First-in-man histotripsy of hepatic tumors: the THERESA trial, a feasibility study

Ablation; Hepatocellular carcinoma; HistotripsyAblación; Carcinoma hepatocelular; HistotriciaAblació; Carcinoma hepatocel·lular; HistotríciaRationale Current hepatic locoregional therapies are limited in terms of effectiveness and toxicities. Given promising pre-clinical results, a first in-human trial was designed to assess the technical effectiveness and safety profile of histotripsy, a noninvasive, non-thermal, non-ionizing focused ultrasound therapy that creates precise, predictable tissue destruction, in patients with primary and secondary liver tumors. Methods A multicenter phase I trial (Theresa Study) was performed in a single country with 8 weeks of planned follow-up. Eight of fourteen recruited patients were deemed eligible and enrolled in the study. Hepatic histotripsy, was performed with a prototype system (HistoSonics, Inc., Ann Arbor, MI). Eleven tumors were targeted in the 8 patients who all had unresectable end-stage multifocal liver tumors: colorectal liver metastases (CRLM) in 5 patients (7 tumors), breast cancer metastases in 1 (1 tumor), cholangiocarcinoma metastases in 1 (2 tumors), and hepatocellular carcinoma (HCC) in 1 (1 tumor). The primary endpoint was acute technical success, defined as creating a zone of tissue destruction per planned volume assessed by MRI 1-day post-procedure. Safety (device-related adverse events) through 2 months was a secondary endpoint. Results The 8 patients had a median age of 60.4 years with an average targeted tumor diameter of 1.4 cm. The primary endpoint was achieved in all procedures. The secondary safety profile endpoint identified no device-related adverse events. Two patients experienced a continuous decline in tumor markers during the eight weeks following the procedure. Conclusions This first-in-human trial demonstrates that hepatic histotripsy effectively destroys liver tissue in a predictable manner, correlating very well with the planned histotripsy volume, and has a high safety profile without any device-related adverse events. Based on these results, the need for more definitive clinical trials is warranted. Trial Registration: Study to Evaluate VORTX Rx (Theresa). NCT03741088. https://clinicaltrials.gov/ct2/show/NCT03741088This study was supported by the funding from Histosonics, Inc

How Pendular Is Human Brachiation? When Form Does Not Follow Function

Brachiation is a form of suspensory locomotion observed only in Primates. The non-human hominoids (e.g., gibbons, orangutans, chimpanzees, and gorillas) are considered specialized brachiators, yet peculiar among the living apes are anatomically modern humans (Homo sapiens), who have forgone this locomotor mode in favor of bipedal striding. Humans can, however, brachiate and seem to have retained the locomotor capabilities of their arboreal ancestors. However, the mechanics of human brachiation have not been quantified. In this study, we evaluate how closely human brachiation conforms to the expectations of simple pendular motion using triaxial accelerometry and high-speed videography. These data are compared to specialized brachiating non-human primates. We found that humans have lower energy recovery than siamangs (Symphalangus syndactylus) during brachiation and have shorter observed pendular periods than expected compared to other primates. We demonstrate that relatively long forelimb length and high grip forces, a proxy for global forelimb force-generating potential, act as the main driving factors to reduce energetic costs through effective pendular recovery. These data are the first to assess the strategies humans adopt to perform a behavior they are not anatomically specialized to execute and places them within a comparative framework amongst other brachiating primates. We show that although humans demonstrate behavioral flexibility during brachiation (e.g., differing mediolateral and vertical center of mass positional movement patterns), anatomical features are the primary driver of variation in brachiation performance

The Association between Common Vitamin D Receptor Gene Variations and Osteoporosis: A Participant-Level Meta-Analysis

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures. Design: Prospective multicenter large-scale association study. Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. Participants: 26 242 participants (18 405 women). Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures