Peritoneal metastasis : intraperitoneal chemotherapy administration to overcome chemoresistance

La carcinose péritonéale est une atteinte néoplasique métastatique de la séreuse péritonéale caractérisée par la diffusion de multiples nodules tumoraux. Son pronostic est sombre, marqué par une chimiorésistance. Les traitements intrapéritonéaux, développés pour délivrer des drogues de chimiothérapie anti-cancéreuse directement au contact de ces nodules, ont permis d’améliorer en partie les résultats oncologiques de cette pathologie. Le principe est de mettre à profit la barrière péritonéo-plasmatique pour administrer des posologies plus élevées de drogues, directement au contact des nodules, et ainsi majorer leur cytotoxicité. En stratégie curative, la chimiothérapie intrapéritonéale est associée à une chirurgie de cytoréduction (CRS) complète et son efficacité est majorée par l’adjonction d’une hyperthermie (ChimioHyperthermie IntraPéritonéale - CHIP). Si ce traitement combiné a transformé le pronostic de patients sélectionnés, les résultats restent insatisfaisants. Par exemple les patients atteints de carcinose d’origine colorectale présentent un taux de survie globale à 5 ans de 40% lorsqu’ils sont éligibles à la CRS-CHIP et une médiane de survie de l’ordre de 16 mois quand le traitement se cantonne à de la chimiothérapie systémique.Une meilleure compréhension des mécanismes cellulaires impliqués dans cette chimiorésistance est donc nécessaire pour déterminer de nouvelles cibles thérapeutiques. Les protéines de choc thermique jouent un rôle fondamental dans l’homéostasie protéique intracellulaire en agissant comme protéines chaperonnes et en régulant l’architecture du cytosquelette. L’Hsp27 (ou HspB1) en particulier est impliquée dans la réponse à différents stress cellulaires comme le choc thermique, le stress oxydatif et l’exposition aux drogues de chimiothérapie. Via des mécanismes finement régulés, Hsp27 exerce une protection garantissant la survie cellulaire, en adaptant ses niveaux d’expression, d’oligomérisation et de phosphorylation. Le taux d’Hsp27 est dès lors augmenté dans la plupart des cancers et apparaît comme marqueur fort de mauvais pronostic. Cela en fait un acteur clé de la chimiorésistance et une cible thérapeutique potentielle.Parmi les thérapeutiques ciblées basées sur l’ARN, les oligonucléotides antisens (ASO) sont des molécules issues du génie génétique capables de bloquer spécifiquement la traduction d’un ARN messager cible en protéine. L’apatorsen, un ASO anti-Hsp27 de deuxième génération, a été développé pour bloquer la synthèse d’Hsp27 au sein de la cellule cancéreuse et ainsi rétablir la chimiosensibilité. Après avoir mis en place un modèle de carcinose péritonéale colorectale traitée par CRS et CHIP chez le rat, nous avons étudié in vitro et in vivo, l’effet de l’adjonction de l’apatorsen au traitement standard de cette maladie. Nos résultats ne montrent pas de gain significatif de survie et donnent lieu à une discussion sur cette stratégie de traitementPeritoneal carcinomatosis is a neoplasic metastatic process of the peritoneal serous lining characterized by the spread of multiple tumoral nodules. The prognosis of such attempt is very poor, characterized by a global chemoresistance. Intraperitoneal treatments were developed to improve drug’s cytoxicity by delivering them directly on nodules. The principle is to take advantage of the peritoneal-plasma barrier that allows to deliver higher drug’s concentration directly onto nodules and so to improve cytotoxicity. In curative intent strategy intraperitoneal chemotherapy is combined to a complete surgical cytoreduction (CRS) and to hyperthermia to enhance efficiency (Hyperthermic Intraperitoneal Chemotherapy - HIPEC). Thanks to this strategy overall survival improved in selected patients but still be flawed. For example, patients with colorectale peritoneal carcinomatosis present a 40% five-year overall survival, whereas those not eligible to that aggressive treatment present a 16 months median survival. So a better understanding of cellular molecular mechanisms responsible for this chemoresistance that will allow identifying new therapeutic targets is needed. Heat shock proteins play a fundamental role in intracellular protein homeostasis by acting as chaperone and regulating cytoskeleton architecture. In particular, Hsp27 acts as a regulator of the cellular response to various stress, such as thermic choc, oxidative stress, exposition to antineoplasic drugs. Through finely regulated process, Hsp27 exerts a cytoprotective role to guaranty cell survival, by adapting its level of expression, oligomerization and phosphorylation. As so Hsp27 is a key actor of chemoresistance and a designated therapeutic target.Antisens oligonucleotides are a new class of molecular targeted treatment able to specifically block the traduction into protein of a messenger RNA. Apatorsen, a second generation anti-Hsp27 ASO, has been developed to decrease Hsp27 levels in neoplastic cells and so restore chemosensitivity.After establishing a colorectal peritoneal carcinomatosis rat model with CRS and HIPEC, we studied in vitro and in vivo the effect of the apatorsen adjunction to this standard treatment. Our results did not show a significant survival improvement and give rise to a discussion upon this treatment strateg

