Cavo-portal transposition in rat: a new simple model

<p>Abstract</p> <p>Background</p> <p>Liver transplantation in presence of diffuse portal vein thrombosis is possible by using caval blood as portal inflow, through cavo-portal transposition. However, clinical results are heterogeneous and experimental studies are needed, but similar hemodynamic conditions are difficult to obtain, especially in small animals. Herein we describe a new simple model of cavo-portal transposition in rat.</p> <p>Methods</p> <p>Spontaneous porto-systemic shunts are induced by subcutaneous transposition of the spleen. The presence of porto-caval shunts through the spleen permits the interruption of the main portal vein without splanchnic hemodynamic consequences. Cavo-portal transposition is achieved by anastomosing the inferior vena cava and the main portal vein after division of the pancreatic-duodenal vein.</p> <p>Results</p> <p>Selective angiography revealed total splanchnic blood diversion to the systemic venous circulation through the neoformed collaterals; macroscopical examination showed the absence of any signs of acute portal hypertension with normal liver and gut appearance.</p> <p>Conclusion</p> <p>This model of cavoportal transposition is simple, effective and it simulates the clinical hemodynamic condition since the porto-systemic shunts induced by splenic subcutaneous transposition correspond to the physiological inframesocolic collaterals during chronic portal thrombosis in man.</p

Liver resection vs radiofrequency ablation in single hepatocellular carcinoma of posterosuperior segments in elderly patients

Background: Liver resection and radiofrequency ablation are considered curative options for hepatocellular carcinoma. The choice between these techniques is still controversial especially in cases of hepatocellular carcinoma affecting posterosuperior segments in elderly patients. Aim: To compare post-operative outcomes between liver resection and radiofrequency ablation in elderly with single hepatocellular carcinoma located in posterosuperior segments. Methods: A retrospective multicentric study was performed enrolling 77 patients age ≥ 70-years-old with single hepatocellular carcinoma (≤ 30 mm), located in posterosuperior segments (4a, 7, 8). Patients were divided into liver resection and radiofrequency ablation groups and preoperative, peri-operative and long-term outcomes were retrospectively analyzed and compared using a 1:1 propensity score matching. Results: After propensity score matching, twenty-six patients were included in each group. Operative time and overall postoperative complications were higher in the resection group compared to the ablation group (165 min vs 20 min, P &lt; 0.01; 54% vs 19% P = 0.02 respectively). A median hospital stay was significantly longer in the resection group than in the ablation group (7.5 d vs 3 d, P &lt; 0.01). Ninety-day mortality was comparable between the two groups. There were no significant differences between resection and ablation group in terms of overall survival and disease free survival at 1, 3, and 5 years. Conclusion: Radiofrequency ablation in posterosuperior segments in elderly is safe and feasible and ensures a short hospital stay, better quality of life and does not modify the overall and disease-free survival

