Genetic variants in the glutathione S-transferase genes and survival in colorectal cancer patients after chemotherapy and differences according to treatment with oxaliplatin.

INTRODUCTION: The glutathione S-transferase (GST) enzymes are involved in the detoxification of a range of carcinogenic compounds as well as chemotherapeutic agents. Therefore, genetic variants in the GST genes could influence survival in patients with colorectal cancer (CRC). Results from previous studies have been inconsistent and therefore we investigated the association between the GSTP1 ile105val polymorphism and the copy number variants of the GSTM1 and GSTT1 genes and survival in CRC patients treated with adjuvant/palliative chemotherapy. PATIENTS AND METHODS: We included 755 CRC patients with stage II-IV disease from two population-based studies carried out in Germany. Genotyping of the GSTP1 polymorphism was carried out using fluorescence-based melting curve analysis and copy number variants were determined using a multiplex PCR. Survival analysis was carried out using the Cox regression model, adjusting for age, sex, UICC stage, cancer site, and radiation therapy. RESULTS: Compared with noncarriers, CRC patients who were homozygote carriers of GSTM1 had significantly poorer survival after treatment with oxaliplatin [hazard ratio (HR) 2.25, 95% confidence interval (CI) 0.93-5.44] than those not treated with oxaliplatin (HR 0.64, 95% CI 0.30-1.34; P for heterogeneity=0.031). The association was significant in metastatic CRC patients treated with oxaliplatin (HR 3.59, 95% CI 1.29-10.03). Neither the GSTP1 105val allele nor the GSTT1 deletion was significantly associated with CRC survival. CONCLUSION: Our data suggest that GSTM1 may be a predictive marker for oxaliplatin therapy; however, independent large studies are warranted to confirm these results.

Reduced efficacy of the Plk1 inhibitor BI 2536 on the progression of hepatocellular carcinoma due to low intratumoral drug levels.

Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.

Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography.

PURPOSE: To compare, in a pilot study, acoustic radiation force impulse (ARFI) imaging technology integrated into a conventional ultrasonography (US) system with both transient elastography (TE) and serologic fibrosis marker testing for the noninvasive assessment of liver fibrosis. MATERIALS AND METHODS: Informed consent was obtained from all subjects, and the local ethics committee approved the study. ARFI imaging involved the mechanical excitation of tissue with use of short-duration acoustic pulses to generate localized displacements in tissue. The displacements resulted in shear-wave propagation, which was tracked by using US correlation-based methods and recorded in meters per second. Eighty-six patients with chronic viral hepatitis underwent TE, ARFI imaging, and serum fibrosis marker testing. Results were compared with liver biopsy findings, which served as the reference standard. RESULTS: ARFI imaging (rho = 0.71), TE (rho = 0.73), and serum fibrosis marker test (rho = 0.66) results correlated significantly with histologic fibrosis stage (P < .001). Median ARFI velocities ranged from 0.84 to 3.83 m/sec. Areas under the receiver operating characteristic curve for the accuracy of ARFI imaging, TE, and serum fibrosis marker testing were 0.82, 0.84, and 0.82, respectively, for the diagnosis of moderate fibrosis (histologic fibrosis stage, > or = 2) and 0.91, 0.91, and 0.82, respectively, for the diagnosis of cirrhosis. CONCLUSION: ARFI imaging is a promising US-based method for assessing liver fibrosis in chronic viral hepatitis, with diagnostic accuracy comparable to that of TE in this preliminary study. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/252/2/595/DC1.