Abdelkader Taibi

Ce travail doctoral a pour but d'évaluer la sensibilité des cellules CT-26 murines de cancer colorectal (CCR) à des impulsions de 10 nanosecondes, à haute fréquence et haute intensité (nsPEF). Après avoir développé un modèle de souris de métastases péritonéales coliques (MPc), nous avons étudié la réponse histologique in vivo selon une nouvelle classification (Peritoneal Regression Grading Score) spécifique des MPc. La fibrose a été analysée par microscopie multiphotonique, la prolifération (KI67, DAPI) et l'expression des facteurs immunologiques (CD3, CD4, CD8) par histologie classique. Nous avons démontré que les nsPEFs exercent un effet dose-réponse sur les cellules CT-26 et dans le modèle murin de MPc, en induisant la mort cellulaire et en modifiant la morphologie des mitochondries après perméabilisation de la membrane plasmique. De plus, une réponse immunitaire spécifique des lymphocytes T CD8 +, ainsi qu'une forte réponse histologique viennent renforcer l’effet anti-tumoral des nsPEFs. Ainsi, ces impulsions nanosecondes semblent être une alternative thérapeutique à confirmer dans des études expérimentales afin notamment d’en évaluer son innocuité sur le péritoine sain et d’améliorer l’ergonomie du système d’application.

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) improves local drug delivery and has shown promising results for treating peritoneal surface malignancies (PSMs); however, comparative data on the performance of different PIPAC nozzles in disease-bearing models are limited. Objective: This study aimed to evaluate the therapeutic efficacy of three PIPAC nozzles in a rabbit model of PSM. Methods: Nine immunocompetent New Zealand rabbits received intraperitoneal injections of VX2 tumor cells to induce PSM. The animals were randomized into three groups ( n = 3) and treated with oxaliplatin-based PIPAC using CapnoPen ^® , HurriChem™, or MCR-4 TOPOL ^® nozzles on days 8, 15, and 21. Evaluations included the Peritoneal Cancer Index (PCI), tumor weight, histopathology (Peritoneal Regression Grading Score [PRGS]), imaging, and markers of proliferation (Ki-67) and apoptosis (TUNEL). The final results, including autopsy, were obtained on day 26. Results: CapnoPen ^® showed a trend toward improved tumor regression, with significantly lower PCI scores at euthanasia. After the third PIPAC, the mean PCI was lower in the CapnoPen ^® group compared with MCR-4 TOPOL ^® (6.33 vs. 13.3; p = 0.041). Tumor weights were also lowest in the CapnoPen ^® group. Mean PRGS values were 2.14 (CapnoPen ^® ), 2.75 (HurriChem™), and 3.49 (MCR-4), with a significant difference between CapnoPen ^® and MCR-4 ( p = 0.033). All devices significantly reduced PCI compared with controls from a previous study (no chemotherapy: 21.6; p < 0.01). Conclusion: This initial study suggests that the type of PIPAC nebulizer may influence therapeutic efficacy in a rabbit model with peritoneal metastasis, highlighting the need for further controlled studies to confirm these preliminary findings

Background: Animal models are essential for testing new pressurized intraperitoneal aerosol chemotherapy (PIPAC) protocols; however, no immunocompetent animal model of peritoneal surface malignancies (PSMs) treated with PIPAC has been established. This study evaluated the feasibility, safety, and oncological efficacy of PIPAC in a rabbit PSM model. Methods: The study was conducted in two phases: (1) Feasibility Assessment: Three healthy rabbits underwent three consecutive PIPAC procedures (saline) at weekly intervals. The rabbits’ well-being, morbidity, mortality, and histological changes were monitored. (2) Treatment Phase: Rabbits with PSM were treated with PIPAC using oxaliplatin, cisplatin-doxorubicin, or saline. Parameters such as animal well-being, ascites volume, morbidity, Peritoneal Cancer Index (PCI), histological response (Peritoneal Regression Grading Score [PRGS]), tumor cell proliferation/apoptosis, and circulating tumor DNA (ctDNA) levels were assessed. Results: PIPAC was feasible and safe, with no increased morbidity or mortality. PIPAC demonstrated antitumor efficacy with lower PCI (control 21.6 vs. oxaliplatin 9.2 vs. cisplatin-doxorubicin 10.2; p < 0.001), improved histological response (PRGS: control 3.38 vs. oxaliplatin 1.95 vs. cisplatin-doxorubicin 1.85; p = 0.01), and reduced tumor cell proliferation (control 5.3% vs. oxaliplatin 0.82% vs. cisplatin-doxorubicin 0.62%; p < 0.0001). ctDNA levels showed promise for monitoring treatment response, warranting further investigation. Conclusion: This study confirms the feasibility and effectiveness of PIPAC with oxaliplatin or cisplatin-doxorubicin in rabbits with PSM. The model provides a foundation for future research on PIPAC protocols and related treatments.

The 2022 PSOGI (Peritoneal Surface Oncology Group International) and RENAPE (French Network for Rare Peritoneal Malignancies) consensus on hyperthermic intraperitoneal chemotherapy (HIPEC) was a comprehensive effort aimed at standardizing treatment protocols for various peritoneal malignancies. This initiative is critical due to the wide range of technical variations in HIPEC procedures and the resulting need for standardization to ensure consistent and effective patient care and meaningful audit of multicenter data.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a valuable therapeutic alternative for patients with peritoneal metastases. PIPAC uses a hyaluronic acid-based gel to reduce surgically induced adhesions. The aim of this study was to evaluate the effects of the hyaluronic acid-based gel on tumor dissemination. First, we explored whether the survival of CT26 luciferase-expressing murine colonic tumor cells was correlated with the dose of HyaRegen® Gel, and we determined the half-maximal inhibitory concentration (the IC50) of the gel. Next, we performed an in vitro study of cell survival rates after gel application on day 0 (D0) and day 1 (D1). Finally, we intraperitoneally administered the gel to mice with immunocompetent BALB/c colonic peritoneal metastases (on D0, D5, D10, D14, and D18). Tumor growth was regularly monitored using a bioluminescence assay (on D11, D17, and D21). After all mice had been sacrificed on D21, the body weights and the volumes of intraperitoneal ascites were measured; the Peritoneal Carcinosis Index (PCI) and Ki-antigen 67 scores were calculated. The IC50 value was 70 μL of gel in a total volume of 100 μL. The cell survival rates on D4 were identical in the control group and the two groups that had been treated with gel on D0 and D1. The bioluminescence levels over time were similar in the gel and control groups. The PCI scores were 35.5 ± 2.89 for the control group and 36 ± 2.45 for the gel group (p = 0.8005). The mean Ki-67 index percentages were 37.28 ±1 1.75 for the control group and 34.03 ± 8.62 for the gel group (p = 0.1971). This in vitro and in vivo study using a mouse model of immunocompetent metastatic peritoneal cancer did not reveal any pro- or anti-tumoral effect of HyaRegen® Gel. These findings indicate that the gel can be used to treat PIPACs with minimal apprehension.