Evaluation in usual practice of the bevacizumab-FOLFIRI combination for the first-line treatment of patients with unresectable metastatic colorectal cancer treated in 2006: focus on resected patients and oncogeriatrics: AVASTIN OUEST cohort of the Observatory of Cancer of the Brittany and Pays de la Loire Areas (Observatoire dédié au Cancer Bretagne / Pays de la Loire).

BACKGROUND: In 2006, bevacizumab, a targeted therapy agent was combined with FOLFIRI for the firstline treatment of patients with unresectable metastatic colorectal cancer. METHODS/RESULTS: A study on a homogenous series of 111 patients from the Brittany and Pays de la Loire areas who received bevacizumab-FOLFIRI as first-line treatment in 2006 showed the following results: 51 responses, 29 stabilisations, 21 progressions and 10 cases of toxicity prior to assessment. Median overall survival (OS) was 25.1 months and median progression-free survival was 10.2 months. Surgery secondary to treatment tripled median OS which reached 59.2 months in resected patients versus 18.8 months in unresected patients. Comparison of patients aged more or less than 70 years showed no differences in terms of benefits or risks. CONCLUSION: Bevacizumab-FOLFIRI could be administered as part of a routine care protocol to elderly patients previously evaluated by a geriatric assessment and validated by a multidisciplinary staff.

En 2006, bevacizumab-FOLFIRI représente la thérapie ciblée administrable dès la première ligne chez les patients porteurs d'un cancer colorectal métastatique non opérable. Une série homogène de 111 patients colligés en région Bretagne et Pays de la Loire ayant reçu du bevacizumab- FOLFIRI en première ligne en 2006 révèle les résultats suivants: 51 réponses, 29 stabilités, 21 progressions et 10 toxicités avant évaluation. La médiane de survie globale (OS) est de 25,1 mois et la médiane de survie sans progression (PFS) de 10,2 mois. Dans le cas d'une chirurgie secondaire, l'OS médian triple de 18,8 mois chez les patients non réséqués versus 59,2 mois ceux réséqués. En comparant les sujets âgés de plus et de moins de 70 ans, aucune différence n'a été mise en évidence en termes de bénéfice ou de risque. Bevacizumab-FOLFIRI pourrait être administré en pratique courante chez les personnes âgées sous couvert d'une évaluation gériatrique et d'une approche multidisciplinaire.

High prevalence of advanced fibrosis in association with the metabolic syndrome in a Belgian prospective cohort of NAFLD patients with elevated ALT. Results of the Belgian NAFLD registry.

INTRODUCTION: Non-alcoholic Fatty Liver Disease (NAFLD) is increasingly recognised as a source of liver related morbidity and mortality. Hard data on epidemiology and natural history are scarce. AIM: To study demographic and metabolic characteristics of the NAFLD patients seen by Belgian hepatologists. METHODS: Belgian hepatologists filled in a questionnaire for every newly diagnosed NAFLD patient between January 1st and December 31st 2004. Liver biopsy was advised if ALT > 1.5 x ULN and if 3/5 of the criteria for the metabolic syndrome (MS) (ATPI-II) were present, but was not mandatory. Biopsy was scored using the Brunt classification. RESULTS: 230 patients were prospectively included in 9 centres; 54% were males; mean age was 49.4 +/- 13.9 y; mean BMI was 30.6 +/- 4.6 kg/m2. The MS was present in 53%. In 16% formerly undiagnosed diabetes was discovered. 51% had a liver biopsy: 25% met the criteria, 26% did not. Grading did not differ between patients with or without MS. Staging was significantly more severe in patients with MS (2.43 +/- 1.25 vs. 1.73 +/- 1.18, p < 0.001). A subgroup of patients with GGT > 5 x ULN were significantly older (55.9 vs. 47.64 y, p = 0.02), more frequently diabetic (53% vs. 23%, p = 0.01) and had more advanced fibrosis (3.42 vs. 1.08, p = 0.008). ALT levels were variable. CONCLUSIONS: The MS is highly prevalent in Belgian NAFLD patients and is associated with more severe disease. Mild to moderate fibrosis is frequent, and the proposed criteria for liver biopsy are not accurate in selecting these patients. Patients with elevated GGT constitute a subgroup with more advanced disease.