Epidemiology of psychiatric disorders following cytoreductive surgeries plus hyperthermic intraperitoneal chemotherapy: a prospective cohort analysis

Abstract The peritoneal surface malignancy (PSM) is an advanced disease, the prognosis of which has been radically improved since the development of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). These procedures are associated with many complications. However, very few data are available regarding the psychiatric morbidities that might occur. The present study assessed the epidemiology of depressive mood and anxiety during the 6 months following the procedure. The analysis of a prospective cohort that included patients who underwent CRS with or without HIPEC between December 2016 and December 2019 was performed. A total of 115 patients were included. During the 6-months follow-up, the mean (SD) Hospital Anxiety and Depression Scale –D (HADS-D) score was 7.8 (48) and a significant increase compared with the pre-operative period (t(49) = − 4.36, p < 0.005) was found. Thirty-seven patients (32%) had a HADS-D score higher than 7. The incidence of a HADS-D score higher than 7 during the follow-up was 0.05 patient per patient-month. Anxiety and the overall mental disorders intensity scores also increased. The results showed an important increase of mental disorders and their intensity during the 6-months following a CRS with or without HIPEC

Anatomy of the Right Anterior Sector of the Liver and Its Clinical Implications in Surgery

BACKGROUND: Surgery remains the gold standard both for delimited hepatocellular carcinoma by selective anatomic liver segentectomy and for colorectal liver metastases by parenchymal sparing liver resection. Right anterior sector (RAS) (segments V-VIII; Couinaud) is the largest and most difficult sector to operate on. A better knowledge of its segmentation could prevent postoperative remnant liver ischemia and its impacts on patient's survival. METHODS: A literature search was conducted in PubMed for papers on anatomy and surgery of the right anterior sector. RESULTS: Segmentation of the RAS depended of the anatomic variations of the third-order portal branches. Cranio-caudal segmentation was the most commonly found (50-53%), followed by ventro-dorsal (23-26%), trifurcation (13-20%), and quadrifurcation types (5-11%). Ventral and dorsal partial or total subsegmentectomy seemed accessible in 47 to 50% of patients, including bifurcation, trifurcation, and quadrifurcation types, and could spare up to 22% of the total liver volume. The RAS hepatic vein was present in 85-100% of the patients and could be used as a landmark between RAS dorsal and ventral part in 63% of patients. Reported overall morbidity rate of RAS subsegmentectomy ranged from 33 to 59% among studies with a postoperative major complication rate (Clavien-Dindo ??III) ranging around 18% and a biliary leakage rate from 16 to 21%. In-hospital reported mortality rate was low (0-3%), and results were comparable to "classic" liver resections. RAS subsegmentectomy remains a complex procedure; median operating time ranged from 253 to 520 min and median intraoperative blood loss reached 1255 ml. CONCLUSION: Better knowledge of RAS anatomy could allow for parenchymal preservation by using subsegmentectomy of the RAS, selective or as a part of a major hepatectomy

Post-operative weight loss affects 3-year survival in patients with gastric adenocarcinoma after gastrectomy and hyperthermic intraperitoneal chemotherapy

International audienceAbstract Background Bevacizumab—a humanized monoclonal antibody—has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted. Methods This study is a double‐blind multicenter randomized phase 2 trial with a 1:1 active‐treatment‐to‐placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3‐month period before and after treatment. Results A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention‐to‐treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% ( p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group ( p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions ( p = 0.03). Fifty‐nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm. Conclusion Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure

Negative-Pressure Wound Therapy for Open Abdomen in Surgical Reintervention after Curative Surgery of Peritoneal Malignancy Increases the Risk of Recurrence

