Glutathlone S-transferases (alpha, mu, theta, and pi) are a family of detoxifying enzymes which catalyze the conjugation of glutathione to electrophilic compounds. About 50% of the human population has the GSTM1 0/0 genotype resulting in the lack of the mu transferase enzyme. This population has approximately 50% less total hepatic glutathione S-transferase activity. It has been suggested that this genotype is associated with an increased risk of toxin-induced disease. For example, adults with alcohol-induced liver disease have an increased frequency of the GSTM1 0/0 genotype, while adults with primary biliary cirrhosis do not. No published data exists on the frequency of the GSTM1 0/0 genotype in childhood liver diseases.Purpose: To establish the frequency of the GSTM1 0/0 genotype in children who receive liver transplantation for biliary atresia/cirrhosis, hepatitis, or α1 antitrypsin deficiency. Methods: DNA was purified from native liver specimens from children undergoing liver transplantation, and from donor splenocytes. Differential PCR amplification was used to evaluate the GSTM1 genotype in 137 donor spleen specimens and 178 recipient liver specimens. Results: The GSTM1 0/0 frequency observed was 48% (66/137) in controls, 54% (54/100) in children with biliary atresia/biliary cirrhosis, 65% (17/26) in children with α1 antitrypsin deficiency, and 44% (22/50) in children with hepatitis. Children with α1 antitrypsin deficiency showed a trend towards an increased frequency of GSTM1 0/0 compared to controls (p=0.10, Chi-Square).Conclusions: The GSTM1 0/0 genotype does not appear to be an important risk factor for the development of liver failure in children with biliary atresia/cirrhosis or hepatitis. Increased patient numbers will be necessary to determine whether an increased GSTM1 0/0 genotype frequency occurs in children with liver failure secondary to α1 antitrypsin deficiency.
The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last three decades, despite the improvement in the outcome of younger adults during this same time due to the use of hematopoietic stem cell transplantation and intensive cytarabine consolidation. Older adults can not tolerate intensive therapy due to poor performance status, impaired organ function, and comorbid illnesses. Tipifarnib is an oral farnesyl transferase inhibitor with activity in the treatment of myelodysplastic syndrome (MDS) and high-risk AML patients. The primary objective of study S0432 was to test whether any of four different regimens of tipifarnib is sufficiently effective and tolerable therapy for previously untreated AML in patients of age 70 or over to warrant phase III study. Patients could not be considered candidates for, or must have declined, conventional induction chemotherapy. Patients had to have adequate renal and hepatic function, and the white blood cell (WBC) count had to be less than 30,000/cmm at the time of registration. Eligible patients could have a history of MDS, but could not have received AML induction chemotherapy or stem cell transplantation. Patients were randomized to receive either 600 mg or 300 mg of tipifarnib twice daily for either 21 consecutive days or 7 days every other week. Cycles were repeated every 28 days until disease progression or unacceptable toxicity. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) were to receive three additional cycles and then discontinue therapy. Patients achieving partial remission (PR) or with stable disease could continue treatment until progression of AML. If none of the first 15 patients on an arm achieved CR, CRi or PR, then accrual to that arm would be closed. However, all 4 treatment arms continued to full accrual. Three hundred forty-eight patients were registered between September 15, 2004 and February 15, 2006. Eighteen patients were excluded from analysis due to diagnosis other than AML, WBC above 30,000/cmm, no protocol therapy, and incorrect regimen administered. The median age in each arm was 78 years. The following are the treatment regimens: arm 1, 600 mg twice daily for 21 days; arm 2, 600 mg twice daily for 7 days every other week; arm 3, 300 mg twice daily for 21 days; arm 4, 300 mg twice daily for 7 days every other week. 041b061a72