Prevention of trauma-induced cochlear fibrosis using intracochlear application of anti-inflammatory and antiproliferative drugs.

Cochlear fibrosis is a common finding following cochlear implantation. Evidence suggests that cochlear fibrosis could be triggered by inflammation and epithelial-to-mesenchymal cell transition (EMT). In this study, we investigate the mechanisms of cochlear fibrosis and the risk/benefit ratio of local administration of the anti-inflammatory drug dexamethasone (DEX) and antimitotic drug aracytine (Ara-C). Cochlear fibrosis was evaluated in cochlear fibrosis models of rat cochlear slices in vitro and in KLH-induced immune labyrinthitis and platinum wire cochlear implantation-induced fibrosis in vivo. Cochleae were invaded with tissue containing fibroblastic cells expressing α-SMA (alpha smooth muscle actin), which along with collagen I, fibronectin, and laminin in the extracellular matrix, suggests the involvement of a fibrotic process triggered by EMT in vitro and in vivo. After perilymphatic injection of an adenoviral vector expressing GFP in vivo, we demonstrated that the fibroblastic cells derived from the mesothelial cells of the scalae tympani and vestibuli. Activation of inflammatory and EMT pathways was further assessed by ELISA analysis of the expression of IL-1ß and TGF-ß1. Both markers were elevated in vitro and in vivo, and DEX and Ara-C were able to reduce IL-1ß and TGF-ß1 production. After 5days of culture in vitro, quantification of calcein-positive cells revealed that Ara-C was 30-fold more efficient in preventing fibrosis, and provoked less sensory hair cell loss, than DEX. In KLH-induced immune labyrinthitis and platinum wire-implanted models, Ara-C was more efficient in preventing proliferation of fibrosis with less side effects on hair cells and neurons than DEX. In conclusion, DEX and Ara-C both prevent fibrosis in the cochlea. Analysis of the risk/benefit ratio favors the use of Ara-C for preventing cochlear fibrosis.

Predictors of infarct artery patency after prehospital thrombolysis: the multicentre, prospective, observational OPTIMAL study.

OBJECTIVE: To identify predictors of early TIMI 3 flow patency of the infarct-related artery after prehospital thrombolysis in patients with ST-segment elevation myocardial infarction (STEMI) using data from a "real-world" population, and to develop a nomogram for triaging patients to emergency angiography. DESIGN: Multicentre, observational, prospective, cohort study. SETTING: 79 Hospitals in France with a prehospital mobile intensive care unit and a coronary care unit with 24 h access to coronary angiography. PATIENTS: 997 Patients with STEMI. INTERVENTIONS: All patients received prehospital thrombolysis within 6 h of symptom onset and angiography was performed within 6 h of thrombolysis. MAIN OUTCOME MEASURES: Coronary patency (TIMI flow). RESULTS: The median age of the population was 59 years and the sample comprised 18% women. After multivariable logistic regression analysis, predictors of TIMI 3 flow in the infarct-related artery were current/previous smoking (odds ratio (OR) = 1.60, 95% confidence interval 1.15 to 2.22), < or =5 leads with ST-segment elevation before thrombolysis (OR = 1.59, 1.12 to 2.25), Killip class I (OR = 1.96, 1.05 to 3.67), chest pain relief (OR = 1.62, 1.17 to 2.25) and ST-segment resolution > or =70% (OR = 1.76, 1.29 to 2.38). A nomogram was developed to assess the probability of TIMI 3 flow, according to smoking status, number of leads with ST elevation before thrombolysis, Killip class, chest pain relief and ST-segment resolution. CONCLUSIONS: This study provides quantitative data for predicting success of prehospital thrombolysis. The nomogram is a simple tool for predicting likelihood of coronary patency, based on clinical and electrocardiographic data. It may help to identify patients who require emergency angiography and rescue percutaneous coronary intervention.

Long-term clinical outcome after percutaneous coronary interventions in the elderly: results for 512 consecutive patients.

AIMS: Elderly patients are increasingly being referred for percutaneous coronary intervention (PCI), but there is a paucity of current data on the long-term outcome of elective PCI in elderly patients. We sought to define the risks facing elderly patients undergoing contemporary PCIs. METHODS AND RESULTS: Retrospectively, in a single-centre registry, we studied the mortality and the outcome of 512 consecutive patients > 75 years old who underwent PCI, between January 1st 2000 and December 31st 2001. Clinical endpoints included in-hospital mortality; major adverse cardiovascular and cerebro-vascular events (MACCE) defined by the components of death, myocardial infarction, stroke, and repeat coronary revascularisation (target vessel revascularisation or not) by surgery or PCI, within the hospitalisation period and at long-term follow up. We compared 315 patients 75-79 years old (group I) with 197 patients > 80 years old (group II). In-hospital mortality and MACCE rates were not different between the two groups. Independent predictors of in-hospital major events found by multivariate analysis were: ST-segment elevation myocardial infarction or STEMI (Odds Ratio [OR]=2.58, 95% CI=1.15-5.78), left ventricular ejection fraction or LVEF <40% (OR=4.98, 95% CI=2.19-11.36) and prior coronary artery bypass grafting or CABG (OR=3.13, 95% CI=1.06-9.26). Mean long-term follow-up was 51.3 months. Death was significantly more frequent in the older group (42% vs 26%, p<0.0001). Independent predictors of long-term mortality found by multivariate analysis were: LVEF < 40% (Hazard Ratio=4.12, 95% CI=2.69-6.32), creatinine rate (HR=1.00, 95% CI=1.00-1.006) use cut-off see table and prior carotid surgery or stroke (HR=2.2, 95% CI=1.19-4.14). CONCLUSIONS: Although age is not an independent predictive factor of morbidity or mortality, co-morbidities in the elderly strongly influence long-term clinical outcomes after PCI.

Coxsackie adenovirus receptor and alpha nu beta3/alpha nu beta5 integrins in adenovirus gene transfer of rat cochlea.

This study was designed to determine whether Coxsackie adenovirus receptor (CAR) and alpha nu beta3/alpha nu beta5 integrin co-receptors are involved in adenovirus gene transfer in the rat cochlea. We find that CAR and integrin co-receptors are expressed in every cell subtype transduced by the adenoviral vector Ad5 DeltaE1-E3/cytomegalovirus/green fluorescent protein (GFP) on cochlear slices in vitro. The spiral ganglion neurons, which do not express CAR, were not transduced by the virus. Blocking these receptors by monoclonal antibodies decreased transgene expression, whereas disrupting tight junctions with ethylenediaminetetraacetic acid led to an increased transgene expression. However, sensory hair cells and strial cells also expressing CAR and alpha nu integrins were not transduced by the vector. GFP expression was also studied in vivo. Perilymphatic perfusion of adenovirus in vivo did not affect hearing and only cells lining the perilymphatic spaces were transduced. Endolymphatic perfusion resulted in low-frequency hearing loss and although some cells of the organ of Corti were efficiently transduced, the sensory and the strial cells were not. Transduced sensory and strial cells were occasionally observed in cochleas after single shot of adenovirus. Pretreatment with anti-CAR and anti-alpha nu antibodies decreases GFP expression in vivo, suggesting that the CAR/alpha nu integrin pathway is involved in adenovirus transduction in the cochlea.

[Percutaneous embolisation of a iatrogenic fistula between the internal mammary artery and the coronary vein]. / Embolisation percutanée d'une fistule iatrogène entre l'artère mammaire interne et la veine coronaire. Revue de la littérature à propos d'une observation.

Latrogenic fistula between the aorta and coronary vein is a rare complication of coronary bypass surgery due to accidental venous or arterial graft onto a coronary vein. The authors report a case of a patient admitted to hospital 2 months after coronary bypass surgery for cardiac failure due to a iatrogenic fistula by implantation of the left internal mammary artery on the great coronary vein. This presentation led to the choice of percutaneous embolisation of the fistula by the release of 6 coils. Based on a review of the literature, this clinical case illustrates the feasibility and value of percutaneous embolisation of iatrogenic fistulae.

[Coronary-bronchial artery fistula and two-vessel coronary disease treated by embolisation of the anastomosis and coronary angioplasty]. / Fistule coronaro-bronchique et lesions coronaires bitronculaires, traitées par embolisation de l'anastomose puis par angioplastie coronaire.

Coronary-bronchial artery fistulae are rare and may present with broncho-pulmonary haemorrhage and myocardial ischaemia. The authors report the case of a coronary-bronchial artery fistula associated with bronchiectasis responsible for haemoptysis and discovered at coronary angiography performed during an acute coronary syndrome. Radical treatment by embolisation of this fistula allowed the use of platelet inhibitors and anticoagulants for the coronary angioplasty performed secondarily. This method is an interesting alternative to surgical ligature.

