Abstract A030: Investigating the feasibility of <i>in-vivo</i> histotripsy ablation for osteosarcoma using an orthotopic murine model and a canine model of spontaneous disease
Bibliographic record
Abstract
Abstract Osteosarcoma (OS) is the most commonly occurring primary bone tumor in pediatric cancer patients and dogs, with estimated incidences of 3-4 cases per 1 million and 14 cases per 100,000, respectively. The biological similarities shared between human and canine OS and increased OS prevalence in dogs allows the dog to serve as an effective comparative oncology research model. Current standard of care treatment results in a 70% median 5-year survival for humans and a 10-12-month median survival for dogs, and these survival expectations have not improved in 30 years. There is a critical need for novel treatment options to improve the prognosis for OS patients. The objective of this study was to investigate the ablative (murine, canine) and immunological (canine) effects of histotripsy, a novel focused ultrasound tissue ablation technique, for OS. We utilized orthotopic xenograft murine models with induced canine (D17) or human (143B) OS tumors. Ablative outcomes were assessed grossly and microscopically via histopathological evaluation, and treatment effects on limb functionality were evaluated by monitoring lameness, grip capacity, nesting behavior, and body weight for the duration of the study. Fifteen client-owned dogs with suspected OS were enrolled into a clinical trial and underwent histotripsy treatment 24 hours prior to standard of care limb amputation surgery. Ablative outcomes were assessed grossly and microscopically via histopathological evaluation after surgical excision of treated tumors. Immunological outcomes were evaluated by peripheral blood samples collected pretreatment, 24 hours, and 2 weeks post treatment for immune cell phenotyping via flow cytometry to evaluate the systemic immune response. Locally, changes in the tumor immune microenvironment were assessed at both the cellular and molecular levels. Targeted ablation of the tumor tissue was achieved in both the murine models and the canine patients. Ablation was evident by gross and microscopic evaluation where loss of cellular architecture, lytic and coagulative necrosis and delineation of treated and untreated tumor regions were observed. In the mice, decreased limb function due to inflammation after histotripsy ablation resolved within 5-7 days post treatment. The dogs did not exhibit any increase in lameness after histotripsy ablation. The only clinical adverse event experienced by canine patients was mild transient dermal erythema at the treatment site. Our results suggest systemic immunomodulation evident by increases in CD4+ and CD8+ T lymphocyte populations post treatment and changes in monocyte expression of CD62L and CD80. Locally, we observed an upregulation in genes related to chemotaxis, regulation of inflammation, and immunogenic cell death in treated tumor samples compared to untreated samples. In conclusion our preliminary results suggest that histotripsy treatment has both immunotherapeutic and ablative potential and support the development of histotripsy as a tumor ablation technique and immunotherapeutic for OS. Citation Format: Alayna N. Hay, Lauren Ruger, Haleigh Hixson, Jessica Gannon, Alex Simon, Hannah Sheppard, Sheryl Coutermarsh-Ott, Elaina Davis, Katharine Kierski, Brittany Ciepluch, Nathan Neufeld, Eli Vlaisavljevich, Joanne Tuohy. Investigating the feasibility of in-vivo histotripsy ablation for osteosarcoma using an orthotopic murine model and a canine model of spontaneous disease [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A030.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".