Evaluating the safety of high-intensity focused ultrasound treatment for rectal endometriosis: results from a French prospective multicentre study including 60 patients.

STUDY QUESTION: Is increasing the intensity of high-intensity focused ultrasound (HIFU) by 30% in the treatment of rectal endometriosis a safe procedure? SUMMARY ANSWER: This study demonstrates the safety of a 30% increase in the intensity of HIFU in the treatment of rectal endometriosis, with no Clavien-Dindo Grade III complications overall, and namely no rectovaginal fistulae. WHAT IS KNOWN ALREADY: A feasibility study including 20 patients with rectal endometriosis demonstrated, with no severe complications, a significant improvement in digestive disorders, dysmenorrhoea, dyspareunia, and health status, although the volume of the endometriosis nodule did not appear to be reduced. STUDY DESIGN, SIZE, DURATION: A prospective multicentre cohort study was conducted between 2020 and 2022 with 60 patients with symptomatic rectal endometriosis. Following the failure of medical treatment, HIFU treatment was offered as an alternative to surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: As the main objective of this study was to examine safety, all adverse events observed during the 6 months of follow-up were analysed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and Clavien-Dindo classifications. Secondary objectives included evaluating the evolution of symptoms using validated questionnaires: gynaecological and digestive pain symptoms with a visual analogue scale, health status with the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire, average post-operative daily pain level, and analgesic medication required in the 10 days following treatment. MRI was also performed at Day 1 to detect early complications. Finally, we performed a blinded MRI review of the evolution of the nodule at 6 months post-treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The procedure was performed under spinal anaesthesia for 30% of the patients. The median duration of treatment was 32 min. Fifty-five patients left the hospital on Day 1. MRI scans performed on Day 1 did not highlight any early-onset post-operative complication. Using the Clavien-Dindo classification, we listed 56.7% Grade I events, 3.4% Grade II events, and no events Grade III or higher. At 1, 3, and 6 months, all gynaecologic, digestive and general symptoms, as well as health status, had significantly improved. The evolution of the nodule was also significant (P < 0.001) with a 28% decrease in volume. LIMITATIONS, REASONS FOR CAUTION: The main objective was safety and not effectiveness. The study was not randomized and there was no control group. WIDER IMPLICATIONS OF THE FINDINGS: HIFU treatment for rectal endometriosis results in an improvement of symptoms with low morbidity; as such, for selected patients, it could be a valuable alternative to surgical approaches following the failure of medical treatment. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the company EDAP TMS. Professors Dubernard and Rousset are consultants for EDAP TMS. Dubernard received travel support from EDAP-TMS. Dr F. Chavrier received industrial grants from EDAP-TMS. He has developed a device for generating focused ultrasonic waves with reduced treatment time. This device has been patented by EDAP-TMS. Dr Lafon received industrial grants from EDAP-TMS; he declares that EDAP-TMS provided funding directly to INSERM to support a young researcher chair in therapeutic ultrasound, which is unrelated to the current study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04494568.

Transrectal high-intensity focused ultrasound (HIFU) for management of rectosigmoid deep infiltrating endometriosis: results of Phase-I clinical trial.

