Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Normal Parathyroid Glands Are Most Often Seen on Neck Ultrasound.

RATIONALE AND OBJECTIVES: The dogma is that normal parathyroid glands (PTGs) are not visible on ultrasound (US). Recently, several studies have shown that PTGs present these US features: ovoid structure, homogeneous and hyperechoic. The primary objective was to assess the detection rate, standard size and locations of normal PTGs in a population of patients consulting for thyroid US exam. The secondary objective was to determine if the presence of a goiter or a thyroiditis could modify the visualization of normal PTGs. METHOD: Single-center prospective study on 192 patients based on the typical US appearance previously described to identify one or more PTGs. RESULTS: One or more PTGs were visualized in 75% of patients (144/192). They were visualized preferentially at the lower pole of the thyroid gland and in the infra-thyroid region (66%). The mean (± SD) size of normal PTGs was 5.68 mm (± 1,42 mm)×4.05 mm (± 1,03 mm)×2,68 mm (± 0,61 mm) and mean volume was 33.3 mm3 (± 17.75 mm3). The presence of a goiter made the search for PTGs more difficult whereas the presence of thyroiditis facilitated it. CONCLUSION: The US detection rate of PTGs is high (75%). The identification of PTGs could be particularly useful in the preoperative assessment before total thyroidectomy or parathyroid surgery. It could reduce the risk of postoperative hypoparathyroidism and improve the accuracy of postoperative US surveillance of thyroid cancer. Better knowledge of the usual anatomical location of normal PTGs could also enable better detection of abnormal glands.

Clinico-pathological factors associated with radioiodine refractory differentiated thyroid carcinoma status.

PURPOSE: Risk factors for developing radioiodine refractory thyroid cancer (RAIR-TC) have rarely been analyzed. The purpose of the present study was to find clinical and pathological features associated with the occurrence of RAIR-disease in differentiated thyroid cancers (DTC) and to establish an effective predictive risk score. METHODS: All cases of RAIR-DTC treated in our center from 1990 to 2020 were retrospectively reviewed. Each case was matched randomly with at least four RAI-avid DTC control patients based on histological and clinical criteria. Conditional logistic regression was used to examine the association between RAIR-disease and variables with univariate and multivariate analyses. A risk score was then developed from the multivariate conditional logistic regression model to predict the risk of refractory disease occurrence. The optimal cut-off value for predicting the occurrence of RAIR-TC was assessed by receiver operating characteristic (ROC) curves and Youden's statistic. RESULTS: We analyzed 159 RAIR-TC cases for a total of 759 controls and found 7 independent risk factors for predicting RAIR-TC occurrence: age at diagnosis ≥ 55, vascular invasion, synchronous cervical, pulmonary and bone metastases at initial work-up, cervical and pulmonary recurrence during follow-up. The predictive score of RAIR-disease showed a high discrimination power with a cut-off value of 8.9 out of 10 providing 86% sensitivity and 92% specificity with an area under the curve (AUC) of 0.95. CONCLUSION: Predicting the occurrence of RAIR-disease in DTC patients may allow clinicians to focus on systemic redifferentiating strategies and/or local treatments for metastatic lesions rather than pursuing with ineffective RAI-therapies.

SFE-AFCE-SFMN 2022 consensus on the management of thyroid nodules: Synthesis and algorithms.

The SFE-AFCE-SFMN 2022 consensus deals with the management of thyroid nodules, a condition that is a frequent reason for consultation in endocrinology. In more than 90% of cases, patients are euthyroid with benign and non-progressive nodules that do not warrant specific treatment. The clinician's objective is to detect malignant thyroid nodules at risk of recurrence and death, toxic nodules responsible for hyperthyroidism or compressive nodules warranting treatment. The diagnosis and treatment of thyroid nodules requires close collaboration between endocrinologists, nuclear medicine physicians and surgeons but also involves other specialists. Therefore, this consensus statement was established jointly by 3 societies, the French Society of Endocrinology (SFE), the French Association of Endocrine Surgery (AFCE) and the French Society of Nuclear Medicine (SFMN); the various working groups included experts from other specialties (pathologists, radiologists, pediatricians, biologists, etc.). This specific text is a summary chapter taking up the recommendations from specific sections and presenting algorithms for the exploration and management of thyroid nodules.

Outcomes of active surveillance of EU-TIRADS 5 thyroid nodules.

