Biomedical subjects

Christophe Hennequin

Publications and source records attributed to Christophe Hennequin.

At least 19 recordsLinked to original sources

PubMed2026

High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9·5 years (IQR 8·5-10·3), 5-year progression-free survival was 91·4% (95% CI 87·0-94·4) in the dose-escalation group versus 88·1% (83·2-91·6) in the control group, and 10-year progression-free survival was 83·6% (77·8-88·0) versus 72·2% (65·3-78·0; stratified HR 0·56, 95% CI 0·40-0·78, p<0·0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged↗

PubMed2006

Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth.

Little information is available about the molecular mechanisms responsible for polyene resistance in pathogenic yeasts. A clinical isolate of Candida glabrata with a poor susceptibility to polyenes, as determined by disk diffusion method and confirmed by determination of MIC, was recovered from a patient treated with amphotericin B. Quantitative analysis of sterols revealed a lack of ergosterol and an accumulation of late sterol intermediates, suggesting a defect in the final steps of the ergosterol pathway. Sequencing of CgERG11, CgERG6, CgERG5, and CgERG4 genes revealed exclusively a unique missense mutation in CgERG6 leading to the substitution of a cysteine by a phenylalanine in the corresponding protein. In addition, real-time reverse transcription-PCR demonstrated an overexpression of genes encoding enzymes involved in late steps of the ergosterol pathway. Moreover, this isolate exhibited a pseudohyphal growth whatever the culture medium used, and ultrastructural changes of the cell wall of blastoconidia were seen consisting in a thinner inner layer. Cell wall alterations were also suggested by the higher susceptibility of growing cells to Calcofluor white. Additionally, complementation of this isolate with a wild-type copy of the CgERG6 gene restored susceptibility to polyenes and a classical morphology. Together, these results demonstrated that mutation in the CgERG6 gene may lead to a reduced susceptibility to polyenes and to a pseudohyphal growth due to the subsequent changes in sterol content of the plasma membrane.

Antifungal Agents↗

PubMed2006

Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation.

PURPOSE: The high rate of toxicity is the limitation of myeloblastive regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. METHODS AND MATERIALS: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). RESULTS: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). CONCLUSIONS: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population size in the subgroup analysis.

Adolescent↗

PubMed2006

Long-term results of endobronchial brachytherapy: A curative treatment?

PURPOSE: To evaluate outcomes after high-dose-rate endobronchial brachytherapy (HDR-EBBT) for limited lung carcinoma. METHODS: A total of 106 patients with endobronchial lung cancer and not eligible for surgery or external beam radiotherapy, without nodal or visceral metastases, were treated with HDR-EBBT. They had developed disease relapse after surgery (n = 43) or external beam radiotherapy (n = 27) or had early lung cancer with respiratory insufficiency (n = 36). Treatment consisted of six fractions of 5 or 7 Gy, usually delivered 1 cm from the source. RESULTS: The complete histologic response rate, evaluated at 3 months after HDR-EBBT, was 59.4%. At 3 and 5 years, the local control, overall survival, and cause-specific survival rates were 60.3% and 51.6%, 47.4 and 24%, and 67.9 and 48.5%, respectively. Factors significantly associated with local failure were high tumor volume (tumor length >2 cm, bronchial obstruction >25%, tumor visibility on CT scan) and previous endoscopic treatment. Cause-specific survival, but not overall survival, was significantly associated with local control, probably because of the high rate of deaths not related to lung cancer. Five deaths were attributed to the HDR-EBBT procedure (two from fatal hemoptysis and three from bronchial necrosis). CONCLUSION: High-dose-rate-EBBT achieved a long-term cause-specific survival rate of 50% of the patients with localized endobronchial carcinoma and could be considered curative.

Adenocarcinoma↗

PubMed2006

Candida as a risk factor for mortality in peritonitis.

