Citations

175 Background: 177 Lu-PSMA-617, a PSMA-directed radionuclide therapy, is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of 177 Lu-PSMA-617 in low volume (LV) and high volume (HV) mCRPC, classified using the CHAARTED criteria. Methods: We conducted a retrospective review of the Mayo Clinic Prostate Cancer Registry, including mCRPC patients treated with 177 Lu-PSMA-617 at Mayo Clinic Rochester, MN, from August 2017 to August 2024. Patients were categorized based on CHAARTED criteria, which define high-volume disease by the presence of visceral metastases and/or four or more bone metastases, with at least one outside the vertebral column and pelvis. PSA-response rate (PSA-RR), overall survival (OS), PSA-progression-free survival (PSA-PFS), and radiographic progression-free survival (rPFS) were analyzed using Kaplan-Meier curves with log-rank tests, as well as uni- and multivariate Cox regression. Results: Of the 264 patients treated with 177 Lu-PSMA-617, 83 were classified as LV (median follow-up: 17.1 months) and 177 as HV (median follow-up: 13.7 months). LV patients had lower serum PSA levels (P < 0.0001), higher hemoglobin levels (P < 0.0001), and a longer time from diagnosis to treatment initiation (10.3 years vs. 7.2 years, P = 0.04). In the HV group, 92% had bone metastases, 60% had lymph node involvement, 54% had both, and 35% had visceral metastases. In the LV group, 64% had bone metastases, 84% had lymph node involvement, 25% had both, and none had visceral metastases. Median OS was 14.4 months for HV patients and 17.6 months for LV patients (P < 0.0001). Median PSA-PFS was 11.4 months for HV patients and 13 months for LV patients. Median rPFS was 9.1 months for HV patients and 10.6 months for LV patients. PSA-RR significantly differed between groups (P < 0.0001). In the HV group, 20% achieved CR (PSA < 0.2 ng/mL), 29% had PR (PSA decreased by ≥50%), 16% experienced SD, and 35% had PD (PSA increased ≥25% from nadir). In contrast, the LV group had 51% achieving CR, 10% achieving PR, 18% with SD, and 11% with PD. Conclusions: Lower disease volume in mCRPC is strongly associated with improved outcomes following 177 Lu-PSMA-617 therapy. These findings suggest that tumor burden is a key predictor of response to PSMA radioligand therapy.

Abstract Tooth enamel, the hardest vertebrate tissue, is crucial for mastication and dental protection. Its formation depends on the enamel organ (EO), a specialized epithelial structure derived from oral epithelium. How uniform oral epithelium differentiates into diverse EO cell types remains unclear. While p63 , an ectodermal development master regulator, is essential for dental placode formation, its specific roles in EO development have been obscured by early arrest in p63 knockout mice. Using single-cell RNA sequencing from mouse incisors, we show p63 expression across all EO cell types with both shared and distinct functions. Through trajectory reconstruction, we identify p63 ’s role in regulating both amelogenic (AmG) and non-AmG lineage commitment during EO development. Comparative transcriptome analyses reveal that p63 regulates the Krt8-to-Krt5 transition during AmG cell differentiation, paralleling its function in skin development. This parallel is reinforced by comparative motif discovery showing shared transcription factor usage, particularly p63 and AP-2 family members. Chromatin accessibility analyses further illustrate that p63 mediates this transition through chromatin landscape remodeling. These findings demonstrate that p63 co-opts the Krt8-to-Krt5 transition mechanism from skin development for EO formation. Summary statement This study reveals how p63 repurposes a skin keratinization mechanism for tooth enamel formation, providing novel insights into how specialized dental tissues develop and potential therapeutic targets for enamel disorders.

AbstractCases of myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) co‐occurring with neoplasms have been reported. In this international, retrospective cohort study in South Korea and the USA, 16 of 445 (3.6%) patients with MOGAD had concurrent neoplasm within 2 years of MOGAD onset, resulting in a standardized incidence ratio for neoplasm of 3.10 (95% confidence interval [CI], 1.77–4.81; P < 0.001) when compared to the age‐ and country‐adjusted incidence of neoplasm in the general population. However, none of the nine tumor tissues obtained demonstrated MOG immunostaining. The slightly increased frequency without immunohistopathological evidence suggest with true paraneoplastic MOGAD is extremely rare.

AbstractEUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS.A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure.A total of 109 patients were included. Technical success was achieved in 108 of 109 (99.1%) and initial clinical success in 106 of 109 (97.2%). Long-term clinical success was achieved in 98 of 109 (89.9%) over a median follow-up of 140 days (range 30–1188). On multivariable analysis (MVA), acalculous cholecystitis (odds ratio [OR] 15.93, 95% confidence interval [CI] 1.22–208.52, P = 0.04) and the occurrence of a LAMS-specific AE (OR 63.60, 95% CI 5.08–799.29, P <0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not.EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P &lt; 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P &lt; 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P &lt; 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P &lt; 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Objective To define the natural history, patterns of recurrence and treatment modalities for local prostate cancer (PCa) recurrence following radical prostatectomy (RP) and radiation therapy (RT), and to investigate factors that could predict metastasis‐free survival (MFS) in this unique patient population. Methods We queried a prospectively maintained PCa registry to identify men developing in‐field recurrence (IFR) following RP and RT from 2008 to 2021 at a single institution. IFR was defined as biopsy‐proven recurrent PCa or the presence of persistent positron emission tomography‐avid lesions in the prior radiation field without evidence of metastasis. Cox regression was conducted to determine predictors of MFS. Kaplan–Meier methods were used to calculate MFS, cancer‐specific survival (CSS) and overall survival (OS) for patients in three primary therapy categories: cryoablation, androgen deprivation therapy (ADT) alone, and surveillance. Results Of 4575 patients from our registry, 108 (2.3%) with IFR were identified. The median (interquartile range [IQR]) time to IFR from salvage treatment was 78 (50–126) months. A total of 29 patients (26%) were managed with cryoablation, 23 (21%) with ADT, and 28 (25%) with surveillance. The median (IQR) follow‐up was 76 (48–100) months. There were no statistically significant differences in MFS ( P = 0.67) or OS ( P = 0.07) among the three primary treatment cohorts. Patients treated with ADT or cryoablation had longer CSS compared to patients managed with surveillance ( P = 0.047). Conclusions We found that IFR may present years after completion of primary treatment for PCa. While curative management strategies may be attempted, local and distant metastatic recurrence is common and often requires systemic therapy.

Background: About 25% of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) have chronic total occlusion (CTO) at non-culprit artery. However, the prognostic impact of CTO in these patients is still unclear. Aims: We aimed to investigate the impact of CTO at non-culprit artery on 1-year mortality in patients with AMI-CS using the multicenter registry of cardiogenic shock. Methods: A total of 1,247 patients presented with cardiogenic shock (CS) were enrolled in the SMART-RESCUE registry between January 2014 and December 2018. After exclusion of non-ischemic cause shock, ischemic cardiomyopathy, failed or no revascularization, vasospasm, and patients undergoing coronary artery bypass surgery, 695 patients underwent percutaneous coronary intervention (PCI). Among these, we analyzed 536 patients with multivessel disease (MVD) according to the presence of CTO at non-culprit artery. The study endpoint was a 1-year all-cause mortality. We also examined the incidence of 1-year cardiac death, and in-hospital death or renal replacement therapy (RRT). Results: A 141 patients (26.3%) of study population had CTO lesion at non-culprit artery. The CTO group had more patients with diabetes mellitus, and lesser patients with ST-elevation myocardial infarction. Although initial left ventricular ejection fraction was lower in CTO group (28.5 vs. 34.1%, P=0.005), initial systolic blood pressure (73.8 vs. 73.2 mmHg, P=0.822) and the level of lactate (6.6 vs. 6.4 mmol/L, P=0.804) were similar in both groups. Venoarterial extracorporeal membrane oxygenation was applied in 206 patients (38.4%), and its use rate was comparable in 2 groups (40.4 vs. 37.7%, P=0.571). Pre- (32.9 vs. 22.9, P <0.001) and post-PCI SYNTAX score (16.7 vs. 5.3, P <0.001) was significantly higher in CTO group. In CTO group, 53 patients (37.6%) had CTO at left main or left anterior descending artery, and only 19 patients (13.5%) in CTO group received PCI for CTO. In multivariate analysis, all-cause mortality at 1-year was significantly higher in CTO group (51.8 vs. 40.5%, hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.09-1.90, P=0.011). The incidences of 1-year cardiac death (45.4 vs. 32.4%, HR 1.55, 95% CI 1.15-2.10, P=0.004) and in-hospital death or RRT (46.8 vs. 36.5%, P=0.031) were also higher in CTO group. Conclusions: Non-culprit CTO lesion was associated with higher 1-year mortality in patients with AMI-CS and multivessel disease.

ABSTRACT Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host’s immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428–e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8 ], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, “rhinocerebral mucormycosis.” A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.