[Prognosis scores to help revascularization for ischemic heart failure]. / Scores pronostiques pour la revascularisation des myocardiopathies ischémiques.

AIMS: Patients suffering from coronary heart disease with ventricular systolic dysfunction present a bad prognosis and should be potentially revascularized. Up to now, surgery appeared to be the most feasible revascularization technique for such patients. Aims of this study were to assess the influence of different treatments (surgery, angioplasty or exclusively medical treatment) on clinical outcome and to establish a prognostic score practitioners to select the most appropriate therapy adapted to their patient profiles. METHOD: From 1995 to 2000, 492 patients were included in this cohort: 365 in the angioplasty group, 96 in the surgical group and 31 in the medical group. Kaplan Meier curves were made with a multivariate analysis to determine the significant predictive factors of mortality and major adverse cardiac events. RESULTS: After a mean follow-up of 32 +/- 19 months, there was no statistical difference in mortality rate between the groups. However, the survival rate without MACE is higher in the surgical group, intermediate in the angioplasty group and lower in the medical group. Using the significant predictive factors of MACE in multivariate analysis, a prognostic score has been established in order to discriminate three categories of severity. For each category, angioplasty was compared with surgery in terms of the event-free-survival rate. For the two extreme categories (severe and non-severe), both treatments were equal. For the intermediate category, surgery obtained greater results. CONCLUSION: This prognostic score could help physicians in choosing the appropriate revascularization technique to treat patients with severe ischemic heart failure.

Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up.

Herpes simplex virus (HSV) infections are very common in the general population and among immunocompromised patients. Acyclovir (ACV) is an effective treatment which is widely used. We deemed it essential to conduct a wide and coordinated survey of the emergence of ACV-resistant HSV strains. We have formed a network of 15 virology laboratories which have isolated and identified, between May 1999 and April 2002, HSV type 1 (HSV-1) and HSV-2 strains among hospitalized subjects. The sensitivity of each isolate to ACV was evaluated by a colorimetric test (C. Danve, F. Morfin, D. Thouvenot, and M. Aymard, J. Virol. Methods 105:207-217, 2002). During this study, 3900 isolated strains among 3357 patients were collected; 55% of the patients were immunocompetent. Only six immunocompetent patients excreted ACV-resistant HSV strains (0.32%), including one female patient not treated with ACV who was infected primary by an ACV-resistant strain. Among the 54 immunocompromised patients from whom ACV-resistant HSV strains were isolated (3.5%), the bone marrow transplantation patients showed the highest prevalence of resistance (10.9%), whereas among patients infected by human immunodeficiency virus, the prevalence was 4.2%. In 38% of the cases, the patients who excreted the ACV-resistant strains were treated with foscarnet (PFA), and 61% of them developed resistance to PFA. The collection of a large number of isolates enabled an evaluation of the prevalence of resistance of HSV strains to antiviral drugs to be made. This prevalence has remained stable over the last 10 years, as much among immunocompetent patients as among immunocompromised patients.

A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss.

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Local application of sodium thiosulfate prevents cisplatin-induced hearing loss in the guinea pig.

Cisplatin (CDDP), an anticancer drug used extensively to treat a broad range of neoplasms, has strong ototoxic side effects. Sodium thiosulfate (STS) has been described as a protective agent against CDDP toxicity, but it also reduces CDDP's antitumoral cytotoxicity. To maintain the antitumoral effectiveness of systemic administration of CDDP, a strategy has been developed to apply STS directly into the cochlea. Perfusion of STS into the cochleae of guinea pigs completely prevented CDDP-induced hearing loss, with no change in either compound action potential (CAP) or distortion product otoacoustic emission (DPOAE) audiograms during the time course of the treatment. Histological analysis revealed a minimal loss of outer hair cells (OHCs) in the organ of Corti and no damage to the marginal cells of the stria vascularis as seen in animals exposed to CDDP. Cytocochleograms prepared 6 days after CDDP exposure showed that STS treatment protected more than 92.8% of OHCs and IHCs destined to die. Furthermore, it prevented CDDP-induced mitochondrial damage and subsequent translocation of cytochrome c, DNA fragmentation, and suppressed the apoptotic and necrotic hair cell degeneration. These results suggest that local application of STS may be an interesting strategy to prevent CDDP ototoxicity in patients undergoing CDDP chemotherapy.

[The best of 2001. Coronary angioplasty or post-interventional cardiology]. / L'essentiel de 2001 en angioplastie coronaire. Ou la cardiologie post-interventionnelle.

RAVEL, a major advance, represents the cardinal event of the year, if not the last ten years. For the first time zero-rate restenosis has been obtained by the placing of a stent coated with a drug with cytostatic properties. This trial puts the first steps of focal chemotherapy delivered by an endoprosthesis into a clinical form. This spectacular result begs to be confirmed in the long term, as well as in the numerous angiographic forms of stenosis currently indicating the placing of a stent. Such a result in the preventive treatment of restenosis of course casts a shadow on the curative intrastent treatment of restenosis, and especially on intra-coronary radiation. In the areas of acute coronary syndromes, and more particularly of myocardial infarction, the trials of pharmacological interventions have multiplied, bringing scattered information which everyone will find of relevance, and which by the wide choice that they suggest, give the prescriber a real degree of freedom. CAPTIM reveals that the clinical results of pre-hospital lysis followed by angioplasty (usually pre-planned) are identical to those of a primary angioplasty. This is good news for the numerous patients who are victims of an MI far from a centre equipped with interventional facilities. These studies, which do not summarize all the latest interventional work, testify to the evolution of the discipline which, currently controlling the area surrounding angiography of stenosis, is directed towards the focal and systemic pharmacological approach to the lesion.

Determination of HCV genotype using two antibody assays and genome typing.

Two serotyping assays for hepatitis C virus (Serotyping 1-6 assay; Murex, UK and RIBA Serotyping SI; Chiron, USA) were compared to a standardized genotyping assay (Inno-LiPA HCV II; Innogenetics, Belgium) using serum samples collected from 126 patients chronically infected with hepatitis C virus. Serotyping was positive in 87% and 80% of the samples tested with Murex and Chiron, respectively, and concordant with genotyping in 93% and 88%, respectively. Sequence analysis of the NS5b region of 15 samples with discrepant typing results confirmed the Inno-LiPA finding in all instances. The Murex enzyme immunoassay serotyping method was less sensitive for identifying genotype 2 (P<0.05). The concordance with genotyping of the RIBA serotyping method was lower for genotype 2 than for the other genotypes (P<0.05).

Comparison of direct coronary stenting with and without balloon predilatation in patients with stable angina pectoris. BET (Benefit Evaluation of Direct Coronary Stenting) Study Group.

The purpose of this study was to compare the effects of stent placement with and without balloon predilatation on duration of the procedure, reduction of procedure-related costs, and clinical outcomes. Although preliminary trials of direct coronary stenting have demonstrated promising results, the lack of randomized studies with long-term follow-up has limited the critical evaluation of the role of direct stenting in the treatment of obstructive coronary artery disease. Between January and September 1999, 338 patients were randomly assigned to either direct stent implantation (DS+; 173 patients) or standard stent implantation with balloon predilatation (DS-; 165 patients). Baseline clinical and angiographic characteristics were similar in the 2 groups. Procedural success was achieved in 98.3% of patients assigned to DS+ and 97.5% of patients assigned to DS- (p = NS), with a crossover rate of 13.9%. Compared with DS-, DS+ conferred a dramatic reduction in procedure-related cost ($956.4 +/- $352.2 vs $1,164.6 +/- $383.9, p <0.0001) and duration of the procedure (424.2 +/- 412.1 vs 634.5 +/- 390.1 seconds, p < 0.0001). At 6-month follow-up, the incidence of major adverse cardiac events including death, angina pectoris, myocardial infarction, congestive heart failure, repeat angioplasty, or coronary artery bypass graft surgery was 5.3% in DS+ and 11.4% in DS- (p = NS). Multivariate analysis demonstrated that major adverse cardiac events rates were related to stent length of 10 mm (relative risk [RR] 3.25, 95% confidence intervals [CI] 1.36 to 7.78; p = 0.008), stent diameter of 3 mm (RR 2.69, 95% CI 1.03 to 7.06; p = 0.043), and complex lesion type C (RR 2.83, 95% CI 1.02 to 7.85; p = 0.045). Thus, in selected patients, this prospective randomized study shows the feasibility of DS+ with reduction in procedural cost and length, and without an increase in in-hospital clinical events and major adverse cardiac events at 6-month follow-up.

Genetic heterogeneity of hypervariable region 1 of the hepatitis C virus (HCV) genome and sensitivity of HCV to alpha interferon therapy.

Hepatitis C virus (HCV) populations persist in vivo as a mixture of heterogeneous viruses called quasispecies. The relationship between the genetic heterogeneity of these variants and their responses to antiviral treatment remains to be elucidated. We have studied 26 virus strains to determine the influence of hypervariable region 1 (HVR-1) of the HCV genome on the effectiveness of alpha interferon (IFN-alpha) therapy. Following PCR amplification, we cloned and sequenced HVR-1. Pretreatment serum samples from 13 individuals with chronic hepatitis C whose virus was subsequently eradicated by treatment were compared with samples from 13 nonresponders matched according to the major factors known to influence the response, i.e., sex, genotype, and pretreatment serum HCV RNA concentration. The degree of virus variation was assessed by analyzing 20 clones per sample and by calculating nucleotide sequence entropy (complexity) and genetic distances (diversity). Types of mutational changes were also determined by calculating nonsynonymous substitutions per nonsynonymous site (K(a)) and synonymous substitutions per synonymous site (K(s)). The paired-comparison analysis of the nucleotide sequence entropy and genetic distance showed no statistical differences between responders and nonresponders. By contrast, nonsynonymous substitutions were more frequent than synonymous substitutions (P

[Implantation of long coronary stents. Immediate and long-term results]. / Implantation de stents coronaires longs. Résultats immédiats et à long terme.

There have been few clinical reports of the long term results of implantation of long coronary stents. The authors performed a retrospective study of the long term results of 213 implantations of long stents (20 mm long) in 202 patients. These results were compared with those obtained in patients implanted with short stents (< 20 mm long) during the same period (630 implantations in 530 patients). The angiographic and clinical success rates were respectively 96.5 and 95.4% in the "long stent" group compared with 97.2 and 94.9% in the "short stent" group. In the "long stent" group, at 6, 12 and 24 months (follow-up, the cumulative incidence of nex revascularisation procedures of the target lesion were 9.8, 14.3 and 20.6% respectively, whereas the cumulative incidences of major cardiac events (mortality, infarction, angina, coronary bypass surgery and angioplasty) for the same periods were 12.7, 21.1 and 40% respectively. There was no significant differences compared with the "short stent" group concerning all these events. However, after 6 months, there was a tendency for more major cardiac events and for more new revascularisation procedures of the target lesion in the "long stent" group. In multivariate analysis, the independent predictive factors for major cardiac events were: a Jeopardy score > 6 (p = 0.002), and the complex nature of the lesion (B2 or C) (p = 0.045), whereas the indépendant risk factors for a new revascularisation procedure of the target lesion were: minimal luminal diameter after the procedure, a Jeopardy score > 6, complex lesions, diabetes and the reference diameter of the stented arterial segment. The authors conclude that although the length of the stent as such is not a long term predictive factor, the complexity of the lesion and the severity of the coronary disease which are more common in the "long stent" group explain the non-significant tendency for a higher incidence of major cardiac events in this group.

Molecular evidence for nosocomial transmission of hepatitis C virus in a French hemodialysis unit.

A systematic virological follow-up of hemodialysis patients identified 11 cases of de novo hepatitis C virus (HCV) infection in the same unit that were not due to blood transfusion. There were three groups of infection, each occurring within a period of 3 months: four infections with genotype 1b, two infections with genotype 1b, and five infections, four with genotype 1a and one with genotype 5a. The possibility of patient-to-patient transmission was addressed by sequencing the first hypervariable region of the HCV genome in sera taken shortly after infection. Phylogenetic analysis indicated clustering of most of the cases of de novo infections. Sequence homologies identified potential contaminators among already infected patients. All patients who were infected with closely related HCV isolates were found to have been treated in the same area and during the same shift or on the previous one. These infections could have been due to occasional breaches of the usual hygiene measures. Strict adhesion to hygiene standards and routines, continuously supervised, remains the key rule in the management of dialysis patients. Nevertheless, the isolation of patients with HCV could reduce the risk of infection because occasional lapses of preventive hygiene measures or unpredictable accidents can always take place in a hemodialysis unit. This policy needs to be evaluated by large-scale prospective studies.

Intermittent selection pressure with zidovudine plus zalcitabine treatment reduces the emergence in vivo of zidovudine resistance HIV mutations.