OBJECTIVE: The clinical significance of Candida cultured from peritoneal fluid specimens remains a matter of debate. None of the studies that have addressed this issue have clearly distinguished between community-acquired peritonitis and nosocomial peritonitis. The current study tried to differentiate the pathogenic role of Candida in these two clinical settings and assess its importance on outcome. DESIGN: A multiple-center, retrospective, case-control study was conducted in intensive care unit patients. The interaction between mortality rates and type of patients was assessed. In the case of a significant interaction, a separate analysis of mortality and morbidity was planned. SETTING: Seventeen intensive care units in teaching and nonteaching hospitals. PATIENTS: Cases were patients operated on for peritonitis with Candida cultured from the peritoneal fluid, whereas controls were operated patients free from yeast. Cases and controls were matched for type of infection, Simplified Acute Physiology Score II, age, and time period of hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The following characteristics were collected: demographic variables, underlying disease, severity score, site of infection, microbiological features, and anti-infective treatments. Survival was defined as the main outcome criterion and morbidity variables as secondary criteria. Odds ratios of mortality were calculated. Matching was achieved in 91 cases and 168 controls. Matching criteria, clinical characteristics, and mortality rate were not statistically different between cases and controls. A significant interaction was demonstrated between mortality rates and type of infection, leading to separate analysis of patients with community-acquired peritonitis and nosocomial peritonitis. The subgroup analysis demonstrated an increased mortality rate only in nosocomial peritonitis with fungal isolates (48% vs. 28% in controls, p<.01). Upper gastrointestinal tract site (odds ratio, 4.9; 95% confidence interval, 1.6-14.8) and isolation of Candida species (odds ratio, 3.0; 95% confidence interval, 1.3-6.7, p<.001) were found to be independent risk factors of mortality in nosocomial peritonitis patients. CONCLUSIONS: Isolation of Candida species appears to be an independent risk factor of mortality in nosocomial peritonitis but not in community-acquired peritonitis.

Aged↗

PubMed2006

[Erythropoietin and radiation therapy].

Hypoxia is now recognized as a major explanation of tumor radioresistance and is an important prognostic factor in head and neck and cervical cancers. Anemia, which had also a negative impact on cancer prognosis, increase tumor hypoxia. But we do not know actually if anemia has a direct role in tumor resistance or if it only reflect aggressiveness of the disease. Some trials have demonstrated that erythropoietin could increase the hemoglobin level during radiation courses. The only published randomised trial, performed in head and neck cancers, did not find any benefit for erythropoietin ; moreover, a deleterious effect was demonstrated. Possible explanations for this paradoxal result were discussed, particularly biological hypothesis and statistical bias.

Anemia↗

PubMed2006

Gastro-intestinal lymphomas.

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Clinical Trials as Topic↗

PubMed2005

Estimating late adverse events using competing risks after autologous stem-cell transplantation in aggressive non-Hodgkin lymphoma patients.

BACKGROUND: Consolidative autologous stem-cell transplantation (ASCT) is a valuable option in high-risk or disease recurrence large-cell non-Hodgkin lymphoma patients (NHL); however, its long-term toxicity must still be assessed. METHODS: Among the 439 lymphoma patients transplanted at our institution from January 1, 1993, to January 1, 2002, 158 exhibited aggressive NHL. The median age of the patients was 46 years (range, 18-69), 98 males and 60 females. Ninety (57%) patients received first-line ASCT. The median number of prior chemotherapy regimens was 2 (range, 1-10). Thirty-eight (24%) patients received total body irradiation conditioning. Here we report the adverse events which occurred at least 30 days after ASCT and before disease recurrence. RESULTS: After a median follow-up of 3 years, the overall and disease-free survival rates were 61% and 55%, respectively. Sixty-eight late adverse events affected 43 (27%) patients, leading to a cumulative incidence of 34% at 3 years. Infections were the most frequent adverse events (n = 13), followed by neurologic (n = 12), pulmonary (n = 6), or cardiovascular (n = 4). Eight malignancies were diagnosed (six solid, two hematologic), leading to a cumulative incidence of 3.7% at 3 years. Taking into account the competing risks, multivariate analysis revealed that the number of progressions (relative risk [RR] = 2.68) and a mitoxantrone-containing conditioning regimen (RR = 2.98) significantly increased the incidence of late toxicity. CONCLUSION: ASCT is effective in patients with aggressive NHL with a poor prognosis. However, careful long-term follow-up of survivors is recommended because of the increase in malignant and nonmalignant toxicities.

