Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Qualitative comparison of coronary angiograms between 4 French catheters with an advanced cardiovascular injection system and 6 French catheters with manual injection.

OBJECTIVES: This study aimed to test whether advanced cardiovascular injection (ACI) via 4 French (Fr) catheters is more advantageous than manual injection with 6 Fr catheters. BACKGROUND: For coronary angiography, proponents of contrast media ACI believe it utilizes smaller-diameter catheters when compared with manual injection, without compromising the quality of the angiogram, and has the potential to reduce the amount of contrast used and lessen the use of closure devices. METHODS: In a prospective study, 200 consecutive patients referred for elective coronary angiography were randomized to standard 6 Fr catheters with manual injection versus 4 Fr catheters with ACI. The study's primary endpoint is the quality of the coronary angiogram. Secondary endpoints include groin complications, utilization of closure devices, and volume of contrast media. Thirty-six patients who underwent ad hoc percutaneous coronary intervention were excluded from the analysis. RESULTS: The final analysis included 80 patients treated with 4 Fr catheters with ACI and 84 patients treated with 6 Fr catheters with manual injection. The groups had similar demographic and clinical characteristics. The quality of the angiogram was similar between groups with the exception of more left coronary sinus flush with 4 Fr catheters (3.57 ± 1.1 vs. 2.98 ± 0.9, P < 0.001) and less closure device use with 4 Fr (25 vs. 71.4%, P < 0.01) compared to 6 Fr catheters. The procedure duration, volume of contrast used, vascular complications, and time to ambulation were similar between groups (all P > 0.05). CONCLUSIONS: 4 Fr diagnostic catheters with ACI offer similar quality coronary angiograms, similar rates of vascular complications, procedure duration, contrast used, and time to ambulation, but have a significantly lesser need for closure devices compared to the 6 Fr system with manual injection.

Simple and economical HandClench Relaxometer device for reliable and sensitive measurement of grip myotonia in myotonic dystrophy.

Grip myotonia and weakness are attractive treatment response biomarkers in clinical trials of myotonic dystrophy type 1 (DM1). There is a need to develop simple, patient-friendly and reproducible methods of quantifying grip myotonia in multisite trial settings. We designed a HandClench Relaxometer (HCR) that measures grip myotonia and strength. In contrast with the existing quantitative myometry (QMA) setup, the HCR is portable, economical, can be used with any laptop and generates automated command prompts. We demonstrate the feasibility and reliability of HCR device in twenty DM1 individuals and ten age-matched controls; patients returned for follow up within two months. The device showed excellent day to day reproducibility (ICC >0.80) in patients. The HCR device detected myotonia in milder muscle disease and measured longer myotonia duration than QMA indicating enhanced sensitivity for quantifying myotonia in DM1. The reaction time to the relax but not squeeze command was delayed and showed warm up similar to myotonia in DM1. HCR outcomes were correlated with key pinch strength, hand dexterity test, and fat replacement in the MRI of the long finger flexor muscles. Use of the HCR is warranted for grip myotonia and strength measurements in longitudinal observational and interventional studies of DM1.

Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.

Skeletal muscle water T2 as a biomarker of disease status and exercise effects in patients with Duchenne muscular dystrophy.

The purpose of this study was to examine exercise effects on muscle water T2 in patients with Duchenne muscular dystrophy (DMD). In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T2 and R2 (1/T2) by the tri-exponential model. Muscle water R2 was measured again at 3 hours after an ankle dorsiflexion exercise. The muscle fat fraction was higher in DMD participants than in controls (p < .001) except in the tibialis posterior muscle. Muscle water T2 was measured independent of the degree of fatty degeneration in DMD muscle. At baseline, muscle water T2 was higher in all but the extensor digitorum longus muscles of DMD participants than controls (p < .001). DMD participants had a lower muscle torque (p < .001) and exerted less power (p < .01) during exercise than controls. Nevertheless, muscle water R2 decreased (T2 increased) after exercise from baseline in DMD subjects and controls with greater changes in the target muscles of the exercise than in ankle plantarflexor muscles. Skeletal muscle water T2 is a sensitive biomarker of the disease status in DMD and of the exercise response in DMD patients and controls.

Respiratory magnetic resonance imaging biomarkers in Duchenne muscular dystrophy.

OBJECTIVE: To examine the diaphragm and chest wall dynamics with cine breathing magnetic resonance imaging (MRI) in ambulatory boys with Duchenne muscular dystrophy (DMD) without respiratory symptoms and controls. METHODS: In 11 DMD boys and 15 controls, cine MRI of maximal breathing was recorded for 10 sec. The lung segmentations were done by an automated pipeline based on a Holistically-Nested Network model (HNN method). Lung areas, diaphragm, and chest wall motion were measured throughout the breathing cycle. RESULTS: The HNN method reliably identified the contours of the lung and the diaphragm in every frame of each dataset (~180 frames) within seconds. The lung areas at maximal inspiration and expiration were reduced in DMD patients relative to controls (P = 0.02 and <0.01, respectively). The change in the lung area between inspiration and expiration correlated with percent predicted forced vital capacity (FVC) in patients (rs  = 0.75, P = 0.03) and was not significantly different between groups. The diaphragm position, length, contractility, and motion were not significantly different between groups. Chest wall motion was reduced in patients compared to controls (P < 0.01). INTERPRETATION: Cine breathing MRI allows independent and reliable assessment of the diaphragm and chest wall dynamics during the breathing cycle in DMD patients and controls. The MRI data indicate that ambulatory DMD patients breathe at lower lung volumes than controls when their FVC is in the normal range. The diaphragm moves normally, whereas chest wall motion is reduced in these boys with DMD.