OBJECTIVES: Deep infiltrating endometriosis (DIE) of the rectosigmoid is associated with painful symptoms. When medical treatment is ineffective, surgical resection remains the standard treatment, despite significant risk of adverse events. High-intensity focused ultrasound (HIFU) is a minimally invasive ablative procedure. Focal One® is a transrectal HIFU (TR-HIFU) device used in prostate cancer treatment. The primary objective of this study was to confirm the feasibility of treatment with TR-HIFU in patients presenting with posterior DIE with rectosigmoid involvement. We also assessed its safety and clinical efficacy in this context. METHODS: This was a non-controlled, prospective, Phase-I clinical trial in a French University Hospital which is a multidisciplinary center for management of endometriosis. Included were patients older than 25 years, without plans to conceive within 6 months, who presented with a single lesion of posterior DIE, with rectosigmoid invasion, after failure of hormonal therapy. All lesions were assessed preoperatively using transvaginal sonography and magnetic resonance imaging. Patients completed questionnaires on gynecological and intestinal symptoms (similar to a visual analog scale (VAS)), and on quality of life (Medical Outcomes Study 36-item short-form survey (SF-36) and, for the second half of patients recruited, symptom scoring system for constipation (KESS), female sexual function index (FSFI) and endometriosis health profile short-version score (EHP-5)), before, and at 1, 3 and 6 months after, TR-HIFU treatment with a Focal One real-time ultrasound-guided HIFU device. RESULTS: Twenty-three consecutive patients were included in the study between September 2015 and October 2019. All 23 lesions were visualized, giving a detection rate of 100%. Twenty lesions were treated ('feasibility rate', 87.0%): in 13 the whole lesion was treated and in seven the lesion was treated partially. The mean duration of the TR-HIFU procedure was 55.6 min. We observed a significant improvement in VAS score at 6 months, with differences relative to preoperative scores as follows, for: dysmenorrhea (-3.6, P = 0.004), dyspareunia (-2.4, P = 0.006), diarrhea (-3.0, P = 0.006), constipation (-3.0, P = 0.002), dyschezia (-3.2, P = 0.003), false urge to defecate (-3.3, P = 0.007), posterior pelvic pain (-3.8, P = 0.002) and asthenia (-3.8, P = 0.002). There was also a significant improvement in the SF-36 score, with an increase at 6 months relative to the preoperative score in both the physical component summary (+ 9.3%, P = 0.002) and mental component summary (+ 10.9%, P = 0.017). No major complications occurred during or after any procedure. CONCLUSIONS: TR-HIFU therapy for posterior DIE is feasible. If its efficacy and safety are confirmed, it could be a minimally invasive alternative to surgery for the treatment of rectosigmoid endometriosis. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound-induced Cavitation enhances the efficacy of Chemotherapy in a 3D Model of Pancreatic Ductal Adenocarcinoma with its microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is supported by a complex microenvironment whose physical contribution to chemoresistance could be overcome by ultrasound (US) therapy. This study aims to investigate the ability of US-induced inertial cavitation in association with chemotherapy to alter tumor cell viability via microenvironment disruption. For this purpose, we used a 3D-coculture PDAC model partially mimicking the tumor and its microenvironment. Coculture spheroids combining DT66066 cells isolated from KPC-transgenic mice and murine embryonic fibroblasts (iMEF) were obtained by using a magnetic nanoshuttle method. Spheroids were exposed to US with incremental inertial cavitation indexes. Conditions studied included control, gemcitabine, US-cavitation and US-cavitation + gemcitabine. Spheroid viability was assessed by the reduction of resazurin and flow cytometry. The 3D-coculture spheroid model incorporated activated fibroblasts and produced type 1-collagen, thus providing a partial miniature representation of tumors with their microenvironment. Main findings were: (a) Gemcitabine (5 µM) was significantly less cytotoxic in the presence of KPC/iMEFs spheroids compared with KPC (fibroblast-free) spheroids; (b) US-induced inertial cavitation combined with Gemcitabine significantly decreased spheroid viability compared to Gemcitabine alone; (c) both cavitation and chemotherapy affected KPC cell viability but not that of fibroblasts, confirming the protective role of the latter vis-à-vis tumor cells. Gemcitabine toxicity is enhanced when cocultured spheroids of KPC and iMEF are exposed to US-cavitation. Although the model used is only a partial representation of PDAC, this experience supports the hypothesis that US-inertial cavitation can enhance drug penetration and cytotoxicity by disrupting PDAC microenvironment.

Imaging of shear waves induced by Lorentz force in soft tissues.

This study presents the first observation of elastic shear waves generated in soft solids using a dynamic electromagnetic field. The first and second experiments of this study showed that Lorentz force can induce a displacement in a soft phantom and that this displacement was detectable by an ultrasound scanner using speckle-tracking algorithms. For a 100 mT magnetic field and a 10 ms, 100 mA peak-to-peak electrical burst, the displacement reached a magnitude of 1 µm. In the third experiment, we showed that Lorentz force can induce shear waves in a phantom. A physical model using electromagnetic and elasticity equations was proposed. Computer simulations were in good agreement with experimental results. The shear waves induced by Lorentz force were used in the last experiment to estimate the elasticity of a swine liver sample.

Dual-mode transducers for ultrasound imaging and thermal therapy.