The development of mutations conferring drug resistance was investigated in 49 antiretroviral-naive asymptomatic HIV-1 subjects with CD4+ cell counts of 250-500/mm3 given intermittent (6-week courses, 6 weeks apart) or continuous treatment with zidovudine (AZT) plus zalcitabine (ddC) over 54 weeks. The concentration of human immunodeficiency virus type 1 RNA in the plasma and the CD4 cell counts were measured every 6 weeks. The rate of decrease of HIV-1 RNA concentration in plasma after a 6-week course of AZT + ddC was similar for each treatment cycle (approximately 1-log reduction). The plasma HIV-1 RNA concentration returned to its initial level at each treatment interruption. The mean CD4 cell counts after 54 weeks in the two treatment groups were similar. Genotype analysis by sequencing the reverse transcriptase coding region from plasma viral RNA on treatment showed a lower frequency of AZT resistance mutations after 54 weeks in patients given intermittent treatment (18%) than in those treated continuously (79 %, P < 0.001). No mutations conferring ddC resistance or multidideoxynucleoside resistance were observed in either group. These findings may have clinical implications for long-term treatment strategies.

Cochlear effects of mesna application into the middle ear.

Mesna (sodium 2-mercapto-ethane sulphonate) belongs to a class of thiol compounds that produce mucolysis by disrupting the disulphide bonds of the mucus polypeptide chains. The registered indications of mesna include the treatment of pathologies of the respiratory tract and, in oncology, the prevention of toxic lesions of the urinary tract by antineoplastic agents. In the E.N.T. Clinic of the University of Parma, it has been found that mesna can be used to facilitate the dissection of the various tissue layers in any surgical procedure. One of these indications is surgical treatment of cholesteatoma, which is mainly composed by keratin, a protein rich is disulphide bonds that are easily disrupted by mesna. The aim of this study was to evaluate the toxicity of mesna application into the middle ear on the cochlear anatomy and physiology. Three groups of guinea pigs were used as subjects. Mesna solution (10 or 20%) was applied in one ear, while the opposite ear received a placebo (saline solution). Toxicity of mesna was assessed by means of transmission electron microscopy (TEM), scanning electron microscopy (SEM), and auditory brain-stem response (ABR). TEM and SEM did not show any toxic effect on cochlear morphology. There were no differences in ABR thresholds and wave III amplitude and latency between mesna-treated and control ears.

Better efficacy of a 12-month interferon alfa-2b retreatment in patients with chronic hepatitis C relapsing after a 6-month treatment: a multicenter, controlled, randomized trial. Le Groupe D'étude et De Traitement du Virus De L'hépatite C (Get.Vhc).

We studied the efficacy of three interferon alfa-2b (IFN-2b) regimens for the retreatment of patients with chronic hepatitis C (CHC) with prior complete response followed by relapse. Consecutive patients with CHC who had a complete biochemical response but relapse after a first course of 6 months of IFN with 3 million units (MU) given subcutaneously three times per week were enrolled in the study. Six to 24 months after the end of the first treatment, the patients were randomly assigned to receive IFN with either the same regimen (group 1), a regimen of 12 months with 3 MU (group 2), or a regimen of 6 months with 10 MU (group 3). Sustained biochemical response was defined as normal serum alanine transaminase (ALT) values during the follow-up and sustained virological response as a clearance of hepatitis C virus (HCV) RNA from the serum at the end of follow-up (6 months' posttreatment). Histological improvement was defined as a decrease of 1 point in Metavir score between the first liver biopsy and a biopsy performed at 6 months' postretreatment. Two hundred forty-seven patients were randomized: 75 to group 1, 91 to group 2, and 81 to group 3. In an intent-to-treat analysis, 12%, 36.3%, and 18.5% of patients had a sustained biochemical response after retreatment in groups 1, 2, and 3, respectively (P <.001); 13. 8%, 32.4%, and 17.2% of patients had a sustained virological response after retreatment in groups 1, 2, and 3, respectively (P <. 05). A low viral load and patients in group 2 were independently associated with a sustained biochemical response. A low Knodell score index before treatment, patients with a high level of ALT before retreatment, genotype 3, low viral load, and patients in group 2 were independently associated with sustained virological response. Younger age, a high level of ALT, a low level of gamma-glutamyl transferase before retreatment, low viral load, and patients in group 2 were independently associated with sustained biochemical and virological response. Among the 80 patients with repeated liver biopsies, 47.6% had improved histological activity scores; this improvement was associated with a sustained biochemical and virological response. In patients with CHC initially treated with 3 MU of IFN given subcutaneously three times per week over a 6-month period, and who subsequently developed a relapse after a biochemical response, retreatment with a regimen of 3 MU of IFN given three times per week for 12 months produced better biochemical and virological sustained response rates than regimens involving a higher dose or a shorter duration of retreatment. The biochemical and virological sustained response was associated with histological improvement.