Correlation of genotype, phenotype, and mRNA expression of CYP2D6 and CYP2C19 in peripheral blood leukocytes (PBLs).

INTRODUCTION: The genetic polymorphism of drug metabolizing enzymes of the cytochrome P450 (CYP) families, especially CYP2D6 and CYP2C19, is the most important cause of variable responses of many drugs. Enzyme activity ranges from complete deficiency, so called poor metabolizers (PMs), to an ultrafast metabolism. While PMs and extensive metabolizers (EMs) can be well distinguished by genotyping, phenotyping is necessary to subdivide EMs from intermediate metabolizers (IMs). The aim of the study was to evaluate if messenger RNA (mRNA) concentration for CYP-enzymes in peripheral blood leukocytes (PBLs) will be predictive of systemic enzyme activity, allowing an easy and safe determination of metabolic activity. METHODS: The genotype, phenotype, and mRNA-expression in PBLs were evaluated in 124 healthy Caucasian volunteers (males and females, age range 23 - 59 years) on three occasions (every 4 weeks). Genotyping was performed by Taqman allelic discrimination on the most common null alleles for CYP2D6 (*3, *4, *6, *7, and *8) and CYP2C19 (*2 and *3). For phenotyping CYP2D6, dextromethorphan/dextrorphan metabolic ratios were determined in collected urine (8 hours) after administration of 30 mg dextromethorphan. For phenotyping CYP2C19, we used the plasma concentration ratio of omeprazole/hydroxyomeprazole 4 hours after ingestion of 40 mg omeprazole. mRNA-expression in PBLs for CYP2D6 and CYP2C19 was measured by Taqman real-time PCR before medication and 4 hours afterwards. RESULTS: Genotyping for CYP2D6 and CYP2C19 showed a regular distribution of EMs and PMs compared to studies of a comparable population. The median dextromethorphan/dextrorphan metabolic ratio was 0.47 in EMs/IMs and 2.29 in PMs. The median omeprazole/hydroxyomeprazole metabolic ratio was 3.06 in EMs/IMs and 35.29 in PMs. CYP2D6 and CYP2C19 mRNA expression was detected without evidence of correlation to the respective metabolic ratio. CONCLUSION: The results do not support the concept of using mRNA expression profiles for CYP2D6 and CYP2C19 enzymes in PBLs for prediction of systemic enzyme activity.

Locoregional therapy for cholangiocarcinoma.

PURPOSE OF REVIEW: Cholangiocarcinoma has a poor prognosis. Surgical resection offers the only curative option and usually requires a major hepatic resection in addition to resection of the cholangiocarcinoma. Unfortunately, curative resection is possible in only about 30% of patients due to locally advanced disease, distant metastases or comorbidity in elderly patients. Even after resection, the recurrence rate is approximately 60%, resulting in a low 5-year overall survival (OS). In unresectable cholangiocarcinoma OS with systemic chemotherapy is less than 1 year. Since most cholangiocarcinoma patients develop distant metastases at late stages only, locoregional therapy is an interesting therapeutic strategy. Here, we review the locoregional concepts of cholangiocarcinoma therapy. RECENT FINDINGS: Locoregional therapy studies in patients with intrahepatic cholangiocarcinoma employing radiofrequency ablation (RFA), transarterial chemoembolization (TACE) or external as well as internal radiation therapy yielded promising results in the last couple of years. SUMMARY: In conclusion, locoregional therapies have been shown to be effective in patients with intrahepatic cholangiocarcinoma. Local tumour control may prolong OS and can be achieved by locoregional interventions applied either sequentially or in combination with systemic chemotherapies.

Current state of nonsurgical therapies for cholangiocarcinoma.

Cholangiocarcinomas (CCCs) are rare tumors that are derived from the epithelial cell lining of the bile ducts. They can be classified as intrahepatic, extrahepatic-perihilar and extrahepatic-distal tumors. The prognosis of CCCs is poor as, in many cases, they are diagnosed at advanced stages, at which point curative surgical resection is not possible. Furthermore, most patients will experience a tumor recurrence despite initial complete CCC resection. Therefore, alternative/additional therapeutic strategies are needed to improve tumor- and recurrence-free survival after surgery as well as tumor control in patients with advanced disease. In clinical practice, apart from systemic chemotherapies for the therapeutic management of CCCs, locoregional as well as multimodal strategies are available, including external and internal radiation therapies. This review focuses on the currently available nonsurgical therapies for patients with CCCs, alone or in combination with other modalities, and on evolving therapeutic concepts that are being explored in clinical studies.

Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy.

BACKGROUND: Unresectable cholangiocarcinoma (CCC) has a poor prognosis. Patients with intrahepatic CCC have a very limited benefit from systemic chemotherapy (ChT). The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of conventional transarterial chemoembolization (cTACE) with mitomycin-C and of irinotecan-eluting beads (iDEB-TACE), and to retrospectively compare them with ChT with oxaliplatin and gemcitabine. MATERIALS AND METHODS: Between June 2002 and June 2010, three independent prospective trials were carried out and compared retrospectively. Following predefined study protocols, 26 patients with histologically proven intrahepatic CCC were treated with iDEB-TACE (200 mg irinotecan), 10 patients were treated with cTACE using 15 mg mitomycin-C mixed with 5-10 ml of ionized oil (lipiodol), followed by embolization with gelfoam, and 31 patients received systemic ChT with gemcitabine and oxaliplatin. Treatment response and progression-free survival (PFS) were assessed by computer tomography or MRI every 2 months according to Response Evaluation Criteria in Solid Tumors. Clinical and laboratory data were assessed for side-effects according to National Cancer Institute-Common Toxicity Criteria. RESULTS: iDEB-TACE resulted in PFS of 3.9 months and overall survival (OS) of 11.7 months, compared with a PFS of 1.8 months and OS of 5.7 months, respectively, in patients treated with cTACE, and a PFS of 6.2 months and OS of 11.0 months, respectively, in patients treated with oxaliplatin and gemcitabine. The medium follow-up of patients treated with iDEB-TACE was 12 months; 2 months after treatment, 13 patients (50%) had progressive disease, 11 patients (42%) had stable disease, and one patient had a partial response and became eligible for secondary liver resection. Local tumor control was achieved in 66% of patients; 4% had a partial response, 62% had stable disease, and 27% progressive disease. Common Toxicity Criteria grade III or IV toxicities for iDEB-TACE were abdominal pain (n=7), hepatic abscess (n=1), pleural empyema due to biliary leakage (n=1), and one death due to cholangitis with hepatic failure in a patient with liver cirrhosis. No hematological side-effects were observed. Almost every patient experienced a 'postembolization syndrome' with low-grade fever, nausea, and abdominal pain for up to 2 weeks. CONCLUSION: This is the first study demonstrating that treatment of patients suffering from intrahepatic CCC with iDEB-TACE is safe in patients with normal liver function, and results in a prolongation of PFS and OS. Local tumor control, PFS and OS seem similar to systemic ChT with oxaliplatin and gemcitabine, but superior to cTACE.