Intraperitoneal aerosolization of albumin-stabilized paclitaxel nanoparticles (Abraxane™) for peritoneal carcinomatosis : a phase I first-in-human study

Background: Nanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane (TM)) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol (TM)). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer. Methods: Eligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m(2) using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses. Discussion: ABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy

Radio-Frequency Plasma Polymerized Biodegradable Carrier for in vivo Release of Cis-Platinum

A low pressure plasma process based on plasma deposition has been used to develop a drug delivery strategy. In this study, a drug delivery system based on different layers of plasma co-polymerized Poly ε-caprolactone-Polyethylene glycol (PCL-PEG) co-polymers was deposited on biocompatible substrates. Cis-platinum (118 μgm/cm2) was used as an anti-cancer drug and incorporated for local delivery of the chemotherapeutic agent. The co-polymer layers and their interaction with cancer cells were analyzed by scanning electron microscopy. Our study showed that the plasma-PCL-PEG coated cellophane membranes, in which the drug, was included did not modify the flexibility and appearance of the membranes. This system was actively investigated as an alternative method of controlling localized delivery of drug in vivo. The loading of the anti-cancer drug was investigated by UV-VIS spectroscopy and its release from plasma deposited implants against BALB/c mice liver tissues were analyzed through histological examination and apoptosis by TUNEL assay. The histological examination of liver tissues revealed that when the plasma-modified membranes encapsulated the cis-platinum, the Glisson\u27s capsule and liver parenchyma were damaged. In all cases, inflammatory tissues and fibrosis cells were observed in contact zones between the implant and the liver parenchyma. In conclusion, low pressure plasma deposited uniform nano-layers of the co-polymers can be used for controlled release of the drug in vivo

Thrombopoietin Secretion by Human Ovarian Cancer Cells

The thrombopoietin (TPO) gene expression in human ovary and cancer cells from patients with ovarian carcinomatosis, as well as several cancer cell lines including MDA-MB231 (breast cancer), K562 and HL60 (Leukemic cells), OVCAR-3NIH and SKOV-3 (ovarian cancer), was performed using RT PCR, real-time PCR, and gene sequencing. Human liver tissues are used as controls. The presence of TPO in the cells and its regulation by activated protein C were explored by flow cytometry. TPO content of cell extract as well as plasma of a patient with ovarian cancer was evaluated by ELISA. The functionality of TPO was performed in coculture on the basis of the viability of a TPO-dependent cell line (Ba/F3), MTT assay, and Annexin-V labeling. As in liver, ovarian tissues and all cancer cells lines except the MDA-MB231 express the three TPO-1 (full length TPO), TPO-2 (12 bp deletion), and TPO-3 (116 pb deletion) variants. Primary ovarian cancer cells as well as cancer cell lines produce TPO. The thrombopoietin production by OVCAR-3 increased when cells are stimulated by aPC. OVCAR-3 cell’s supernatant can replace exogenous TPO and inhibited TPO-dependent cell line (Ba/F3) apoptosis. The thrombopoietin produced by tumor may have a direct effect on thrombocytosis/thrombosis occurrence in patients with ovarian cancer

Rosuvastatin Counteracts Vessel Arterialisation and Sinusoid Capillarisation, Reduces Tumour Growth, and Prolongs Survival in Murine Hepatocellular Carcinoma

Background and Aims. An arterial blood supply and phenotypic changes of the sinusoids characterise the liver vasculature in human hepatocellular carcinoma (HCC). We investigated the effects of rosuvastatin on liver vessel anomalies, tumour growth and survival in HCC. Methods. We treated transgenic mice developing HCC, characterized by vessel anomalies similar to those of human HCC, with rosuvastatin. Results. In the rosuvastatin group, the survival time was longer (P < .001), and liver weight (P < .01) and nodule surface (P < .01) were reduced. Rosuvastatin decreased the number of smooth muscle actin-positive arteries (P < .05) and prevented the sinusoid anomalies, with decreased laminin expression (P < .001), activated hepatic stellate cells (P < .001), and active Notch4 expression. Furthermore, rosuvastatin inhibited endothelial cell but not tumour hepatocyte functions. Conclusions. Rosuvastatin reduced the vessel anomalies and tumour growth and prolonged survival in HCC. These results represent new mechanisms of the effects of statin on tumour angiogenesis and a potential target therapy in HCC