Analysis of the blurring in stencil lithography.

A quantitative analysis of blurring and its dependence on the stencil-substrate gap and the deposition parameters in stencil lithography, a high resolution shadow mask technique, is presented. The blurring is manifested in two ways: first, the structure directly deposited on the substrate is larger than the stencil aperture due to geometrical factors, and second, a halo of material is formed surrounding the deposited structure, presumably due to surface diffusion. The blurring is studied as a function of the gap using dedicated stencils that allow a controlled variation of the gap. Our results show a linear relationship between the gap and the blurring of the directly deposited structure. In our configuration, with a material source of approximately 5 mm and a source-substrate distance of 1 m, we find that a gap size of approximately 10 microm enlarges the directly deposited structures by approximately 50 nm. The measured halo varies from 0.2 to 3 microm in width depending on the gap, the stencil aperture size and other deposition parameters. We also show that the blurring can be reduced by decreasing the nominal deposition thickness, the deposition rate and the substrate temperature.

Clinical trial: a randomized trial of pegylated-interferon-alpha-2a plus ribavirin with or without amantadine in treatment-naïve or relapsing chronic hepatitis C patients.

BACKGROUND: The combination therapy of pegylated-interferon-alpha2a plus ribavirin is considered as the standard of care for patients with chronic hepatitis C. A sustained viral response is obtained in 40-50% of naïve patients with genotype 1 and in around 80% of naïve patients with genotype 2 or 3. AIM: To assess whether amantadine, added to the conventional combination therapy, could improve the treatment efficacy. METHODS: In all, 630 patients (intent-to-treat population) with chronic hepatitis C were randomized into two groups: 316 patients (treatment group) received pegylated-interferon-alpha2a (180 microg once weekly) plus ribavirin (1000-1200 mg/daily) with amantadine (200 mg/daily); 314 patients (control group) received pegylated-interferon-alpha2a (180 microg once weekly) plus ribavirin (1000-1200 mg/daily) without amantadine. The duration of the treatment was 48 weeks for genotypes 1, 4, 5 and 6, and 24 weeks for genotypes 2 and 3. RESULTS: There was no statistically significant difference between treatments groups for any of the variables tested for. Subgroups of patients likely to take advantage of the addition of amantadine were not identified. CONCLUSIONS: This large study definitely excludes the role of amantadine in addition of conventional combination therapy in the treatment of chronic hepatitis C patients.

Long-term (7-year-) treatment with lamivudine monotherapy in HBV-associated glomerulonephritis.

Glomerulonephritis (GN) is an uncommon but well-described complication of chronic hepatitis B virus (HBV) infection. HBV-related membranous nephropathy (MN) may lead to renal failure in 1/3 of the patients and spontaneous remission is rare. There is no standard therapy for HBV-associated MN. We report a case of a 28-year-old man with HBV-associated MN due to pre-core HBV mutant with complete remission under an ongoing 7-year lamivudine monotherapy.

A pilot observational survey of hepatitis C in Belgium.

AIM OF THE STUDY: There is a lack of epidemiological data on hepatitis C (HCV) infected patients in Belgium. Therefore our purpose was to address this important question and to evaluate the feasibility of a national HCV observatory. PATIENTS AND METHODS: From November 2003 to November 2004, every new patient prospectively seen for HCV antibody positivity in 9 Belgian hospital centres was recorded and a standardised 10-items questionnaire was completed during the consultation, including a Quality of Live (QOL) visual analogue scale. RESULTS: Three hundred and eighteen consecutive patients were recruited. Fifty five percent were male with a median age of 45 y (11-87 y). The main risk factors for infection were IV drug use (27%), blood transfusion (23%), and invasive medical procedure (11%). On the QOL scale, ranging from 0 and 100, mean value was 61 +/- 31. Transaminases were abnormal in 66% with a median elevation 2 times above normal value. HCV RNA was positive in 87% with a viral load above 800 000 IU/ml in 42%. Genotype 1 was predominant (59%), followed by genotypes 3 (19%) and 4 (14%). A liver biopsy was performed in 190 patients, with minimal fibrosis (METAVIR F0-F1) in 43%, moderate fibrosis (F2) in 35% and advanced stages (F3-F4) in 22%. Antiviral treatment was not considered in 53% because of normal ALT (30%), old age (7%), minimal histological stage (6%) or patient refusal (4%). CONCLUSIONS: This study highlights the feasibility of a national HCV survey using a simple questionnaire. This pilot study could be generalised throughout Belgium, and, if repeated, could allow a regular assessment of the changes in epidemiology and management of HCV infection in our country.

[How to interpret a hyperferritinemia?]. / Comment interpréter une élévation de la ferritine sérique?

The presence of hyperferritinemia has to rule out acquired causes such as chronic inflammatory disorders, hemolytic anemia, liver diseases as hepatitis B or C, alcohol abuse and non alcoholic fatty liver disease, specially in patients with normal transferrine saturation. Genetic testing for hemochromatosis is systematically indicated in all patients with elevated transferrine saturation. When an iron overload is demonstrated in the absence of these classic causes, second-line genetic testing should be considered to exclude non HFE hemochromatosis. The aim of this paper is to propose a practical algorithm in the diagnosis of hyperferritinemia and to precise the diagnostic and therapeutic management of genetic hemochromatosis.

Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study.

To assess the efficacy of the combination of long-acting release (LAR) octreotide and tamoxifen (TMX) for the treatment of advanced hepatocellular carcinoma (HCC). A total of 109 patients with advanced HCC were randomised to receive octreotide LAR combined with TMX (n=56) (experimental treatment group) or TMX alone (n=53; control group). The clinical, biological and tumoural parameters were recorded every 3 months until death. Primary end point was patient survival; secondary end points were the impact of therapy on tumour response, quality of life and variceal bleeding episodes. Univariate and multivariate analyses were performed for assessment of specific prognostic factors. The median survival was 3 months (95% CI 1.4-4.6) for the experimental treatment group and 6 months (CI 95% 2-10) for the control group (P=0.609). There was no difference in terms of alpha-foetoprotein (alpha-FP) decrease, tumour regression, improvement of quality of life and prevention of variceal bleeding between the two groups. Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, alpha-FP level <400 ng ml(-1) and Okuda stage I. The combination of octreotide LAR and TMX does not influence survival, tumour progression or quality of life in patients with advanced HCC.

[Hepatitis C in women planning a pregnancy: current opinions]. / L'hépatite C chez la femme en âge de procréer. Etat de la question.

Chronic hepatitis C (VHC) is a worldwide public health issue. The mother-to-child transmission could be the main cause of hepatitis C infection in children. Despite the risk of histological injuries, chronic hepatitis C is not a contra-indication to pregnancy. In patients with VHC, there is no evidence that the outcome could be modified. In co-infected patients (VIH-VHC), a caesarean should be proposed taking into account the significant risk of mother-to-child transmission. Breast-feeding is not contra-indicated. Systematic screening of VHC, discussed in this article, could be proposed in woman planning a pregnancy.

Severe acute pancreatitis associated with peliosis hepatis in a patient with systemic lupus erythematosus.

Acute pancreatitis is an unusual complication of systemic lupus erythematosus but can also stem from immunosuppressive therapy. Although abnormal liver tests are commonly seen in SLE, peliosis hepatis is very rarely described. We report here the first case of SLE associating a severe acute pancreatitis with peliosis hepatis who responded well to the immunosuppressive therapy. As suggested by the favourable outcome in this case, the presence of peliosis hepatis in SLE cannot not be held as a strong argument against an aggressive immunosuppressive therapy.

Hemodynamic, metabolic and hormonal responses to oral glibenclamide in patients with cirrhosis receiving glucose.

