Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial.

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects.

The chiral antidepressant venlafaxine (VEN) is both a serotonin and a norepinephrine uptake inhibitor. CYP2D6 and CYP3A4 contribute to its metabolism, which has been shown to be stereoselective. Ten CYP2D6 genotyped and depressive (F32x and F33x, ICD-10) patients participated in an open study on the pharmacokinetic and pharmacodynamic consequences of a carbamazepine augmentation in VEN non-responders. After an initial 4-week treatment with VEN (195 +/- 52 mg/day), the only poor metabolizer out of 10 depressive patients had the highest plasma concentrations of S-VEN and R-VEN, respectively, whereas those of R-O-demethyl-VEN were lowest. Five non-responders completed the second 4-week study period, during which they were submitted to a combined VEN-carbamazepine treatment. In the only non-responder to this combined treatment, there was a dramatic decrease of both enantiomers of VEN, O-demethylvenlafaxine, N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine in plasma, which suggests non-compliance, although metabolic induction by carbamazepine cannot entirely be excluded. The administration of carbamazepine [mean +/- SD, range: 360 +/- 89 (200-400) mg/day] over 4 weeks did not result in a significant modification of the plasma concentrations of the enantiomers of VEN and its O- and N-demethylated metabolites in the other patients. In conclusion, these preliminary observations suggest that the combination of VEN and carbamazepine represents an interesting augmentation strategy by its efficacy, tolerance and absence of pharmacokinetic modifications. However, these findings should be verified in a more comprehensive study.

High rate of completion of preventive therapy for latent tuberculosis infection among asylum seekers in a Swiss Canton.

BACKGROUND: Preventive treatment may avoid future cases of tuberculosis among asylum seekers. The effectiveness of preventive treatment depends in large part on treatment completion. METHODS: In a prospective cohort study, asylum seekers of two of the Swiss Canton Vaud migration centres were screened with the Interferon Gamma Release Assay (IGRA). Those with a positive IGRA were referred for medical examination. Individuals with active or past tuberculosis were excluded. Preventive treatment was offered to all participants with positive IGRA but without active tuberculosis. The adherence was assessed during monthly follow-up. RESULTS: From a population of 393 adult migrants, 98 (24.9%) had a positive IGRA. Eleven did not attend the initial medical assessment. Of the 87 examined, eight presented with pulmonary disease (five of them received a full course of antituberculous therapy), two had a history of prior tuberculosis treatment and two had contraindications to treatment. Preventive treatment was offered to 75 individuals (4 months rifampicin in 74 and 9 months isoniazid in one), of whom 60 (80%) completed the treatment. CONCLUSIONS: The vulnerability and the volatility of this population make screening and observance of treatment difficult. It seems possible to obtain a high rate of completion using a short course of treatment in a closely monitored population living in stable housing conditions.

Supracricoid partial laryngectomy with cricohyoidoepiglottopexy in patients with radiation therapy failure.

BACKGROUND: To assess functional results, complications, and success of larynx preservation in patients with recurrent squamous cell carcinoma after radiotherapy. METHODS: From a database of 40 patients who underwent supracricoid partial laryngectomy (SCPL) with cricohyoidoepiglottopexy (CHEP) from June 2001 to April 2006, eight patients were treated previously with radiotherapy due to squamous cell carcinoma of the glottic region and were treated for recurrence at the site of the primary cancer. RESULTS: SCPL with CHEP was performed in six men and two women with a mean age of 67 years due to recurrence and/or persistence at a mean time of 30 months postradiotherapy (in case #8 after concomitant chemoradiotherapy). Bilateral neck dissection at levels II-V was performed in six patients. Only case #8 presented metastasis in one node. In case #5, Delphian node was positive. It was possible to preserve both arytenoids in five cases. Definitive surgical margins were negative. Complications were encountered in seven patients. Follow-up was on average 44 months (range: 20-67 months). Organ preservation in this series was 75%, and local control was 87%. Overall 5-year survival was 50%. CONCLUSIONS: In selected patient with persistence and/or recurrence after radiotherapy due to cancer of the larynx, SCPL with CHEP seems to be feasible with acceptable local control and toxicity. Complications may occur as in previously non-irradiated patients. These complications must be treated conservatively to avoid altering laryngeal function.

Efficacy of enzyme replacement therapy in Fabry disease.

Enzyme replacement therapy has recently been introduced to treat Fabry disease, a rare X-linked lysosomal storage disorder. The disease occurs due to deficient activity of alpha-galactosidase A, leading to progressive accumulation of globotriaosylceramide in multiple organs and tissues. Renal, cardiac and cerebrovascular manifestations of the disease result in premature death in both hemizygous males and heterozygous females. This paper outlines the clinical signs, symptoms and diagnosis of Fabry disease, and the development of the two available enzyme replacement therapies -- agalsidase alfa and agalsidase beta. Agalsidase alfa and agalsidase beta are produced in a human cell line and in Chinese hamster ovary cells, respectively, resulting in products with the same amino acid sequence as the native human enzyme, but with different patterns of glycosylation. Correct post-translational glycosylation is important in terms of the pharmacokinetics, biodistribution, clinical efficacy and tolerability of genetically engineered protein therapeutics. Differences in glycosylation, which may affect immunogenicity and mannose-6-phosphate receptor-mediated cellular internalisation of administered enzyme, possibly account for the differences in dosing, clinical effects and safety profiles reported for agalsidase alfa and agalsidase beta.