Adolescent↗

PubMed2005

Invasive Saccharomyces infection: a comprehensive review.

BACKGROUND: Saccharomyces cerevisiae (also known as "baker's yeast" or "brewer's yeast") is mostly considered to be an occasional digestive commensal. However, since the 1990s, there have been a growing number of reports about its implication as an etiologic agent of invasive infection. A particular feature of such infections is their association with a probiotic preparation of Saccharomyces boulardii (a subtype of S. cerevisiae) for treatment various diarrheal disorders. METHODS: We collected published case reports, through May 2005, of invasive Saccharomyces infection by use of a Medline query. Epidemiological and clinical charts and therapeutic strategies were analyzed. RESULTS: We found 92 cases of Saccharomyces invasive infection. Predisposing factors were similar to those of invasive candidiasis, with intravascular catheter and antibiotic therapy being the most frequent. Blood was the most frequent site of isolation (for 72 patients). S. boulardii accounted for 51.3% of fungemias and was exclusively isolated from blood. Compared with patients infected with S. cerevisiae, patients infected with S. boulardii were more frequently immunocompetent and had a better prognosis. Saccharomyces invasive infection was clinically indistinguishable from an invasive candidiasis. Overall, S. cerevisiae clinical isolates exhibited low susceptibility to amphotericin B and azole derivatives. However, global outcome was favorable in 62% of the cases. Treatment with intravenous amphotericin B and fluconazole, in combination with central vascular catheter removal, were effective therapeutic options. CONCLUSION: Saccharomyces organisms should now be added to the growing list of emerging fungal pathogens. Special caution should be taken regarding the use of S. boulardii probiotic preparations.

Female↗

PubMed2005

Proteomic changes associated with inactivation of the Candida glabrata ACE2 virulence-moderating gene.

Inactivation of the gene encoding the transcriptional activator Ace2 in the fungal pathogen Candida glabrata results in an almost 200-fold increase in virulence characterised by acute mortality and a massive over-stimulation of the pro-inflammatory arm of the innate immune system. In this study we have adopted a proteomics approach to identify cellular functions regulated by C. glabrata Ace2 that might contribute to this increase in virulence. A two-dimensional polyacrylamide gel electrophoresis map of the C. glabrata proteome was constructed. We identified a total of 123 proteins, 61 of which displayed reproducible and statistically significant alterations in their levels following inactivation of ACE2. Of these, the levels of 32 proteins were elevated, and 29 were reduced in ace2 cells. These data show that Ace2 influences metabolism, protein synthesis, folding and targeting, and aspects of cell growth and polarisation. Some of these functions are likely to contribute to the effects of Ace2 upon the virulence of C. glabrata.

Candida glabrata↗

PubMed2005

Anal carcinomas in HIV-positive patients: high-dose chemoradiotherapy is feasible in the era of highly active antiretroviral therapy.

BACKGROUND: Anal carcinoma, a common disease in HIV-positive patients, is usually treated with chemoradiotherapy. Generally tolerance was poor before the availability of highly active antiretroviral therapies. We report our experience of treating anal carcinoma in the era of new antiviral drugs. PATIENTS AND METHODS: Between 1997 and 2001, nine men on highly active antiretroviral therapies with good immune status before chemoradiotherapy received concomitant chemoradiotherapy consisting of 5-fluorouracil and cisplatinum, and high-dose radiotherapy (60-70 Gy) for anal carcinoma. Six cancers were Stage I, two were Stage II, and one was Stage III. CD4+ cell counts were <200/ml for four patients, between 200/ml and 500/ml for four, and >500/ml for one. RESULTS: All patients received the planned dose of radiation (> or = 60 Gy). The chemotherapy dose was reduced 25 percent in six patients. Overall treatment time was 58 days. Grade 3 hematologic or skin toxicity occurred in four patients. No association was observed between high-grade toxicity and CD4+ cell count. None of the patients developed opportunistic infections during follow-up. Eight patients were disease-free after a median follow-up of 33 months. Among them, four had no or minor anal function impairment at the last follow-up visit. One patient with T4N2 disease relapsed locally one year after treatment and underwent salvage abdominoperineal excision. CONCLUSION: High-dose chemoradiotherapy for anal carcinomas is feasible with low toxicity in HIV-positive patients treated with highly active antiretroviral therapies. Local control is similar to that obtained for HIV-negative patients.

Adult↗

PubMed2005

Telomere length control and transcriptional regulation of subtelomeric adhesins in Candida glabrata.

The pathogenic yeast Candida glabrata is able to bind in vitro to human epithelial cells. This interaction depends on expression of the adhesin Epa1p. The genome contains a number of EPA1 paralogues which localize to the subtelomeric regions of the C. glabrata. We have identified three hyperadherent mutants of C. glabrata. The first has an insertion adjacent to EPA7, an EPA1-related adhesin. The others disrupt the SIR3 and RIF1 genes of C. glabrata. We show that SIR3 and RIF1 are required for subtelomeric silencing in C. glabrata and that RIF1 regulates telomere length in C. glabrata. We show that the hyperadherent phenotype of the sir3Delta and rif1Delta deletion strains depends primarily on derepression of two novel members of the EPA gene family -EPA6 and EPA7. The sir3Delta and rif1Delta mutants show increased colonization of the kidney in a murine model of disseminated infection and this hypercolonization depends, at least in part, on derepression of EPA6 and EPA7. The analysis here is the first evidence that multiple EPA genes encode adhesins and demonstrates that transcription of at least two of these adhesins is regulated by subtelomeric silencing.

Animals↗

PubMed2005

A role for PKCzeta in potentiation of the topoisomerase II activity and etoposide cytotoxicity by wortmannin.

Enhanced cytotoxicity of etoposide by wortmannin, an inhibitor of enzymes holding a phosphatidylinositol 3-kinase domain, was investigated in eight cell lines proficient or deficient for DNA double-strand break repair. Wortmannin stimulated the decatenating activity of topoisomerase II, promoted etoposide-induced accumulation of DNA double-strand breaks, shifted the specificity for cell killing by etoposide from the S to G1 phase of the cell cycle, and potentiated the cytotoxicity of etoposide through two mechanisms. (a) Sensitization to high, micromolar amounts of etoposide required integrity of the nonhomologous end-joining repair pathway. (b) Wortmannin dramatically increased the susceptibility to low, submicromolar amounts of etoposide in a large fraction of the cell population irrespective of the status of ATM, Ku86, and DNA-PKCS. It is shown that this process correlates depression of phosphatidylinositol 3-kinase-dependent phosphorylation of the atypical, zeta isoform of protein kinase C (PKCzeta). Stable expression of a dominant-negative, kinase-dead mutant of PKCzeta in a tumor cell line reproduced the hypersensitivity pattern induced by wortmannin. The results are consistent with up-regulation of the topoisomerase II activity in relation to inactivation of PKCzeta and indicate that PKCzeta may be a useful target to improve the efficiency of topoisomerase II poisons at low concentration.

Androstadienes↗

PubMed2005

Long term hematologic recovery after autologous stem cell transplantation in lymphoma patients: impact of the number of prefreeze and post-thaw CD34+ cells.