Medical imaging is a vital component of high intensity focused ultrasound (HIFU) therapy, which is gaining clinical acceptance for tissue ablation and cancer therapy. Imaging is necessary to plan and guide the application of therapeutic ultrasound, and to monitor the effects it induces in tissue. Because they can transmit high intensity continuous wave ultrasound for treatment and pulsed ultrasound for imaging, dual-mode transducers aim to improve the guidance and monitoring stages. Their primary advantage is implicit registration between the imaging and treatment axes, and so they can help ensure before treatment that the therapeutic beam is correctly aligned with the planned treatment volume. During treatment, imaging signals can be processed in real-time to assess acoustic properties of the tissue that are related to thermal ablation. Piezocomposite materials are favorable for dual-mode transducers because of their improved bandwidth, which in turn improves imaging performance while maintaining high efficiency for treatment. Here we present our experiences with three dual-mode transducers for interstitial applications. The first was an 11-MHz monoelement designed for use in the bile duct. It had a 25x7.5 mm(2) aperture that was cylindrically focused to 10mm. The applicator motion was step-wise rotational for imaging and therapy over a 360 degrees, or smaller, sector. The second transducer had 5-elements, each measuring 3.0x3.8 mm(2) for a total aperture of 3.0x20 mm(2). It operated at 5.6 MHz, was cylindrically focused to 14 mm, and was integrated with a servo-controlled oscillating probe designed for sector imaging and directive therapy in the liver. The last transducer was a 5-MHz, 64-element linear array designed for beam-formed imaging and therapy. The aperture was 3.0x18 mm(2) with a pitch of 0.280 mm. Characterization results included conversion efficiencies above 50%, pulse-echo bandwidths above 50%, surface intensities up to 30 W/cm(2), and axial imaging resolutions to 0.2 mm. The second transducer was evaluated in vivo using porcine liver, where coagulation necrosis was induced up to a depth of 20 mm in 120 s. B-mode and M-mode images displayed a hypoechoic region that agreed well with lesion depth observed by gross histology. These feasibility studies demonstrate that the dual-mode transducers had imaging performance that was sufficient to aid the guidance and monitoring of treatment, and could sustain high intensities to induce coagulation necrosis in vivo.

Fatal Epstein-Barr virus primo infection in a 25-year-old man treated with azathioprine for Crohn's disease.

We report a case of Epstein-Barr virus (EBV) primo infection with the development of successive infectious mononucleosis, hemophagocytic lymphohistiocytosis, and B-cell lymphoproliferative disorder in a patient treated with azathioprine for Crohn's disease. This case report suggests that specific EBV-related clinical and virological management should be considered when treating a patient with inflammatory bowel disease with azathioprine.

Process-based analysis of waste management systems: a case study.

This paper presents an analysis, using process simulation, of the waste management system applied in a collection basin located in the south of Paris (France). The study was conducted in close cooperation with the "SYCTOM of Paris agglomeration", an operator in charge of managing 2.5 milliontons/yr of municipal solid waste in the Paris area. The analysis includes a description of the current situation of waste management in this collection basin, the construction and calibration of a simulator that reproduces this situation, the simulation of scenarios that account for possible future changes in waste flows and treatment options and finally a comparison of scenario results. Results illustrate the interest of a process-based approach to waste management systems. Such an approach is complementary to life cycle analyses, which usually rely on more generic descriptions of waste treatment units. The detailed analysis of a waste management system using local data on waste streams and treatment units provides technical indicators of system efficiency expressed in terms of recycling rates, energy recovery, emission fluxes and costs. Such information can help reach a consensus with respect to the actual situation of waste management and provides decision-makers with quantitative arguments that can be brought into the public debate.

Morphological analysis of the interstitial ultrasonic ablation in porcine liver in vivo.

BACKGROUND: The shape of the induced thermal ablation area is as important as its dimension. The aim of this study was to analyze the size reproducibility and the aspect of the interstitial ultrasonic ablation obtained by a planar transducer in porcine liver in vivo. METHODS: Five pigs were used. Two complete ultrasonic lesions were made in each animal under pedicle clamping. All the lesions underwent MR examination on day 7 and then a histological analysis. RESULTS: The tested probe has the advantage of providing a step-by-step and highly directional treatment in the target zone. The ultrasonic lesions presented as well-defined and homogenous areas of tissue coagulation. The lesion volumes ranged from 8.1 to 92.3 cm3 with an averaged lesion length of 56 mm at gross examination. Three-dimensional reconstruction of the lesions from the MR images showed cylindrical and conical shapes. Large intrahepatic vessels distorted the lesion shape, and the vicinity of the application to the liver surface increased significantly the volume of the ultrasonic necrosis. Histological examination showed complete necrosis in the area of damage. CONCLUSION: The ultrasonic ablation has a regular shape, always with sharply defined borders. However, it showed some variability in the size of the induced lesions.

