B Chauffert

Centre Hospitalier Universitaire d'Amiens, Amiens, Picardie, France

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Publications (242)699.65 Total impact

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    ABSTRACT: Prognosis of unresectable glioblastoma remains poor despite temozolomide-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with temozolomide-based chemoradiation for unresectable glioblastoma. Patients with unresectable glioblastoma, age 18-70, IK>50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m2, every 2 weeks for 4 cycles before radiotherapy (60 Gy), concomitant oral temozolomide, 75 mg/m2/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral temozolomide, 75 mg/m2/day during radiotherapy, and 150-200 mg/m2 for 5 days every 28 days for 6 months. Use of bevacizumab was allowed at progression in the control arm. Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression free survival at 6 month (PFS-6 ) from 50 to 66 %. The primary objective was not achieved, and only 30/60 patients were alive without progression at 6 months (50.0% (IC95% [36.8; 63.1]) in the BEV/IRI arm when 37/60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. Median overall survival was not different between the two arms (11.1 months). Main toxicities were 3 fatal intracranial bleedings, 3 bile duct or digestive perforations/infections (1 fatal), and 6 thrombotic episodes in BEV/IRI arm, whereas there was 1 intracranial bleeding, 2 bile duct or digestive perforations/infections (1 fatal) and 1 thrombotic episode in the control arm. Neo-adjuvant and adjuvant BEV/IRI, combined with temozolomide-radiation, is not recommended for further evaluation in first line treatment of unresectable glioblastoma. number 2008-002775-28 (NCT01022918).
    Annals of Oncology 04/2014; · 7.38 Impact Factor
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    ABSTRACT: BackgroundA phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC).AimTo estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life.Methods Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20% of patients.ResultsTwenty-one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5-, 10- and 15-mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST, elevated γ-glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months – not reached); the median overall survival was 24.5 months (95% CI 14.7 months – not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly.Conclusions Using drug-eluting beads, the maximum-tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559).
    Alimentary Pharmacology & Therapeutics 04/2014; · 4.55 Impact Factor
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    ABSTRACT: Background Heated intraperitoneal chemotherapy (HIPEC) treats residual microscopic disease after cytoreductive surgery. In experimental models, the open HIPEC technique has shown a higher and more homogenous concentration of platinum in the peritoneum than achieved using the closed technique. A 25-cm H2O pressure enhances the penetration of oxaliplatin. Because pressure is easier to set up with the closed technique, high pressure may counterbalance the drawbacks of this technique versus open HIPEC, and a higher pressure may induce a higher penetration. Because higher concentration does not mean deeper penetration, a study of tissues beneath the peritoneum is required. Finally, achieving a deeper penetration (and a higher concentration) raises the question of the passage of drugs through the surgical glove and the surgeon's safety. Methods Four groups of pigs underwent HIPEC with oxaliplatin (150 mg/L) for 30 minutes in open isobaric pressure and pressure at 25 cm H2O, and closed pressure at 25 and 40 cm H2O. Systemic absorption and peritoneal mapping of the concentration of platinum were analyzed, as well as in the retroperitoneal tissue and the surgical gloves. Results Blood concentrations were higher in open groups. In the parietal surfaces, the concentrations were not different between the isobaric and the closed groups (47.08, 56.39, and 48.57 mg/kg, respectively), but were higher in the open high-pressure group (85.93 mg/kg). In the visceral surfaces, they were lower in the closed groups (3.2 and 3.05 mg/kg) than in the open groups (7.03 and 9.56 mg/kg). Platinum concentrations were similar in the deep retroperitoneal tissue when compared between isobaric and high-pressure procedures. No platin was detected in the internal aspect of the gloves. Conclusion The use of high pressure during HIPEC does not counterbalance the drawbacks of closed techniques. The tissue concentration of oxaliplatin achieved with the open techniques is higher, even if high pressure is applied during a closed technique. Open 25 cm H2O HIPEC achieved the highest tissue penetration of oxaliplatin, but did not enhance the depth of oxaliplatin penetration. High pressure did not enhance the risk of HIPEC.