BACKGROUND: Autologous Stem Cell Transplantation (ASCT) with Peripheral Blood Stem Cells is widely used as consolidation in lymphoma patients. The rapidity and stability of cell engraftment correlate with the number of CD34+ cells in the autograft. However, whether CD34+ cells should be quantified before or after cryopreservation remains unclear. PATIENTS AND METHODS: Of 173 consecutive patients who underwent ASCT in our department from Nov 1, 1995 to Nov 1, 2000, 133 (78 %) were alive without relapse at one year. We report here the results for 106 patients whose hematologic data were available. RESULTS: At one year, the hemoglobin was normal in 47% of the patients, the leukocytes, in 77% and the platelets, in 60%. Only 33% had a normal blood count. We observed a significant correlation between prefreeze and post-thaw CD34+ cell numbers (r = 0.77). However, multivariate analysis using the Cox model with smoothing splines to assess the best cut-off point for these numbers demonstrated that the only independent predictive factor for a normal blood count after one year was a prefreeze number of CD34+ cells above 5.10(6)/kg. CONCLUSION: An optimal long-term hematologic recovery after ASCT required a number of prefreeze CD34+ cells of at least 5.10(6)/kg.

Adolescent↗

PubMed2005

[Targeted therapies and radiotherapy].

Targeted therapies are at this moment the subject of an intensive research program. Their action is, however, for most of them, cytostatic, and their combination with classical cytotoxic approaches, as radiotherapy, is logical. A lot of experimental data are now available, regarding interactions between radiations and EGF-receptor inhibitors, antiangiogenic therapies, farneysltransferase inhibitors and cell cycle inhibitors. These experimental results are reviewed, and possible mechanisms of interactions are discussed. Preliminary clinical results are reported and criticized. In conclusion, the combination of radiotherapy and targeted therapies seems a promising approach, particularly with the inhibitors of the EGFR pathway and anti-vascular treatments, and require the continuation and intensification of the clinical trials.

Angiogenesis Inhibitors↗

PubMed2004

Large-scale exploration of growth inhibition caused by overexpression of genomic fragments in Saccharomyces cerevisiae.

We have screened the genome of Saccharomyces cerevisiae for fragments that confer a growth-retardation phenotype when overexpressed in a multicopy plasmid with a tetracycline-regulatable (Tet-off) promoter. We selected 714 such fragments with a mean size of 700 base-pairs out of around 84,000 clones tested. These include 493 in-frame open reading frame fragments corresponding to 454 distinct genes (of which 91 are of unknown function), and 162 out-of-frame, antisense and intergenic genomic fragments, representing the largest collection of toxic inserts published so far in yeast.

Cloning, Molecular↗

PubMed2004

Genome evolution in yeasts.

Identifying the mechanisms of eukaryotic genome evolution by comparative genomics is often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. The hemiascomycete yeasts, with their compact genomes, similar lifestyle and distinct sexual and physiological properties, provide a unique opportunity to explore such mechanisms. We present here the complete, assembled genome sequences of four yeast species, selected to represent a broad evolutionary range within a single eukaryotic phylum, that after analysis proved to be molecularly as diverse as the entire phylum of chordates. A total of approximately 24,200 novel genes were identified, the translation products of which were classified together with Saccharomyces cerevisiae proteins into about 4,700 families, forming the basis for interspecific comparisons. Analysis of chromosome maps and genome redundancies reveal that the different yeast lineages have evolved through a marked interplay between several distinct molecular mechanisms, including tandem gene repeat formation, segmental duplication, a massive genome duplication and extensive gene loss.

Chromosomes, Fungal↗

PubMed2003

The complete mitochondrial genome sequence of the pathogenic yeast Candida (Torulopsis) glabrata.

We report here the complete sequence of the mitochondrial (mt) genome of the pathogenic yeast Candida glabrata. This 20 kb mt genome is the smallest among sequenced hemiascomycetous yeasts. Despite its compaction, the mt genome contains the genes encoding the apocytochrome b (COB), three subunits of ATP synthetase (ATP6, 8 and 9), three subunits of cytochrome oxidase (COX1, 2 and 3), the ribosomal protein VAR1, 23 tRNAs, small and large ribosomal RNAs and the RNA subunit of RNase P. Three group I introns each with an intronic open reading frame are present in the COX1 gene. This sequence is available under accession number AJ511533.

Adenosine Triphosphatases↗