductive potential. Consequently, there is increasing demand for uterus‐sparing, minimally invasive alternatives that provide effective symptom control with lower morbidity and preservation of fertility. Among the evolving treatment options, three image‐guided, minimally invasive therapies have gained particular attention: Uterine Artery Embolization (UAE), Radiofrequency Ablation (RFA), and High‐Intensity Focused Ultrasound (HIFU). Uterine Artery Embolization (UAE), also known as uterine fibroid embolization (UFE), is a well‐established endovascular procedure in which embolic agents are introduced via catheterization of the uterine arteries, inducing ischemia and infarction of fibroids. Performed under conscious sedation or regional anesthesia, UAE has demonstrated significant reductions in fibroid volume and symptom relief in over 80% of appropriately selected patients. All image‐guided techniques are especially beneficial for women who desire uterine preservation, have contraindications to surgery, or wish to avoid major operative interventions. In comparison with UAE, Radiofrequency Ablation (RFA) uses targeted thermal energy to induce coagulative necrosis within fibroid tissue. This approach can be delivered via laparoscopic, transcervical, or transvaginal routes, depending on the platform. The Sonata® System integrates intrauterine ultrasound guidance with energy delivery, enabling precise fibroid targeting with minimal myometrial damage. RFA is associated with shorter recovery and less intraoperative blood loss, though it is more suitable for smaller or fewer fibroids and may be less ideal for extensive disease. Together, these advancements reflect a paradigm shift in fibroid management—driven by demographic trends, racial disparities, patient preferences, and technological innovations—toward evidence‐based, uterus‐preserving therapies tailored to individual patient needs. This article discusses details of each technique including the procedure, benefits and complications and also the impact on particular situations such as pregnancy. Some key points common to each technique are also mentioned.

Importance Cardiovascular (CV) disease is the leading cause of death globally for both men and women, yet women remain historically underrepresented in CV clinical trials, despite facing a disproportionately high burden of morbidity and mortality in many forms of CV disease. Objective To determine the representation of women across a broad range of CV trials. Evidence Review The participation of women in CV trials registered on ClinicalTrials.gov from 2017 to 2023 was systematically determined through the extraction of publicly available information. Data were extracted to identify the country of study, disease type, trial size, clinical intervention, and age of the participants. The proportion of women and the ratio of number of female to male participants (F:M ratio) were calculated for each trial. The women’s participation:prevalence ratio (PPR) was estimated for each trial based on the relative prevalence of the disease by sex in the specified region. Findings A total of 1079 registered CV trials were identified, including 1 396 104 participants, of whom 571 641 (41.0%) were women. The F:M ratio was significantly lower for studies on arrhythmia (median [IQR], 0.5), coronary heart disease (median [IQR], 0.39 [0.33-0.70]), acute coronary syndrome (median [IQR], 0.32 [0.24-0.51]), and heart failure (median [IQR], 0.51 [0.32-0.87]) but higher for obesity (median [IQR], 1.44 [1.08-4.50]) and pulmonary hypertension (median [IQR], 2.86 [1.50-3.97]) trials. The F:M ratio was higher for trials on lifestyle interventions (median [IQR], 1.51 [0.77-3.24]) than for drug trials. PPRs were low for clinical trials on coronary heart disease (median [IQR], 0.66 [0.50-0.86]), acute coronary syndrome (median [IQR], 0.79 [0.51-0.87]), and stroke (median [IQR], 0.74 [0.61-0.95]). Representation of women in CV trials varied by disease state, region, intervention, and sponsor type. Conclusions and Relevance These findings highlight both progress and persistent challenges in representation of women within CV trials. These gaps not only limit the generalizability of trial outcomes but also perpetuate inequities in evidence-based care for women with CV conditions.

BACKGROUND: Whereas antiphospholipid syndrome (APS) is best known for increasing the risk of macrovascular thrombosis, APS vasculopathy is characterized by the abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of small blood vessels in the skin, kidneys, and heart, among other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. METHODS: To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing. CCN1 (cellular communication network factor 1) and CCN2 were identified in skin and kidney biopsies by immunofluorescence microscopy and in plasma by ELISA. Healthy dermal MVECs were cultured with APS patient–derived serum or immunoglobulin G (IgG), and relevant signaling pathways were characterized using quantitative PCR, immunoblotting, and immunofluorescence microscopy. The proliferation and migration of vascular smooth muscle cells were determined after exposure to conditioned medium from APS IgG–stimulated MVECs. A mouse model of APS IgG–accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model. RESULTS: Increased endothelial cell expression of CCN1 and CCN2 was identified by single-cell RNA sequencing and further confirmed in APS skin by microscopy as well as in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered the upregulation of CCN1 and CCN2 via Toll-like receptor 4– and YAP1 (yes-associated protein 1)–mediated signaling. CCN2, originating from APS IgG–stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, phenotypes that were inhibited by an anti-CCN2 antibody or depletion of EGFR (epidermal growth factor receptor). We further observed increased expression of CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with an anti-CCN2 monoclonal antibody significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG–accelerated neointima formation. CONCLUSIONS: This study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and vascular smooth muscle cells. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy, providing potential therapeutic targets for patients.