Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity.

The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.

CYP2D6 in the brain: genotype effects on resting brain perfusion.

The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain, such as the hippocampus, thalamus, hypothalamus and the cortex, but its function in the brain is not well understood. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N=188 healthy individuals and compared with brain perfusion levels at rest, which may reflect an ongoing biological process regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. Relative to N=42 matched extensive metabolizers, N=14 poor metabolizers were associated with 15% higher perfusion levels in the thalamus (P=0.03 and 0.003). Effects were also present in the whole (N=188) sample divided into metabolizer groups, or finely graded into seven CYP2D6 activity levels. A weaker effect was observed in the right hippocampus (P=0.05). An exploratory analysis, extended to the whole brain, suggested the involvement of CYP2D6 in regions associated with alertness or serotonergic function. These findings support the hypothesis of a functional role of CYP2D6 in the brain.

Genetic variants of the insulin receptor substrate-1 are influencing the therapeutic efficacy of oral antidiabetics.

AIM: The therapeutic efficacy of oral hypoglycaemic drugs varies between individuals, and pharmacogenetic factors contribute to this variability. The Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) has been shown to play a role in insulin signal transduction and therapeutic failure to sulphonylurea drugs. METHODS: We studied the association between the IRS-1 polymorphism and the haemoglobin A1c (HbA1c) level in diabetic patients treated with insulinotropic versus non-insulinotropic hypoglycaemic drugs as a marker for the efficacy of an antidiabetic treatment. Genotyping of the IRS-1 Arg(972) variant was performed in type 2 diabetes patients treated with either sulphonylurea drugs, glinides or insulin or with metformin, acarbose or glitazones using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Significantly higher HbA1c levels were observed in carriers of the Arg(972) variant after treatment with insulinotropic drugs compared to wild-type carriers (8.3 vs. 7.6%, p = 0.005, independent t-test). Furthermore, patients with secondary failure to insulinotropic hypoglycaemic drugs switching finally to insulin showed even higher HbA1c levels in carriers of Arg(972) compared to wild-type (8.7 vs. 7.6%, p = 0.005, independent t-test). CONCLUSIONS: Thus, we were able to replicate the earlier findings of an association between the IRS-1 Arg(972) variant and secondary failure to sulphonylurea drugs, and further observed a general association between HbA1c and this polymorphism in type 2 diabetes patients treated with insulinotropic hypoglycaemic drugs but not with metformin.

[CYP2D6-, CYP2C9- and CYP2C19-based dose adjustments: when do they make sense?]. / CYP2D6-, CYP2C9- und CYP2C19-basierte Arzneimitteldosisanpassungen: Wann sind sie sinnvoll?

The efficacy of a drug therapy is influenced by many different factors such as age, weight, comorbidity and co-medication, which vary between patients, as well as fixed parameters such as gender and pharmacogenetic characteristics. Many enzymes involved in drug metabolism are genetically polymorphic, which means that their activity differs depending on a certain genotype. Drugs will be metabolized slowly in individuals who are carriers of a genetic polymorphism, leading to absent or decreased enzyme activity, and these individuals are at particular risk for adverse drug reactions or therapeutic failure. On the other hand, drug therapy could be ineffective if the drug is metabolized too fast because of a genetic polymorphism. The knowledge of these polymorphisms before beginning a drug therapy could help in choosing the right drug in a safe dosage. In particular, three polymorphic drug metabolizing enzymes are responsible for the metabolism of many commonly used drugs. These enzymes, belonging to the cytochrome P450 (CYP) family, are CYP2D6, CYP2C9 and CYP2C19. Besides beta-blockers and antidepressants, several drugs used in cancer therapy, as well as PPIs, NSAIDs, vitamin K-antagonists and oral antidiabetics are metabolized via these enzymes. Especially for drugs with a narrow therapeutic index and a high risk for the development of adverse drug effects, genotyping could be helpful when choosing the right drug in the optimal dosage for individual patients.

Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients.

This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.

[State of the art of pharmacogenetic diagnostics in drug therapy]. / Stand der Pharmakogenetik in der klinischen Arzneimitteltherapie.

Individual differences in the effect and side effect of drugs are partly due to genetic factors (genetic polymorphisms). The responsible polymorphisms lie in genes encoding for drug metabolism and transport but also in direct and indirect drug targets. While genetic variants in pharmacokinetic structures exert effects on drug efficacy via the differences in drug exposure, polymorphisms in drug targets can directly affect clinical efficacy and may lead to a broad variation spectrum between inefficacy and severe side effects. However, at present, our knowledge on genetic variants in drug targets is less detailed than the knowledge on pharmacogenetic variability within drug metabolism. A goal of pharmacogenetic diagnostics implemented in clinical practice is to better predict the individual drug effects on the basis of molecular-genetic profiles. Therapy recommendations can be given as dose adjustments, in particular in the case of polymorphisms of drug metabolizing enzymes which will lead to less variable drug concentrations. At present there are few examples of the application of pharmacogenetic tests in Germany in order to improve and individualize drug therapy. The reasons for this are multifold. On the one hand it is due to the limited awareness of pharmacogenetics; on the other hand it may be due to the lack of fast and economical availability of the appropriate laboratory tests. The most important reason, however, may be that most results of pharmacogenetic research are so far not translated into therapeutically usable conclusions and therapy recommendations. Thus, testing for a genotype without concrete consequences for the drug therapy of an individual patient does not make sense. Pharmacogenetic research, thereby, stands in many cases at the threshold to clinical applicability and in many cases, for instance for the genotyping for thiopurine methyltransferase polymorphisms prior to azathioprine therapy or of dihydropyrimidine dehydrogenase polymorphisms prior to treatment with 5-fluorouracil, as well as for diagnostics of CYP2D6 before therapy with certain tricyclic antidepressants and neuroleptics, one would ask already today whether a such drug therapy is still responsible without pharmacogenetic diagnostics.