BACKGROUND: In patients with cirrhosis, glucose may induce splanchnic and renal vasodilation. Since the antidiabetic sulfonylurea glibenclamide is known to induce splanchnic and renal vasoconstriction in portal hypertensive animals, this drug may inhibit glucose-induced hemodynamic responses in patients with cirrhosis. The aim of the present study was to investigate, in patients with cirrhosis, the short-term effects of glibenclamide on hemodynamic and humoral responses to glucose. METHODS: Patients were randomly assigned to receive either glibenclamide (5-mg tablet) or a placebo. All patients received an infusion of 10% glucose (62.5 ml/h for 12 h) that was started at the same time as glibenclamide or placebo administration. Studies were performed prior to and 90 min after glibenclamide or placebo. RESULTS: Glibenclamide (i.e. glibenclamide plus glucose) significantly increased plasma insulin concentrations and glycemia while placebo (i.e. glucose alone) significantly increased glycemia but did not change plasma insulin levels. Glibenclamide did not significantly change the hepatic venous pressure gradient while this value was significantly increased following glucose alone. Glibenclamide did not significantly change renal blood flow and glomerular filtration rate while glucose alone significantly increased renal blood flow without affecting the glomerular filtration rate. Glibenclamide significantly decreased cardiac index while glucose alone did not change this value. CONCLUSIONS: In patients with cirrhosis receiving glucose, glibenclamide blunted glucose-induced splanchnic and renal vasodilation. In addition, glibenclamide per se induced a decrease in cardiac index. These findings should be taken into account when glibenclamide is administered to patients with cirrhosis and type 2 diabetes.

Evidence based medicine and extradigestive manifestations of Helicobacter pylori.

A putative pathogenetic role has been ascribed to Helicobacter pylori in several extradigestive diseases, including vascular (atherosclerosis and ischaemic heart disease, primary Raynaud phenomenon, primary headache), autoimmune (Sjögren's syndrome, Henoch-Schönlein purpura, autoimmune thyroiditis, idiopathic arrythmias, Parkinson's disease, nonarterial anterior optic ischemic neuropathy), and skin diseases (chronic idiopathic urticaria, rosacea, alopecia areata), sideropenic anemia, growth retardation, late menarche, extragastric MALT lymphoma, diabetes mellitus, hepatic encephalopathy, sudden infant death syndrome, and anorexia of aging. We examine critically the strength of the evidence linking these diseases to Helicobacter pylori, using ischaemic heart disease as an example of epidemiological techniques, and skin diseases as an example of treatment studies. By the standards of evidence-based medicine, studies have been often of low quality. The best evidence usually is not indicative of a role for Helicobacter pylori in these diseases.

Elevated circulating cardiac troponin I in patients with cirrhosis.

It has been shown that certain patients with cirrhosis have asymptomatic cardiac abnormalities that have not yet been explained. Thus, cardiac troponin I, a specific marker of myocardial injury, has been measured in patients with cirrhosis without previous cardiac disease. Thirty-two consecutive patients (age 49 +/- 11) with cirrhosis and normal ECG were selected, 22 of which were alcoholic. Hemodynamic investigations were performed. Left ventricular function and mass were evaluated by echocardiography. Serum creatine kinase MB mass, myoglobin, and cardiac troponin I concentrations were measured. Cardiac troponin I concentrations were elevated in 10 patients (32%) (range 0.06-0.25 microg/L) whereas creatine kinase MB mass and myoglobin were normal in all patients. Abnormal troponin I values were not related to the severity of cirrhosis, to the degree of portal hypertension, or to other hemodynamic values. In contrast, elevated serum cardiac troponin I concentrations were related to a decreased stroke-volume index (P <. 05) and a decreased left ventricular mass (P <.05). These results show a high prevalence of slightly elevated serum cardiac troponin I in patients with cirrhosis, especially in those with alcoholic cirrhosis. Elevated troponin I is associated with subclinical left ventricular myocardial damage. These findings may be linked to a lack of left ventricular adaptation in certain patients with cirrhosis and alcoholic cardiomyopathy.

Concomitant chemoradiotherapy followed, where feasible, by surgery for cancer of the esophagus.

