Citations

Abstract Rationale High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

Background: Intracardiac thrombosis (ICT) during liver transplantation (LT) is a rare but life-threatening complication with limited data regarding its risk factors, management, and outcomes. This study aimed to identify factors associated with ICT development, define predictors of intraoperative outcomes, and propose a novel classification and management algorithm for ICT. Methods: A multicenter, international retrospective case-control study was conducted on liver transplant recipients from seven centers between January 2005 and December 2023. ICT cases were identified through transesophageal echocardiography (TEE) or autopsy and matched 1:1 with controls. Results: Among 11 077 liver transplant recipients screened, 133 patients (1.2%) developed ICT. ICT occurred predominantly after reperfusion (58%). Compared to controls, ICT cases exhibited higher preoperative international normalized ratio ( P = 0.001) and fibrinogen levels ( P = 0.014). Post-reperfusion syndrome ( P < 0.001), disseminated intravascular coagulation ( P < 0.001), and primary graft failure ( P = 0.002) were also more common in the ICT group. Continuous veno-venous hemofiltration during surgery (odds ratio [OR] 8.20, 95% confidence interval [CI]: 2.09–38.1; P = 0.004) was associated with ICT development. ICT was associated with markedly higher rates of cardiac arrest ( P < 0.001) and intraoperative mortality ( P < 0.001), with thrombus location in the left heart chambers representing a significant predictor of mortality (OR 20.7, 95% CI: 6.25–81.3; P < 0.001). ICT grades 2 and 3 were associated with a markedly increased risk of intraoperative cardiac arrest ( P < 0.05). Importantly, delayed use of TEE was strongly associated with intraoperative death (OR 6.27, 95% CI: 1.45–27.1; P = 0.014). The 90-day mortality was 43% in ICT cases compared to 4.5% in controls, while 1-year mortality was 46% versus 10.5%, respectively. Conclusions: ICT during LT is a rare but severe complication associated with intraoperative mortality and poor short-term survival. Coagulation profile and intraoperative management play critical roles in ICT development. The early use of TEE enables timely diagnosis and intervention, improving patient outcomes. We propose a novel ICT classification offering a systematic framework for risk stratification and management to mitigate progression and mortality.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Abstract Rationale Pulmonary hypertension (PH) in interstitial lung disease (ILD) lacks approved therapies. Objectives The Pulmonary Vascular Research Institute GoDeep metaregistry collects real-world data of patients with PH from international PH referral centers. Methods Patients with ILD-PH and relevant subgroups (idiopathic interstitial pneumonia [IIP], idiopathic pulmonary fibrosis [IPF]) were stratified by pulmonary vascular resistance (PVR). Kaplan-Meier survival analyses and adjusted Cox proportional hazards models were employed, additionally accounting for immortal time bias, sensitivity analyses, Heller explained relative risk statistics, and target trial emulation framework analysis. Measurements and Main Results Among 34,482 patients, 940 with hemodynamically fully characterized incident ILD-PH (median age, 67 [IQR, 59–74] yr) were identified. A total of 62% had severe ILD-PH with PVR &gt;5 Wood units (WU) and poor survival rates (29% and 18% at 3 and 5 yr), significantly worse than patients with ILD-PH with PVR ≤5 WU and patients with pulmonary arterial hypertension. Survival was poorest in severe IPF-PH. A total of 59% of all patients ILD-PH received PH-targeted therapy, predominantly phosphodiesterase-5 inhibitors (PDE5is). PDE5i treatment was consistently associated with significantly improved survival in patients with severe PH (hazard ratios of 0.537 [0.370–0.781], 0.461 [0.233–0.913], and 0.435 [0.215–0.8] for IIP-PH, IPF-PH, and IIP-PH with nintedanib/pirfenidone background therapy), but not in patients with less severe hemodynamic impairment, supported by sensitivity analyses, Heller statistics, and target trial emulation framework analysis. The survival statistics of patients with PDE5i-treated IIP-PH or IPF-PH were validated in the independent COMPERA registry. Combination therapy with PDE5is and inhaled prostacyclin analogues was superior to monotherapy using PDE5is (hazard ratio, 0.341; 0.205–0.566). Conclusions Prognosis in ILD-PH was generally very poor and was related to PH severity. PDE5i treatment in severe IIP-PH and IPF-PH was associated with improved survival, which is to be further verified in controlled trials.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (&lt;3 vs 3-6 vs &gt;6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer and uterine sarcoma. The NCCN Cervical Uterine Panel meets at least annually to review comments from reviewers within their institutions; examine relevant new data from publications, abstracts, and recent FDA approvals; and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s deliberations on the new FIGO 2023 staging system and updates on the new systemic therapy recommendations for the management of endometrial cancer.

Context.— A clinic was created for patients to review their explanted organs with a pathologist. Objective.— To prospectively investigate the benefits of this type of clinic as perceived by both transplant patients and their pathologists. Design.— In this prospective study, patients participated in a videotaped viewing of heart and/or lung explants by the patient and their guest(s) and pathologist (December 2017–August 2022). Patients received a 3D-printed replica of their explant. After viewing the explanted organ, patients and their guests participated in an interview to assess their experiences. Video-reflexive ethnography was used by pathologists for data collection and practice improvement. Results.— Of 143 patients who viewed their explanted organ, 21 patients consented to having the organ-viewing session taped and to participate in a postviewing interview. The study group was comprised of 12 men; the median age was 57.5 years (range, 29–67 years). Five pathologists took part in reflexive sessions. The clinics were viewed positively by patients, providing an opportunity to better understand their disease. Pathologists had a similarly positive experience and gained important insights to patient journeys. Proposals for improvement were brought forward from both patients and pathologists. Conclusions.— Video-reflexive ethnography provided the opportunity for patients and pathologists to reflect on patient-pathology clinic appointments. This work serves as a template to build out pathology-based clinics.

Background: Lymphaticovenous anastomosis (LVA) is an effective surgical treatment for extremity lymphedema. Indocyanine green (ICG) fluorescent lymphography, the traditional standard for imaging lymphatic vessels, has limitations, including difficulty depicting deeper or congested lymphatics and contraindication in iodine hypersensitivity. This study evaluated contrast-enhanced ultrasound (CEUS) with microbubbles for identifying lymphatic vessels for LVA and compared it with ICG lymphography. Methods: In this single-center retrospective review, intraoperative CEUS with intradermal injection of microbubble suspension (Lumason, Bracco Diagnostics, Inc.) was used in patients before LVA surgery between October 2019 and February 2023. Pre- or intraoperative ICG lymphography was also used to identify target lymphatic vessels. All patients diagnosed with primary or secondary extremity lymphedema who underwent LVA were included. Technical success rate was defined as lymphatic vessels identified by CEUS that led to successful LVAs. Descriptive statistics were used. Results: Thirty-two patients underwent LVA surgery, with a mean age of 58.5 ± 13.9 years. CEUS identified lymphatic vessels in all 32 patients, including 7 in whom ICG failed. Two patients with ICG allergy underwent CEUS only. CEUS identified more candidate lymphatics per patient (5.3 ± 4.2) compared with ICG (2.5 ± 2.7). Of the 182 anastomoses, 96 (52.8%) were identified by both CEUS and ICG, 75 (41.2%) by CEUS only, and 11 (6%) by ICG only. Conclusions: CEUS is a promising tool for identifying lymphatic vessels in patients with lymphedema undergoing LVA, particularly when ICG lymphography is inadequate or contraindicated.