In vitro evaluation of an oscillating dual-mode ultrasound probe for sector imaging and directive therapy.

Interstitial probes have been shown as effective devices to deliver high-intensity ultrasound therapy. Here, cylindrically-focused dual-mode transducers with either one or 5-elements were characterized, and a monoelement probe was evaluated in vitro. In therapy mode, the transducers were maximally efficient (> or =70%) at 5.6 MHz with surface intensities up to 20 W/cm(2). In imaging mode, fractional bandwidths were 46% and 50+/-4% (ave+/-std) for the monoelement and 5-element transducers respectively. Axial and lateral resolutions were 0.5 mm and 1.0 mm, respectively, for both transducers as measured with a point scatterer in the focal plane. After characterization, the oscillating probe was used to image and apply therapy to porcine liver. B-mode images over a 140 degrees sector were formed before and after therapy, which was applied for 90 s at each of 5 angles separated by 20 degrees (e.g. -40 degrees , -20 degrees, 0 degrees, 20 degrees, 40 degrees) to form a composite lesion. Transducer surface intensity was 18 W/cm(2). Therapy was interrupted at 125 ms intervals to collect pulse/echo data along the therapy axes. Data were displayed in real-time as an M-mode image to monitor therapy. B-mode images adequately represented the liver tissue. M-mode image data agreed well with the formation of lesions in the liver.

[Ultrasound interstitial mini invasive probes for thermal ablation in liver: feasibility study in vivo]. / Sondes ultrasonores interstitielles mini-invasives pour l'ablation thermique dans le foie: étude de faisabilité in vivo.

High intensity ultrasounds are routinely used for thermal ablation of some cancers. However, for treating hepatic tumours with physical agents, RF applicators and cryoprobes are still preferred. The goal of the present study was to demonstrate the feasibility of using interstitial ultrasound probes in liver following two approaches: percutaneous and intra-tissular or endo vascular. In vivo trials on a porcine model demonstrated the minimally invasive nature of both procedures. Homogeneous and reproducible thermal lesions, up to 20 mm deep, were obtained. The work on these two original approaches deserves to be completed with more extended prospective studies. The association with an imaging method will have to be studied before proceeding to clinical trials.

Interstitial devices for minimally invasive thermal ablation by high-intensity ultrasound.

Interstitial ultrasound applicators have been proposed for treating deep-seated tumours that cannot be reached with extra-corporeal high-intensity focused ultrasound. In addition, interstitial ultrasound offers several advantages compared with conventional ablation technology (radiofrequency, microwaves, cryotherapy) in terms of penetration, speed of coagulation, ability to direct and control the thermal lesion and compatibility with image monitoring. The ultrasound source is brought as close as possible to the target in order to minimize the effects of attenuation and phase aberration along the ultrasound pathway. The present paper is a review of the interstitial applicators that were described during the last decade in the literature. It is presented in three sections. The technical aspects common to all applicators are first described. For example, most-described applicators are sideview applicators whose active element is water-cooled and operates at rather high frequency (above 3 MHz) in order to promote heating. Then the different potential techniques for monitoring treatment administered by the interstitial route are presented and illustrated through a review of image-guided interstitial thermal ablation. Three major techniques of imaging are used for guiding interstitial treatment: MRI, ultrasound and fluoroscopy. The third section goes in to further detail on diverse described medical applications.

Bloodless partial nephrectomy with a new high-intensity collimated ultrasonic coagulating applicator in the porcine model.

