Change in Objectively Measured Activity Levels Resulting from the EMPOWER Study Lifestyle Intervention.

Purpose: To examine changes in physical activity (PA) during a behavioral weight-loss intervention and determine baseline factors associated with PA goal achievement. Methods: Overweight/obese community-dwelling adults with valid PA accelerometer data (N=116; mean age 51.7 years; 89% female; 83% non-Hispanic White) were recruited into a single-arm prospective cohort study examining the effects of a 12-month intervention that included 24 in-person group sessions, weight-loss, calorie, fat gram, and PA goals, self-monitoring, and feedback. Minutes of moderate-to-vigorous (MV) PA and steps were measured using a waist-worn accelerometer (ActiGraph GT3x) at baseline, 6 months, and 12 months. Achievement of the 150 minute/week MVPA goal was examined using total minutes and bout minutes (i.e., counting only PA occurring in bouts ≥10 minutes in length). Change in PA was analyzed using non-parametric tests for multiple comparisons. Associations of factors with meeting the PA goal were modeled using binary logistic regression. Results: At 6 months, there were increases from baseline in MVPA (median [p25, p75]: 5.3 [-0.9, 17.6] minutes/day) and steps (863 [-145, 2790] steps/day), both p<0.001. At 12 months, improvements were attenuated (MVPA: 2.4 [-2.0, 11.4] minutes/day, p=0.047; steps: 374[-570, 1804] p=0.14). At 6 months, 33.6% of individuals met the PA goal (using total or bout minutes). At 12 months, the percent meeting the goal using total MVPA [31%] differed from bout MVPA [22.4%]. Male gender (OR=4.14, p=0.027) and an autumn program start (versus winter; OR=3.39, p=0.011) were associated with greater odds of goal achievement at 6 months. Conclusions: The intervention increased PA goal achievement at 6 and 12 months with many making clinically meaningful improvements. Our results suggest female participants may require extra support toward improving PA levels.

Correction: Discovery and clinical introduction of first-in-class imipridone ONC201.

[This corrects the article DOI: 10.18632/oncotarget.11814.].

Covid-19 shelter-at-home and work, lifestyle and well-being in desk workers.

BACKGROUND: Emerging cross-sectional reports find that the COVID-19 pandemic and related social restrictions negatively affect lifestyle behaviours and mental health in general populations. AIMS: To study the longitudinal impact of COVID-19 on work practices, lifestyle and well-being among desk workers during shelter-at-home restrictions. METHODS: We added follow-up after completion of a clinical trial among desk workers to longitudinally measure sedentary behaviour, physical activity, sleep, diet, mood, quality of life and work-related health using validated questionnaires and surveys. We compared outcomes assessed before and during COVID-19 shelter-at-home restrictions. We assessed whether changes in outcomes differed by remote working status (always, changed to or never remote) using analysis of covariance (ANCOVA). RESULTS: Participants (N = 112; 69% female; mean (SD) age = 45.4 (12.3) years; follow-up = 13.5 (6.8) months) had substantial changes to work practices, including 72% changing to remote work. Deleterious changes from before to during shelter-at-home included: 1.3 (3.5)-h increase in non-workday sedentary behaviour; 0.7 (2.8)-point worsening of sleep quality; 8.5 (21.2)-point increase in mood disturbance; reductions in five of eight quality of life subscales; 0.5 (1.1)-point decrease in work-related health (P < 0.05). Other outcomes, including diet, physical activity and workday sedentary behaviour, remained stable (P ≥ 0.05). Workers who were remote before and during the pandemic had greater increases in non-workday sedentary behaviour and stress, with greater declines in physical functioning. Wake time was delayed overall by 41 (61) min, and more so in workers who changed to remote. CONCLUSIONS: Employers should consider supporting healthy lifestyle and well-being among desk workers during pandemic-related social restrictions, regardless of remote working status.

Pilot Study of Hyperpolarized 13C Metabolic Imaging in Pediatric Patients with Diffuse Intrinsic Pontine Glioma and Other CNS Cancers.

