Citations

10027 Background: Thoracic radiotherapy (RT) is a risk factor for cardiac disease among survivors of childhood cancer based on studies considering RT doses to the entire heart. Dose to specific cardiac substructures may provide more precise dose-response associations to guide RT planning. We report associations between RT dose to cardiac substructures and risk of specific cardiac outcomes. Methods: We determined the cumulative incidences of CTCAE grade 3 – 5 coronary artery disease (CAD), heart failure (HF), and valvular disease (VD) among 25,481 5-year childhood cancer survivors diagnosed 1970 – 1999 in the CCSS. Median age at diagnosis was 6.1 years (0 – 20 years) and at last follow-up 29.8 years (5.6 – 65.9 years). For the 12,228 individuals receiving RT, fields were reconstructed on an age scaled computational phantom. Mean doses to the entire heart, cardiac chambers, valves, and left main, anterior descending (LAD), circumflex, and right coronary (RCA) arteries were estimated. Adjusted piecewise exponential models (including cumulative anthracycline dose) evaluated associations between mean RT dose to each structure and outcomes. Results: At 30 years from diagnosis, the cumulative incidences of grades 3 – 5 CAD, HF, and VD were 2.3% (95% CI 2.0 – 2.5), 2.6% (95% CI 2.4 – 2.9), and 0.6% (95% CI 0.5 – 0.8) respectively. Low dose RT (mean 5 – 9.9 Gy) to the RCA (relative rate [RR] = 2.6, 95% CI 1.6 – 4.1, p < 0.001), LAD (RR = 1.9, 95% CI 1.1 – 3.3, p = 0.019), and left ventricle (RR = 2.2, 95% CI 1.3 – 3.7, p = 0.002) was associated with increased risk of CAD relative to those not exposed; mean dose of 5 – 9.9 Gy to the entire heart was not (RR = 1.1, 95% CI = 0.8 – 1.6, p = 0.59). Table shows the associated cumulative incidences of CAD for these structures. Mean RT doses of 5 – 9.9 Gy to the aortic valve (RR = 4.6, 95% CI 1.5 – 14.0, p = 0.008) and tricuspid valve (RR = 5.5, 95% CI 2.0 – 15.1, p = 0.001) were associated with risk of VD compared to those with no RT; mean heart dose 5 – 9.9 Gy was not (RR = 0.6, 95% CI = 0.2 – 1.3, p = 0.16). No cardiac structure was significantly associated with an increased risk of HF at a mean dose of 5 – 9.9 Gy. Mean RT doses below 5 Gy were not associated with increased risks of CAD, HF, or VD; doses ≥10 Gy to nearly all substructures and the entire heart were. Conclusions: Low dose RT to the coronary arteries and cardiac valves (5 – 9.9 Gy) from RT is associated with increased risk of CAD and VD, respectively. Sensitivity to low dose RT may vary across the heart and doses to specific structures may be more predictive of late cardiac disease than whole heart dose. These data can guide RT planning to prioritize substructures for avoidance.[Table: see text]

Abstract In response to the coronavirus disease 2019 (COVID-19) pandemic, the Cardio-Oncology and Imaging Councils of the American College of Cardiology offers recommendations to clinicians regarding the cardiovascular care of cardio-oncology patients in this expert consensus statement. Cardio-oncology patients—individuals with an active or prior cancer history and with or at risk of cardiovascular disease—are a rapidly growing population who are at increased risk of infection, and experiencing severe and/or lethal complications by COVID-19. Recommendations for optimizing screening and monitoring visits to detect cardiac dysfunction are discussed. In addition, judicious use of multimodality imaging and biomarkers are proposed to identify myocardial, valvular, vascular, and pericardial involvement in cancer patients. The difficulties of diagnosing the etiology of cardiovascular complications in patients with cancer and COVID-19 are outlined, along with weighing the advantages against risks of exposure, with the modification of existing cardiovascular treatments and cardiotoxicity surveillance in patients with cancer during the COVID-19 pandemic.

Abstract Background: MRX34 is a liposomal nanoparticle formulation with an encapsulated mimic of the naturally occurring microRNA-34 (miR-34), which is lost or expressed at reduced levels in many tumors. miR-34 inhibits key oncogenic pathways by repressing multiple important oncogenes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ/β, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also represses the expression of PD-L1 and DGKζ, thereby possibly triggering an anti-tumor immune response and cancer cell death. A multicenter Phase 1 clinical trial of MRX34 is being conducted in patients with advanced malignancies. Methods: Eligible patients were enrolled in a standard 3 + 3 dose escalation study and were given a MRX34 starting dose of 10 mg/m2, administered intravenously (IV) twice weekly (BIW) for 3 weeks in 28-day cycles. Enrollment is ongoing into a second MRX34 dosing schedule, daily x 5 (QD x 5) in 21-day cycles. The primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for the two dosing schedules. Secondary objectives include assessments of safety, tolerability and the pharmacokinetic profile of MRX34 after intravenous dosing as well as to assess any biological and clinical activity. Results: As of July 2015, 75 patients with advanced solid tumors were enrolled and evaluable: 44 Caucasians, 47 males, a median age of 61 years and a median of 4 prior treatments. Histologies included 30 hepatocellular carcinoma (HCC), 7 pancreatic cancer, 4 cholangiocarcinoma, 3 each of bladder, breast, colorectal, cervix and lung. The remaining 19 patients represented various other malignancies &lt;3 patients each. The 110 mg/m2 was deemed to be the MTD for the BIW dosing schedule. The MTD has not been determined yet for the QD x 5 schedule and dose escalation is continuing. The current dose levels are 70 mg/m2 QD x 5 for HCC and 93 mg/m2 QD x 5 for other solid tumors. The following treatment-emergent, all-causality adverse events (AEs) were most frequent among 47 patients in BIW cohorts vs 28 patients in QD x 5 cohorts: fever (64% vs 61%), fatigue (57% vs 39%), chills (57% vs 36%), back pain (55% vs 36%), nausea (49% vs 39%), diarrhea (43% vs 11%), headache (34% vs 14%), vomiting (32% vs 11%), anorexia (26% vs 14%), abdominal pain (23% vs 21%), dyspnea (23% vs 14%), insomnia (23% vs 14%), and dehydration (23% vs 4%). Most frequent grade 3/4 laboratory abnormalities were: lymphopenia (36% vs 71%), neutropenia (26% vs 36%), hyponatremia (26% vs 7%), AST elevation (26% vs 29%), leukopenia (23% vs 36%), hyperglycemia (19% vs 36%), thrombocytopenia (17% vs 29%), anemia (11% vs 21%), alkaline phosphatase elevation (11% vs 21%), and ALT elevation (9% vs 21%). One patient with HCC and another patient with melanoma achieved confirmed partial responses per RECIST. Conclusions: MRX34 has a manageable safety profile with confirmed partial responses in two patients with advanced HCC and melanoma. Due to better tolerability, QD x 5 schedule has been chosen for further study. Following MTD determination, enrollment will soon begin into the QD x 5 expansion cohorts for selected tumors. Citation Format: Muhammad Shaalan Beg, Andrew Brenner, Jasgit Sachdev, Samuel Ejadi, Mitesh Borad, Yang-Kon Kang, Ho Lim, T-Y Kim, Andreas Bader, Jay Stoudemire, Susan Smith, Sinil Kim, David Hong. Safety, tolerability, and clinical activity of MRX34, the first-in-class liposomal miR-34 mimic, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C43.

