Kazushi Numata

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer.

Circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer.

Use of fusion imaging combining contrast-enhanced ultrasonography with a perflubutane-based contrast agent and contrast-enhanced computed tomography for the evaluation of percutaneous radiofrequency ablation of hypervascular hepatocellular carcinoma

OBJECTIVEnWe evaluated the efficacy of fusion imaging, which fuses contrast-enhanced ultrasonography images with arterial-phase, contrast-enhanced CT images as a reference on a single screen in real time, for the evaluation of the effectiveness of radiofrequency ablation for treatment of hypervascular hepatocellular carcinoma.nnnMATERIALS AND METHODSnEighty hepatocellular carcinoma lesions with a maximum diameter of between 1 and 3 cm that were scheduled for treatment with radiofrequency ablation were enrolled in this prospective study. After bolus injection of perflubutane-based contrast agent, fusion imaging combining contrast-enhanced ultrasonography images and arterial-phase, contrast-enhanced CT images was performed one day after radiofrequency ablation. We used two functions, which were subsets of the fusion imaging, to confirm the location of the hepatocellular carcinoma lesions in the ablated areas and to evaluate the presence or absence of an adequate safety margin. Contrast-enhanced CT was performed one month after the ablation. Two blinded observers reviewed the images obtained using both modalities to evaluate the effect of ablation.nnnRESULTSnWhen the one-month contrast-enhanced CT images were used as the reference standard, the sensitivity, specificity, and accuracy of the one-day fusion imaging for the diagnosis of adequate ablation were 97%, 83%, and 96%, respectively; the kappa value for the agreement between the findings obtained using the two modalities was 0.75.nnnCONCLUSIONnFusion imaging combining contrast-enhanced ultrasonography images and arterial-phase, contrast-enhanced CT images as a reference appears to be a useful method for the early evaluation of the efficacy of radiofrequency ablation for the treatment of hypervascular hepatocellular carcinoma.

Hepatic Arterial Infusion Therapy with a Fine Powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

OBJECTIVEnWe retrospectively evaluated the antitumor effect, survival and toxicities of hepatic arterial infusion therapy using a fine powder formulation of cisplatin (cisplatin powder) in hepatocellular carcinoma patients with portal vein tumor thrombosis.nnnMETHODSnTwenty-four patients classified as Child-Pugh class A or B underwent a single session of hepatic arterial infusion therapy using cisplatin powder. The treatment was repeated every 4-6 weeks in patients with no evidence of tumor progression or unacceptable toxicity. The treatment response was evaluated using contrast-enhanced computed tomography performed 1 month after each treatment. The survival rate was evaluated using the Kaplan-Meier method, and predictors of a better outcome were identified using univariate analysis.nnnRESULTSnThe mean follow-up period was 11.2 months (range, 1.3-44.2 months). A total of 57 sessions of intra-arterial infusion (1-6 sessions per patient; mean, 2.4 sessions) with cisplatin powder were performed. A complete response and a partial response were obtained in one and four patients, respectively (objective response rate = 20.8%). The median survival time for all the patients was 7.0 months; the median survival times for the 5 responders and 19 non-responders were 37.3 and 5.6 months, respectively. The 1- and 2-year survival rates were 38% and 16%, respectively. Significant prognostic factors related to survival were the therapeutic effect, patient age and serum alanine aminotransferase level. Severe adverse reactions resulting in treatment discontinuation were not observed, and all the toxicities were successfully managed using conservative treatment.nnnCONCLUSIONSnHepatic arterial infusion therapy with a fine powder formulation of cisplatin was safe, well-tolerated and might help to prolong the life span of advanced hepatocellular carcinoma patients with portal vein tumor thrombosis.

Novel Lens culinaris agglutinin-reactive fraction of α-fetoprotein: a biomarker of hepatocellular carcinoma recurrence in patients with low α-fetoprotein concentrations

