Publications by authors named "Michel Rivoire"

76 Publications

Second primary cancers: a retrospective analysis of real world data using the enhanced medical research engine ConSoRe in a French comprehensive cancer center.

Int J Clin Oncol 2021 Jun 5. Epub 2021 Jun 5.

Leon Berard Cancer Center, Claude Bernard University of Lyon I, 28 Rue Laennec, 69008, Lyon, France.

Background: Second primary cancers (SPC) account for 18% of all cancers. We used the enhanced medical/health data mining tool ConSoRe to search aggregated data, analyze electronic patient records (EPR), and better characterize patients with SPC.

Methods: This retrospective cohort study used ConSoRe to identify EPRs from patients with SPC referred to the regional cancer center Leon Bérard from 1993 to 2017, and examined characteristics of patients with SPC, frequencies of first primary cancer (FPC) localization in the global population of patients with SPC, and time to SPC. Data set was extracted on January 1, 2018.

Results: Among 296,530 EPRs, we identified 157,187 patients with FPC, including 13,002 (8%) patients with SPC. Between 2000 and 2010, the rate of SPC was 34%, and 52% of SPC were identified in the last years (2010-2017). In men, main cancers were head and neck cancer, lymphoma, and prostate carcinoma accounting for 15.6%, 12.8%, and 10.5% of FPC, while the three most common SPC were head and neck cancer (13.2%), lung cancer (11.8%) and lymphoma (9.2%). In women, breast cancers, lymphoma, and skin cancers accounted for 48.8%, 8%, and 5.1% of first cancers, and for 31.1%, 7% and 6% of SPC.

Conclusion: The data mining tool ConSoRe contributes to access to real world data, and to better characterize patients with SPC. Expanding such approach to any comprehensive center will allow a global overview of the follow-up of patients with cancer, and help to improve long-term management and adapt surveillance.
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http://dx.doi.org/10.1007/s10147-021-01963-3DOI Listing
June 2021

Evaluation of Ultrasonic Attenuation in Primary and Secondary Human Liver Tumors and Its Potential Effect on High-Intensity Focused Ultrasound Treatment.

Ultrasound Med Biol 2021 Jul 22;47(7):1761-1774. Epub 2021 Apr 22.

LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Univ Lyon, Lyon, France. Electronic address:

Primary and secondary liver tumors are completely different diseases but are usually treated similarly using high-intensity focused ultrasound (HIFU). However, the acoustic parameters of these tissues are not well documented. In this study, attenuation coefficients were evaluated in fresh primary (N = 8) and secondary (N = 13) human liver tumor samples recovered by hepatectomy. The average attenuation coefficients of the primary and secondary liver tumors were 0.10 ± 0.03 and 0.20 ± 0.04 Np/cm/MHz, respectively. The average attenuation coefficients of the liver tissue surrounding the primary and secondary tumors were 0.16 ± 0.07 and 0.07 ± 0.02 Np/cm/MHz, respectively. Numerical simulations performed using these values revealed that completely different HIFU ablation patterns were created in primary and secondary liver tumors using the same exposure parameters. The dimensions of a typical HIFU lesion were two times larger in secondary liver tumors than in primary tumors. HIFU treatment parameters should be set properly according to the acoustic properties of the diseased liver tissue.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.03.014DOI Listing
July 2021

Hepatitis B virus Core protein nuclear interactome identifies SRSF10 as a host RNA-binding protein restricting HBV RNA production.

PLoS Pathog 2020 11 12;16(11):e1008593. Epub 2020 Nov 12.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR5286, Centre Léon Bérard, Lyon, France.

Despite the existence of a preventive vaccine, chronic infection with Hepatitis B virus (HBV) affects more than 250 million people and represents a major global cause of hepatocellular carcinoma (HCC) worldwide. Current clinical treatments, in most of cases, do not eliminate viral genome that persists as a DNA episome in the nucleus of hepatocytes and constitutes a stable template for the continuous expression of viral genes. Several studies suggest that, among viral factors, the HBV core protein (HBc), well-known for its structural role in the cytoplasm, could have critical regulatory functions in the nucleus of infected hepatocytes. To elucidate these functions, we performed a proteomic analysis of HBc-interacting host-factors in the nucleus of differentiated HepaRG, a surrogate model of human hepatocytes. The HBc interactome was found to consist primarily of RNA-binding proteins (RBPs), which are involved in various aspects of mRNA metabolism. Among them, we focused our studies on SRSF10, a RBP that was previously shown to regulate alternative splicing (AS) in a phosphorylation-dependent manner and to control stress and DNA damage responses, as well as viral replication. Functional studies combining SRSF10 knockdown and a pharmacological inhibitor of SRSF10 phosphorylation (1C8) showed that SRSF10 behaves as a restriction factor that regulates HBV RNAs levels and that its dephosphorylated form is likely responsible for the anti-viral effect. Surprisingly, neither SRSF10 knock-down nor 1C8 treatment modified the splicing of HBV RNAs but rather modulated the level of nascent HBV RNA. Altogether, our work suggests that in the nucleus of infected cells HBc interacts with multiple RBPs that regulate viral RNA metabolism. Our identification of SRSF10 as a new anti-HBV restriction factor offers new perspectives for the development of new host-targeted antiviral strategies.
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http://dx.doi.org/10.1371/journal.ppat.1008593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707522PMC
November 2020

Sphincter-saving surgery for ultra-low rectal carcinoma initially indicated for abdominoperineal resection: Is it safe on a long-term follow-up?

J Surg Oncol 2021 Jan 24;123(1):299-310. Epub 2020 Oct 24.

Department of Radiotherapy, Institut régional du Cancer de Montpellier (ICM) - Val d'Aurelle, Montpellier, France.

Background: Rate of abdominoperineal resection (APR) varies from countries and surgeons. Surgical impact of preoperative treatment for ultra-low rectal carcinoma (ULRC) initially indicated for APR is debated. We report the 10-year oncological results from a prospective controlled trial (GRECCAR 1) which evaluate the sphincter saving surgery (SSR).

Methods: ULRC indicated for APR were included (n = 207). Randomization was between high-dose radiation (HDR, 45 + 18 Gy) and radiochemotherapy (RCT, 45 Gy + 5FU infusion). Surgical decision was based on tumour volume regression at surgery. SSR technique was standardized as mucosectomy (M) or partial (PISR)/complete (CISR) intersphincteric resection.