Association between a high number of isolated lymph nodes in T1 to T4 N0M0 colorectal cancer and the microsatellite instability phenotype

Hypothèse : Les carcinomes colorectaux de stade I ou II microsatellites instables (MSI) sont caractérisés par plus de ganglions lymphatiques isolés sur la pièce de résection par rapport à leurs homologues microsatellites stables (MSS). Conception : Étude prospective. Patients : Le statut MSI a été déterminé de façon prospective chez 135 patients opérables, par l’utilisation d’une PCR pentaplex. Puis, les défauts de réparation des mésappariements de l’ADN ont été étudiés par immunohistochimie. Résultats : Parmi les 82 cancers colorectaux de stade I ou II, 11 étaient MSI et 71 MSS, avec une moyenne (écart-type) de 23,6 (3,1) et 13,7 (1,0) ganglions négatifs, respectivement (p = .001). Le nombre moyen de ganglions pour tous les cancers colorectaux de stade I ou II analysés dans notre hôpital était de 15. La prévalence des MSI dans les tumeurs avec plus de 15 ganglions prélevés était de 25 % (9 sur 36) et 82 % (9 sur 11) des tumeurs MSI appartenaient à ce groupe. Conclusions : Un nombre élevé de ganglions isolés en cas de cancer colorectal de stade I ou II est associé au phénotype MSI. Le bon pronostic qui est habituellement associé à des tumeurs ayant un nombre élevé de ganglions N0 pourrait refléter la prévalence élevée des MSI chez ces tumeurs. Le nombre de ganglions examinés comme un critère de qualité doit être utilisé avec prudence. Limiter le phénotypage MSI aux tumeurs colorectales de stade I ou II ayant plus que le nombre moyen de ganglions identifie presque toutes les tumeurs MSI.Hypothèse : Les carcinomes colorectaux de stade I ou II microsatellites instables (MSI) sont caractérisés par plus de ganglions lymphatiques isolés sur la pièce de résection par rapport à leurs homologues microsatellites stables (MSS). Conception : Étude prospective. Patients : Le statut MSI a été déterminé de façon prospective chez 135 patients opérables, par l’utilisation d’une PCR pentaplex. Puis, les défauts de réparation des mésappariements de l’ADN ont été étudiés par immunohistochimie. Résultats : Parmi les 82 cancers colorectaux de stade I ou II, 11 étaient MSI et 71 MSS, avec une moyenne (écart-type) de 23,6 (3,1) et 13,7 (1,0) ganglions négatifs, respectivement (p = .001). Le nombre moyen de ganglions pour tous les cancers colorectaux de stade I ou II analysés dans notre hôpital était de 15. La prévalence des MSI dans les tumeurs avec plus de 15 ganglions prélevés était de 25 % (9 sur 36) et 82 % (9 sur 11) des tumeurs MSI appartenaient à ce groupe. Conclusions : Un nombre élevé de ganglions isolés en cas de cancer colorectal de stade I ou II est associé au phénotype MSI. Le bon pronostic qui est habituellement associé à des tumeurs ayant un nombre élevé de ganglions N0 pourrait refléter la prévalence élevée des MSI chez ces tumeurs. Le nombre de ganglions examinés comme un critère de qualité doit être utilisé avec prudence. Limiter le phénotypage MSI aux tumeurs colorectales de stade I ou II ayant plus que le nombre moyen de ganglions identifie presque toutes les tumeurs MSI

Consensus statement for treatment protocols in pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Objectives: Safe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics. Methods: The expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance). Results: Twenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m(2)) and cisplatin (10.5 mg/m(2)) was endorsed by 20/ 22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m(2) (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of &gt;= 8/10. Conclusions: The current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research

Le chirurgien et les anti-angiogéniques

Le chirurgien doit connaître l'importance de l'angiogenèse dans la cicatrisation. Il doit aussi savoir utiliser les anti-angiogéniques pour modifier les situations cliniques et rendre curative une chirurgie potentiellement inefficace. Toutefois, ces nouvelles stratégies nécessitent au quotidien des indicateurs biologiques capables de quantifier les activités tissulaires, ce qu'actuellement nous n'avons pas, de même que nous ne disposons pas d'indicateur capable de prédire une sensibilité tumorale aux anti-angiogéniques

Association entre un nombre élevé de ganglions isolés et le statut microsatellite instable en cas de cancer colorectal T1-4N0M0

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF