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

Gene expression regulation in the context of mouse interspecific mosaic genomes

The testis transcriptome of mouse strains containing homozygous segments of Mus spretus origin in a Mus musculus background was analyzed

A Multi-centre, Single Arm, Non-randomized, Prospective European Trial to Evaluate the Safety and Efficacy of the HistoSonics System in the Treatment of Primary and Metastatic Liver Cancers (#HOPE4LIVER)

Hepatocellular carcinoma; Histotripsy; Non-thermal ablationCarcinoma hepatocelular; Histotricia; Ablación no térmicaCarcinoma hepatocel·lular; Histotrícia; Ablació no tèrmicaPurpose Image-guided thermal ablation are established treatment options for non-surgical patients with primary and metastatic liver cancers. However, there are limitations with nonuniformity of cancer tissue destruction, heat sink effect and the risk of thermal ablative injury. The current non-thermal ablative techniques have high risk of local recurrence and are not widely adopted. Histotripsy is a treatment technology that destroys targeted tissue under ultrasound visualization via mechanical destruction through the precise application of acoustic cavitation and can offer the potential of non-invasive, non-thermal and non-ionizing radiation cancer treatment. The aim of this multi-centre non-randomized phase I/II trial is to assess the initial safety and efficacy of the prototype investigational ‘System’ in the treatment of primary and metastatic liver cancers. Methods/Design All non-surgical patients with primary/metastatic liver cancers having had previous liver directed therapy, radiation therapy or image-guided ablation may be offered image-guided Histotripsy as per trial protocol. The co-primary endpoints are technical success and procedural safety. Technical success is determined, at ≤ 36 h post procedure, by evaluating the histotripsy treatment size and coverage. The procedural safety is defined by procedure related major complications, defined as Common Terminology Criteria for Adverse Events (CTCAE version 5) grade 3 or higher toxicities, up to 30 days post procedure. This phase I/II trial has intended to recruit up to 45 patients to show safety and efficacy of image-guided histotripsy in liver cancers.This trial study is funded by HistoSonics

Association among the R.E.N.A.L. nephrometry score and clinical outcomes in patients with small renal masses treated with percutaneous contrast enhanced ultrasound radiofrequency ablation

An association between the R.E.N.A.L. nephrometry score (RNS) and clinical outcomes in patients with a small renal mass (SRM) has been proposed. We analyzed clinical outcomes according to the RNS in patients with a SRM treated with percutaneous contrast enhanced ultrasound (CEUS) radiofrequency ablation (RFA). Patients with a SRM, who underwent RFA between January 2005 and March 2015, were retrospectively identified. The association between RNS and clinical outcomes was evaluated using parametric and non-parametric analysis. We analyzed 163 SRMs in 149 consecutive patients. The mean age was 71.7 years. Mean follow-up time was 33.3 months ±20.6 (2-102). The mean RNS was 5.6 ±1.52 (4-11). A total of 121 (74.2%) cases were of low complexity and 42 (25.8%) were medium complexity. We identified 11 cases of tumor persistence (6.7%). The mean RNS was 5.58 in the cases with no persistence and 5.73 in the cases with persistence (p = 0.788). We identified 15 (9.2%) cases of recurrence. The mean RNS was 5.57 ±0.1 (4-11) in the cases without recurrence and 5.73 ±0.4 (4-9) in recurrence cases (p = 0.804). Of the 76 biopsy proven RCC cases, 8 (10.5%) cases of recurrence were observed, 5 in the low complexity group and 3 in the medium complexity group (p = 0.690). A total of 9 (5.5%) cases of complications were observed, with 5 (4.3%) in the low complexity group and 4 cases in the medium complexity group (p = 0.23). The mean length of stay was 1.5 days with a significant difference between low and medium complexity groups (1.3 vs. 2.1 days, p = 0.02). The mean difference between preoperative eGFR and estimated eGFRat 12 months was -3.08 mL / min ±13.3 (-49.4-34.1) and was significant (p = 0.008).However, this variation did not show significant differences between the low and medium complexity groups (p = 0.936). All-cause mortality was 11.7%, 14 cases (11.6%) in the low complexity group and 5 (11.9%) in the medium complexity group (p = 1.0). No cases of renal cell carcinoma (RCC) specific mortality were identified. The RNS was not associated with tumor persistence, recurrence, cancer specific mortality, complications or renal function 12 months after the first treatment, showing significant difference only in length of hospital stay between low and medium complexity groups

Fidgetin-Like1 Is a Strong Candidate for a Dynamic Impairment of Male Meiosis Leading to Reduced Testis Weight in Mice

Chantier qualité GAInternational audienceBACKGROUND: In a previous work, using an interspecific recombinant congenic mouse model, we reported a genomic region of 23 Mb on mouse chromosome 11 implicated in testis weight decrease and moderate teratozoospermia (∼20-30%), a Quantitative Trait Locus (QTL) called Ltw1. The objective of the present study is to identify the gene underlying this phenotype. RESULTS: In the present study, we refined the QTL position to a 5 Mb fragment encompassing only 11 genes. We showed that the low testis weight phenotype was due to kinetic alterations occurring during the first wave of the spermatogenesis where we could point out to an abnormal lengthening of spermatocyte prophase. We identify Fidgetin-like 1 (Fignl1) as the gene underlying the phenotype, since if fulfilled both the physiological and molecular characteristics required. Indeed, amongst the 11 positional candidates it is the only gene that is expressed during meiosis at the spermatocyte stage, and that presents with non-synonymous coding variations differentiating the two mouse strains at the origin of the cross. CONCLUSIONS: This work prompted us to propose Fignl1 as a novel actor in mammal's male meiosis dynamics which has fundamental interest. Besides, this gene is a new potential candidate for human infertilities caused by teratozoospermia and blockades of spermatogenesis. In addition this study demonstrates that interspecific models may be useful for understanding complex quantitative traits

Oriented zinc oxide nanorods: A novel saturable absorber for lasers in the near-infrared

Zinc oxide (ZnO) nanorods (NRs) oriented along the crystallographic [001] axis are grown by the hydrothermal method on glass substrates. The ZnO NRs exhibit a broadband (1–2 µm) near-IR absorption ascribed to the singly charged zinc vacancy VZn−1. The saturable absorption of the ZnO NRs is studied at ≈1 µm under picosecond excitation, revealing a low saturation intensity, ≈10 kW/cm2, and high fraction of the saturable losses. The ZnO NRs are applied as saturable absorbers in diode-pumped Yb (≈1.03 µm) and Tm (≈1.94 µm) lasers generating nanosecond pulses. The ZnO NRs grown on various optical surfaces are promising broadband saturable absorbers for nanosecond near-IR lasers in bulk and waveguide geometries

ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment

T-lymphocytes; Oncolytic viruses; Tumor microenvironmentLinfocitos T; Virus oncolíticos; Microambiente tumoralLimfòcits T; Virus oncolítics; Microambient tumoralBackground ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes. Methods In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×1011 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed. Results In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort. Conclusions ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.This work was supported by Circio, the study sponsor (no grant number)

Identification of Quantitative Trait Loci responsible for embryonic lethality in mice assessed by ultrasonography

Chantier qualité GAInternational audienceRecurrent Spontaneous Abortion (RSA) is a frequent pathology affecting 1 to 5% of couples. In ~50 % of cases, the aetiology is unknown suggesting a subtle interaction between genetic and environmental factors. Previous attempts to describe genetic factors using the candidate gene approach have been relatively unsuccessful due to the physiological, cellular and genetic complexity of mammalian reproduction. Indeed, fertility can be considered as a quantitative feature resulting from the interaction of genetic, epigenetic and environmental factors. Herein, we identified Quantitative Trait Loci (QTL) associated with diverse embryonic lethality phenotypes and the subsequent embryonic resorption in 39 inter-specific recombinant congenic mice strains, using in vivo ultrasound bio-microscopy. The short chromosomal intervals related to the phenotypes will facilitate the study of a restricted number of candidate genes which are potentially dysregulated in patients affected by RSA

Comparative spectroscopic and thermo-optic study of Tm: LiLnF4 (Ln = Y, Gd, and Lu) crystals for highly-efficient microchip lasers at ~2 μm

We report on a detailed comparative study of the spectroscopic and thermo-optic properties of tetragonal Tm:LiLnF4 (Ln = Y, Gd, and Lu) crystals indicating their suitability for highly-efficient microchip lasers diode-pumped at ~791 nm and operating at ~1.91 μm. An a-cut 8 at.% Tm:LiYF4 micro-laser generated 3.1 W of linearly polarized output at 1904 nm with a slope efficiency of η = 72% and a laser threshold of only 0.24 W. The internal loss for this crystal is as low as 0.0011 cm-1. For 8 at.% Tm:LiGdF4 and 12 at.% Tm:LiLuF4 lasers, the output power reached ~2 W and η was 65% and 52%, respectively. The thermal lens in all Tm:LiLnF4 crystals is weak, positive and low-astigmatic. The potential for the Tm:LiLnF4 lasers to operate beyond ~2 μm due to a vibronic coupling has been proved. The Tm:LiYF4 vibronic laser generated 375 mW at 2026-2044 nm with η = 31%. The Tm:LiLnF4 crystals are very promising for passively Q-switched microchip lasers

Spherical probe for the thermophysical characterization of regoliths for planetary exploration using frequency methods

© 2022 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/The objective of this paper is to analyse the capability of a spherical thermoprobe, recently proposed as a 3D heat flux sensor for regoliths, and additionally to characterize the thermophysical properties of regoliths. The sensor is based on the spherical structure of a Mars wind sensor. The characterization is carried out using frequency methods. Extensive experimental results have been obtained with eight regolith simulants made of glass microbeads. Errors in thermal conductivity and diffusivity are smaller than ± 7%, for these simulants.Funded in part by MICINN, grants no. RTI2018-098728-B-C33 and PID2021-126719OB-C42, and ESA contract 4000128070/19/NL/KML for the MiniPINS study.Peer ReviewedPostprint (published version