Results: Overall SSR rate was 85% (72% ISR), postoperative morbidity 27%, with no mortality. There were no significant differences between the HDR and RCT groups: 10-year overall survival (OS10) 70.1% versus 69.4%, respectively, 10.2% local recurrence (9.2%/14.5%) and 27.6% metastases (32.4%/27.7%). OS and disease-free survival were significantly longer for SSR (72.2% and 60.1%, respectively) versus APR (54.7% and 38.3%). No difference in OS10 between surgical approaches (M 78.9%, PISR 75.5%, CISR 65.5%) or tumour location (low 64.8%, ultralow 76.7%).

Conclusion: GRECCAR 1 demonstrates the feasibility of safely changing an initial APR indication into an SSR procedure according to the preoperative treatment tumour response. Long-term oncologic follow-up validates this attitude.
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http://dx.doi.org/10.1002/jso.26249DOI Listing
January 2021

Fast and Selective Ablation of Liver Tumors by High-Intensity Focused Ultrasound Using a Toroidal Transducer Guided by Ultrasound Imaging: The Results of Animal Experiments.

Ultrasound Med Biol 2020 12 3;46(12):3286-3295. Epub 2020 Sep 3.

LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Univ Lyon, F-69003, Lyon, France. Electronic address:

This study demonstrated that high-intensity focused ultrasound (HIFU) produced with an intra-operative toroidal-shaped transducer causes fast, selective liver tumor ablations in an animal model. The HIFU device is composed of 256 emitters working at 3 MHz. A 7.5 MHz ultrasound imaging probe centered on the HIFU transducer guided treatment. VX2 tumor segments (25 mg) were implanted into the right lateral liver lobes of 45 New Zealand rabbits. The animals were evenly divided into groups 1 (toroidal HIFU ablation), 2 (surgical resection) and 3 (untreated control). Therapeutic responses were evaluated with gross pathology and histology 11 d post-treatment. Toroidal transducer-produced HIFU ablation (average ablation rate 10.5 cc/min) allowed fast and homogeneous tumor treatment. Sonograms showed all ablations. VX2 tumors were completely coagulated and surrounded by safety margins without surrounding-organ secondary HIFU lesions. HIFU group tumor volumes at autopsy (39 mm) were significantly lower than control group volumes (2610 mm, p < 0.0001). HIFU group tumor metastasis (27%) was lower than resected (33%) and control (67%) group metastasis. Ultrasound imaging, gross pathology and histology results supported these outcomes. HIFU procedures had no complications. Rabbit liver tumor ablation using a toroidal HIFU transducer under ultrasound imaging guidance might therefore be an effective intra-operative treatment for localized liver metastases.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.08.001DOI Listing
December 2020

Antiviral activity of PLK1-targeting siRNA delivered by lipid nanoparticles in HBV-infected hepatocytes.

Antivir Ther 2020 ;25(3):151-162

Cancer Research Center of Lyon (CRCL), INSERM U1052, Lyon, France.

Background: A link between HBV and PLK1 was clearly evidenced in HBV-driven carcinogenesis, and we have also recently shown that PLK1 is a proviral factor in the early phases of HBV infection. Moreover, we have shown that BI-2536, a small molecule PLK1 inhibitor, was very efficient at inhibiting HBV DNA neosynthesis, notably by affecting nucleocapsid assembly as a result of the modulation of HBc phosphorylation. Yet, as small molecule kinase inhibitors often feature poor selectivity, a more specific and safer strategy to target PLK1 would be needed for a potential development against chronic HBV infections.

Methods: Here, we analysed using both freshly isolated primary human hepatocytes and differentiated HepaRG, the anti-HBV properties of an LNP-encapsulated PLK1-targeting siRNA. Standard assays were used to monitor the effect of LNP siPLK1, or controls (LNP siHBV and LNP siNon-targeting), on HBV replication and cell viability.

Results: A dose as low as 100 ng/ml of LNP-siPLK1 resulted in a >75% decrease in secreted HBV DNA (viral particles), which was comparable to that obtained with LNP siHBV or 10 µM of tenofovir (TFV), without affecting cell viability. Interestingly, and in contrast to that obtained with TFV, a strong inhibition of viral RNA and HBe/HBsAg secretions was also observed under LNP siPLK1 treatment. This correlated with a significant intracellular decrease of vRNA accumulation, which was independent of any change in cccDNA levels, thus suggesting a transcriptional or post-transcriptional modulation. Such an effect was not obtained with a biochemical approach of PLK1 inhibition, suggesting an enzymatic-independent role of PLK1.

Conclusions: This study emphasizes that a specific PLK1 inhibition could help in achieving an improved HBsAg loss in CHB patients, likely in combination with other HBsAg-targeting strategies.
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http://dx.doi.org/10.3851/IMP3361DOI Listing
January 2020

Two-dimensional-cultures of primary human hepatocytes allow efficient HBV infection: Old tricks still work!

J Hepatol 2020 08 16;73(2):449-451. Epub 2020 May 16.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France; Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.1016/j.jhep.2020.03.042DOI Listing
August 2020

[French Society for Surgical Oncology (SFCO) guidelines for the management of surgical oncology in the pandemic context of COVID 19].

Bull Cancer 2020 05 6;107(5):524-527. Epub 2020 Apr 6.

Université de Montpellier, institut de cancérologie de Montpellier (ICM), département de chirurgie oncologique, Montpellier, France.

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http://dx.doi.org/10.1016/j.bulcan.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135219PMC
May 2020

Full-length 5'RACE identifies all major HBV transcripts in HBV-infected hepatocytes and patient serum.

J Hepatol 2020 07 20;73(1):40-51. Epub 2020 Feb 20.

INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France. Electronic address:

Background & Aims: Covalently closed circular DNA (cccDNA) is the episomal form of the HBV genome that stably resides in the nucleus of infected hepatocytes. cccDNA is the template for the transcription of 6 major viral RNAs, i.e. preC, pg, preS1/2, S and HBx RNA. All viral transcripts share the same 3' end and are all to various degrees subsets of each other. Especially under infection conditions, it has been difficult to study in depth the transcription of the different viral transcripts. We thus wanted to develop a method with which we could easily detect the full spectrum of viral RNAs in any lab.

