Targeting Myocardial Energetics in Nonobstructive Hypertrophic Cardiomyopathy (nHCM): The Role of Ninerafaxstat.

Use of Free Light Measurements in Clinical Trials of Novel Agents in Multiple Myeloma.

In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardiomyopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardiomyopathy NHCM. We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption ( O2) and minute ventilation/carbon dioxide ratio (V E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP). Elevations in PCWP (> or = 15 mm Hg), PASP (> or =30 and > or = 40 mm Hg), PADP (> 15 mm Hg) and MPAP (> or = 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP > or = 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP > or = 40 mm Hg (77%/100%), 0.86 for MPAP > 20 mm Hg (83%/79%), and 0.84 for PCWP > or = 15 mm Hg (80%/76%). CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease characterized by unexplained left ventricular hypertrophy, often resulting from pathogenic variants of sarcomeric protein genes. Conventional treatments, such as the use of beta blockers or calcium channel blockers, focus on symptomatic control but do not address the underlying hypercontractility at the sarcomere level. Recent advances in molecular understanding have led to the development of cardiac myosin inhibitors that directly modulate sarcomeric function by reducing myosin–actin cross-bridge formation and adenosine triphosphatase (ATPase) activity. Mavacamten and aficamten have shown promising results in phase 2 and 3 clinical trials, improving symptoms, exercise capacity, and left ventricular outflow tract gradients in patients with obstructive HCM. This review summarizes the current understanding of HCM pathophysiology, diagnostic strategies, and conventional treatments with a focus on the mechanisms of action of myosin inhibitors, clinical evidence supporting their use, and future directions for improvement. We also discuss their potential applications in non-obstructive HCM and the importance of precision medicine guided by genetic profiling.

&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cardiac myosin inhibitors are new medications found to change the course of hypertrophic cardiomyopathy (HCM) by altering cardiomyocyte contractility. This systematic review and meta-analysis aimed to investigate the effects on hemodynamic and cardiac function changes with mavacamten and aficamten in obstructive and non-obstructive hypertrophic cardiomyopathy.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;&amp;nbsp;&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A meta-analysis of randomized controlled trials was conducted following PRISMA standards. We searched PubMed, Scopus, and Cochrane CENTRAL from December 2025 to February 2026 and assessed studies comparing cardiac myosin inhibitors with placebo groups and analyzed results based on hemodynamic and cardiac functional changes, including left ventricular ejection fraction (LVEF), resting left ventricular outflow tract (LVOT), and post-Valsalva LVOT. Other outcomes such as New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, serious adverse events, pVO₂, and NT-proBNP were evaluated. RevMan was used to perform statistical analyses.&amp;nbsp;&lt;/p&gt; &lt;p&gt;&lt;strong&gt;&amp;nbsp;&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Result: &lt;/strong&gt;Seven RCTs, including 883 patients, were analyzed. Treatment with myosin inhibitors demonstrated significant improvement in resting LVOT (MD -59.38, 95% CI: -63.24 to -55.52) and post-Valsalva LVOT gradients (MD -58.05, 95% CI: -67.28 to -48.81) compared with placebo. LVEF decreased significantly in the myosin inhibitor group (MD &amp;minus;4.38, 95% CI &amp;minus;6.71 to &amp;minus;2.06). Myosin inhibitors significantly improved NYHA class (RR 2.15, 95% CI 1.80 to 2.57) and KCCQ scores (MD 7.36, 95% CI 4.71 to 10.01) versus&lt;strong&gt; &lt;/strong&gt;placebo. NT-proBNP&lt;strong&gt; &lt;/strong&gt;was significantly decreased in the myosin inhibitor group (MD -16.61%, 95%CI: -26.85 to -6.38). PVO₂ and serious adverse events were similar between groups.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;&amp;nbsp;&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our systematic review meta-analysis found that myosin inhibitors significantly improved resting and post-Valsalva LVOT gradients, reduced LVEF, improved NYHA class and NT-proBNP, and had similar pVO₂ and serious adverse events compared to placebo.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;&amp;nbsp;&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Key words: &lt;/strong&gt;Myosin inhibitors, hypertrophic cardiomyopathy, mavacamten, aficamten&lt;/p&gt;

Optimizing diastolic filling by pacing in nonobstructive hypertrophic cardiomyopathy