Dissémination métastatique du cancer colorectal : de la clinique à la recherche

L'invasion tumorale est une caractéristique typique du cancer dont la dissémination métastatique est l'issue finale. Bien que largement considérée comme un processus inefficace, la dissémination métastatique reste la principale cause de décès par cancer dans les tumeurs malignes. Dans le cas du cancer colorectal (CCR), environ 20 % des patients présentent une maladie métastatique au moment du diagnostic et 30 % développeront une maladie métastatique au cours de la surveillance. Contrairement à d'autres tumeurs gastro-intestinales, les stratégies à visée curative peuvent améliorer la survie des patients sélectionnés avec un CCR métastatique. Les sites de dissémination métastatique sont bien établis dans les cancers, mais les mécanismes à l'origine des différentes voies de dissémination du CCR n'ont pas été complètement élucidés. Leur décryptage représente donc un enjeu majeur d'actualité en raison de son impact pronostique. Les cellules cancéreuses peuvent se propager soit sous forme de cellules isolées, soit sous forme d'amas de plusieurs cellules (clusters) avec des modifications spécifiques sur le plan moléculaire et phénotypique. Notre équipe a récemment identifié des sphères tumorales à polarité inversée (TSIP) dans l'effusion péritonéale des patients avec des CCR avancés constituant des nouveaux intermédiaires tumoraux d'invasion collective.L'objectif de cette thèse était d'étudier différents aspects de la dissémination métastatique du CCR en utilisant le modèle de métastases hépatiques (MHCCR) et péritonéales (MPCCR) d'origine colorectale portant un intérêt particulier vers les résultats cliniques de la chirurgie chez les patients métastatiques, la biologie moléculaire au niveau de la tumeurs primitive à la base du type de dissémination métastatique et le modelé l'invasion collective médiée par les TSIPs. Dans notre premier article, nous avons rapporté le mode de dissémination métastatique chez des patients présentant une récidive après traitement curatif de MPCCR afin d'explorer le concept de voies métastatiques préférentielles dans différents sous-types de CCR. De plus, nous avons évalué les différentes stratégies curatives dans les récidives péritonéales ou extra-péritonéales en terme de résultats à court et à long terme.Dans la deuxième étude, nous avons évalué la propagation métastatique préférentielle des CCR à travers un' analyse différentielle d'expression et un' analyse d'enrichissement fonctionnel des données RNA-Seq des tumeurs primitives avec des MHCCR et MPCCR isolées. Nous avons identifié 61 gènes différentiellement exprimés dans les CCR ayant différents sites métastatiques associées à une augmentation significative de la réponse immunitaire et de l'invasion épithéliale dans les CCR-Péritoine et de l'activation des voies de prolifération et métabolique dans les CCR-Foie. Nous avons ensuite analysé la corrélation clinico-pathologique et leur impact pronostique dans l'ensemble des données de la base TCGA. Dans le dernier projet, nous avons étudié les propriétés métastatiques des clusters et des TSIP, en tant que marqueurs d'invasion collective, dans un modèle murin d'injection intra-splénique. Nous avons montré que les clusters et les TSIP présentent un potentiel métastatique significativement plus élevé que les cellules isolées en terme de taux de métastases hépatiques en reproduisant au niveau du site métastatique des caractéristiques histologiques similaires à la tumeur d'origine. En raison du taux plus élevé de TSIP dans certains sous-types de CCR, nous avons enfin évalué l'impact pronostique des TSIP dans une cohorte monocentrique rétrospective de CCR mucineux. Dans l'ensemble, ces études fournissent des informations intéressantes pour une meilleure compréhension de la propagation métastatique et peuvent contribuer à intégrer une approche personnalisée dans la prise en charge des patients atteints d'un CCR.Tumour invasion is a typical feature of cancer of which metastatic dissemination is the fatal outcome. Although widely considered as an inefficient process, metastatic spread remains the main cause of cancer death in solid malignancies. In colorectal cancer (CRC), about 20% of patients have disseminated disease at the time of diagnosis and another 30% will develop a metastatic disease during surveillance. Different from other gastrointestinal tumours, curative-intent strategies could improve clinical outcomes in selected metastatic CRC patients. Patterns of distant metastatic sites are well-established in human cancers, but the mechanisms driving the CRC metastatic routes are not completely explored. Therefore, deciphering the complex mechanisms underlying cancer dissemination is a current major issue according to their clinical implications in term of prognosis. Cancer cells can spread either as single isolated cells or as clusters of several cells with specific molecular and phenotypical changes. Our Team recently identified tumour spheres with inverted polarity (TSIPs) in peritoneal effusion from advanced CRC as new collective tumour intermediates.The objective of the current thesis was to study the metastatic dissemination of CRC from different perspectives using the model of colorectal liver and peritoneal metastases moving from the results of surgery in metastatic disease, to the distant spread pattern of primary tumours using molecular biology and with a specific focus on the TSIPs-mediated collective invasion.In our first article, I reported the pattern of metastatic dissemination in patients with recurrent disease after curative treatment of metastatic disease in order to explore the concept of preferential metastatic routes in different CRC subtypes. Moreover, we assessed the results of different iterative curative strategies in peritoneal or extra peritoneal relapses in term of short- and long-term outcomes.In the second manuscript, we investigated the preferential metastatic spread of CRC by comparing the differential gene expression profile and functional analysis of primary tumours with isolated CRLM and CRPM, We identified distinct genes signatures in primary CRC with different metastatic sites, that promote higher expression of immune response and epithelial invasion in CRC- and activation of proliferation and metabolic pathways in CRC-Liver samples. Thereafter, we explored their clinico-pathological correlation and prognostic impact in TCGA dataset.In the last project, we studied the metastatic properties of clusters and TSIPs, as markers of collective invasion, in a mouse model of intra-splenic injection. We showed that clusters and TSIPs display a significantly higher metastatic potential compared to single cells in term of metastatic rate and recapitulate native histology in distant hepatic metastases. According to higher rates of TSIPs in different CRC subtypes, we finally evaluated the prognostic impact of TSIPs in a retrospective monocentric dataset of mucinous CRC. Overall, these studies provide interesting insights to a better understanding of metastatic spread and may promote a personalized approach in the management of CRC patients

Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients. Feasibility of nonanatomic resection in difficult tumor locations