Methods: We set up an HBV full-length 5'RACE (rapid amplification of cDNA ends) method with which we measured and characterized the full spectrum of viral RNAs in cell culture and in chronically infected patients.

Results: In addition to canonical HBx transcripts coding for full-length X, we identified shorter HBx transcripts potentially coding for short X proteins. We showed that interferon-β treatment leads to a strong reduction of preC and pgRNAs but has only a moderate effect on the other viral transcripts. We found pgRNA, 1 spliced pgRNA variant and a variety of HBx transcripts associated with viral particles generated by HepAD38 cells. The different HBx RNAs are both capped and uncapped. Lastly, we identified 3 major categories of circulating RNA species in patients with chronic HBV infection: pgRNA, spliced pgRNA variants and HBx.

Conclusions: This HBV full-length 5'RACE method should significantly contribute to the understanding of HBV transcription during the course of infection and therapy and may guide the development of novel therapies aimed at targeting cccDNA.

Lay Summary: Especially under infection conditions, it has been difficult to study the different hepatitis B virus transcripts in depth. This study introduces a new method that can be used in any standard lab to discriminate all hepatitis B viral transcripts in cell culture and in the serum of patients.
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http://dx.doi.org/10.1016/j.jhep.2020.01.028DOI Listing
July 2020

Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.

Lancet Gastroenterol Hepatol 2020 05 7;5(5):465-474. Epub 2020 Feb 7.

Department of Colorectal Surgery, Haut-Lévèque Hospital, CHU Bordeaux, France.

Background: GRECCAR 2 was the first multicentre, randomised trial to compare local excision with total mesorectal excision in downstaged low rectal cancer. Encouraging oncological results were noted at 3 years' follow-up but needed to be corroborated with longer follow-up. In this study, we aimed to report the 5-year oncological outcomes, including local recurrence, metastatic disease, and survival.

Methods: Patients age 18 years and older with T2T3 low rectal cancer, of maximum size 4 cm, who were clinically good responders after chemoradiotherapy (residual tumour ≤2 cm) were randomly assigned before surgery to either local excision or total mesorectal excision. Randomisation was centralised and not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was performed if pathological tumour stage was ypT2-3. The primary objective of this study was to assess the 5-year oncological outcomes of local recurrence, metastatic disease, disease-free survival, overall survival, and cancer-specific mortality, which were the secondary endpoints of GRECCAR 2. We used Kaplan-Meier estimates and Cox modelling to estimate and compare recurrence and survival in modified intention-to-treat and as-treated populations. This trial was registered with ClinicalTrials.gov, number NCT00427375.

Findings: Between March 1, 2007, and Sept 24, 2012, 148 patients who were good clinical responders were randomly assigned to treatment, three patients were excluded after randomisation (because they had metastatic disease, tumour >8 cm from anal verge, or withdrew consent), leaving 145 for analysis: 74 in the local excision group and 71 in the total mesorectal excision group. Median follow-up was 60 months (IQR 58-60) in the local excision group and 60 months (57-60) in the total mesorectal excision group. 23 patients died and five were lost to follow-up. In the local excision group, 26 had a completion total mesorectal excision for ypT2-3 tumour. In the modified intention-to-treat analysis, there was no difference between the local excision and total mesorectal excision groups in 5-year local recurrence (7% [95% CI 3-16] vs 7% [3-16]; adjusted hazard ratio [HR] 0·71 [95% CI 0·19-2·58]; p=0·60), metastatic disease (18% [CI 11-30] vs 19% [11-31]; 0·86 [0·36-2·06]; p=0·73), overall survival (84% [73-91] vs 82% [71-90]; 0·92 [0·38-2·22]; p=0·85), disease-free survival (70% [58-79] vs 72% [60-82]; 0·87 [0·44-1·72]; p=0·68), or cancer-specific mortality (7% [3-17] vs 10% [5-20]; 0·65 [0·17-2·49]; p=0·53).

Interpretation: The 5-year results of this multicentre randomised trial corroborate the 3-year results, providing no evidence of difference in oncological outcomes between local excision and total mesorectal excision. Local excision can be proposed in selected patients having a small T2T3 low rectal cancer with a good clinical response after chemoradiotherapy.

Funding: National Cancer Institute of France.
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http://dx.doi.org/10.1016/S2468-1253(19)30410-8DOI Listing
May 2020

In vitro transformation of primary human hepatocytes: Epigenetic changes and stemness properties.

Exp Cell Res 2019 11 23;384(2):111643. Epub 2019 Sep 23.

INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. Electronic address:

Human hepatocarcinogenesis is a complex process with many unresolved issues, including the cell of origin (differentiated and/or progenitor/stem cells) and the initial steps leading to tumor development. With the aim of providing new tools for studying hepatocellular carcinoma initiation and progression, we developed an innovative model based on primary human hepatocytes (PHHs) lentivirus-transduced with SV40, HRAS with or without hTERT. The differentiation status of these transduced-PHHs was characterized by RNA sequencing (including lncRNAs), and the expression of some differentiation markers confirmed by RT-qPCR and immunofluorescence. In addition, their transformation capacity was assessed by colony formation in soft agar and tumorigenicity evaluated in immune-deficient mice. The co-expression of SV40 and HRAS in PHHs, in association or not with hTERT, led to the emergence of transformed clones. These clones exhibited a poorly differentiated cell phenotype with expression of stemness and mesenchymal-epithelial transition markers and gave rise to cancer stem cell subpopulations. In vivo, they resulted in poorly differentiated hepatocellular carcinomas with a reactivation of endogenous hTERT. These experiments demonstrate for the first time that non-cycling human mature hepatocytes can be permissive to in vitro transformation. This cellular tool provides the first comprehensive in vitro model for identifying genetic/epigenetic changes driving human hepatocarcinogenesis.
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http://dx.doi.org/10.1016/j.yexcr.2019.111643DOI Listing
November 2019

Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection.

J Hepatol 2019 12 23;71(6):1086-1098. Epub 2019 Jul 23.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France. Electronic address:

Background & Aims: Liver macrophages can be involved in both pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLMs) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDMs or M2-MDMs, respectively).