OBJECTIVES: To evaluate the long-term hemostatic efficacy of a new high-intensity collimated ultrasonic (HICU) applicator for open subhilar partial nephrectomy (PN) in the porcine model. METHODS: An applicator was designed with a planar 3.78-MHz HICU transducer and a reflector to optimize the delivery of acoustic energy to coagulate renal tissue. Six female pigs underwent right PN, followed at day 7 by left PN. The 6 pigs were killed on day 14. The treatment consisted of delivering HICU to a lower pole subhilar location, under a vascular clamp, then releasing the clamp, and cutting the kidney lower pole. The immediate and delayed hemostatic efficacy, treatment parameters, blood loss, complications, and renal function were evaluated at each surgical event and at necropsy. RESULTS: Perfect hemostasis was achieved with all 12 kidneys, with a mean treatment time of 7.2 minutes (range 5 to 9.2). The mean proportion of resected parenchyma was 21% (range 14% to 32%). No renal function impairment and no major complications were recorded. At necropsy, no secondary hematoma was observed, and three urinomas (25%) were found. CONCLUSIONS: Our HICU applicator has shown promising results during PN in the pig model with no other method of hemostasis. More studies are needed to refine our probe for laparoscopic surgery, improve its ergonomics, and extend our experiments to human laparoscopic nephron-sparing surgery.

[Patentability of living material: public health concerns (1/2)]. / Brevetabilité du vivant, la santé publique concernée (1/2).

A TOPICAL SUBJECT: The patentability of living material provokes debate in the scientific and medical world, but also concerns the political and legal circles. REGARDING PATENTS: Laws govern intellectual property rights and patients. There are contradictory arguments advanced by those who are in favour or who are opposed to patents, and particular problems related to the patenting of living organisms, particularly since the progress made in genomic research. ESSENTIAL PUBLIC HEALTH REQUIREMENTS: It is important to underline the limits imposed by the protection of intellectual property, regarding the access by all to any progress issued from research. The provisions must be widened in order to bypass the patents, when the health and nutrition of populations are at stake. It is essential to come to the universal accessibility, particularly in developing countries, to all innovations and that all knowledge be shared.

Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo).

In this study, we show that upon thrombopoietin (Tpo) stimulation the two adapter proteins Gab1 and Gab2 are strongly tyrosine phosphorylated and associated with Shc, SHP2, PI 3-kinase and Grb2 in mpl-expressing UT7 cells. Although Gab1 and Gab2 seem to mediate overlapping biological signals in many cells, only Gab1 is expressed and phosphorylated in response to Tpo in primary human megakaryocytic progenitors; furthermore, it associates with the same proteins. Although a low level of tyrosine phosphorylated IRS-2 protein is also detected in PI 3-kinase immunoprecipitates, Gab proteins are the essential proteins associated with PI 3-kinase after Tpo stimulation. We demonstrate that, albeit no association is detected between the Tpo receptor mpl and Gab proteins, Y112 located in the C-terminal cytoplasmic domain of mpl is required for Gab1/2 tyrosine phosphorylation. Gab proteins are not tyrosine phosphorylated after Tpo stimulation of UT-7 and Ba/F3 cells expressing a mpl mutant lacking Y112. Moreover, no activation of the PI 3-kinase/Akt pathway is observed in cells expressing this mpl mutant. Finally, we show that this mutant does not allow cell proliferation, thereby confirming that PI 3-kinase activation is required for Tpo-induced cell proliferation.

Cylindrical thermal coagulation necrosis using an interstitial applicator with a plane ultrasonic transducer: in vitro and in vivo experiments versus computer simulations.

Extracorporeal HIFU techniques still cannot be used to treat tumours of the digestive tract, therefore an interstitial applicator has been developed to fill this gap. The object of the study was to validate the use of a plane ultrasonic transducer in an interstitial applicator to obtain large sector based or cylindrical coagulation necrosis. Two very different shot sequences were performed in vitro and in vivo and compared with numerical calculations. Each sequence consisted of 20 shots. After each shot the applicator was rotated through an angle of 18 degrees. Each shot in sequence 1 lasted 20 s, with a 2-min interval between shots which can be considered as independent. The second sequence involved coupling the shots so that each benefits from the heat deposited by the preceding ones. The first shot lasted 20 s to establish the lesion, then the duration of the subsequent 19 shots was 10 s to take into account the temperature rise due to preceding shots. In both cases, it was shown that cylindrical necrosis resulted in vivo and in vitro: 20 mm diameter and 8mm in height. The dimensions and the shapes of the necrosed volumes agreed with numerical predictions: the necrosed area induced by sequence 1 had a serrated border, whereas that of the second sequence was much more uniform. It was also shown that, for the two sequences, less than 20 s were necessary to coagulate the tissues in each direction. The results with sequence 2 showed that coupling the shots could be used to reduce treatment time without modifying the necrosed volume.