HomeCirculation: Cardiovascular ImagingVol. 10, No. 5A Good Heart Is Hard to Find Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Good Heart Is Hard to FindEven Early in Hypertrophic Cardiomyopathy Dai-Yin Lu, MD and Theodore P. Abraham, MD Dai-Yin LuDai-Yin Lu From the Johns Hopkins HCM Center of Excellence, Baltimore, MD. and Theodore P. AbrahamTheodore P. Abraham From the Johns Hopkins HCM Center of Excellence, Baltimore, MD. Originally published5 May 2017https://doi.org/10.1161/CIRCIMAGING.117.006325Circulation: Cardiovascular Imaging. 2017;10:e006325Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease; yet, despite several decades of research, there is no specific disease-modifying therapy. Patients most often present with reduced exercise tolerance, heart failure, and cardiac arrhythmias. The discovery of specific HCM-causing mutations, advances in molecular medicine, and improved diagnostic techniques have generated substantial interest in identifying new HCM-specific therapies and more importantly determining the optimal timing for initiation of such therapy. Research into mechanisms underlying the clinical symptoms and complications in HCM has varied from genetics to molecular and cellular pathways. For some time, there has been burgeoning evidence that cardiac metabolism may play an important role in mediating the clinical consequences of HCM.1,2See Article by Güçlü et alDecreased efficiency in adenosine triphosphate utilization is a common feature of cardiomyocytes carrying diverse mutations. Crilley et al1 reported a decreased phosphocreatine-to-adenosine triphosphate in 7 HCM carriers without left ventricular hypertrophy by the use 31P spectroscopy, suggesting that a compromised energetic state may play a role in the early manifestation of hypertrophy. We previously demonstrated that myocardial phosphocreatine was significantly decreased by 24% in HCM patients with a β-myosin heavy chain mutation compared with controls; pseudo-first-order creatine kinase rate constant was 26% lower and the forward creatine kinase flux 44% lower in HCM.3 However, in this study, myocardial strain did not correlate with the metabolic indexes. Investigations of cardiac energetics have generally used magnetic resonance spectroscopy.Positron emission tomography (PET) introduces a new level for imaging cardiac pathophysiology using physiological tracers labeled with C-11, N-13, O-15, and F-18, which allow the synthesis of naturally occurring and biologically active compounds. Use of radiolabeled compounds allow for better in vivo quantification of specific biological processes. These PET techniques have unique advantages while investigating the role of cardiac energy metabolism in maintaining cardiac performance as a pump.4 A direct estimate of the tricarboxylic acid cycle using C-11 acetate as a PET tracer can offer insights into myocardial oxidative metabolism. C-11 acetate is rapidly absorbed by myocytes, converted to acetylCoA, and metabolized to CO2 and water through the tricarboxylic acid cycle via oxidative phosphorylation.5 The myocardial clearance rate after intravenous administration of C-11 acetate correlates closely with myocardial oxygen consumption measured by arterial-venous difference of oxygen.6 While metabolic studies with C-11 palmitate or FDG studies are dependent on plasma substrate levels, C-11 acetate metabolism is independent of concentration of energy substrates for the myocardium.7 In the heart, there is close coupling between myocardial oxygen consumption (MVO2) and its mechanical function. Mechanical efficiency is defined as the ratio of useful energy (eg, stroke work) to oxygen consumed and is ≈25% under normal conditions.8 Mechanical efficiency is reduced in heart failure, and increased energy expenditure relative to performed work likely contributes to disease progression.9 Mechanical efficiency is calculated by dividing the estimates of external work (mean arterial pressure, stroke volume, and heart rate) by the product of MVO2 and left ventricular mass. The numerator is obtained via imaging such as magnetic resonance or echocardiography and the denominator (MVO2) by PET-based C-11 assay.In this issue of Circulation: Cardiovascular Imaging, Güçlü et al's10 report investigate myocardial efficiency and energetics in genotype-positive–phenotype-negative HCM subjects (G+P−) versus obstructive HCM patients using cardiac magnetic resonance and 11C-acetate PET imaging. Myocardial external efficiency (MEE) was reduced in G+P− compared with normal controls but was further decreased in obstructive HCM. The authors demonstrate that reduced MEE at the early stage of HCM (G+P−) is largely caused by a decrease in cardiac external work and slight increase in MVO2. At the advanced stage of HCM (hypertrophic obstructive cardiomyopathy [HOCM]), MEE was reduced because of a significant decrease in oxygen consumption per gram tissue.In this study, a reduction in MEE was not accompanied by regional contractile abnormality early in the disease (G+P− had similar peak systolic circumferential strain to controls) but was reduced in HOCM, interestingly, only in the septal but not in the lateral wall. The authors postulate that these nonuniform changes in contractile efficiency were related to the secondary negative remodeling effects of the septal hypertrophy.The authors further investigated the impact of outflow tract obstruction by monitoring changes in myocardial geometry, contractility, and mechanical efficiency pre- and post-myectomy. Compared with aortic stenosis patients undergoing aortic valve replacement, patients with HOCM undergoing septal myectomy had less reverse remodeling, as evidenced by a smaller decrease in left ventricular end-diastolic volume, left ventricular end-systolic volume, and left ventricular mass. Furthermore, there was no significant change in global systolic circumferential strain, MVO2, and MEE post-myectomy, while all parameters improved postaortic valve replacement. The deterioration of MEE post-myectomy was largely related to adverse changes in