PURPOSE: To conduct a multicenter phase II study of a concomitant combination of chemotherapy and radiotherapy followed by surgery, where feasible, in patients with nonmetastatic esophageal tumor, stratified on operability at diagnosis. METHODS: Each cycle consisted of fluorouracil (5FU) 800 mg/m2/d by continuous intravenous (IV) infusion on days 1 to 5, cisplatin (CDDP) 50 mg/m2/d IV bolus on days 1 and 8, hydroxyurea (HU) 1.5 or 2 g/d orally on days 8 to 12 and concomitant radiotherapy 20 Gy in 10 fractions over 12 days. All patients were to receive two cycles on days 1 and 22. If feasible, surgery was performed 3 to 6 weeks after cycle two completion. Otherwise, a third cycle was administered. RESULTS: Eighty-eight patients were included between September 1990 and September 1993. Of the 47 operable patients, 41 (87%) underwent surgery and 38 (81%) had a complete resection. No residual primary tumor was found in the surgical specimen in 17 cases (36%), and only microscopic foci in 13 (28%). Two-year overall and disease-free survival probabilities were 51% (95% confidence interval [CI]; 37 to 65) and 43% (95% CI, 28 to 57), respectively. Among the 41 inoperable patients, 12 (29%) became operable. Seven (17%) had complete resection, two incomplete resection, and three exploratory surgery. Two-year overall and disease-free survival probabilities were 29% (95% CI, 15 to 43) and 27% (95% CI, 13 to 40), respectively. Five deaths occurred during chemoradiotherapy, six postoperatively and four in patients with evidence of cancer. Five late complications (one myelopathy) were observed. CONCLUSION: Despite a high histologic response rate in initially operable patients, overall survival was similar to that observed in other preoperative chemoradiation series because of substantial toxicity.

[Esophageal cancer: did combined treatments improve prognosis?]. / Cancer de l'oesophage: les traitements combinés ont-ils amélioré le pronostic?

Prognosis of esophageal cancer is very poor. Five-year survival does not exceed 20% after radical surgery, the best available treatment. Unfortunately, only 40% of the patients are amenable to surgery because of poor general status and/or locoregional extension. Adjuvant treatment did not yield survival improvement. Preoperative radiotherapy (three randomized trials) or postoperative radiotherapy (one randomized trial) showed only a decrease of regional relapses, perhaps only for the nodes negative patients. Neoadjuvant chemotherapy obtains some interesting response rate (20-60%), but there has been no evidence yet for survival improvement. Recently, promising results were presented after combination of radiotherapy and chemotherapy. In this paper, we review the present status of combined treatment for esophageal cancer. Our multicentric group (OSOF) is now completing a phase II trial, that should soon form the basis for a phase III prospective study.

[Brain metastasis of choriocarcinoma in males. Apropos of a case. Review of the literature]. / Métastases cérébrales du choriocarcinome chez l'homme. A propos d'un cas. Revue de la littérature.

A 22 year-old male patient had a choriocarcinoma of the mediastinum metastatic to the brain, liver, lung and skin. He was treated with five cycles of chemotherapy containing cisplatinum, vinblastine, VP16 and bleomycin and he achieved a partial remission. Then he developed a progressive disease exclusively located to the brain and he died of an intracranial hemorrhage. The autopsy showed the mediastinum and the lung being free of residual trophoblastic tumor. Pure choriocarcinoma is rare in males, but brain metastases are frequently present in this case. Therapeutic guidelines are uncertain, so they must refer to the experience obtained in gestational choriocarcinoma. Two groups of patients are individualized both in male germ cell tumors and in placental choriocarcinoma: one group of patients with brain metastases at diagnosis, with a better prognosis, and one group of patients with brain metastases occurring in the course of the disease, with a poor outcome. The risk of intratumoral hemorrhage is common to all varieties of choriocarcinoma brain metastases and is not lowered by greater effectiveness of the chemotherapy. Brain metastases found at the moment of the choriocarcinoma diagnosis require chemotherapy and radiotherapy and in some selected cases, a surgical removal.

Split course interstitial brachytherapy with a source shift: the results of a new iridium implant technique versus single course implants for salvage irradiation of base of tongue cancers in 55 patients.