Methods: PLMs or primary blood monocytes, either ex vivo differentiated into M1-MDMs or M2-MDMs, were exposed to HBV and their activation followed by ELISA or quantitative reverse transcription PCR (RT-qPCR). Liver biopsies from HBV-infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses.

Results: HBc protein was present within the macrophages of liver biopsies taken from HBV-infected patients. Macrophages from HBV-infected patients also expressed higher levels of anti-inflammatory macrophage markers than those from non-infected patients. Ex vivo exposure of naive PLMs to HBV led to reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDMs secreted less IL-6 and IL-1β, whereas M2-MDMs secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDMs, but not those produced by HBV-exposed M1-MDMs, decreased HBV infection of hepatocytes.

Conclusions: Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour the establishment of infection.

Lay Summary: Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance of infection. It impairs the production of the antiviral cytokine IL-1β, while promoting that of IL-10 in the microenvironment. This phenotype can be recapitulated in naive liver macrophages or monocyte-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an "easy to implement" mechanism of inhibition.
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http://dx.doi.org/10.1016/j.jhep.2019.06.032DOI Listing
December 2019

Systemic chemotherapy plus cetuximab after complete surgery in the treatment of isolated colorectal peritoneal carcinoma: COCHISE phase II clinical trial.

BMC Res Notes 2019 Jul 22;12(1):450. Epub 2019 Jul 22.

Clinical Research and Clinical Epidemiology Unit (ISO 9001 Certified), Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France.

Objective: The primary objective of this non-randomised phase II study was to evaluate the combination of systemic chemotherapy plus cetuximab after complete cytoreductive surgery (CCS) for treatment of isolated colorectal peritoneal carcinoma (CRPC). This multicentre, prospective phase II clinical trial was conducted in seven national cancer referral centres, however research published during study recruitment indicated cetuximab treatment as ineffective in patients with mutated KRAS genes, leading to an additional exclusion criterion to the current protocol, excluding patients with mutated KRAS genes. This significantly impacted recruitment and the study did not achieve the necessary recruitment of 46 patients.

Results: Fourteen patients underwent CCS and were included in the study, however one did not provide informed consent and another received only one cycle of chemotherapy leading to 12 patients in the per protocol population for analysis. Adjuvant Folfox Cetuximab was administered when CCS was achieved for patients > 18 years with histologically proven CRPC and no other metastatic disease (liver, lungs, lymphadenopathy, etc.). CRPC median index was 5.00 (range: 1-17). Median PFS was 12.3 months [95% CI (3.7-28.2)] with 8.3% [95% CI (0.5-31.1)] and 0% PFS at 3 and 5 years respectively. Median OS was 43.4 months [95% CI (16.8-60)]. Trial registration Clinical Trials NCT00766142, October 3, 2008. Retrospectively registered.
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http://dx.doi.org/10.1186/s13104-019-4476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647143PMC
July 2019

Building a collaboration to improve surgical research through EORTC/ESSO 1409-CLIMB study: A prospective liver metastasis database with an integrated quality assurance program.

Eur J Surg Oncol 2019 Oct 30;45(10):1870-1875. Epub 2019 May 30.

Institut Bergonié, Université de Bordeaux, Bordeaux, France.

The challenges of conducting surgical oncology trials have resulted to low quantity and poor quality research [1,2]. Considering the definitive role of surgery to offer cure, immediate response to improve surgical research is needed [3]. The European Organization for Research and Treatment of Cancer (EORTC) and the European Society of Surgical Oncology (ESSO) share the vision to achieve excellent surgical research and care for cancer patients. Building on their complimentary expertise, they embarked on a pilot project to map out challenges and initiate a sustainable collaboration to advance cancer surgery research in Europe. This pilot project is EORTC-ESSO 1409 GITCG/ ESSO-01: A Prospective Colorectal Liver Metastasis Database with an Integrated Quality Assurance Program (CLIMB). This article will describe the challenges, milestones and vision of both organizations in setting up this collaboration.
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http://dx.doi.org/10.1016/j.ejso.2019.05.028DOI Listing
October 2019

Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial.

Cells 2019 05 28;8(6). Epub 2019 May 28.

Department of Surgical Oncology, Institut Curie, PSL Research University, 75005 Paris, France.

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p=0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p<0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.
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http://dx.doi.org/10.3390/cells8060516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627974PMC
May 2019

Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis.

J Clin Oncol 2019 08 14;37(23):2028-2040. Epub 2019 May 14.

1Centre Hospitalier Universitaire (CHU) Lyon Sud, Lyon, France.

Purpose: Gastric cancer (GC) with peritoneal metastases (PMs) is a poor prognostic evolution. Cytoreductive surgery (CRS) yields promising results, but the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial. Here we aimed to compare outcomes between CRS-HIPEC versus CRS alone (CRSa) among patients with PMs from GC.

Patients And Methods: From prospective databases, we identified 277 patients with PMs from GC who were treated with complete CRS with curative intent (no residual nodules > 2.5 mm) at 19 French centers from 1989 to 2014. Of these patients, 180 underwent CRS-HIPEC and 97 CRSa. Tumor burden was assessed using the peritoneal cancer index. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of HIPEC and account for confounding factors.

Results: After IPTW adjustment, the groups were similar, except that median peritoneal cancer index remained higher in the CRS-HIPEC group (6 2; = .003). CRS-HIPEC improved overall survival (OS) in both crude and IPTW models. Upon IPTW analysis, in CRS-HIPEC and CRSa groups, median OS was 18.8 versus 12.1 months, 3- and 5-year OS rates were 26.21% and 19.87% versus 10.82% and 6.43% (adjusted hazard ratio, 0.60; 95% CI, 0.42 to 0.86; = .005), and 3- and 5-year recurrence-free survival rates were 20.40% and 17.05% versus 5.87% and 3.76% ( = .001), respectively; the groups did not differ regarding 90-day mortality (7.4% 10.1%, respectively; = .820) or major complication rate (53.7% 55.3%, respectively; = .496).

Conclusion: Compared with CRSa, CRS-HIPEC improved OS and recurrence-free survival, without additional morbidity or mortality. When complete CRS is possible, CRS-HIPEC may be considered a valuable therapy for strictly selected patients with limited PMs from GC.
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http://dx.doi.org/10.1200/JCO.18.01688DOI Listing
August 2019

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases.