Abstract Background: MRX34 is a liposome-formulated double-stranded mimic of tumor suppressor microRNA-34 (miR-34), which is lost or expressed at reduced levels in many solid and hematologic malignancies. miR-34 functions in the p53 tumor suppressor pathway and regulates the expression of more than 20 cancer-related genes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also suppresses stem-like properties in cancer cells and sensitizes cancer cells to cytotoxic and targeted therapies. A multicenter phase I clinical trial of MRX34 is being conducted in patients with unresectable hepatocellular carcinoma or metastatic cancer with liver involvement. Methods: Eligible patients are enrolled in a standard 3 + 3 dose escalation study at MRX34 starting dose of 10 mg/m2, administered IV on days 1, 4, 8, 11, 15, and 18 of 28-day cycles. Dexamethasone premedication was added after the first 2 dose levels. The primary objective is to determine the RP2D, and secondary objectives include assessments of safety, PK and objective response rate (ORR). Response is evaluated by CT/MRI every 8 weeks. Once RP2D has been established, expansion cohort will be treated at the RP2D, with specific focus on determining biological response in tumor biopsy material. The latter will include assessing tumor uptake of miR-34 mimic and down-regulation of target gene expression as was observed in animal models of cancer. Results: Twenty-five patients received study drug, and enrollment is currently ongoing at the 5th dose level (70 mg/m2) and MTD has not been reached. There were 18 Caucasians, 15 males, with a median age of 62.5 years and a median of 4 prior treatments. Liposomal formulation-associated infusion reactions have been observed as characterized by the following treatment emergent adverse events (AEs) out of 20 patients: fever (13), chills (12), fatigue (12), thrombocytopenia (8), diarrhea (8), back/flank pain (6), nausea (6), and neutropenia (4). Most common Gr 3/4 AEs were neutropenia (4), thrombocytopenia (3), fatigue (2), AST/ALT elevation (4) and back/flank pain (2). Addition of pre-dose dexamethasone with higher dose levels ameliorated infusion reactions. One patient died on study from disease progression. One dose-limiting toxicity was observed at the 2nd dose level (20 mg/m2; Gr 3 acute kidney injury associated with nausea, vomiting, diarrhea and dehydration) and one at the 5th dose level (70 mg/m2; Gr 3 increased AST). Conclusions: MRX34 has a manageable safety profile in patients with unresectable primary liver cancer or metastatic cancer with liver involvement. Determination of the R2PD, assessment of clinical response, and analyses of molecular markers are ongoing. Citation Format: Muhammad Shaalan Beg, Mitesh Borad, Jasgit Sachdev, David S. Hong, Susan Smith, Andres Bader, Jay Stoudemire, Sinil Kim, Andrew Brenner. Multicenter phase I study of MRX34, a first-in-class microRNA miR-34 mimic liposomal injection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT327. doi:10.1158/1538-7445.AM2014-CT327

Background Central to the armamentarium of a hand therapist is evaluation for successful orthotic use. Orthoses can have a profound effect on quality of life in persons with amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). The purposes of orthoses are to decrease the effects of muscle imbalance, provide assistance in performance of activities of daily living (ADLs), prevent joint contracture, and relieve pain. There are few published accounts on the usefulness of orthoses and ALS. The purpose of this paper is to expand the body of literature by describing three successful cases. Methods Three cases illustrate effects on weakened proximal muscles, wrist extensors, thenar musculature, and intrinsic muscles. The primary outcome measure is patient report, but functional rating scales, goniometry, quality of life scores, and pinch strength when obtainable are described. Results Due to the progressive nature of the disease, outcome measures can be inconclusive. Patient report of increased life satisfaction and ability to participate in daily life is the critical outcome in these case examples. In all cases, satisfaction increased. Some of the stated changes include the following: ability to manipulate objects, grip, eat, wipe face, hold phone, use iPad®, and adjust hat. Conclusions Upper extremity orthotic use can be a beneficial adjunct contributing to the quality of life for individuals with ALS/MND. We have observed positive responses in pain control, contracture management, functional positioning, and increased independence with the use of orthoses. Designing appropriate means of studying effects of orthosis intervention is deficient in the current scientific literature.