    Surgery 01/2014; · 3.37 Impact Factor
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    ABSTRACT: Sorafenib, an orally-available kinase inhibitor, is the only medical treatment with a proven efficacy against Hepatocellular Carcinoma (HCC). Although the overall clinical efficacy of sorafenib is modest, recent experimental results have uncovered new potential strategies that may increase its clinical benefits. The potential implication of Receptor Tyrosine Kinases (RTKs), such as the Epidermal Growth Factor Receptor (EGFR), in the development of resistance to sorafenib highlights the importance of the RAF kinase pathway. Various strategies aiming to optimize the control exerted over this pathway by combining sorafenib with other targeted molecules (such as anti-EGFR, anti-MEK) are under investigation. Increasing the cytotoxicity of sorafenib in HCC, either through apoptosis or through new forms of non-apoptotic cell death, such as ferroptosis, may also promote more sustained tumour regression. Finally, the heterogeneity of individual responses to sorafenib is increasingly recognized, even though clinically-applicable biomarkers remain to be identified. Here, we discuss how molecular genetics and complementary approaches such as short term culture of tumour samples could help to personalize the use of sorafenib.
    Cancer letters 12/2013; · 4.86 Impact Factor
  • Annals of surgery 10/2013; · 7.90 Impact Factor
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    ABSTRACT: A novel family of cisplatin-type complexes tethered to dibenzo[c,h][1,6]naphthyridin-6-one topoisomerase inhibitor via a polymethylene chain and their nonplatinated counterparts were prepared. Their potential cytotoxicity was assessed in three human colorectal cancer cell lines HCT 116, SW480 and HT-29 and compared to the reference molecules cisplatin and oxaliplatin. Platinated compounds were poorly active whilst nonplatinated dibenzo[c,h][1,6]naphthyridin-6-one moieties exhibited higher cytotoxic properties than cisplatin and oxaliplatin whatever the length of the polymethylene chain; molecules containing the tri- and hexamethylene chain length were the most cytotoxic.
    European journal of medicinal chemistry 09/2013; 69C:719-727. · 3.27 Impact Factor
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    ABSTRACT: Radiotherapy with concomitant and adjuvant temozolomide (six cycles) is the standard treatment after surgery in glioblastoma patients. Few studies have assessed the impact of additional cycles of temozolomide on survival. We conducted a bi-centric retrospective study comparing survival and toxicity according to the number of cycles of adjuvant temozolomide. Fifty-eight patients were included. All patients received radiotherapy with concomitant temozolomide. Thirty-eight patients received six cycles, while 20 received nine or more (median=14) cycles. The risk of recurrence was significantly higher in the group receiving six cycles compared to the other group. Prolonged treatment improved progression-free survival (p=0.03) and overall survival (p=0.01) in multivariate analysis without a significant increase in toxicity. Prolonged administration of temozolomide seems to improve progression-free and overall survival, without increased toxicity. Prospective studies in larger populations are needed to better-define the population to whom it can be proposed and its optimal duration.
    Anticancer research 08/2013; 33(8):3467-74. · 1.71 Impact Factor
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    ABSTRACT: OBJECTIVE: This study examined the effect of systemic chemotherapy on survival in patients with metastatic or non-resectable intrahepatic cholangiocarcinoma. METHODS: This study retrospectively reviewed data from 23 consecutive patients with metastatic cholangiocarcinoma diagnosed and treated in our centre between 2000 and 2007. Patients were eligible if they had intrahepatic cholangiocarcinoma with liver or extrahepatic metastasis and with no prior chemotherapy. Univariate and multivariate analyses were performed to determine the impact of age, sex, presence of extrahepatic metastasis, performance status, type of chemotherapy, number of lines of chemotherapy. RESULTS: The median survival of all patients was 27.7 months (17.8-37.7). Univariate analysis showed that age less than 60 years at diagnosis, good performance status, no extrahepatic liver metastasis and the number of lines of chemotherapy were significantly associated with better survival. Multivariate analysis identified only performance status and the number of lines of chemotherapy as independent predictive factors of survival. CONCLUSION: Our data suggest that iterative chemotherapy may increase survival in patients with metastatic cholangiocarcinoma.