J Vis Exp 2019 01 9(143). Epub 2019 Jan 9.

Department of Surgical Oncology, Centre Léon Bérard; Applications des ultrasons à la thérapie (LabTAU), Institut national de la santé et de la recherche médicale (INSERM), Centre Léon Bérard, Université Lyon 1, Université Lyon.

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% of patients. Surgery has been widely used in association with radiofrequency, cryotherapy, or microwaves to expand the number of treatments performed with a curative intent. Nevertheless, several limitations have been documented when using these techniques (i.e., a traumatic puncture of the parenchyma, a limited size of lesions, and an inability to monitor the treatment in real-time).High-intensity focused ultrasound (HIFU) technology can achieve precise ablations of biological tissues without incisions or radiation. Current HIFU devices are based on an extracorporeal approach with limited access to the liver. We have developed a HIFU device designed for intraoperative use. The use of a toroidal transducer enables an ablation rate (10 cm·min) higher than any other treatment and is independent of perfusion. The feasibility, safety, and accuracy of intraoperative HIFU ablation were evaluated during an ablate-and-resect prospective study. This clinical phase I and IIa study was performed in patients undergoing hepatectomy for liver metastases. The HIFU treatment was performed on healthy tissue scheduled for resection.Liver metastases measuring less than 20 mm will be targeted during phase IIb (currently ongoing). This set-up allows the real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique. Fifteen patients were included in phase I-IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1-2 mm. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm, corresponding to a volume of approximately 7.5 cm. The aim of the ongoing phase IIb is to ablate metastases of less than 20 mm in diameter with a 5 mm margin.
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http://dx.doi.org/10.3791/57964DOI Listing
January 2019

A 96-hour continuous wound infiltration with ropivacaine reduces analgesic consumption after liver resection: A randomized, double-blind, controlled trial.

J Surg Oncol 2019 Jan 27;119(1):47-55. Epub 2018 Nov 27.

Oncology Surgery Department, Centre Léon Bérard, Lyon, France.

Background: Continuous wound infiltration (CWI) with local anesthetics to reduce morphine consumption in postoperative pain management after open liver resection in patients with cancer.

Methods: This single-center randomized double-blind study allocated patients requiring resection of liver metastases to receive a 3.75 mg/mL ropivacaine (ROP) infiltration, followed by a 2 mg/mL ROP CWI, or placebo (P) for 96 hours. Postoperative analgesia included acetaminophen and patient-controlled analgesia morphine pump. The primary endpoint was to investigate the reduction of total morphine consumption (mg/kg) over the first 96 postoperative hours.

Results: Eighty-five patients were recruited, and randomized (ROP: 42, P: 43) between 2009 and 2014. The median morphine consumption significantly decreased in the ROP arm in the first 96 postoperative hours (ROP: 1.0, P: 1.5 mg/kg; P = 0.026). Twenty-three (27%) patients had grade 3 adverse events (ROP: 14, P: 9) and four experienced grade 3 treatment-related adverse events (ROP: mental confusion [n = 1], hallucinations [n = 2], P: hematoma [n = 1]). Two (5%) patients showed a wound inflammation (ROP: 1, P: 1). Nine (11%) patients experienced at least one serious adverse event (ROP: 6, P: 3); none related to treatment.

Conclusion: Preperitoneal CWI of 2 mg/mL ROP significantly reduces intravenous morphine consumption during the 96 postoperative hours resulting in an absolute reduction of 0.5 mg/kg.
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http://dx.doi.org/10.1002/jso.25280DOI Listing
January 2019

20-year assessment of metastatic latency and subsequent time to death after proton therapy for uveal melanomas.

Melanoma Res 2020 06;30(3):272-278

Department of Ophthalmology, Croix-Rousse University Hospital.

The aim of this study was to evaluate metastatic latency and survival after the occurrence of metastases in patients with choroidal/ciliary body melanoma treated with proton therapy. This was a retrospective cohort study. All consecutive patients with choroidal/ciliary body melanoma treated with proton therapy between 1991 and 2010 were included. Overall survival, specific survival (SS), local recurrence-free interval, and metastasis-free interval (MFI) were calculated. There were 508 patients. The mean follow-up was 239.4 months. Overall survival and SS rates were 57.2 and 67.6% at 10 years. Pre-equatorial tumor location, advanced tumor stage, and initial exudative retinal detachment were associated independently with SS. Thirty-three percent of the patients (n = 169) had metastases. Local recurrence-free interval and MFI were 91.3 and 65.7% at 10 years, respectively. MFI was shorter in pre-equatorial, large tumors, and/or tumors with exudative retinal detachment. After the occurrence of metastases, the median survival time was 1.25 years and survival probabilities were 62.1% at 1 year, 26.0% at 2 years, and 6.0% at 5 years. Except for age, none of the baseline clinical factors was associated with survival after metastasis occurrence. SS after metastasis occurrence was longer for metastasis occurring more than 10 years after tumor diagnosis (P =0.010). Death after metastasis is independent of initial tumor characteristics. Small tumors still have a risk for metastases after 10 years. Thus, lifelong follow-up is necessary for uveal melanoma patients. Larger series of metastatic patients are needed to evaluate aggressive multimodal treatments of metastases. Death after metastasis is independent of the initial tumor characteristics. Small tumors contraintuitively have a long-life risk of metastases. MFI is associated independently with pre-equatorial location, tumor stage, and retinal detachment.
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http://dx.doi.org/10.1097/CMR.0000000000000519DOI Listing
June 2020

Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines.

J Innate Immun 2018 5;10(4):339-348. Epub 2018 Jul 5.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard (CLB), Lyon, France.