BACKGROUND AND PURPOSE: Pediatric CNS tumors commonly present challenges for radiographic interpretation on conventional MR imaging. This study sought to investigate the safety and tolerability of hyperpolarized carbon-13 (HP-13C) metabolic imaging in pediatric patients with brain tumors. MATERIALS AND METHODS: Pediatric patients 3 to 18 years of age who were previously diagnosed with a brain tumor and could undergo MR imaging without sedation were eligible to enroll in this safety study of HP [1-13C]pyruvate. Participants received a one-time injection of HP [1-13C]pyruvate and were imaged using dynamic HP-13C MR imaging. We assessed 2 dose levels: 0.34 mL/kg and the highest tolerated adult dose of 0.43 mL/kg. Participants were monitored throughout imaging and for 60 minutes postinjection, including pre- and postinjection electrocardiograms and vital sign measurements. RESULTS: Between February 2017 and July 2019, ten participants (9 males; median age, 14 years; range, 10-17 years) were enrolled, of whom 6 completed injection of HP [1-13C]pyruvate and dynamic HP-13C MR imaging. Four participants failed to undergo HP-13C MR imaging due to technical failures related to generating HP [1-13C]pyruvate or MR imaging operability. HP [1-13C]pyruvate was well-tolerated in all participants who completed the study, with no dose-limiting toxicities or adverse events observed at either 0.34 (n = 3) or 0.43 (n = 3) mL/kg. HP [1-13C]pyruvate demonstrated characteristic conversion to [1-13C]lactate and [13C]bicarbonate in the brain. Due to poor accrual, the study was closed after only 3 participants were enrolled at the highest dose level. CONCLUSIONS: Dynamic HP-13C MR imaging was safely performed in 6 pediatric patients with CNS tumors and demonstrated HP [1-13C]pyruvate brain metabolism.

Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma.

Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/ß receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.

Diffusion Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3-K27M Mutation Using Apparent Diffusion Coefficient Histogram Analysis.

BACKGROUND AND PURPOSE: Diffuse midline gliomas with histone H3 K27M mutation are biologically aggressive tumors with poor prognosis defined as a new diagnostic entity in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. There are no qualitative imaging differences (enhancement, border, or central necrosis) between histone H3 wildtype and H3 K27M-mutant diffuse midline gliomas. Herein, we evaluated the utility of diffusion-weighted imaging to distinguish H3 K27M-mutant from histone H3 wildtype diffuse midline gliomas. MATERIALS AND METHODS: We identified 31 pediatric patients (younger than 21 years of age) with diffuse gliomas centered in midline structures that had undergone assessment for histone H3 K27M mutation. We measured ADC within these tumors using a voxel-based 3D whole-tumor measurement method. RESULTS: Our cohort included 18 infratentorial and 13 supratentorial diffuse gliomas centered in midline structures. Twenty-three (74%) tumors carried H3-K27M mutations. There was no difference in ADC histogram parameters (mean, median, minimum, maximum, percentiles) between mutant and wild-type tumors. Subgroup analysis based on tumor location also did not identify a difference in histogram descriptive statistics. Patients who survived <1 year after diagnosis had lower median ADC (1.10 × 10-3mm2/s; 95% CI, 0.90-1.30) compared with patients who survived >1 year (1.46 × 10-3mm2/s; 95% CI, 1.19-1.67; P < .06). Average ADC values for diffuse midline gliomas were 1.28 × 10-3mm2/s (95% CI, 1.21-1.34) and 0.86 × 10-3mm2/s (95% CI, 0.69-1.01) for hemispheric glioblastomas with P < .05. CONCLUSIONS: Although no statistically significant difference in diffusion characteristics was found between H3-K27M mutant and H3 wildtype diffuse midline gliomas, lower diffusivity corresponds to a lower survival rate at 1 year after diagnosis. These findings can have an impact on the anticipated clinical course for this patient population and offer providers and families guidance on clinical outcomes.

Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism.

PURPOSE: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. EXPERIMENTAL DESIGN: The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. RESULTS: DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. CONCLUSIONS: These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms.