the septal wall, with small yet significant improvements in the lateral wall.The present study provides a comprehensive profile of energetics, mechanics, and mechanical efficiency, using sophisticated techniques, at different stages of HCM. The authors have significant expertise in this field. They have published several papers on the topic with regards to mutation carriers11 and HCM patients12 with consistent results. The current study complements their previous studies and provides unique incremental insights. Although performed in a cross-sectional design, the authors demonstrate the apparently progressive impairment of myocardial efficiency from genotype-positive carriers to phenotype-positive patients. The current study also enlightens us that reduced efficiency coupled with hypertrophy possibly underlies the wall-to-wall differences in contractile efficiency in HCM.Another incremental piece of information is the issue of the primary myopathy in HCM. Their investigation of post-myectomy and postvalve replacement patients highlights the differences between hypertrophy and secondary myopathy related purely to afterload (aortic stenosis) versus a primary myopathy (HCM). Relief of afterload resulted in significant reverse remodeling in aortic stenosis. Relief of afterload in HCM, on the other hand, did not because factors other than afterload, namely, including the primary myopathy, continue to negatively impact the myocardium.In many aspects, this body of work is personally rewarding because it dovetails well with findings from our HCM cohort. We have independently demonstrated concepts germane to this discussion without the advantage of 11C acetate imaging. We have argued for some time that the primary myopathy in HCM is often ignored. In over 100 post-myectomy HCM patients with significant reductions in left ventricular outflow tract gradients, we demonstrated lack of substantial changes in global systolic strain, despite improvements in symptoms and exercise time.13 The present work showing no change in MEE after myectomy fits well with our findings.There are some issues to be mindful of while interpreting the results of the Güçlü study. The sample size is small particularly for the HOCM subgroup. Given the variability in presentation and post-myectomy evolution, one could suspect that postsurgical remodeling likely encompasses a wider range of response than that seen in the presented cohort. Scar burden (≈4% left ventricular mass in HOCM) is smaller than that noted in our experience and in several other large cohorts.14,15 Again, this is likely a function of the small sample size, and in defense of the authors, a larger scar burden would most likely only magnify the lack of reverse remodeling and inability to improve MEE postsurgery. Diastolic strain rates by magnetic resonance are technically challenging, and their value is uncertain. We do not know the temporal resolution of the scans and, therefore, unsure of the reliability and validity of the diastolic strain data. Echo-derived E/e′ data are similarly controversial. There is evidence that E/e′ does not closely correlate with left atrial pressure.16 On an examination of our cohort of >600 patients, we found that E/e′ was not valuable in predicting clinical outcomes in HOCM but useful in nonobstructive HCM at baseline and in HOCM patients after myectomy.17 Therefore, we feel only the post-myectomy E/e′ data in Table 3 are informative. Overall, their conclusions on diastolic function may need further validation. Mean arterial pressure may not represent true afterload and may underestimate external work in obstructive HCM. Inclusion of nonobstructive and labile-obstructive HCM patients who had similar resting left ventricular outflow tract gradients as controls would have been additionally informative.The issue of microvascular ischemia remains a significant confounder. Others and we have shown significant microvascular ischemia in HCM.18,19 Our previous work demonstrates that a nonobstructive HCM cohort with high rates of adverse clinical outcomes had large scar burden and high prevalence of microvascular ischemia.14 Not knowing the ischemia burden and distribution particularly in the HOCM cohort, pre- and post-myectomy, makes it challenging to understand the implications of the MEE and strain findings. While it is the most feasible method to noninvasively measure MVO2,11C acetate provides only a semiquantitative index of oxidative metabolism. Formulae converting clearance rate constants to equivalents of absolute units were derived from small sample sizes in predominantly normal physiological conditions and, therefore, may not accurately extrapolate to pathological states. Furthermore, factors unrelated to oxygen utilization may influence tracer kinetics. Finally,15O2 is considered the gold standard for noninvasive estimation of MVO2 because oxygen is the final electron acceptor in all pathways of aerobic metabolism. This approach yields absolute values of MVO2 and is impervious to the confounding influence of pathological disease states. However, availability, logistics, and data analysis are challenging, making it unreliable and difficult to apply widely.8The authors raise the possibility of early detection of metabolic abnormalities that may prompt early, prephenotype initiation of metabolic modulators that hold out the promise of modifying the course of disease. In that regard, perhexiline, a metabolic modulator that prompts carbohydrate utilization as the preferential substrate by the cardiomyocyte, has shown some promise in HCM. In 46 nonobstructive HCM patients, perhexiline ameliorated cardiac energetic impairment, corrected diastolic dysfunction, and increased exercise capacity.20 Unfortunately, a larger perhexilene clinical trial was recently terminated, and its wider impact on symptomatic HCM patients may have to wait.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Theodore Abraham, MD, Johns Hopkins HCM Center of Excellence, 600 N Wolfe St, the Johns Hopkins Hospital, Baltimore, MD. E-mail [email protected]

