30 november 2023: Zie ook dit artikel: https://kanker-actueel.nl/histotripsy-een-vorm-van-ultra-sound-met-gepulseerde-geluidsgolven-en-gasbellen-blijkt-uitstekende-veilige-en-niet-invasieve-techniek-voor-eliminatie-van-levertumoren-daarbij-gezond-weefsel-sparend.html

30 november 2023: Bron:  2023 Oct; 11(10): 2737. Published online 2023 Oct 9.

Ultra Sound is een al tientallen jaren gebruikte techniek om tumorweefsel te vernietigen. Een speciale vorm van Ultra Sound is Histotripsy een behandeling die door het Histosonic - EdisonTM apparaat wordt gegeven door middel van gepulseerde geluidsgolven om “bellenwolken” te veroorzaken uit gassen die van nature aanwezig zijn in het beoogde tumorweefsel. Deze bellenwolken vormen en storten in microseconden in wanneer een arts / PDT specialist het Edison apparaat op die tumoren richt, waardoor mechanische krachten ontstaan die sterk genoeg zijn om weefsel op cellulair en subcellulair niveau te vernietigen op een niet-invasieve en niet-thermische methode.

De Amerikaanse FDA keurde al in 2018 het Histosonic - Edison apparaat goed en de Histotripsy behandeling om levertumoren niet-invasief te behandelen (zie ook dit artikel).

Maar er lopen in Amerika en Europa ook studies bij verschillende andere vormen van kanker en kwaadaardige tumoren.
Zoals enkele studies bij muizen met osteosarcomen. En Histotripsy blijkt ook in deze studies uitstekende resultaten te geven in volledig verwijderen van het tumorweefsel zonder gezond weefsel te beschadigen. 

Hier een voorbeeld van hoe een tumor van een osteosarcoom reageert:

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Figure 3

Representative B-mode ultrasound images: (A) DLM8 subcutaneous tumor before treatment (red dashed circle); (B) tumor during treatment with cavitation bubble cloud (red arrow); (C) ablated tumor tissue (red dashed circle) with hypoechoic regions (yellow arrow).

En zie Figure 2 voor de resultaten in grafiek

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Figure 2

Feasibility of delivering histotripsy ablation to SQ OS tumors: (A) average tumor diameter in treated and untreated mice from day 1 of tumor cell injection to day 21 (72 h after histotripsy treatment); (B) image of SQ OS tumor on the right flank of the C3H/HeN mouse prior to histotripsy treatment; (C) image of tumor immediately after histotripsy treatment. Error bars are represented as SD.

Op deze pagina staan enkele video's over ontstaan van de Histotripsy en verwijzingen naar studies. Artsen kunnen scholing krijgen om met de Histosonic (Edison TM) te werken met patiënten: https://histosonics.com/education/

Van deze studies is een volledig studierapport gratis in te zien en geeft heel veel gedetailleerde informatie over Ultra Sound met een histotripsy behandeling. Ik heb het abstract uitgebreid met de introductie die goede informatie geeft over met name osteosarcomen enz.:

 2023 Oct; 11(10): 2737.
Published online 2023 Oct 9. doi: 10.3390/biomedicines11102737
PMCID: PMC10604356
PMID: 37893110

Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model

Alayna N. HayFormal analysisData curationWriting – original draftWriting – review & editing,1 Khan Mohammad ImranMethodologyData curationWriting – original draftWriting – review & editing,2,3 Alissa Hendricks-WengerMethodologyData curationWriting – review & editing,2,3,4 Jessica M. GannonMethodologyData curationWriting – original draftWriting – review & editing,4 Jacqueline SerenoData curationWriting – review & editing,2 Alex SimonMethodologyData curationWriting – review & editing,4 Victor A. LopezMethodologyData curationWriting – review & editing,4 Sheryl Coutermarsh-OttFormal analysisData curationWriting – original draftWriting – review & editing,2,5 Eli VlaisavljevichConceptualizationMethodologyResourcesWriting – original draftWriting – review & editingSupervision,4 Irving C. AllenConceptualizationMethodologyResourcesWriting – original draftWriting – review & editingSupervision,2,3 and Joanne L. TuohyConceptualizationMethodologyResourcesWriting – original draftWriting – review & editingSupervisionFunding acquisition1,*
Elisa Belluzzi, Academic Editor


Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.

Keywords: tumor ablation, focused ultrasound, tumor immunology, DLM8 cell line

1. Introduction

Osteosarcoma (OS) is the most commonly occurring primary bone tumor and primarily occurs in children and adolescents [,,,,]. The worldwide incidence in children and adolescents is 3–4.5 cases per 1 million people and accounts for 55% of primary bone tumor diagnoses in children in the United States [,,]. Over 30 years ago, chemotherapeutics were introduced into the standard of care treatment regimen for OS patients, which greatly improved patient survival. However, survival outcomes remain at a median 5-year survival rate of 70% for patients presenting without metastatic disease at the time of diagnosis, and less than 25% for patients with metastatic or recurrent disease [,,,]. The current definitive standard of care treatment for OS consists of surgical resection of the primary bone tumor via limb salvage surgery or amputation with neoadjuvant and adjuvant chemotherapy [,]. Advancements in limb salvage surgeries have resulted in improving quality of life outcomes for OS patients, but these procedures are still associated with complications and risks, including mobility limitations, fracture, infection, and tumor recurrence [,,]. Additionally, limb salvage surgery is an invasive procedure, and often multiple surgeries are required [,,]. Consequently, there is a continued need to advance OS treatment modalities in order to improve patient quality of life and survival. A noninvasive limb salvage treatment option has the potential to immensely improve patient quality of life.