BACKGROUND: Small molecule ONC201 is an investigational anti-tumor agent that upregulates intra-tumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 therapy in advanced cancer patients has been completed and the drug has progressed into Phase II trials in several cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease has a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. METHODS: We investigated the potential combination of VEGF inhibitors such as bevacizumab and its murine-counterpart; along with other anti-angiogenic agents and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) models. We utilized non-invasive imaging and immunohistochemistry to determine potential mechanisms of action. RESULTS: Our results demonstrate significant tumor regression or complete tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. Our results indicate that ONC201 and anti-angiogenic agents act through distinct mechanisms while increasing tumor cell death and inhibiting proliferation. CONCLUSION: With the use of both a murine VEGF inhibitor in syngeneic models, and bevacizumab in human cell line-derived xenografts, we demonstrate that ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising approach for further testing in the clinic for the treatment of CRC.

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation.

BACKGROUND: Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome"). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins. METHODS AND RESULTS: Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B. Select family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Furthermore, evaluation of primary lymphoblasts from a carrier of the translocation showed altered levels of ankyrin-B as well as a reduced expression of downstream ankyrin-binding partners. CONCLUSIONS: Thus, our data conclude that, similar to previously described ANK2 loss-of-function "point mutations", large chromosomal translocations resulting in ANK2 haploinsufficiency are sufficient to cause the human cardiac ankyrin-B syndrome. The unexpected ascertainment of ANK2 dysfunction via the discovery of a chromosomal translocation in this family, the determination of the familial phenotype, as well as the complexities in formulating screening and treatment strategies are discussed.

Discovery and clinical introduction of first-in-class imipridone ONC201.

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.

ONC201 (also called TIC10) is a small molecule that inactivates the cell proliferation- and cell survival-promoting kinases Akt and ERK and induces cell death through the proapoptotic protein TRAIL. ONC201 is currently in early-phase clinical testing for various malignancies. We found through gene expression and protein analyses that ONC201 triggered an increase in TRAIL abundance and cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5. ATF4 was not activated in ONC201-resistant cancer cells, and in ONC201-sensitive cells, knockdown of ATF4 or CHOP partially abrogated ONC201-induced cytotoxicity and diminished the ONC201-stimulated increase in DR5 abundance. The activation of ATF4 in response to ONC201 required the kinases HRI and PKR, which phosphorylate and activate the translation initiation factor eIF2α. ONC201 rapidly triggered cell cycle arrest, which was associated with decreased abundance of cyclin D1, decreased activity of the kinase complex mTORC1, and dephosphorylation of the retinoblastoma (Rb) protein. The abundance of X-linked inhibitor of apoptosis protein (XIAP) negatively correlated with the extent of apoptosis in response to ONC201. These effects of ONC201 were independent of whether cancer cells had normal or mutant p53. Thus, ONC201 induces cell death through the coordinated induction of TRAIL by an ISR pathway.

Expression and function of the Scn5a-encoded voltage-gated sodium channel NaV 1.5 in the rat jejunum.

BACKGROUND: The SCN5A-encoded voltage-gated sodium channel NaV 1.5 is expressed in human jejunum and colon. Mutations in NaV 1.5 are associated with gastrointestinal motility disorders. The rat gastrointestinal tract expresses voltage-gated sodium channels, but their molecular identity and role in rat gastrointestinal electrophysiology are unknown. METHODS: The presence and distribution of Scn5a-encoded NaV 1.5 was examined by PCR, Western blotting and immunohistochemistry in rat jejunum. Freshly dissociated smooth muscle cells were examined by whole cell electrophysiology. Zinc finger nuclease was used to target Scn5a in rats. Lentiviral-mediated transduction with shRNA was used to target Scn5a in rat jejunum smooth muscle organotypic cultures. Organotypic cultures were examined by sharp electrode electrophysiology and RT-PCR. KEY RESULTS: We found NaV 1.5 in rat jejunum and colon smooth muscle by Western blot. Immunohistochemistry using two other antibodies of different portions of NaV 1.5 revealed the presence of the ion channel in rat jejunum. Whole cell voltage-clamp in dissociated smooth muscle cells from rat jejunum showed fast activating and inactivating voltage-dependent inward current that was eliminated by Na(+) replacement by NMDG(+) . Constitutive rat Scn5a knockout resulted in death in utero. NaV 1.5 shRNA delivered by lentivirus into rat jejunum smooth muscle organotypic culture resulted in 57% loss of Scn5a mRNA and several significant changes in slow waves, namely 40% decrease in peak amplitude, 30% decrease in half-width, and 7 mV hyperpolarization of the membrane potential at peak amplitude. CONCLUSIONS & INFERENCES: Scn5a-encoded NaV 1.5 is expressed in rat gastrointestinal smooth muscle and it contributes to smooth muscle electrophysiology.