Different liver cell types are endowed with immunological properties, including cell-intrinsic innate immune functions that are important to initially control pathogen infections. However, a full landscape of expression and functionality of the innate immune signaling pathways in the major human liver cells is still missing. In order to comparatively characterize these pathways, we purified primary human hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells (LSEC), and Kupffer cells (KC) from human liver resections. We assessed mRNA and protein expression level of the major innate immune sensors, as well as checkpoint-inhibitor ligands in the purified cells, and found Toll-like receptors (TLR), RIG-I-like receptors, as well as several DNA cytosolic sensors to be expressed in the liver microenvironment. Amongst the cells tested, KC were shown to be most broadly active upon stimulation with PRR ligands emphasizing their predominant role in innate immune sensing the liver microenvironment. By KC immortalization, we generated a cell line that retained higher innate immune functionality as compared to THP1 cells, which are routinely used to study monocyte/macrophages functions. Our findings and the establishment of the KC line will help to understand immune mechanisms behind antiviral effects of TLR agonists or checkpoint inhibitors, which are in current preclinical or clinical development.
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http://dx.doi.org/10.1159/000489966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757176PMC
October 2019

Major Hepatectomy for Colorectal Liver Metastases in Patients Aged Over 80: A Propensity Score Matching Analysis.

Dig Surg 2018 17;35(4):333-341. Epub 2018 Apr 17.

Institut Hospitalo-Universitaire (IHU), Institute for Minimally Invasive Hybrid Image-Guided Surgery, Université de Strasbourg, Strasbourg, France.

Background: The aim of this study was to evaluate the results of major hepatectomies for metastasis in elderly colorectal cancer patients, for whom limited data exist in the literature.

Methods: From January 2006 to January 2013, 3,034 patients underwent hepatectomy for colorectal liver metastasis in 32 French surgical centers. Repeat hepatectomies were excluded from the study. Based on a 1: 4 propensity score matching model, 42 patients aged ≥80 (OG) were matched with 168 patients <80 years (YG) in order to obtain 2 well-balanced and homogeneous groups with regards to therapy and prognostic factors.

Results: The unmatched cohort consisted of 744 patients (OG: n = 42; YG: n = 702). After PS matching, there was no difference in terms of general morbidity, rates of Dindo-Clavien score ≥III (OG: 16% vs. YG: 21%, p = 0.663), surgical morbidity (OG: 16% vs. YG: 21%, p = 0.663), reoperation (OG:10% vs. YG: 5%, p = 0.263), 90-day mortality (OG: 0% vs. YG:2%, p = 1), and total median hospital stay (OG: 12 vs. YG: 12, p = 0.972). Both groups experienced similar 3- and 5-year overall survival (82 and 82% OG vs.78 and 67% YG) and disease-free survival (40 and 35% OG vs. 45 and 35% YG at 3 and 5 years).

Conclusions: No difference in perioperative and postoperative outcomes and disease-free and overall survival was found. Major hepatectomy in selected octogenarian patients is safe and feasible.
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http://dx.doi.org/10.1159/000486522DOI Listing
November 2018

Direct antiviral properties of TLR ligands against HBV replication in immune-competent hepatocytes.

Sci Rep 2018 03 29;8(1):5390. Epub 2018 Mar 29.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France.

Current therapies for chronic hepatitis B virus (HBV) infections are effective at decreasing the viral load in serum, but do not lead to viral eradication. Recent studies highlighted the therapeutic or "adjuvant" potential of immune-modulators. Our aim was to explore the direct anti-HBV effect of Toll-Like-Receptors (TLR) agonists in hepatocytes. HBV-infected primary human hepatocytes (PHH) or differentiated HepaRG cells (dHepaRG) were treated with various TLR agonists. Amongst all TLR ligands tested, Pam3CSK4 (TLR1/2-ligand) and poly(I:C)-(HMW) (TLR3/MDA5-ligand) were the best at reducing all HBV parameters. No or little viral rebound was observed after treatment arrest, implying a long-lasting effect on cccDNA. We also tested Riboxxol that features improved TLR3 specificity compared to poly(I:C)-(HMW). This agonist demonstrated a potent antiviral effect in HBV-infected PHH. Whereas, poly(I:C)-(HMW) and Pam3CSK4 mainly induced the expression of classical genes from the interferon or NF-κB pathway respectively, Riboxxol had a mixed phenotype. Moreover, TLR2 and TLR3 ligands can activate hepatocytes and immune cells, as demonstrated by antiviral cytokines produced by stimulated hepatocytes and peripheral blood mononuclear cells. In conclusion, our data highlight the potential of innate immunity activation in the direct control of HBV replication in hepatocytes, and support the development of TLR-based antiviral strategies.
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http://dx.doi.org/10.1038/s41598-018-23525-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876392PMC
March 2018

HEPATOFLUO: A prospective monocentric study assessing the benefits of indocyanine green (ICG) fluorescence for hepatic surgery.

J Surg Oncol 2018 Apr 23;117(5):922-927. Epub 2018 Feb 23.

Department of Surgery, Centre Léon Bérard, Lyon, France.

Background And Objectives: Fluorescence imaging using indocyanine green (ICG) is undergoing extensive development. This study aimed to assess the merits of ICG in regard to hepatic surgery.

Methods: Patients with liver lesions that required a resection were eligible. They received an injection of ICG the day before the surgery. Step 1 allowed assessment of use of the medical device under surgical conditions. Steps 2 and 3 assessed the capacity of the MD to detect known tumorous lesions and to spot a predefined area of the liver following injection of ICG into the portal vein (ICGp).

Results: The 1st step allowed for validation of the MD use with three patients. Between 04-2013 and 04-2015, 45 pts were included (40 eligible) in steps 2 and 3. All of the tumorous lesions (95/119) exhibited fluorescence. Four new metastasis were detected in 3 pts, and two missing metastases in 1 pt. False positive were 22%. The maximal depth for detection by fluorescence was 13 mm. Injection of ICGp allowed the corresponding anatomical area to be identified in 16/20 patients.

Conclusion: This study confirmed that intraoperative fluorescence is a helpful and relevant tool for the liver surgeon (NCT 01738217).
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http://dx.doi.org/10.1002/jso.25011DOI Listing
April 2018

Hepatocellular carcinoma-associated depletion of the netrin-1 receptor Uncoordinated Phenotype-5A (UNC5A) skews the hepatic unfolded protein response towards prosurvival outcomes.

Biochem Biophys Res Commun 2018 01 24;495(4):2425-2431. Epub 2017 Dec 24.