OBJECTIVE: Active surveillance of cytologically proven microcarcinomas has been shown as a safe procedure. However, fine needle aspiration biopsy (FNAB) is not recommended by European Thyroid Association (ETA) and American Thyroid Association (ATA) guidelines for highly suspicious nodules ≤ 10 mm. The aim of the study was to assess the outcomes of active surveillance of EU-TIRADS 5 nodules ≤ 10 mm not initially submitted to FNAB. PATIENTS AND METHODS: 80 patients with at least one EU-TIRADS 5 nodule ≤ 10 mm and no suspicious lymph nodes, accepting active surveillance, were included. RESULTS: Mean baseline diameter and volume were 5.4 mm (±2.0) and 64.4 mm3 (±33.5), respectively. After a median follow-up of 36.1 months, a volumetric increase ≥ 50% occurred in 28 patients (35.0%) and a suspicious lymph node in 3 patients (3.8%). Twenty-four patients underwent an FNAB (30.0%) after at least a 1 year follow-up of which 45.8% were malignant, 8.3% benign, 33.3% undetermined and 8.3% nondiagnostic. Sixteen patients (20.0%) underwent conversion surgery after a median follow-up of 57.2 months, confirming the diagnosis of papillary carcinoma in 15/16 cases (not described in 1 histology report), all in remission at 6-12 months postoperative follow-up. CONCLUSION: Applying ETA and ATA guidelines to avoid FNA of EU-TIRADS 5 sub-centimeter nodules and proceeding to active surveillance of such nodules in selected patients is a safe procedure. Thus, US-FNAB could be postponed until the nodule shows signs of progression or a suspicious lymph node appears, with no added risk for the patient.

Impact of age on survival in radioiodine refractory differentiated thyroid cancer patients.

OBJECTIVE: The objectives of our study were to analyze the influence of age on the survival of patients with RAIR-DTC and to determine their prognostic factors according to age. METHODS: This single-center, retrospective study enrolled 155 patients diagnosed with RAIR-DTC. The primary end point was overall survival (OS) according to different cutoff (45, 55, 65, 75 years). Secondary endpoints were progression free survival (PFS) and prognostic factors in patients under and over 65 years. RESULTS: Median OS after RAIR diagnosis was 8.2 years (95% IC: 5.3-9.6). There was no difference according to age with a 65 (P = 0.47) and 55 years old cutoff (P = 0.28). Median OS improved significantly before 45 years old (P = 0.0043). After 75 years old, median OS significantly decreased (P = 0.0008). Median PFS was 2.1 years (95% CI: 0.8-3) in patients < 65 years old, and 1 year in patients ≥ 65 years old (95% CI: 0.8-1.55) with no statistical difference (P = 0.22). There was no impact of age on PFS with any cutoff. In both groups, progressive disease despite 131I treatment reduced OS. In patients < 65 years old, an interval of less than 3 years between the initial diagnosis and the diagnosis of RAIR metastatic disease was predictive of poor survival. In patients > 65 years old, the presence of a mediastinum metastasis was a significant factor for mortality (HR: 4.55, 95% CI: 2.27-9.09). CONCLUSION: In RAIR-DTC patients, a cut-off age of 65 years old was not a significant predictive factor of survival. Forty-five and 75-years-old cutoff were predictive for OS but not PFS.

TIRADS score is of limited clinical value for risk stratification of indeterminate cytological results.

CONTEXT: Thyroid nodules with cytological indeterminate results represent a daily and recurrent issue for patient management. OBJECTIVE: The primary aim of our study was to determine if TIRADS (Thyroid Imaging Reporting and Data System) could be used to stratify the malignancy risk of these nodules and to help in their clinical management. Secondary objective was to estimate if this risk stratification would change after reclassification of encapsulated non-invasive follicular variant of papillary carcinomas (FVPTC) as non-invasive follicular thyroid neoplasm (NIFTP). PATIENTS AND METHODS: Single-center retrospective study of a cohort of 602 patients who were referred for ultrasound-guided fine-needle aspiration from January 2010 to December 2016 with an indeterminate cytological result and in whom histological results after surgery were available. TIRADS score was prospectively determined for all patients included. Nodules that had been classified as FVPTC were submitted to a rereading of histological report and reclassified as NIFTP when judged relevant. A table of malignancy risk crossing Bethesda and TIRADS results was built before and after this reclassification. RESULTS: The study included 602 cytologically indeterminate nodules. TIRADS score was positively correlated with the malignancy rate (P < 0.0001). Risk stratification with TIRADS was significant only in Bethesda V nodules (P = 0.0004). However, the risk of malignancy in this Bethesda V category was always above 45%, whatever the TIRADS score. CONCLUSION: For a clinician facing an indeterminate cytological result for a thyroid nodule, return to TIRADS score is of limited value in most conditions to rule in or rule out malignancy and to guide subsequent management of patients.

Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.

Indications for radioiodine administration in follicular-derived thyroid cancer.

Indications for radioiodine administration after thyroid cancer surgery have shifted in recent years toward personalized management, adapted to the individual risk of tumor progression. The most recent guidelines and studies favor de-escalation in indications for administration, dosage and means of preparation with exogenous recombinant TSH stimulation as treatment of choice. Radioiodine administration has 3 possible objectives: • ablation of normal thyroid tissue remnants in patients with low risk of progression, using low radioiodine activity levels, with the advantage of completing disease staging on whole-body scintigraphy performed after administration of the radioiodine capsule, and of facilitating follow-up by thyroglobulin assay; • adjuvant treatment for suspected microscopic metastases in patients with intermediate or high risk of progression, using higher activity levels, with the theoretic aim of limiting recurrence and mortality; • curative treatment in high-risk patients with proven metastases, using exclusively high activity levels, with a view to improving specific survival. In future, indications for ablation and/or activity prescription may be governed by an algorithm incorporating individual baseline progression risk (essentially founded of pTNM staging) and postoperative data such as thyroglobulin level and neck ultrasound results.

Molecular perspectives in differentiated thyroid cancer.

Progress in understanding the molecular genetics of thyroid cancer in the last 20 years has accelerated recently with the advent of high-throughput sequencing technologies known as Next-Generation Sequencing. Besides classical molecular abnormalities involving the MAPK (Mitogen Activated Protein Kinase) and PI3K (PhosphoInositide 3-Kinase) pathways that play a key role in follicular-derived thyroid tumorigenesis, new molecular abnormalities have been discovered. The major advances in recent years have been the discovery of new somatic driver gene point mutations (such as RASAL1 [RAS protein activator Like 1] mutations in follicular cancer) and/or mutations that have prognostic value (such as TERT [Telomerase reverse transcriptase] promoter mutations); new chromosomal rearrangements, usually having close connection with exposure to ionizing radiation (such as ALK [Anaplastic Lymphoma Kinase] rearrangements); and deregulation of some gene or microRNA expression representing a molecular signature. Progress made in understanding the molecular mechanisms of thyroid cancer offers new perspectives for the diagnosis of the benign or malignant status of a thyroid nodule, to refine prognosis and offer new perspectives of targeted therapy for radioiodine-refractory cancers.

Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial--ANRS HB02 VAC-ADN.

OBJECTIVE: The antiviral efficacy of nucleos(t)ide analogues whose main limitation is relapse after discontinuation requires long-term therapy. To overcome the risk of relapse and virological breakthrough during long-term therapy, we performed a phase I/II, open, prospective, multicentre trial using a HBV envelope-expressing DNA vaccine. DESIGN: 70 patients treated effectively with nucleos(t)ide analogues for a median of 3 years (HBV DNA <12 IU/mL for at least 12 months) were randomised into two groups: one received five intramuscular injections of vaccine (weeks 0, 8, 16, 40 and 44) and one did not receive the vaccine. Analogues were stopped after an additional 48 weeks of treatment in patients who maintained HBV DNA <12 IU/mL with no clinical progression and monthly HBV DNA for 6 months. The primary endpoint was defined as viral reactivation at week 72 (HBV DNA >120 IU/mL) or impossibility of stopping treatment at week 48. RESULTS: Reactivation occurred in 97% of each group after a median 28 days without liver failure but with an HBV DNA <2000 IU/mL in 33%; 99% of adverse reactions were mild to moderate. Immune responses were evaluated by enzyme-linked immunosorbent spot and proliferation assays: there was no difference in the percentage of patients with interferon-γ secreting cells and a specific T-cell proliferation to HBcAg but not to HBsAg after reactivation in each group. CONCLUSIONS: Although it is fairly well tolerated, the HBV DNA vaccine does not decrease the risk of relapse in HBV-treated patients or the rate of virological breakthrough, and does not restore the anti-HBV immune response despite effective viral suppression by analogues. TRIAL REGISTRATION NUMBER: NCT00536627.

[Hereditary hemochromatosis: presenting manifestations and diagnostic delay]. / Hémochromatose héréditaire: circonstances de découverte et délais diagnostiques.

PURPOSE: Hereditary hemochromatosis is characterized by an excessive absorption and progressive accumulation of iron in the liver, the pancreas, the heart, and the joints. Tiredness and joint manifestations occur usually before hepatopathy, diabetes or cardiopathy. Such common and unspecific symptoms seem to be largely unknown and important diagnostic delays have been reported. The aim of this study was to investigate the discovery circumstances and the diagnostic delay. METHODS: A survey was carried out amongst French patients with C282Y homozygous hemochromatosis who were contacted through patients associations or blood centers. RESULTS: The questionnaire was answered by 374 patients. Mean age at diagnosis was 48.6±11.9years. In 53% of the cases, the serum level of ferritin was greater than 1000 µg/L. Diagnosis was based on family genetic survey (29%), or fortuitous analyses showing an abnormal serum ferritin (26%), or clinical manifestations (45%). Main complaints were joint pain, tiredness or liver disease. Only 2.1% consulted for diabetes, cardiopathy or changed complexion. Time to diagnosis was lower than 1 year for 98% of patients who presented with fatigue but from 1 to 15 years for 23.4% and 29% of patients who presented with arthropathy and hepatopathy, respectively. CONCLUSION: For 55% of patients, diagnosis was based on familial genetic survey or fortuitous abnormal results of blood samples. An initial serum level of ferritin greater than 1000 µg/L was a factor of severity for 50% of patient. These two elements must be taken into account to consider a population mass screening. Long time to diagnosis required a sensitization of the population to be aware of the clinical manifestations of hemochromatosis.

[Oncological patients' decision making processes concerning their pain medication at home: a qualitative secondary analysis]. / Entscheidungswege von onkologischen Patienten im Umgang mit Schmerzmedikamenten im häuslichen Umfeld: eine qualitative Sekundäranalyse.

Unrelieved pain affects up to 75 % of cancer patients. Possible reasons for the undertreatment of pain are, amongst others, patient-related barriers towards cancer pain management. However the way patients decide on the use of analgesics remains unclear. The purpose of this qualitative study was to explore decision-making processes of four women and four men with diverse cancers concerning their pain medications. Audiotaped protocols of the 10-week-intervention and interviews of the PEINCA-pilot study provided data for a secondary analysis. This pilot study was conducted at a comprehensive cancer centre in Germany to test the German version of a cancer pain self-management intervention to enhance oncology patients' pain self-management for the first time. The data of purposively selected patients were analysed using content analysis. The results showed that these patients were very ambivalent about their analgesic use. The need to relieve severe pain conflicted with the desire to avoid opioids at any price. Decisions were reconsidered and overturned even after good experiences with analgesics. This study seems to provide a first look into decision-making processes over 10 weeks during a self-management education. Individually tailored counselling by a professional within the education programme helped the patients adopt new attitudes towards analgesics and gradually reduce their pain levels. Previous experiences of the patients and their possible ambivalence towards analgesics should be considered in a pain therapy, and patients should be coached by professionals.

VEGF in the muscular layer of placental blood vessels: immuno-expression in preeclampsia and intrauterine growth restriction and its association with the antioxidant status.

The pathophysiology of preeclampsia (PE), a disorder occurring in 5% of all pregnancies, remains largely unknown, but early placental hypoxia and oxidative stress are known to be involved in the mechanism of the syndrome. Maternal plasma and placental tissue samples were collected from PE, intrauterine growth restriction (IUGR), and normotensive pregnant patients. The immunohistochemical expression of vascular endothelial growth factor (VEGF), malondialdehyde (MDA) production and the activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase GSH-Px) were determined in the placental tissue. F2-isoprostane concentration and the ferric reducing ability of plasma (FRAP) were determined in maternal plasma. We found that the PE and IUGR groups showed a higher expression of VEGF in the muscular layer of fetal chorionic vessels. In addition, increased plasma F2 isoprostane levels and a significant reduction of FRAP in the plasma of PE women, as well as a lower activity of SOD in PE placentas and a higher activity of GSH-Px in IUGR placentas were found. Additionally, lower PlGF and higher sFlt1 levels were observed in the maternal plasma of PE and IUGR than control. We concluded that in a hypoxic environment, the placenta expresses VEGF in the muscular layer of fetal vessels. The development of PE could be related to the increased expression of VEGF, with decreased placental SOD activity and a decrease of both plasma F2-isoprostane and FRAP levels. In turn, the development of IUGR could be related to the association of decreased plasma FRAP levels and increased placental GSH-Px activity.

