Allegheny General Hospital is a large urban hospital located at 320 East North Avenue in Pittsburgh, Pennsylvania, United States. It is part of the larger Allegheny Health Network.
Myasthenia gravis (MG) is driven by the secretion of autoantibodies from pathogenic B cell maturation antigen (BCMA)-expressing plasma cells. In this phase 2b randomized, controlled, double-blind trial, we evaluated Descartes-08, an autologous BCMA-directed mRNA chimeric antigen receptor T cell therapy, in patients with generalized MG (gMG). Patients (n = 26) were randomly allocated to receive once-weekly intravenous infusions of Descartes-08 (n = 15) or placebo (n = 11) over 6 weeks. The primary endpoint was a ≥5-point improvement in the MG Composite (MGC) score at month 3. Secondary endpoints included the mean change from baseline in MGC, MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) scores by month 12. At month 3, the proportion of patients achieving a ≥5-point improvement in the MGC score was significantly higher for those treated with Descartes-08 compared to placebo in the overall population (66.7% (n = 10/15) versus 27.3% (n = 3/11), P = 0.0472) and in a subpopulation of those positive for autoantibodies to the acetylcholine receptor (63.6% (n = 7/11) versus 12.5% (n = 1/8), P = 0.0258). For patients treated with Descartes-08, the changes from baseline in mean MGC, MG-ADL and QMG scores at month 4 were -7.1, -5.5 and -4.8, respectively, with 83.0% of patients achieving a sustained and clinically meaningful response at month 12. Notably, 33.0% of patients achieved minimum symptom expression (MSE) (MG-ADL score ≤1) by month 6, which was sustained through month 12. Among biologic-naive patients, 55.60% achieved MSE by month 6, which was maintained through month 12 without additional treatment. Descartes-08 was generally safe and well tolerated. Infusion-related reactions were the most common adverse events reported (Descartes-08, 80.0% (n = 16/20); placebo, 56.3% (n = 9/16)). In summary, a single course of six once-weekly infusions of Descartes-08 was well tolerated and resulted in sustained clinically meaningful responses among patients with gMG. ClinicalTrials.gov identifier: NCT04146051 .
BACKGROUND:The "Blueberry-on-Top" phenomenon is a novel echocardiographic strain pattern that has been recently described in patients with apical variant hypertrophic cardiomyopathy (ApHCM). It is identified when there is impaired global longitudinal strain (GLS) with paradoxically advanced time to peak strain (TPS) in a hypertrophied apex with relative sparing of the basal segments. On a standard polar map, GLS will have a pale center while TPS will depict a more robust blue center. OBJECTIVES:While the "Blueberry-on-Top" pattern has been observed in a few prior reports, its true prevalence in patients with ApHCM is currently unknown. We sought to examine the prevalence of this strain pattern among patients with ApHCM. METHODS:A series of patients diagnosed with ApHCM by cardiac MRI were included and compared to a series of normal controls. All patients underwent a standard transthoracic echocardiogram (TTE). For uniform reporting, all echocardiogram studies were post-processed using Tomtec, which is a vendor-independent speckle tracking analysis software. RESULTS:From a cohort of 340 patients with HCM, a total of 15 patients with ApHCM were identified and subsequently compared to 15 normal controls. The "Blueberry-on-Top" pattern was observed in 93% (n = 14) of patients with ApHCM, while none of the normal controls had a "Blueberry-on-Top" pattern. We identified a GLS ratio threshold of 1.26 and a normalized time to peak strain (NTPS) ratio threshold of 0.09. When both thresholds are met, the "Blueberry-on-Top" phenomenon has nearly 100% sensitivity and 93% specificity for the diagnosis of ApHCM. We suggest using these parameters as an adjunctive tool for making the clinical diagnosis of ApHCM and integrating them into a more comprehensive approach. CONCLUSION:The newly recognized "Blueberry-on-Top" strain pattern is unique and can be used as a supportive diagnostic feature in ApHCM.
Abstract Purpose The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated. Methods We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989–2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence. Results Results demonstrated that the prognostic value of Ki-67 PI differed by subgroups defined by WHO grade and Simpson grade. For patients with the same Simpson grade (1–3), the predictive accuracy of Ki-67 PI for 10-year recurrence risk was stronger in WHO-2 than in WHO-1. Within WHO-1 and WHO-2 meningiomas, the predictive accuracy of Ki-67 PI increased with higher Simpson grade (1–3). However, no predictive value was observed in Simpson grade 4 resections regardless of WHO grade. Conclusion These findings highlight that Ki-67 PI should be interpreted in the context of both WHO grade and extent of resection, and, if done so, may offer potential value to refine individualized surveillance strategies in meningioma patients with gross total resection in the initial 10-year postoperative timeframe. Findings cannot be extrapolated beyond 10 years, which may be particularly relevant for WHO-1 tumors with low Ki-67 PI and Simpson grade 1 resection.
Abdominal Aortic Aneurysms (AAAs) are localized expansions of the abdominal aorta with complex growth patterns, which offer challenges in accurately characterizing aneurysm growth and morphological evolution using traditional maximum diameter [Formula: see text] assessments. Alternative geometric indices and advanced modeling techniques have emerged to address the limitations inherent to diameter-based metrics. The objective of the present work is to elucidate AAA growth dynamics by comparing linear and exponential growth models and examining their correlations with changes in a geometry-driven rupture proxy index (GDRPI), emphasizing additional geometric indices beyond [Formula: see text]. In a cohort of 40 patients, exponential models exhibited strong correlations with multiple geometric indices, with aneurysm volume (V) and thrombus-related indices demonstrating high predictive relevance. Thrombus-related indices strongly correlated with the maximum value of GDRPI, highlighting their potential utility as supplementary surveillance markers. Growth trajectories showed substantial inter-patient variability; aneurysms with mean volumes exceeding 75 [Formula: see text] predominantly followed linear growth, while smaller aneurysms with mean volumes of 50 [Formula: see text] displayed ambiguous growth patterns. Mixed effects techniques significantly improved growth prediction accuracy (mean [Formula: see text] for linear growth models and [Formula: see text] for exponential growth models). Although linear models slightly outperformed exponential models, both effectively described patient-specific AAA progression when used with mixed effects techniques. Integrating thrombus-related indices and mixed effects growth modeling offers a promising pathway for enhanced geometric characterization of AAAs under surveillance, potentially improving longitudinal growth assessment and individual monitoring strategies.
Background:Extramammary Paget's disease (EMPD) is a rare malignancy of the skin arising in apocrine gland-rich areas, most commonly the vulva, scrotum, and perianal region. Often misdiagnosed due to resemblance to benign dermatologic conditions, EMPD presents diagnostic and therapeutic challenges. While localized disease usually has a favorable prognosis after surgery, metastatic EMPD is rare, with poor outcomes and limited options. Recent molecular profiling has identified human epidermal growth factor receptor 2 (HER2) overexpression as a potential therapeutic target. We present a clinical series of HER2-positive EMPD treated with targeted therapies and review the literature to assess their role in disease control and outcomes. Case Description:We report two cases of metastatic HER2-amplified vulvar EMPD treated with HER2-directed agents, including trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd), and integrate our findings into a narrative review of reported cases. Both patients achieved clinical benefit from HER2-targeted therapy with disease control across sequential regimens. Conclusions:We describe one of the first documented real-world cases of vulvar EMPD treated with T-DXd, showing a meaningful clinical response. HER2-positive metastatic vulvar EMPD may respond to targeted therapy, and T-DXd appears promising for disease control. Molecular HER2 testing should be incorporated into the diagnostic workup to guide therapy selection in this rare malignancy.