    Gastroentérologie Clinique et Biologique 05/2013; · 0.80 Impact Factor
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    ABSTRACT: Background/Aim: Sorafenib is currently the only medical treatment with proven efficacy against hepatocellular carcinoma (HCC). HCC cell lines display heterogeneous sensitivity to sorafenib, but little is known about the sensitivity of clinical tumors. We aimed to examine this aspect. Using experimental tumors generated in nude mice, we set up a technique for short-term culture of HCC fragments. We applied this technique to six human HCC samples obtained from surgical resection. HCC fragments in culture retain their morphology and viability for at least 48 h, permitting an in vitro analysis of the effect of sorafenib on the Extracellular signal-regulated kinase (ERK) cascade. HCC exhibit heterogeneous individual responses, ranging from potent inhibition to paradoxical activation of this oncogenic cascade. Our observations highlight the heterogeneous sensitivity of HCC to sorafenib, and point to the potential interest of short-term culture of tumor fragments for personalizing the medical treatment of HCC.
    Anticancer research 04/2013; 33(4):1415-20. · 1.71 Impact Factor
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    ABSTRACT: The multi-kinase inhibitor sorafenib is currently the treatment of reference for advanced Hepatocellular Carcinoma (HCC). In the present report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumours. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2013; · 6.20 Impact Factor
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    ABSTRACT: BACKGROUND: The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC. PATIENTS AND METHODS: Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1000mg/m(2) bid on days 1-14) every 3weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2400mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180mg/m(2) on day 1) every 2weeks. Patients aged ⩾65years received a lower dose of capecitabine (800mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS: A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively). CONCLUSIONS: This randomised non-comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.
    European journal of cancer (Oxford, England: 1990) 01/2013; · 4.12 Impact Factor
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    ABSTRACT: OBJECTIVE AND BACKGROUND:: Self-expanding metallic stent (SEMS) insertion has been suggested as a promising alternative to emergency surgery for left-sided malignant colonic obstruction (LMCO). However, the literature on the long-term impact of SEMS as "a bridge to surgery" is limited and contradictory. METHODS:: From January 1998 to June 2011, we retrospectively identified patients operated on for LMCO with curative intent. The primary outcome criterion was overall survival. Short-term secondary endpoints included the technical success rate and overall success rate and long-term secondary endpoints included 5-year overall survival, 5-year cancer-specific mortality, 5-year disease-free survival, the recurrence rate, and mean time to recurrence. Patients treated with SEMS were analyzed on an intention-to-treat basis. Overall survival was analyzed after using a propensity score to correct for selection bias. RESULTS:: There were 48 patients in the SEMS group and 39 in the surgery-only group. In the overall population, overall survival (P = 0.001) and 5-year overall survival (P = 0.0003) were significantly lower in the SEMS group than in the surgery-only group, and 5-year cancer-specific mortality was significantly higher in the SEMS group (48% vs 21%, respectively (P = 0.02)). Five-year disease-free survival, the recurrence rate, and the mean time to recurrence were better in the surgery-only group (not significant). For patients with no metastases or perforations at hospital admission, overall survival (P = 0.003) and 5-year overall survival (30% vs 67%, respectively, P = 0.001) were significantly lower in the SEMS group than in the surgery-only group. CONCLUSIONS:: Our study results suggest worse overall survival of patients with LMCO with SEMS insertion compared with immediate surgery.