[Poorly differentiated large cell endocrine carcinoma of the extrahepatic bile ducts]. / Carcinome endocrine peu différencié à grandes cellules des voies biliaires extrahépatiques.

We report a case of a poorly differentiated endocrine large cell carcinoma of the extrahepatic bile ducts in a 73-year-old man, revealed by abdominal pain, jaundice and weight loss. Computed tomography and endoscopic retrograde cholangiography found tumoral stenosis of the main bile duct. Brush cytology detected tumor cells. Pathological examination of the resected bile duct disclosed a high-grade large cell carcinoma with morphological endocrine features and positivity for chromogranin A. This tumor was associated with a minor component of adenocarcinomatous cells. Despite polychemotherapy, the patient had widely metastatic disease a few months later. We discuss here the histogenesis of this tumor as well as its nosological position among the endocrine and mixed tumors of bile ducts.

Liver cell adenomas and portosystemic shunt.

We report the case of a young man who developed multiple liver cell adenomas 13 years after a mesentericocaval shunt. Radiological findings did not provide diagnosis. Histological findings of two biopsied nodules were compatible with liver cell adenoma. Our patient had no known risk factors for liver cell adenomas. We discuss the hypothesis that disturbed hepatic vascularisation could promote the development of liver cell adenomas.

Inflammatory pseudotumor of the common bile duct.

An exceptional cause of obstructive jaundice is reported in the present case. A 51-year-old woman progressively developed jaundice with pruritus, and abdominal ultrasonography revealed dilated intra- and extrahepatic bile ducts. Endoscopic retrograde cholangiography and endoscopic ultrasonography showed a tumor in the distal common bile duct, but failed to determine the nature of the lesion, and the patient underwent a pancreaticoduodenectomy. The final diagnosis was an inflammatory pseudotumor of the common bile duct. Inflammatory pseudotumors are uncommon, without evident pathogenesis, and are described in many organs. The localization in the common bile duct is exceptional. The prognosis is good, and a more conservative approach is possible if the diagnosis is certain before surgery.

Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: Liver cirrhosis may lead to hepatocellular carcinoma (HCC), regardless of its cause. Genetic and/or environmental factors may modulate the risk of HCC. Mutations in the HFE gene are responsible for genetic haemochromatosis, a condition known to be associated with liver cirrhosis, HCC, or both. It has recently been suggested that the C282Y HFE gene mutation may be more frequent in patients with HCC that have developed in the non-cirrhotic liver than in the general population. Whether or not HFE gene mutations are associated with an increased risk of HCC in patients with cirrhosis is unknown. AIM: To assess the prevalence of HFE gene mutations in cirrhotic patients with and without HCC. PATIENTS AND METHODS: A total of 133 consecutive cirrhotic patients with HCC were prospectively studied for the presence of C282Y and H63D mutations. The control group consisted of 100 cirrhotic patients without HCC. We used restriction enzyme digestion of polymerase chain reaction amplified genomic DNA for determination of HFE genotypes. Iron loading was assessed on non- tumoral liver biopsy samples from 89 patients with HCC and 73 patients without HCC. RESULTS: The prevalence of C282Y heterozygotes was similar in patients with and without HCC (5% v 4%, respectively; p=0.65) and did not differ from that expected in the general population. None of the HCC patients was found to be homozygous for C282Y or H63D, nor compound heterozygous. The prevalence of H63D heterozygotes was similar in patients with and without HCC (31% v 38%, respectively; p=0.25). No relation was detected between HFE genotypes and hepatic iron loading in patients with or without HCC. CONCLUSION: C282Y and H63D mutations do not appear to be associated with an increased risk of HCC in patients with cirrhosis.

Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponsive to interferon: a randomized trial.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.