Jaundice caused by rifampicin: 3 cases

Three cases are reported of cholestatic hepatitis occurring during treatment with rifampicin for staphylococcal septicemia (2) and tuberculosis (1). There was no previous history of hepatic affection. The administration of rifampicin caused cholestasis alone. No immunoallergic phenomenon has been shown.     

Kaposi's sarcoma in transplant and HIV-infected patients: an epidemiologic study in Italy and France

BACKGROUND: A follow-up study was conducted in Italy and in France to compare the epidemiology of Kaposi's sarcoma (KS) between human immunodeficiency virus (HIV)-infected people and transplant recipients. METHODS: In all, 8,074 HIV-positive individuals (6,072 from France and 2,002 HIV-seroconverters from Italy) and 2,705 Italian transplant recipients (1,844 kidney transplants, 702 heart transplants, and 159 liver transplants) were followed-up between 1970 and 2004. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed to estimate the risk of KS, as compared to sex- and age-matched Italian and French populations. Incidence rate ratios (IRRs) were used to identify risk factors for KS. RESULTS: A 451-fold higher SIR for KS was recorded in HIV-infected subjects and a 128-fold higher SIR was seen in transplant recipients. Significantly increased KS risks were observed in HIV-infected homosexual men (IRR=9.7 in France and IRR=6.7 in Italy vs. intravenous drug users), and in transplant recipients born in southern Italy (IRR=5.2 vs. those born in northern Italy). HIV-infected patients with high CD4+ cell counts and those treated with antiretroviral therapies had reduced KS risks. In relation to duration of immunosuppression, KS occurred earlier in transplant patients than in HIV-seroconverters. CONCLUSIONS: This comparison highlighted that the risk of KS was higher among HIV-infected individuals than in transplant recipients, and that different co-factors are likely to influence the risk of KS. Moreover, the early KS occurrence in transplant recipients could be associated with different patterns of progressive impairment of the immune function.     

The EPAGE internet guideline as a decision support tool for determining the appropriateness of colonoscopy

BACKGROUND: Few studies have examined how physicians perceive guidelines, much less their perceptions of an Internet presentation of such guidelines. This study assessed physicians' acceptance ofan Internet-based guideline on the appropriateness of colonoscopy. METHODS: Gastroenterologists participating in an international observational study consulted an Internet-based guideline for consecutive patients referred for colonoscopy. The guideline was produced by the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE), using a validated method (RAND). Through the use of questionnaires, physicians were asked their opinions and perspectives of the guideline and website. RESULTS: There were 289 patients included in the study. The mean time for consulting the website was 1.8 min, and it was considered easy to use by 86% of physicians. The recommendations were easily located for 82% of patients and physicians agreed with the appropriateness in 86% of cases. According to the EPAGE criteria, colonoscopy was appropriate, uncertain, and inappropriate in 59, 28, and 13% of patients, respectively. CONCLUSIONS: The EPAGE guideline was considered acceptable and user-friendly and the use, usefulness and relevance of the website were considered acceptable. However, its actual use will depend on the removal of certain organizational and cultural obstacles.     

Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

Mutations in the tumor-suppressor gene p53 have been associated with advanced colorectal cancer (CRC). Irinotecan (CPT-11), a DNA topoisomerase 1 inhibitor, has been recently incorporated to the adjuvant therapy. Since the DNA-damage checkpoint depends on p53 activation, the status of p53 might critically influence the response to CPT-11. We analysed the sensitivity to CPT-11 in the human colon cancer cell line HT29 (mut p53) and its wild-type (wt)-p53 stably transfected subclone HT29-A4. Cell-cycle analysis in synchronised cells demonstrated the activation of transfected wt-p53 and a p21(WAF1/CIP1)-dependent cell-cycle blockage in the S phase. Activated wt-p53 increased apoptosis and enhanced sensitivity to CPT-11. In p53-deficient cells, cDNA-macroarray analysis and western blotting showed an accumulation of the cyclin-dependent kinase (cdk)1/cyclin B complex. Subsequent p53-independent activation of the cdk-inhibitor (cdk-I) p21(WAF1/CIP1) prevented cell-cycle progression. Cdk1 induction was exploited in vivo to improve the sensitivity to CPT-11 by additional treatment with the cdk-I CYC-202. We demonstrate a gain of sensitivity to CPT-11 in a p53-mutated colon cancer model either by restoring wild-type p53 function or by sequential treatment with cdk-Is. Considering that mutations in p53 are among the most common genetic alterations in CRC, a therapeutic approach specifically targeting p53-deficient tumors could greatly improve the treatment outcomes.     

Familial multiple myeloma: report of fifteen families

To further define the frequency, clinical and biological features of familial multiple myeloma we performed a retrospective study of related patients who presented with multiple myeloma. Most cases of familial multiple myeloma were observed in siblings (10/15), in whom the mean age at diagnosis was similar to unrelated multiple myeloma. In successive generations the mean age at diagnosis was lower. Monoclonal component was identical (IgG kappa) in seven families. Familial history of monoclonal gammopathy of undetermined significance was observed in three families. Five other prospective studies of 1263 patients identified four affected families (3.2 per 1000 cases of multiple myeloma), and raise the question of a genetic background in multiple myeloma.     

Updated definition of level VI lymph node classification in the neck

CONCLUSION: This update will enable us to precisely address the involvement pattern of level VI and to standardize treatment procedures in order to refine their indications and eventually improve their results and avoid treatment morbidity. BACKGROUND: The neck level classification is being used worldwide to describe the lymph nodes status of the neck. It provides standardized data to properly evaluate and then improve our protocols for the management of neck metastasis in an evidence-based medical manner. Although level VI treatment is challenging in cancer of the larynx, pharynx, trachea, esophagus, and thyroid, our knowledge about its involvement relies on few non-standardized data, due to the inadequate definition of this region. METHOD: We propose an updated radiological and surgical definition of level VI, with the introduction of two sublevels which fulfill surgical, radiotherapy, radiological, and pathological concerns. RESULTS: Level VIa encompasses prelaryngeal, intercricothyroidal, pretracheal, and perithyroidal nodes. Level VIb encompasses inferior laryngeal nodes. Within the traditional limits of level VI, all lymph nodes lying between the inferior border of the hyoid bone and the inferior border of the cricoid cartilage belong to level VIa. Between the inferior border of the cricoid cartilage and the top of the suprasternal notch, lymph nodes lying in front of the posterior face of the thyroid gland belong to level VIa; those lying behind this boundary belong to level VIb. We also discuss the definition of the superior mediastinal lymph nodes, which should not be mistaken for level VI.     

Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis

Aims

This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration–effect relationship of adalimumab using pharmacokinetic–pharmacodynamic (PK–PD) modelling in patients with rheumatoid arthritis (RA).

Methods

Adalimumab PK and PK–PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated.

Results

Thirty patients treated for RA were analysed. The following pharmacokinetic and PK–PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (V_d/F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day⁻¹ (17%); first-order absorption rate (k_a) = 0.28 day⁻¹; CRP input (k_in) = 22.0 mg l⁻¹ day⁻¹ (65%); adalimumab concentration leading to a 50% decrease in k_in (C₅₀) = 3.6 mg l⁻¹ (88%); baseline DAS28 (DAS₀) = 5.5 mg l⁻¹ (11%); and adalimumab concentration leading to 50% decrease of DAS₀ (IC₅₀) = 11.0 mg l⁻¹ (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection.

Conclusions

This is the first study to describe adalimumab pharmacokinetics and the concentration–effect relationship in RA. A 160 mg loading dose may lead to an increased benefit from treatment in RA patients.