Hypertrophic cardiomyopathy (HCM) represents the most common inherited cardiac disease and a leading cause of heart failure, arrhythmias, and sudden cardiac death in young individuals. For decades, management of HCM has relied on symptom control with β-blockers, calcium channel blockers, disopyramide, or invasive septal reduction in advanced cases. The identification of pathogenic sarcomere variants and the recognition of hypercontractility as a central disease mechanism have paved the way for cardiac myosin inhibitors (CMIs), the first truly disease-specific pharmacological therapy for HCM. Indeed, CMIs represent a revolutionary therapeutic paradigm that redefines the standard of care by translating molecular discovery into clinical application. This review provides a guide to the mechanistic basis of sarcomere modulation, summarizes the clinical evidence for mavacamten and aficamten, and critically evaluates the evolving roles of both medications in obstructive and non-obstructive HCM.

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

Background: Cardiac myosin inhibitors (CMIs) reduce myocardial contractility, alleviating symptoms and improving cardiac function in hypertrophic cardiomyopathy (HCM). They offer a targeted alternative to conventional therapies such as beta-blockers and calcium channel blockers. Research Question: How do cardiac myosin inhibitors compare to placebo (beta-blockers or calcium channel blockers) in improving cardiac structure and function in hypertrophic cardiomyopathy? Methods: A systematic review was conducted according to PRISMA guidelines using PubMed, Google Scholar, Scopus, and ClinicalTrials.gov. Randomized controlled trials (RCTs) assessing CMIs in obstructive and non-obstructive HCM were included. Primary outcomes were changes in Valsalva and resting left ventricular outflow tract gradients (LVOT-G), left ventricular mass index (LVMI), and New York Heart Association (NYHA) functional class. Secondary outcomes included cardiac troponin I (cTnI), left atrial volume index (LAVI), Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS), and NT-proBNP levels. Safety outcomes included treatment-emergent (TEAEs) and serious adverse events (SAEs). Random-effects models were used for pooled analyses. P-value &lt; 0.05 was considered statistically significant. Results: Six RCTs comprising 827 patients (443 CMI vs. 384 placebo) were included. Compared to placebo, CMIs significantly improved NYHA class (RR 2.21; 95% CI: 1.75–2.80; p &lt; 0.00001) and reduced Valsalva LVOT-G (MD −49.41; 95% CI: −53.66 to −45.15; p &lt; 0.00001), resting LVOT-G (MD −42.42; 95% CI: −57.91 to −26.93; p &lt; 0.00001), LVEF (MD −4.74%; 95% CI: −7.22 to −2.26; p = 0.0002), LVMI (MD −21.31; 95% CI: −31.58 to −11.05; p &lt; 0.0001), LAVI (MD −6.94; 95% CI: −8.57 to −5.31; p &lt; 0.00001), NT-proBNP (SMD −13.25; 95% CI: −17.51 to −8.98; p &lt; 0.00001), cTnI (SMD −11.90; 95% CI: −15.07 to −8.72; p &lt; 0.00001), and improved KCCQ-CSS (MD 7.69; 95% CI: 4.92–10.47; p &lt; 0.00001). No significant differences were found in SAEs (RR 1.08; 95% CI: 0.95–1.24; p = 0.24) or TEAEs (RR 1.06; 95% CI: 0.98–1.16; p = 0.15). Subgroup analyses indicated consistent effects across different CMI classes. Conclusion: CMIs significantly improve functional status and reverse structural remodeling in patients with both obstructive and non-obstructive HCM. While a modest decline in LVEF was observed, the overall safety and efficacy profile supports the use of CMIs, particularly in improving patient-centered outcomes.

To describe the emergence of targeted therapies that have led to significant breakthroughs in cancer therapy and completed or ongoing clinical trials of novel agents for the treatment of patients with advanced cancer. The literature was systematically reviewed, based on clinical experience and the use of technologies that improved our understanding of carcinogenesis. Genomics and model systems have enabled the validation of novel therapeutic strategies. Tumor molecular profiling has enabled the reclassification of cancer and elucidated some mechanisms of disease progression or resistance to treatment, the heterogeneity between primary and metastatic tumors, and the dynamic changes of tumor molecular profiling over time. Despite the notable technologic advances, there is a gap between the plethora of preclinical data and the lack of effective therapies, which is attributed to suboptimal drug development for "driver" alterations of human cancer, the high cost of clinical trials and available drugs, and limited access of patients to clinical trials. Bioinformatic analyses of complex data to characterize tumor biology, function, and the dynamic tumor changes in time and space may improve cancer diagnosis. The application of discoveries in cancer biology in clinic holds the promise to improve the clinical outcomes in a large scale of patients with cancer. Increased harmonization between discoveries, policies, and practices will expedite the development of anticancer drugs and will accelerate the implementation of precision medicine. Combinations of targeted, immunomodulating, antiangiogenic, or chemotherapeutic agents are in clinical development. Innovative adaptive study design is used to expedite effective drug development.

Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas. Oncogenes contained within ecDNA can reach high copy numbers and expression levels, and their unequal segregation can result in more rapid copy number changes in response to therapy than is possible through natural selection of intrachromosomal genomic loci. Notably, targeted therapies inhibiting oncogenic pathways have failed to improve glioblastoma outcomes. In this Perspective, we outline reasons for this disappointing lack of clinical translation and present the emerging evidence implicating ecDNA as an important driver of tumour evolution. Furthermore, we suggest that through detection of ecDNA, patient selection for clinical trials of novel agents can be optimized to include those most likely to benefit based on current understanding of resistance mechanisms. We discuss the challenges to successful translation of this approach, including accurate detection of ecDNA in tumour tissue with novel technologies, development of faithful preclinical models for predicting the efficacy of novel agents in the presence of ecDNA oncogenes, and understanding the mechanisms of ecDNA formation during cancer evolution and how they could be attenuated therapeutically. Finally, we evaluate the feasibility of routine ecDNA characterization in the clinic and how this process could be integrated with other methods of molecular stratification to maximize the potential for clinical translation of precision medicines.

BackgroundHypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups.Methods and ResultsWe prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new‐onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow‐up was 3.4±2.8 years. Among the 705 patients with HCM (mean age, 52±15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow‐up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64–4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09–3.45) HCM were associated with more adverse events compared with labile HCM.ConclusionsNonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM.

Efficacy of SGLT2 Inhibitors in Patients With Diabetes and Nonobstructive Hypertrophic Cardiomyopathy

Mesothelin is a cell surface glycoprotein that is present on normal mesothelial cells and overexpressed in several cancers. On immunohistochemical examination of a limited number of ovarian tumors, increased mesothelin expression has been previously noted. The authors evaluated mesothelin expression in 48 patients with ovarian cancer who were screened for participation in phase 1 studies of a recombinant immunotoxin targeting mesothelin. Eligibility criteria for participation in the studies included mesothelin expression by more than 30% of accessible tumor cells. Sections of formalin-fixed paraffin-embedded tumor specimens were evaluated for mesothelin expression by immunohistochemistry using the anti-mesothelin monoclonal antibody K1. Between September 2000 and January 2003, 48 ovarian tumors were analyzed for mesothelin positivity. Mesothelin positivity was noted in 34 of the 48 cases evaluated (71%). These results show that mesothelin is expressed in most epithelial ovarian cancers and that mesothelin expression in ovarian cancers can be evaluated in archival material. Patients whose tumors express mesothelin could be eligible for participation in clinical trials of novel agents targeting mesothelin.

Uterine sarcomas reflect the diversity of sarcoma as a whole. The most common histologies include leiomyosarcoma, high- and low-grade endometrial stromal sarcoma, and adenosarcoma. These are clinically and biologically heterogeneous diseases that are challenging to treat in the advanced setting. Recent advances in our understanding of the cancer biology of uterine sarcomas has improved diagnostic evaluation and therapeutic management. Promising approaches for patients with advanced uterine leiomyosarcoma include targeting DNA damage repair pathways and depleting immunosuppressive macrophage populations. A subset of endometrial stromal sarcomas harbor potentially actionable alterations in the Wnt, cyclin D-CDK4/6-Rb, and MDM2-p53 pathways. There remains an urgent need to translate molecular findings into prospective clinical trials of novel agents for patients with these diseases; progress will depend on academic collaborations and enrollment of patients with uterine sarcoma in biomarker-driven basket studies.