Citations

Introduction: Hypertrophic cardiomyopathy (HCM) carries substantial lifelong morbidity. Mutations in sarcomeric proteins that lead to HCM cause excess contractility, poor relaxation, and inefficient energy utilization. Although obstructive physiology is a prominent feature of disease, approximately 30% of HCM patients experience symptoms in the context of non-obstructive HCM (nHCM). Management options are extremely limited with little other than cardiac transplantation to offer severely affected patients. Mavacamten (MAVA), a first-in-class small molecule, is a selective modulator of cardiac myosin that inhibits the cardiac myosin ATPase to reversibly attenuate cardiac contractility. In addition to its effects on contractility, MAVA has been shown to improve LV compliance in preclinical and clinical studies. The Phase 2 MAVERICK-HCM study is designed to evaluate safety and tolerability, and to provide pilot data on the effects of MAVA on biomarkers, cardiac function, and exercise capacity in nHCM. Methods: This double-blind study will enroll 60 individuals with nHCM (Left ventricular outflow tract gradient <30 mmHg; resting or provoked), NYHA Class II or III, and LVEF ≥55%. Subjects will be randomized 1:1:1 to one of two target plasma drug concentrations (Group 1: ~200 ng/mL and Group 2: ~500 ng/mL) or placebo for 16 weeks. The starting dose of MAVA is 5 mg, with one-step dose titration at Week 6 based on plasma drug concentration. Predefined criteria, including LVEF, will guide study drug discontinuation if indicated. Cardiopulmonary exercise testing will be performed at baseline and Week 16 to assess the impact on exercise capacity. The primary endpoint is the frequency and severity of treatment-emergent adverse events. The study design also includes multiple secondary endpoints including echocardiographic measures of diastolic function, NT-proBNP levels, patient reported outcomes, and physical activity by wearable accelerometer. An independent data monitoring committee will oversee safety. Conclusions: MAVERICK-HCM is testing a novel therapy to improve symptom burden in nHCM; a patient cohort currently lacking effective treatment. By targeting a core molecular mechanism of disease, MAVA has the potential to alter natural history.

Intracellular Ca 2+ regulation in human airway smooth muscle (hASM) involves plasma membrane (PM) Ca 2+ influx, including that triggered by sarcoplasmic reticulum (SR) Ca 2+ depletion, i.e. store‐operated Ca 2+ entry (SOCE). While transient receptor potential channels (e.g. TRPC3, TRPC4) are thought to mediate SOCE, the mechanisms triggering or regulating SOCE are being actively investigated. Recent studies suggest that stromal interaction molecule 1 (STIM1) acts as a signaling mediator between PM and SR, potentially regulating Ca 2+ entry via SOCE. In hASM, fluorescence microscopy and western blot analyses were used to verify the presence of STIM1. SR Ca 2+ depletion with 10μM cyclopiazonic acid (CPA) resulted in increased STIM1 expression in the PM fraction, compared to controls. Transfection with 50nM STIM1 siRNA for 48h significantly decreased STIM1 levels. In cells where [Ca 2+ ] i was measured using fura 2‐AM, SOCE was significantly reduced in cells transfected with STIM1 siRNA. Green‐fluorescent protein (GFP)‐tagged STIM1 transfection showed intracellular localization in non‐stimulated cells, with increased PM staining following CPA exposure. Subsequent immunostaining revealed co‐localization of STIM1 with TRPC3 and TRPC4. These results indicate that STIM1 is present in hASM and suggest a role for this protein in regulating SOCE. This work has been supported by NIH grants UL1RR024150‐01(CR to CMP, CR20 and Early Career Development Award to YSP), HL74309 (GCS), and the Department of Anesthesiology (CMP, YSP), Mayo Clinic College of Medicine, Rochester, MN

AbstractNeuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Background: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. Methods: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. Conclusions: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03470545.

Purpose We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume. Patients and Methods Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years. Results In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade ≥ 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001). Conclusion The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS.

Introduction: The advent of digital slides offers new opportunities within the practice of pathology such as the use of image analysis techniques to facilitate computer aided diagnosis (CAD) solutions. Use of CAD holds promise to enable new levels of decision support and allow for additional layers of quality assurance and consistency in rendered diagnoses. However, the development and testing of prostate cancer CAD solutions requires a ground truth map of the cancer to enable the generation of receiver operator characteristic (ROC) curves. This requires a pathologist to annotate, or paint, each of the malignant glands in prostate cancer with an image editor software - a time consuming and exhaustive process.Recently, two CAD algorithms have been described: probabilistic pairwise Markov models (PPMM) and spatially-invariant vector quantization (SIVQ). Briefly, SIVQ operates as a highly sensitive and specific pattern matching algorithm, making it optimal for the identification of any epithelial morphology, whereas PPMM operates as a highly sensitive detector of malignant perturbations in glandular lumenal architecture.Methods: By recapitulating algorithmically how a pathologist reviews prostate tissue sections, we created an algorithmic cascade of PPMM and SIVQ algorithms as previously described by Doyle el al. [1] where PPMM identifies the glands with abnormal lumenal architecture, and this area is then screened by SIVQ to identify the epithelium.Results: The performance of this algorithm cascade was assessed qualitatively (with the use of heatmaps) and quantitatively (with the use of ROC curves) and demonstrates greater performance in the identification of malignant prostatic epithelium.Conclusion: This ability to semi-autonomously paint nearly all the malignant epithelium of prostate cancer has immediate applications to future prostate cancer CAD development as a validated ground truth generator. In addition, such an approach has potential applications as a pre-screening/quality assurance tool.

We report three cases of solitary fibrous tumor (SFT) arising in the orbit. All patients presented with nontender swelling of the affected eye, and one patient presented with nasolacrimal duct obstruction. All three patients had well-circumscribed tumors that had histologic features identical to those of SFT of the pleura (fibrous mesothelioma). The neoplastic cells were purely fibrogenic. They were reactive with antivimentin and CD-34 and demonstrated no smooth muscle or neural differentiation (nonreactive with antibodies to actin, desmin, and S 100 protein). KP-1 (CD-68) immunoreactivity was present focally within the neoplastic cells in all three tumors; however, it was strongly positive within tumor infiltrating macrophages. Electron microscopy per formed on one tumor showed fine fibroblastic differentiation with phagocytic activity confined to infiltrating macrophages. SFT of the orbit is a distinct pathologic entity that merits distinction within the broad group of orbital fibrous tumors. Int J Surg Pathol 2(3):193-198, 1995