International audienceABSTRACT OBJECTIVE Negative-pressure wound therapy for open abdomen (NPWTOA) helps reduce the risk of abdominal compartment syndrome. However, the risk of recurrence of cancer is unclear when NPWTOA is applied after oncologic resection. The aim of this study was to evaluate the effects of NPWTOA used for major complications on patients treated with cytoreductive surgery for peritoneal malignancy (PM). METHODS All patients who underwent an NPWTOA after potentially curative surgery of PM in a single institution were included. These patients were pair matched 1:3 on the Peritoneal Cancer Index, completeness of cytoreduction using a scoring index, and PM origin with patients who underwent surgical reintervention without NPWTOA after curative surgery of PM. Survival among the two groups was compared using the Kaplan-Meier method. RESULTS Between 2011 and 2017, among 719 curative surgeries for PM, 13 patients underwent an NPWTOA after surgical reintervention. Researchers paired 9 of these patients to 27 others without NPWTOA after surgical reintervention. Median overall survival was 4.8 and 35 months ( P = .391), and median disease-free survival was 4.0 and 13.9 months ( P = .022) for the NPWTOA and non-NPWTOA groups, respectively. CONCLUSIONS The use of the NPWTOA during surgical reintervention after curative surgery for PM may increase the risk of early recurrence

The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is the cause of a worldwide pandemic, currently with limited therapeutic options. The spike glycoprotein and envelope protein of SARS-CoV-2, containing disulfide bridges for stabilization, represent an attractive target as they are essential for binding to the ACE2 receptor in host cells present in the nasal mucosa. Bromelain and Acetylcysteine (BromAc) has synergistic action against glycoproteins by breakage of glycosidic linkages and disulfide bonds. We sought to determine the effect of BromAc on the spike and envelope proteins and its potential to reduce infectivity in host cells. Recombinant spike and envelope SARS-CoV-2 proteins were disrupted by BromAc. Spike and envelope protein disulfide bonds were reduced by Acetylcysteine. In in vitro whole virus culture of both wild-type and spike mutants, SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent

Impact of hyperthermic intraperitoneal chemotherapy on Hsp27 protein expression in serum of patients with peritoneal carcinomatosis

International audienceDespite the strong rationale for combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis, thermotolerance and chemoresistance might result from heat shock protein overexpression. The aim of the present study was thus to determine whether the heat shock protein 27 (Hsp27), a potential factor in resistance to treatment, could have a higher level in serum from patients under this combined therapy. Patients receiving CRS plus HIPEC for peritoneal carcinomatosis (group 1), patients with cancer or a history of cancer undergoing abdominal surgery (group 2), and patients without malignancies undergoing abdominal surgery (group 3) were included. Hsp27 serum levels were determined before and at different times following CRS and HIPEC using enzyme-linked immunosorbent assay. In group 1 (n = 25), the high Hsp27 levels, observed at the end of surgery compared with before (p < 0.0001), decreased during HIPEC, but remained significantly higher than before surgery (p < 0.0005). In groups 2 (n = 11) and 3 (n = 15), surgery did not significantly increase Hsp27 levels. A targeted molecular strategy, inhibiting Hsp27 expression in tumor tissue, could significantly reduce resistance to the combined CRS plus HIPEC treatment. This approach should be further assessed in a clinical phase I trial

Scalloping of the Liver and Spleen on Preoperative CT-Scan of Pseudomyxoma Peritonei Patients: Impact on Prediction of Resectability, Grade, Morbidity and Survival

Pseudomyxoma peritonei (PMP) is ideally treated by cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), leading to significant morbidity. Beyond the histologic grade, the prognosis lies in the completeness of cytoreduction (CC-score of 0/1 vs. 2/3) and the severe complication rate. The mucinous nature of the peritoneal implants sometimes induces liver and/or spleen scalloping on imaging. The predictive value of scalloping was assessed regarding resectability, grade, survival and severe morbidity. This monocentric, retrospective analysis compared CC-0/1 with CC-2/3 groups regarding liver and spleen scalloping parameters, assessed on pre-operative computed tomography (CT) scan, reviewed for the study. In addition, prognostic factors of severe complications and recurrence-free and overall survivals were explored in the CC-0/1 population. Overall, 129 patients were included (109 CC-0/1, 20 CC-2/3), with 58 (45%) exhibiting scalloping. All patients with splenic scalloping also had a liver one. Scalloping was more frequent (75% vs. 39%), with greater median maximal depth (21 vs. 11 mm) and higher PCI (32 vs. 14) in the CC-2/3 population, but was not predictive of either grade or survival. In CC-0/1 patients, survivals and postoperative complications were not affected by scalloping parameters. Scalloping appeared as a marker of advanced PMP, but was not predictive of grade, severe complications, or long-term outcomes

A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers

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