Between January 1973 and December 1984, 55 patients with prior irradiation of the oropharynx underwent salvage irradiation for recurrent (26 patients) or second cancers (29 patients) of the base of tongue. The initial irradiation had delivered from 45 to 80 Gy to the base of tongue. One of two techniques of Iridium implantation was used for salvage. Single course implants, delivering 60 Gy, were used until June 1981 in a total of 31 patients. After June 1981, split course implants with a source shift were used in 24 patients in the hope of decreasing treatment complications. The first and second course of the split course implants delivered 35 and 30 Gy, respectively, at a 1-month interval. The active lines of the second implant were placed parallel to and between the position of the lines of the first implant. This shift in the source position resulted in a more uniform dose within the treated volume with a 60% reduction in the high dose sleeves. The overall 3-year survival was 19% (28% T less than or equal to 3 cm). The overall local failure rate was 45.5% (25/55). The difference between the local failure rate after single course implants (52%) and after split course implants (37.5%) was not statistically significative. The response observed after the first course of a split course implant proved to be a reliable indication of the probability of achieving local control after a full course of treatment: 2/14 failures (14%) if the response was greater than or equal to 75% versus 7/10 (70%) if the response was less than 75% (p less than 0.01). The only complication noted in the 40 patients achieving immediate local control after either implant technique was mucosal necrosis. The introduction of split course implants was followed by a two and a half fold decrease in the incidence of necrosis: 43% (9/21) in the single course group and 16% (3/19) in the split course group (p = 0.05). Interstitial brachytherapy offers an effective and reasonable option for salvage therapy in patients with recurrent and second cancers occurring in the base of tongue even when the tumor arises in a zone that has previously received high dose irradiation. The use of split course implants with a shift in the position of the active lines at the time of the second implant significantly decreases the risk of radionecrosis.

[Radiotherapy with neoadjuvant chemotherapy]. / La radiothérapie avec chimiothérapie première (néo-adjuvante).

Neoadjuvant chemotherapy can be used before radiotherapy to combat microscopic metastatic loci and to facilitate irradiation. Improvement in the survival time by impeding the dissemination of metastases seems to be real for breast cancer, but has not been observed to date in randomized studies of ENT cancers. Neoadjuvant chemotherapy in Hodgkin's disease has improved survival time and tolerance to irradiation, allowing a lowering of the total doses used and the volumes irradiated. In breast and ENT cancers, it has become possible, due to tumor regression, to replace mutilating treatments with more conservative ones consisting of radiotherapy alone, without increasing the risk of local relapse. Indeed, it is in this domain that neoadjuvant chemotherapy is the most useful. Two important conditions must be met for its successful application: a) a sufficiently effective regimen must be chosen, in order to prevent tumor growth prior to irradiation (which would aggravate the prognosis); and b) an accurate identification and localization of the tumor before undertaking any treatment so as to not detract from the effectiveness of the radiotherapy.

[Curative radiotherapy of unresectable bronchial cancer. Apropos of 266 cases without metastasis with 4 to 6 years follow-up (oat cell carcinoma excluded)]. / Radiothérapie à visée curative du cancer bronchique inopérable. A propos de 266 cas non métastasés d'emblée, avec délais d'observation de 4 à 10 ans (anaplasiques à petites cellules exclus).

Two hundred and sixty-six patients with inoperable bronchial carcinomas (oat cell excluded) without apparent metastases were treated with curative doses of radiotherapy. The malignancies were: 72% epidermoid epitheliomas, 11.5% adenocarcinomas, 10% large anaplastic cells and 6.5% without histology. According to the TNM classification, 3.5% were T1, 44% were T2 and 52% were T3. Mediastinal invasion was found in 44% of the cases. The mean age of the patients was 65 years (range 31-90 years). The Karnofsky index was less than or equal to 70 in 40% of the subjects. Unoperability was linked to the extent of local involvement in 59% of the cases and to age, general condition or an insufficient forced expiratory volume in 55% of the patients. Sixty to 65 Gy were administered, either classically fractionated or hypofractionated. After irradiation, 43% of the subjects underwent complete radiological remissions. Fifty-five percent of the patients died with local tumor evolution, 40% with isolated local evolution without associated metastases. The overall survival rate at 5 years was 7%; it was 16% for patients with a normal mediastinum and a Karnofsky index greater than 70 (51 cases); if these parameters were inversed, it was 2.5%. The fractionation protocol, the histological type, the use of chemotherapy (48 cases) did not affect the local control rate nor survival. There were almost no complications with this therapy. Patients frequently experienced functional improvement when curative doses of radiotherapy were applied to all the inoperable, non-metastatic cancers and the percentage of survivors at 5 years was non-negligible.