    Annals of surgery 01/2013; · 7.90 Impact Factor
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    ABSTRACT: Background and Aims. Chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. We describe these lesions and assess risk factors and impacts on postresection morbidity and mortality in naive patients to chemotherapy before the era of bevacizumab. Methods. Noncancerous liver tissue lesions were analysed according to tumour, chemotherapy, surgery, and patient characteristics. Results. Fifty patients aged 62 ± 9.3 years were included between 2003 and 2007. Thirty-three (66%) received chemotherapy, with Folfox (58%), Folfiri (21%), LV5FU2 (12%), or Xelox (9%) regimens. Hepatotoxicity consisted of 18 (36%) cases of severe sinusoidal dilatation (SD), 13 (26%) portal fibrosis, 7 (14%) perisinusoidal fibrosis (PSF), 6 (12%) nodular regenerative hyperplasia (NRH), 2 (4%) steatosis >30%, zero steatohepatitis, and 16 (32%) surgical hepatitis. PSF was more frequent after chemotherapy (21% versus 0%, P = 0.04), especially LV5FU2 (P = 0.02). SD was associated with oxaliplatin (54.5% versus 23.5%, P = 0.05) and low body mass index (P = 0.003). NRH was associated with oxaliplatin (P = 0.03) and extensive resection (P = 0.04). No impact on mortality and morbidity was observed, apart postoperative elevation of bilirubin levels in case of PSF (P = 0.03), longer hospitalization in case of surgical hepatitis (P = 0.03), and greater blood loss in case of portal fibrosis (P = 0.03). Conclusions. Chemotherapy of colorectal liver metastases induces sinusoidal dilatation related to oxaliplatin and perisinusoidal fibrosis related to 5FU, without any impact on postoperative mortality.
    International journal of hepatology. 01/2013; 2013:314868.
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    ABSTRACT: BACKGROUND: There is still no consensus about the best chemotherapeutic agent for transarterial chemoembolization (TACE). A recent in vitro study demonstrated that idarubicin, an anthracycline, was by far the most cytotoxic drug on human hepatocellular carcinoma (HCC) cell lines. Idarubicin is much more lipophilic than doxorubicin, leading to higher cell penetration through lipidic membranes and greater accumulation of the drug in the lipiodol. Furthermore, idarubicin has the ability to overcome multidrug resistance. Therefore, we designed this pilot human study to evaluate the safety and efficacy of lipiodol TACE using idarubicin. METHODS: In 21 consecutive patients treated by lipiodol TACE with idarubicin (10 mg) for HCC, safety data, tumor response (Response Evaluation Criteria in Solid Tumors, mRECIST), time to treatment failure (TTTF), and overall survival were evaluated. RESULTS: Postembolization syndrome was observed after 30.9 % (17 of 55) of sessions. No patient died from a TACE-related complication. No hematological grade 3-5 adverse event was observed. At least one grade 3 or higher adverse event occurred in 19 % (4 of 21) of patients. On imaging, no progression was encountered; four patients (24 %) exhibited stable disease, 12 (57 %) exhibited a partial response, and five (19 %) exhibited a complete response. Median TTTF was 16.7 months (Kaplan-Meier analysis). At 6 months, 94.7 % (95 % confidence interval [CI] 68.1-99.2) of patients did not reach treatment failure, whereas treatment failure was not reached in 50.6 % (95 % CI 21.6-73.9) of patients at 1 year. Overall survival was 83.5 % (95 % CI 57-94.4) at 1 year. CONCLUSION: Idarubicin seems safe and effective in lipiodol TACE of HCC. This warrants further study to determine the potential of this drug to replace doxorubicin for TACE.
    CardioVascular and Interventional Radiology 12/2012; · 2.09 Impact Factor
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    ABSTRACT: Metastatic pancreatic carcinoma is an incurable disease and gemcitabine remains the standard of care in first-line chemotherapy. Recently, fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) demonstrated their superiority in first-line therapy. The objective of this study was to determine the efficacy of FOLFIRINOX in either first- and second-line treatment and to compare its efficacy in regard to the location of the primary tumor. We performed a retrospective analysis of clinical factors associated with patients' survival using a cohort of 42 patients treated by FOLFIRINOX in either first- or second-line (2006-2011) and a control cohort of 42 patients matched on sex and age without FOLFIRINOX treatment was obtained from a previous period of time (2001-2005). The median follow-up was 10 months. The median overall survival was 10 months for the whole cohort and 10 and 12 months for patients treated at first- and second-line, respectively (p<0.05). In this cohort using a multivariate model, among classical prognosis factors, only primary location in the head was associated with poor outcome. The median overall survival was 8 months for patients with primary location in the head and 14 months for patients with primary location in the corpse or tail (p=0.02). In the gemcitabine cohort, the median follow-up was 8 months. Using a multivariate model, only performance status was associated with outcome. The median overall survival was 9 versus 6.5 months for patients with tumor, of the head versus tail or corpse tumor respectively (p<0.05). This retrospective study suggests the same efficacy of FOLFIRINOX used either in first- or second- line therapy for pancreatic cancer. Importantly, FOLFIRINOX compared favorably to gemcitabine only for patients with tumor of the corpse or tail. Further prospective trials are warranted to evaluate the efficacy of FOLFIRINOX in patients with tumor of the head of the pancreas.
    Anticancer research 09/2012; 32(9):4125-30. · 1.71 Impact Factor
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    ABSTRACT: Unresectable glioblastomas with severe neurological impairment at diagnosis have a poor prognosis. The conventional approach using a temozolomide-based chemoradiotherapy has limited efficiency on patients in the RTOG RPA V-VI classes. The activity of the antiangiogenic monoclonal antibody bevacizumab is well defined in recurrent glioblastoma, despite the fact that its impact on survival is not yet established. We wondered if neoadjuvant bevacizumab, used as upfront treatment in combination with a cytotoxic agent, was tolerable and active on neurological signs in patients with severe alteration of the neurological status due to the tumor being located in functional areas. Eight patients received intravenous bevacizumab, 10 mg/kg every 2 weeks, and either oral temozolomide (150-200 mg/m(2)/day for 5 days every 4 weeks) or intravenous fotemustine (80 mg/m(2) every 2 weeks). After an average of 5 cycles of bevacizumab, a clinical improvement of neurological functions was recorded in 8/8 patients who could then receive radiotherapy at a conventional dose (60 Gy in 30 fractions) with continuation of bevacizumab and the cytotoxic agent. Four out of the 8 patients benefited from a durable stabilization and experienced an unusually long survival in such a bad situation at diagnosis. In conclusion, neoadjuvant bevacizumab with chemotherapy appears to be feasible and efficient in a category of patients from the RTOG RPA V-VI classes, by allowing the completion of full-dose radiotherapy. A clinical trial is planned to confirm these retrospective observations.
    Case Reports in Oncology 09/2012; 5(3):530-6.
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    ABSTRACT: BACKGROUND:: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) achieve good results in selected patients with peritoneal carcinomatosis. High intra-abdominal pressure could enhance the penetration of chemotherapy drugs. The aim of this study was to compare the effects of high pressure and hyperthermia when used separately and when combined in terms of blood and tissue absorption of oxaliplatin in a swine model of intraperitoneal chemotherapy. METHODS:: Four groups of 5 pigs each underwent laparotomy and open intraperitoneal chemotherapy with oxaliplatin at a constant concentration (150 mg/L) for 30 minutes in normothermia and atmospheric pressure (group 1), or hyperthermia (42°C) and atmospheric pressure (group 2), or normothermia and high pressure (25 cm H2O) (group 3), or hyperthermia and high pressure (group 4). High pressure was achieved thorough a water column over the abdomen. Systemic absorption and abdominal tissue mapping of the penetration of oxaliplatin in each group were studied. RESULTS:: Blood concentrations of oxaliplatin were similar in the different groups. Hyperthermia achieved higher concentrations in visceral surfaces (P = 0.0014), but not in parietal surfaces. High pressure enhanced diffusion of the drug in both the visceral and parietal peritoneum (P = 0.0058 and P = 0.0044, respectively). The combination of hyperthermia and high pressure significantly increased the penetration of oxaliplatin and achieved the highest tissue concentrations (10.39 mg/kg vs 5.48 mg/kg; P = 0.00001 in the visceral peritoneum, and 66.16 mg/kg vs 35.62 mg/kg; P = 0.0003 in the parietal peritoneum). CONCLUSIONS:: Open high-pressure HIPEC with oxaliplatin is feasible in the pig. Hyperthermia enhances diffusion in the visceral peritoneum, whereas high pressure is effective in the visceral and parietal peritoneum. The combination of the two achieves the highest tissue concentrations of oxaliplatin.