INSERM U1052 & CNRS UMR5286, Cancer Research Centre of Lyon, Lyon, France; University of Lyon, Lyon, France; DevWeCan Laboratories of Excellence Network (Labex), Lyon, France. Electronic address:

In the liver, HBV and HCV infections, exposure to toxics, genetic and metabolic disorders may induce endoplasmic reticulum (ER) stress and the unfolding protein response (UPR). The UPR allows cells to reach ER homeostasis after lumen overload, but also fosters survival of damaged cells and therefore HCC onset. Dependence receptors such as UNC5A trigger apoptosis when unbound to their ligands. We have previously shown that the main dependence receptor ligand, netrin-1, could protect cells against UPR-induced apoptosis through sustained translation. In this study, we show that UNC5A is cumulatively downregulated by the UPR at the transcriptional level in vitro and at the translational level both in vitro and in vivo. We have found that the 5'-untranslated region of the UNC5A mRNA shares a certain homology degree with that of netrin-1, suggesting linked translational regulatory mechanisms, at least during the initial stages of the UPR. RNAi and forced expression studies identified UNC5A as a modulator of cell death in the context of the UPR. UNC5A decrease of association with polysomes and expression oriented cells towards UPR-associated hepatocytic survival. Such data indicate that cooperation between the UPR and UNC5A depletion as previously observed by ourselves in HCC patients samples may foster liver cancer development and growth.
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http://dx.doi.org/10.1016/j.bbrc.2017.12.129DOI Listing
January 2018

Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial.

Lancet 2017 07 7;390(10093):469-479. Epub 2017 Jun 7.

Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique du CHU de Bordeaux, Université Bordeaux, Bordeaux, France.

Background: Organ preservation is a concept proposed for patients with rectal cancer after a good clinical response to neoadjuvant chemotherapy, to potentially avoid morbidity and side-effects of rectal excision. The objective of this study was to compare local excision and total mesorectal excision in patients with a good response after chemoradiotherapy for lower rectal cancer.

Methods: We did a prospective, randomised, open-label, multicentre, phase 3 trial at 15 tertiary centres in France that were experts in the treatment of rectal cancer. Patients aged 18 years and older with stage T2T3 lower rectal carcinoma, of maximum size 4 cm, who had a good clinical response to neoadjuvant chemoradiotherapy (residual tumour ≤2 cm) were centrally randomly assigned by the surgeon before surgery to either local excision or total mesorectal excision surgery. Randomisation, which was done via the internet, was not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was required if tumour stage was ypT2-3. The primary endpoint was a composite outcome of death, recurrence, morbidity, and side-effects at 2 years after surgery, to show superiority of local excision over total mesorectal excision in the modified intention-to-treat (ITT) population (expected proportions of patients having at least one event were 25% vs 60% for superiority). This trial was registered with ClinicalTrials.gov, number NCT00427375.

Findings: From March 1, 2007, to Sept 24, 2012, 186 patients received chemoradiotherapy and were enrolled in the study. 148 good clinical responders were randomly assigned to treatment, three were excluded (because they had metastatic disease, tumour >8 cm from anal verge, and withdrew consent), and 145 were analysed: 74 in the local excision group and 71 in the total mesorectal excision group. In the local excision group, 26 patients had a completion total mesorectal excision. At 2 years in the modified ITT population, one or more events from the composite primary outcome occurred in 41 (56%) of 73 patients in the local excision group and 33 (48%) of 69 in the total mesorectal excision group (odds ratio 1·33, 95% CI 0·62-2·86; p=0·43). In the modified ITT analysis, there was no difference between the groups in all components of the composite outcome, and superiority was not shown for local excision over total mesorectal excision.

Interpretation: We failed to show superiority of local excision over total mesorectal excision, because many patients in the local excision group received a completion total mesorectal excision that probably increased morbidity and side-effects, and compromised the potential advantages of local excision. Better patient selection to avoid unnecessary completion total mesorectal excision could improve the strategy.

Funding: National Cancer Institute of France, Sanofi, Roche Pharma.
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http://dx.doi.org/10.1016/S0140-6736(17)31056-5DOI Listing
July 2017

Efficacy of high-intensity focused ultrasound-assisted hepatic resection (HIFU-AR) on blood loss reduction in patients with liver metastases requiring hepatectomy: study protocol for a randomized controlled trial.

Trials 2017 02 6;18(1):57. Epub 2017 Feb 6.

Department of Surgical Oncology, Centre Léon Bérard, 28 Rue Laennec, Lyon, 69008, France.

Background: Liver resection is the only potentially curative treatment for colorectal liver metastases (LM). It is considered a safe procedure, but is often associated with blood loss during liver transection. Blood transfusions are frequently needed, but they are associated with increased morbidity and risk of recurrence. Many surgical devices have been developed to decrease blood loss. However, none of them has proven superior to the standard crushing technique. We developed a new, powerful intra-operative high-intensity focused ultrasound (HIFU) transducer which destroys tissue by coagulative necrosis. We aim to evaluate whether HIFU-assisted liver resection (HIFU-AR) results in reduced blood loss.

Methods: This is a prospective, single-centre, randomized (1:1 ratio), comparative, open-label phase II study. Patients with LM requiring a hepatectomy for ≥ 2 segments will be included. Patients with cirrhosis or sinusoidal obstruction syndrome with portal hypertension will be excluded. The primary endpoint is normalized blood loss in millilitres per square centimetre of liver section plane. Secondary endpoints are: total blood loss, transection time, transection time per square centimetre of liver area, haemostasis time, clip density on the liver section area, rate and duration of the Pringle manœuvre, rate of patients needing a blood transfusion, length of hospital stay, morbidity, patients with positive resection margin, and local recurrence. Assuming a blood loss of 7.6 ± 3.7 mL/cm among controls, the study will have 85% power to detect a twofold decrease of blood loss in the experimental arm, using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.05 two-sided significance level. Twenty-one randomized patients per arm are required. Considering the risk of contraindications at surgery, up to eight patients may be enrolled in addition to the 42 planned, with an enrolment period of 24 months. Randomization will be stratified by surgeon.

Discussion: We previously demonstrated the safety and efficacy of intra-operative HIFU in patients operated on for LM. We also demonstrated the efficacy of HIFU-AR in a preclinical study. Participants in the HIFU-AR group of this randomized trial can expect to benefit from reduced blood loss and decreased ischemia of liver parenchyma.

Trial Registration: Clinicaltrial.gov, NCT02728167 . Registered on 22 March 2016.
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http://dx.doi.org/10.1186/s13063-017-1801-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294714PMC
February 2017

Thermal Ablation of the Pancreas With Intraoperative High-Intensity Focused Ultrasound: Safety and Efficacy in a Porcine Model.

Pancreas 2017 02;46(2):219-224

From the *Department of Surgical Oncology, Centre Léon Bérard; and †Univ Lyon, INSERM, LabTau, Lyon, France.

Objective: New focal destruction technologies such as high-intensity focused ultrasound (HIFU) may improve the prognosis of pancreatic ductal adenocarcinoma. Our objectives were to demonstrate the safety and efficacy of intraoperative pancreatic HIFU ablation in a porcine model.

Methods: In a porcine model (N = 12), a single HIFU ablation was performed in either the body or tail of the pancreas, distant to superior mesenteric vessels. All animals were sacrificed on the eighth day. The primary objective was to obtain an HIFU ablation measuring at least 1 cm without premature death.

Results: In total, 12 HIFU ablations were carried out. These ablations were performed within 160 seconds and on average measured 20 (15-27) × 16 (8-26) mm. The primary objective was fulfilled in all but 1 pig. There were no premature deaths or severe complications. High-intensity focused ultrasound treatment was associated with a transitory increase in amylase and lipase levels, and pseudocysts were observed in half of the pigs without being clinically apparent. All ablations were well delimited at both gross and histological examinations.

Conclusions: Intraoperative thermal destruction of porcine pancreas with HIFU is feasible. Reproducibility and safety have to be confirmed when applied close to mesenteric vessels and in long-term preclinical studies.
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http://dx.doi.org/10.1097/MPA.0000000000000720DOI Listing
February 2017

Identification of intra-hepatic communicating veins through the arch sign on CT-scan.

Surg Radiol Anat 2017 Jun 25;39(6):673-677. Epub 2016 Oct 25.

Department of Surgical Oncology, Centre Léon Bérard, 28 Rue Laennec, 69008, Lyon, France.

Purpose: Knowledge of vascular outflow is essential in liver surgery. Communicating veins between the right hepatic vein (RHV) and the middle hepatic vein (MHV) have been described and allowed us to perform new surgical procedures. The aim of this study was to predict the existence of intra-hepatic venous anastomosis by identifying communicating veins on 2D CT-scan imaging.

Methods: We retrospectively analysed data from 32 patients operated on for liver tumours between 2004 and 2013 who underwent a bisegmentectomy VI-VII enlarged to the RHV and/or a bisegmentectomy VII-VIII and/or a left hepatectomy enlarged to the MHV and who had pre and post-operative CT-scans. Patients with cirrhosis were excluded. We first analysed post-operative images and, in patients with a proven collateral vein, looked for evidence of this on pre-operative imaging. We then validated this pre-operative sign against post-operative imaging.

Results: Collaterals from both the RHV and the MHV formed an arch visible on pre-operative imaging which predicted the development of intrahepatic venous anastomosis in 20 patients. In 14 patients, a perfect match between the arch sign and development of collaterals was observed (n = 28). Sensitivity, specificity, negative and positive predictive values were 87, 80, 80, and 87%, respectively. Positive and negative likelihood ratio tests were 4.3 and 0.16, respectively.

Conclusion: Communicating veins between the RHV and the MHV are frequent and can be predicted by the arch sign on 2D CT-scan. Hence the arch sign can be very useful when planning liver surgery.
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http://dx.doi.org/10.1007/s00276-016-1762-2DOI Listing
June 2017

Portal supply of segment IV of the liver based on CT-scan.

Surg Radiol Anat 2017 May 18;39(5):471-476. Epub 2016 Oct 18.

Department of Surgical Oncology, Léon Bérard Cancer Centre, 28 Rue Laennec, 69008, Lyon, France.

Background: The portal vascularization of segment IV (S4) of the liver has not been well described. Knowledge of the portal supply to S4 is of great interest for liver surgery and for interventional radiological procedures. This study aimed to analyse the distribution of portal vein branches supplying S4.

Methods: We retrospectively analysed data from patients operated on for liver tumours between 2007 and 2016. Patients with involvement of S4 branches or the left portal vein, previous liver surgery or poor quality imaging were excluded. Branches originating from the right portal vein and/or from the transverse part of the left portal vein (TPLPV) and/or from the umbilical part of the portal vein (UPLPV) were identified.

Results: In 102 patients who underwent a right hepatectomy, S4 was vascularized by 2-8 branches of the left portal vein, with 84.3 % of patients having 3-6 branches. Only eleven patients (10.8 %) had portal branches originating from the TPLPV, with no impact on the number of branches coming from the UPLPV. Three patients (2.9 %) had one branch from the right portal vein. In patients with only two or three branches supplying S4, the branches had a larger diameter and typically arose from a short common trunk which divided further within its first centimetres.

Conclusions: Portal vascularization of S4 varies widely (2-8 branches) between patients and originates predominantly from the junction between the left portal vein and the round ligament. There is no anatomical rationale to divide S4 into S4a and S4b.
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http://dx.doi.org/10.1007/s00276-016-1761-3DOI Listing
May 2017

CRP Predicts Safe Patient Discharge After Colorectal Surgery.

Ann Surg 2018 02;267(2):e33

Centre Léon Bérard, Department of Surgical Oncology, Lyon, France, Univ Lyon, Inserm, U1032, LabTau, Lyon, Lyon, France, Groupe francophone de réhabilitation améliorée après chirurgie (GRACE) Digestive and Hepatobiliary Surgery Department, Estaing University Hospital, Clermont-Ferrand, France Centre Léon Bérard, Department of Surgical Oncology, Lyon, France Centre Léon Bérard, Department of Surgical Oncology, Lyon, France, Univ Lyon, Inserm, U1032, LabTau, Lyon, Lyon, France Digestive and Hepatobiliary Surgery Department, Estaing University Hospital, Clermont-Ferrand, France, Groupe francophone de réhabilitation améliorée après chirurgie (GRACE).

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http://dx.doi.org/10.1097/SLA.0000000000001983DOI Listing
February 2018