Acute liver toxicity with ifosfamide in the treatment of sarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Ifosfamide is a chemotherapy agent infrequently associated with liver toxicity. To the best of our knowledge, this report is the first to describe serious liver toxicity associated with ifosfamide used in combination with doxorubicin that caused acute but fully reversible liver failure and encephalopathy. This report reviews the possible mechanisms by which ifosfamide causes this adverse effect.</p> <p>Case report</p> <p>A 61-year-old Caucasian woman who presented with an inoperable right neck mass due to synovial sarcoma was treated with standard-dose ifosfamide and doxorubicin. Within 24 hours of completing the first cycle of chemotherapy, she developed significant derangements in liver function, with a 250-fold increase in transaminase and associated synthetic function impairment and encephalopathy. No other causes of liver failure were identified. Both biochemical tests and encephalopathy were reversed after supportive management and treatment with <it>N</it>-acetylcysteine. No liver toxicity was observed with subsequent cycles of chemotherapy with doxorubicin alone.</p> <p>Conclusion</p> <p>This case highlights the possibility that chemotherapy agents can cause rare and idiosyncratic toxicities, so physicians must be vigilant for drug reactions, especially when patients do not respond to usual treatment.</p

Acute liver toxicity with ifosfamide in the treatment of sarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Ifosfamide is a chemotherapy agent infrequently associated with liver toxicity. To the best of our knowledge, this report is the first to describe serious liver toxicity associated with ifosfamide used in combination with doxorubicin that caused acute but fully reversible liver failure and encephalopathy. This report reviews the possible mechanisms by which ifosfamide causes this adverse effect.</p> <p>Case report</p> <p>A 61-year-old Caucasian woman who presented with an inoperable right neck mass due to synovial sarcoma was treated with standard-dose ifosfamide and doxorubicin. Within 24 hours of completing the first cycle of chemotherapy, she developed significant derangements in liver function, with a 250-fold increase in transaminase and associated synthetic function impairment and encephalopathy. No other causes of liver failure were identified. Both biochemical tests and encephalopathy were reversed after supportive management and treatment with <it>N</it>-acetylcysteine. No liver toxicity was observed with subsequent cycles of chemotherapy with doxorubicin alone.</p> <p>Conclusion</p> <p>This case highlights the possibility that chemotherapy agents can cause rare and idiosyncratic toxicities, so physicians must be vigilant for drug reactions, especially when patients do not respond to usual treatment.</p

CYP3A4 and CYP3A5 genotyping by Pyrosequencing

BACKGROUND: Human cytochrome P450 3A enzymes, particularly CYP3A4 and CYP3A5, play an important role in drug metabolism. CYP3A expression exhibits substantial interindividual variation, much of which may result from genetic variation. This study describes Pyrosequencing assays for key SNPs in CYP3A4 (CYP3A4*1B, CYP3A4*2, and CYP3A4*3) and CYP3A5 (CYP3A5*3C and CYP3A5*6). METHODS: Genotyping of 95 healthy European and 95 healthy African volunteers was performed using Pyrosequencing. Linkage disequilibrium, haplotype inference, Hardy-Weinberg equilibrium, and tag SNPs were also determined for these samples. RESULTS: CYP3A4*1B allele frequencies were 4% in Europeans and 82% in Africans. The CYP3A4*2 allele was found in neither population sample. CYP3A4*3 had an allele frequency of 2% in Europeans and 0% in Africans. The frequency of CYP3A5*3C was 94% in Europeans and 12% in Africans. No CYP3A5*6 variants were found in the European samples, but this allele had a frequency of 16% in the African samples. Allele frequencies and haplotypes show interethnic variation, highlighting the need to analyze clinically relevant SNPs and haplotypes in a variety of ethnic groups. CONCLUSION: Pyrosequencing is a versatile technique that could improve the efficiency of SNP analysis for pharmacogenomic research with the ultimate goal of pre-screening patients for individual therapy selection

Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti

BACKGROUND: Implementation of the World Health Organization's DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives. METHODS: Using decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US$. RESULTS: Starting in 2003, DOTS expansion in Haiti is anticipated to cost$4.2 million and result in 63,080 fewer tuberculosis cases, 53,120 fewer tuberculosis deaths, and net societal savings of $131 million, over 20 years. Current government spending for tuberculosis is high, relative to the per capita income, and would be only slightly lower with DOTS. Societal savings would begin within 4 years, and would be substantial in all scenarios considered, including higher HIV seroprevalence or drug resistance, unchanged incidence following DOTS expansion, or doubling of initial and ongoing costs for DOTS expansion. CONCLUSION: A modest investment for DOTS expansion in Haiti would provide considerable humanitarian benefit by reducing tuberculosis-related morbidity, mortality and costs for patients and their families. These benefits, together with projected minimal Haitian government savings, argue strongly for donor support for DOTS expansion

Altered Metabolic Signature in Pre-Diabetic NOD Mice

Altered metabolism proceeding seroconversion in children progressing to Type 1 diabetes has previously been demonstrated. We tested the hypothesis that non-obese diabetic (NOD) mice show a similarly altered metabolic profile compared to C57BL/6 mice. Blood samples from NOD and C57BL/6 female mice was collected at 0, 1, 2, 3, 4, 5, 6, 7, 9, 11, 13 and 15 weeks and the metabolite content was analyzed using GC-MS. Based on the data of 89 identified metabolites OPLS-DA analysis was employed to determine the most discriminative metabolites. In silico analysis of potential involved metabolic enzymes was performed using the dbSNP data base. Already at 0 weeks NOD mice displayed a unique metabolic signature compared to C57BL/6. A shift in the metabolism was observed for both strains the first weeks of life, a pattern that stabilized after 5 weeks of age. Multivariate analysis revealed the most discriminative metabolites, which included inosine and glutamic acid. In silico analysis of the genes in the involved metabolic pathways revealed several SNPs in either regulatory or coding regions, some in previously defined insulin dependent diabetes (Idd) regions. Our result shows that NOD mice display an altered metabolic profile that is partly resembling the previously observation made in children progressing to Type 1 diabetes. The level of glutamic acid was one of the most discriminative metabolites in addition to several metabolites in the TCA cycle and nucleic acid components. The in silico analysis indicated that the genes responsible for this reside within previously defined Idd regions

The COSMIN checklist for evaluating the methodological quality of studies on measurement properties: A clarification of its content

<p>Abstract</p> <p>Background</p> <p>The COSMIN checklist (COnsensus-based Standards for the selection of health status Measurement INstruments) was developed in an international Delphi study to evaluate the methodological quality of studies on measurement properties of health-related patient reported outcomes (HR-PROs). In this paper, we explain our choices for the design requirements and preferred statistical methods for which no evidence is available in the literature or on which the Delphi panel members had substantial discussion.</p> <p>Methods</p> <p>The issues described in this paper are a reflection of the Delphi process in which 43 panel members participated.</p> <p>Results</p> <p>The topics discussed are internal consistency (relevance for reflective and formative models, and distinction with unidimensionality), content validity (judging relevance and comprehensiveness), hypotheses testing as an aspect of construct validity (specificity of hypotheses), criterion validity (relevance for PROs), and responsiveness (concept and relation to validity, and (in) appropriate measures).</p> <p>Conclusions</p> <p>We expect that this paper will contribute to a better understanding of the rationale behind the items, thereby enhancing the acceptance and use of the COSMIN checklist.</p