In a similar manner to many cancers, the cellular interactions that occur in the tumor microenvironment (TME) in OS result in immunosuppression, contributing to OS progression and metastatic disease development, which is the major contributing factor to OS mortality [,,,]. Thus, more recent approaches for developing novel OS treatments have focused on immunomodulation in efforts to stimulate an antitumor immune response to moderate metastatic disease development [,,,,]. The novel focused ultrasound technique, histotripsy, has been shown to ablate targeted tumor tissue and induce immunomodulation to stimulate an antitumor immune response [,,,,,,,,,]. Histotripsy is thus an exciting technique that can potentially treat primary and metastatic OS to improve treatment and survival outcomes.

Histotripsy is a precise, nonthermal, noninvasive, focused ultrasound technique that utilizes high-amplitude ultrasound pulses to generate acoustic cavitation to mechanically homogenize targeted tissue [,,,,,]. Histotripsy has previously been employed in humans to ablate prostate tissue, heart valves, and liver tumors [,,,] and in canines for experimentally induced prostate tumors [], spontaneously occurring primary bone tumors [,,,], and soft tissue sarcomas [,]. Preclinical rodent models have demonstrated effective ablation of liver tumors [], melanoma [], renal cell carcinoma [], and pancreatic [] tumors and have also reported that the resulting disruption of targeted tissue causes the release of immunogenic cellular proteins, which stimulates a proinflammatory/antitumor immune response [,,,,,]. The destruction of tumors with histotripsy leads to the release of tumor antigens and damage-associated molecular patterns (DAMPs), such as high mobility group box-1 (HMGB-1), orchestrating an antitumor immune response [,,,]. Furthermore, an increased infiltration of cytotoxic T-lymphocytes (CTLs) into the tumor microenvironment is observed after histotripsy treatment, as is an increase in tumor antigen recognition and tumor cell cytotoxicity [,,,,]. In longer-term preclinical studies, the abscopal immune response associated with histotripsy was reported to decrease metastases within 20 days after histotripsy treatment [,,]. A clinical trial investigating histotripsy hepatic tumor ablation observed a decrease in the growth of non-histotripsy-treated tumors in study patients []. Histotripsy has the potential to serve as both a primary tumor ablation modality and to stimulate an antitumor immune response. However, in the context of OS, much remains to be investigated regarding the potential of employing histotripsy ablation and the associated immunomodulatory effects.

The current study was conducted to investigate the ablative and preliminary immunological outcomes associated with histotripsy ablation of OS in the syngeneic C3H/HeN mouse and DLM8 cell line models. Ablation outcomes were evaluated histologically immediately after histotripsy and 72 h after treatment. We analyzed the expression of immune activation genes Il6IfnγIl-1βIl10Il13, and Pdl1 and characterized immune cell populations within the TME 72 h after treatment. We hypothesized that histotripsy ablation would result in disruption of the targeted OS tumors, yield acellular debris, and stimulate a proinflammatory immune response. Our results indicate successful targeted ablation of OS tumors and suggest that histotripsy modulates the TME, thus supporting the potential of histotripsy as a treatment modality for OS.

Funding Statement

National Institutes of Health (1R21EB030182-01, R01CA269811). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author Contributions

A.N.H.—data analysis and primary contributor for manuscript writing and revision. K.M.I.—procedure execution, data curation, data analysis, manuscript writing, and revision. A.H.-W.—procedure execution, data curation, data analysis, and manuscript revision. J.M.G.—procedure execution, data curation, data analysis, and manuscript revision. J.S.—procedure execution, data curation, and manuscript revision. A.S.—procedure execution, data curation, data analysis, and manuscript revision. V.A.L.—procedure execution, data curation, data analysis, and manuscript revision. S.C.-O.—performed all histological data curation and analysis, manuscript writing, and revision. E.V.—study design, data review, project management, and manuscript revision. I.C.A.—project conceptualization, methodology, resources, project management, and manuscript revision. J.L.T.—project conceptualization, methodology, data analysis, resources, and manuscript revision. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The animal study protocol was approved by the Institutional Review Board (or Ethics Committee) of Virginia Tech (protocol number 21-063 and approved 2021-4).

Informed Consent Statement

Not applicable.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, [J.L.T.], upon reasonable request. The data are not publicly available due to privacy.

Conflicts of Interest

Eli Vlaisavljevich has an ongoing research partnership and financial relationship with HistoSonics, Inc. No other authors have conflict of interest to report. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.


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