    Annals of surgery 05/2012; · 7.90 Impact Factor
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    ABSTRACT: Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context.
    International Journal of Cancer 04/2012; 131(12):2961-9. · 6.20 Impact Factor
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    ABSTRACT: In order to improve the pharmacological profile of the anticancer drug cisplatin, several new acridine-based tethered (ethane-1,2-diamine)platinum(II) complexes connected by a polymethylene chain were synthetized. Activity-structure relationship between amide or ester functionalities was explored by changing acridine-9-carboxamide into acridine-9-carboxylate chromophore. The in vitro cytotoxicity of these new complexes was assessed in human colic HCT 116, SW480 and HT-29 cancer cell lines. Series of complexes bearing the acridine-9-carboxylate chromophore displayed higher cytotoxic effect than acridine-9-carboxamide complexes, with gradual effect according to the size of the polymethylene linker.
    Journal of inorganic biochemistry 02/2012; 110:51-7. · 3.25 Impact Factor
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    ABSTRACT: The usual treatments for pleural malignancies are mostly palliative. In contrast, peritoneal malignancies are often treated with a curative intent by cytoreductive surgery and intraperitoneal chemotherapy. As pressure has been shown to increase antitumor efficacy, we applied the concept of high-pressure intracavitary chemotherapy to the pleural space in a swine model. Cisplatin and gemcitabine were selected because of their antineoplasic efficacy in vitro in a wide spectrum of cancer cell lines. The pleural cavity of 21 pigs was filled with saline solution; haemodynamic and respiratory parameters were monitored. The pressure was increased to 15-25 cm H2O. This treatment was associated with pneumonectomy in 6 pigs. Five pigs were treated with chemotherapy under pressure. The combination of gemcitabine (100 mg/l) and cisplatin (30 mg/l) was highly cytotoxic in vitro. The maximum tolerated pressure was 20 cm H20, due to haemodynamic failure. Pneumonectomy was not tolerated, either before or after pleural infusion. Five pigs survived intrapleural chemotherapy associating gemcitabine and cisplatin with 20 cm H2O pressure for 60 min. High-pressure intrapleural chemotherapy is feasible in pigs. Further experiments will establish the pharmacokinetics and determine whether the benefit already shown in the peritoneum is also obtained in the pleura.
    World Journal of Surgical Oncology 01/2012; 10:29. · 1.09 Impact Factor

Publication Stats

3k Citations
699.65 Total Impact Points

Institutions

  • 2013
    • Centre Hospitalier Universitaire d'Amiens
      Amiens, Picardie, France
  • 2012–2013
    • Université de Picardie Jules Verne
      Amiens, Picardie, France
  • 2001–2013
    • Centre Georges-François Leclerc
      Dijon, Bourgogne, France
  • 1998–2013
    • University of Burgundy
      Dijon, Bourgogne, France
  • 1990–2013
    • Centre Hospitalier Universitaire de Dijon
      Dijon, Bourgogne, France
  • 2011
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
  • 2008–2009
    • Centre Hospitalier Régional et Universitaire de Besançon
      Becoinson, Franche-Comté, France
    • Agence française de lutte contre le dopage
      Saint-Germain, Pays de la Loire, France
  • 1987–2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2005
    • University of Franche-Comté
      Becoinson, Franche-Comté, France
  • 2004
    • The Australian Society of Otolaryngology Head & Neck Surgery
      Evans Head, New South Wales, Australia
  • 1984–2001
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1992–1995
    • CHRU de Strasbourg
      Strasburg, Alsace, France