BACKGROUND: Surgical resection for hepatocellular carcinoma (HCC) in cirrhotic patients remains controversial because of high morbidity and recurrence rates. Laparoscopic resection of liver tumors has recently been developed and could reduce morbidity. The aim of this study was to evaluate retrospectively our results for laparoscopic liver resection (LLR) for HCC including lesions in the posterosuperior segments of the liver in terms of feasibility, outcome, recurrence and survival. MATERIALS AND METHODS: Between June 2005 and February 2009, we performed 20 LLR for HCC. Median age of the patients was 66 years. The underlying cirrhosis was staged as Child A in 17 cases and Child B in 3. RESULTS: LLR included anatomic resection in six cases and nonanatomic resection in 14. Eleven procedures were associated in nine (45%) patients. Median tumor size and surgical margins were 3.1 cm and 15 mm, respectively. A conversion to laparotomy occurred in one (5%) patient for hemorrhage. Mortality and morbidity rates were 0% and 15% (3/20). Median hospital stay was 8 days (range: 5-16 days). Over a mean follow-up period of 26 months (range: 19-62 months), 10 (50%) patients presented recurrence, mainly at distance from the surgical site. Treatment of recurrence was possible in all the patients, including orthotopic liver transplantation in three cases. CONCLUSIONS: LLR for HCC in selected patients is a safe procedure with good short-term results. It can also be proposed in tumor locations with a difficult surgical access maintaining a low morbidity rate and good oncological adequacy. This approach could have an impact on the therapeutic strategy of HCC complicating cirrhosis as a treatment with curative intent or as a bridge to liver transplantation

Immunotherapy and Hepatocellular Cancer: Where Are We Now?

Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as &ldquo;adjuvants&rdquo; to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner

Postoperative hepatic arterial chemotherapy in high-risk patients as adjuvant treatment after resection of colorectal liver metastases - a randomized phase II/III trial – PACHA-01 (NCT02494973)

International audienceBACKGROUND:After curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, 'modern' systemic chemotherapy alone.METHODS/DESIGN:This study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival).DISCUSSION:If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients.TRIAL REGISTRATION:ClinicalTrials.gov, NCT02494973 . Trial registration date: July 10, 2015

Complete cytoreductive surgery plus HIPEC for peritoneal metastases from unusual cancer sites of origin: results from a worldwide analysis issue of the Peritoneal Surface Oncology Group International (PSOGI)

<p><b>Aim:</b> The aim of this study was to assess the outcomes of patients operated on for peritoneal metastases from unusual cancer sites of origin, meaning apart from peritoneal metastases (PM) from colorectal, gastric and epithelial ovarian carcinomas, pseudomyxoma peritonei and mesothelioma.</p> <p><b>Patients and methods:</b> A questionnaire concerning patients treated with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for PM arising from unusual cancer sites of origin was sent to all centres, which routinely performed HIPEC, through the Peritoneal Surface Oncology Group International and the RENAPE network.</p> <p><b>Results:</b> Between September 1990 and June 2016, 850 procedures for unusual cases were performed in 781 patients, in 53 centres worldwide. Nearly two-thirds of the procedures were performed for three indications: rare ovarian carcinoma (<i>n</i> = 224), sarcoma (<i>n</i> = 189) and neuroendocrine tumours (<i>n</i> = 127). The median PCI was 12 [0–39]. Grade III–IV postoperative complications occurred in 272 patients (41%). Nineteen patients (2.9%) died postoperatively. After a median follow-up of 46 months, median overall survival (OS) was 39 months [33.18–44.05]. Five-year OS rate was 38.7%. For the three main indications, 5-year OS was significantly greater in patients with PM from rare ovarian carcinoma (57.7%), than that of patients with PM from neuroendocrine tumours (39.9%), and from sarcoma (29.3%) (<i>p</i> < 0.0001).</p> <p><b>Conclusions:</b> CRS and HIPEC appear to be safe and effective in patients with peritoneal metastases from unusual cancer sites of origin, especially from rare ovarian carcinomas, PM from neuroendocrine tumours. The respective roles of CRS and HIPEC remain unclear and should be evaluated.</p

Selective mesenteric vein angiography after cavo-portal transposition: splanchnic flow is shunted to the vena cava system through the neo-formed porto-caval shunts

<p><b>Copyright information:</b></p><p>Taken from "Cavo-portal transposition in rat: a new simple model"</p><p>http://www.biomedcentral.com/1471-2482/7/18</p><p>BMC Surgery 2007;7():18-18.</p><p>Published online 16 Aug 2007</p><p>PMCID:PMC1988786.</p><p></p> smv = superior mesenteric vein, spv = splenic vein, icv = intercostal veins, itv = internal thoracic vein, tev = thoraco-epigastric vein, sev = superficial epigastric vein