Dose Imaging Detectors for Radiotherapy Based on Gas Electron Multipliers.

New techniques in charged particle therapy and widespread use of modern dynamic beam delivery systems demand new beam monitoring devices as well as accurate 2D dosimetry systems to verify the delivered dose distribution. We are developing dose imaging detectors based on gas electron multipliers (GEM) with the goal of improving dose measurement linearity, position and timing resolution, and to ultimately allow pre-treatment verification of dose distributions and dose delivery monitoring employing scanning beam technology. A prototype 10×10 cm(2) double-GEM detector has been tested in the 205 MeV proton beam using electronic and optical readout modes. Preliminary results with electronic cross-strip readout demonstrate fast response and single-pixel (4 mm) position resolution. In optical readout mode, the line spread function of the detector was found to have σ=0.7 mm. In both readout modes, the detector response was linear up to dose rates of 50 Gy/min, with adequate representation of the Bragg peak in depth-dose profile measurements.

Experience with use of multiplane transesophageal echocardiography to guide closure of atrial septal defects using the amplatzer device.

By providing unlimited imaging planes, multiplane transesophageal echocardiography (MTEE) should improve real-time guidance of interventional procedures. The potential advantages of MTEE in this scenario have not been systematically evaluated. We retrospectively reviewed our experience with MTEE-guided Amplatzer device closure of atrial septal defects (ASDs) MTEE angles used to obtain images for guiding all measurements and maneuvers were recorded. These angles were compared to the range of MTEE angles that are postulated to be available from biplane TEE. Images obtained using MTEE angles from 21 degrees to 70 degrees and from 111 degrees to l59 degrees were defined as only obtainable by MTEE. The MTEE probe was successfully introduced in all (89) patients. Thirteen patients (15%) had multiple defects. Ninety-five devices (5-32 mm in diameter) were deployed. In 66% of patients, balloon sizing and device deployment necessitated imaging planes that are only obtainable by MTEE. All devices were well positioned, with no impingement on inflows or outflows. At follow-up, 79 of 89 (88.7%) patients had no residual ASDs. Each of the remaining 10 patients (11.3%) had a small (<3 mm) residual defect. MTEE played an important role in guiding device closure of ASD, particularly during the phases of balloon sizing and device deployment.

Estimation of right ventricular free-wall mass using two-dimensional echocardiography.

Echocardiographic methods based on geometric models have long been in use for estimating left ventricular mass, but there is currently no similar method for estimating right ventricular (RV) free-wall mass. We hypothesized that a one-quarter prolate ellipsoid model could be used with two-dimensional echocardiography to approximate RV mass. Over a 2-year period 39 patients who had both a complete cardiac magnetic resonance imaging (MRI) scan and an echocardiogram within 2 weeks of each other were retrospectively analyzed. MRI-derived RV mass was used as the standard for comparison. Echocardiographic RV mass was estimated using three equations based on the geometric model. Linear regression analysis was performed to determine the correction factors used in the final formulae. The formula with the lowest standard error of the estimate was then prospectively analyzed for accuracy using a separate group of 88 subjects. The most accurate echocardiographic equation derived was RV mass = 5.84 (apical four-chamber RV cavity planar area) (RV free-wall thickness) + 1. Compared to MRI-RV mass the correlation coefficient was 0.97 and the standard error of the estimate was 16.8%. The positive and negative predictive values for diagnosing RV hypertrophy were 95% and 88%, respectively. We conclude that RV free-wall mass can be estimated by two-dimensional echocardiography using a one-quarter prolate ellipsoid shell model.