BackgroundLens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3) is a specific marker used to detect hepatocellular carcinoma (HCC). However, its clinical utility is not sufficient in patients with low total AFP concentrations because of limitations in instrument sensitivity. Recent advances have led to the introduction of a highly sensitive AFP-L3% assay (sensitive AFP-L3%), provided by a novel on-chip, liquid-phase binding assay. This cross-sectional study was conducted to evaluate the clinical significance of the sensitive AFP-L3% in determining HCC recurrence in patients with low total AFP concentrations.MethodsA total of 370 consecutive patients with HCC were screened within 1–3xa0months of locoregional treatment, and 215 of the 370 patients showed serum AFP <20xa0ng/ml. Total AFP, sensitive AFP-L3%, and des-gamma-carboxy prothrombin (DCP) were measured in those 215 patients and HCC recurrence was evaluated by radiological findings. Optimal cutoff values of the markers for detecting HCC recurrence were obtained on the basis of receiver operating characteristic (ROC) curve.ResultsThe area under the ROC curve of the total AFP, sensitive AFP-L3%, and DCP in HCC patients with serum AFP <20xa0ng/ml were 0.638, 0.724, and 0.779, respectively. The diagnostic accuracies of the total AFP, sensitive AFP-L3%, and DCP were 60.9% (cutoff value 5xa0ng/ml), 67.7% (cutoff value 7%), and 64.6% (cutoff value 40xa0ng/ml), respectively.ConclusionsThe new sensitive AFP-L3% assay provides great utility in determining HCC recurrence in patients with low AFP concentrations. Further studies focusing on the combinatorial use of the markers (total AFP, sensitive AFP-L3%, and DCP) are required.

Usefulness of US-CT 3D dual imaging for the planning and monitoring of hepatocellular carcinoma treatment using HIFU

PURPOSEnWe evaluated the safety and usefulness of high-intensity focused ultrasound (HIFU) assisted by ultrasound-computed tomography three-dimensional (US-CT 3D) dual imaging for the treatment of hepatocellular carcinoma (HCC).nnnMATERIALS AND METHODSnHIFU ablation was performed in 13 patients with small HCC (≤3 lesions, ≤3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under ultrasound guidance. By transferring the sagittal or axial plane of the 3D US and the CT volume data into the ZioM900, multiplanar reconstruction images were displayed in a manner resembling conventional monitor US to assist the HIFU treatment.nnnRESULTSnOverall, 69% (9/13) of the patients in whom good visualization using B-mode sonography could not be obtained because of the influence of multi-reflections, rib shadows, and unclear tumor margins were successfully treated under the guidance of US-CT 3D dual imaging. In 5 of the 13 patients, multi-reflections were responsible for the poor visualization. In 2 cases, the tumor was poorly visualized because of a rib shadow. In one case, the margin of the tumor was too unclear to be detected using ultrasography. The 3D US images obtained as part of the US-CT 3D dual imaging had a high resolution and were useful for examining the area of HCC invasion and for determining the extent of the ablation area. The CT images, which are not influenced by bone shadows or multi-reflections, were useful for detecting the tumors and for visualizing the presence of the intestines in the sonication zone. HIFU treatments were successfully performed in all the patients with the assistance of US-CT 3D dual imaging.nnnCONCLUSIONnUS-CT 3D dual imaging is useful for HIFU treatment for HCC, compensating for the occasionally poor visualization provided by US monitor.

Hyperecho in ultrasound images during high-intensity focused ultrasound ablation for hepatocellular carcinomas

High-intensity focused ultrasound (HIFU) is a noninvasive method that can cause complete coagulation necrosis without requiring the insertion of any instruments. The hyperechoic grayscale change (hyperechoic region) is used as a sign that the treated lesion has been completely coagulated. The purpose of this study was to evaluate the first hyperechoic region during treatment using HIFU ablation according to various conditions, such as the sonication power, the depth of the tumor from the surface of the skin, and the shield rate. HIFU treatment was performed in 20 patients. The HIFU system (Chongqing Haifu Tech, Chongqing, China) was used under ultrasound guidance. Complete coagulation was achieved in 17 cases. Hyperechoic region were detected after HIFU ablation in 17 patients. The size of the hyperechoic region at a depth of >50 mm was significantly smaller than that at a depth of ≤50 mm. The number and power of the sonications for areas at a depth of >50 mm were significantly larger than those for areas at a depth of ≤50 mm. The number and power in cases with a shield rate of 31-60% were significantly larger than those in cases with a shield rate of 0-30%. When the shield rate was 0%, a hyperechoic region occurred, even when a maximum sonication power was not used. In all three cases with tumors located at a depth of greater than 70 mm and a shield rate of larger than 60%, a hyperechoic region was not seen. In conclusion, hyperechoic regions are easy to visualize in cases with tumors located at a depth of ≤50 mm or shield rates of 0-30%.

Effects of IL-28B gene polymorphism on response to peginterferon plus ribavirin combination therapy for genotype 2 chronic hepatitis C

Interleukin (IL)‐28B gene polymorphism is closely linked with treatment response to peginterferon plus ribavirin combination therapy for hepatitis C virus genotype 1. However, few studies have reported its effects on therapy for genotype 2. We aimed to examine the effects of IL‐28B gene polymorphism on treatment response in hepatitis C virus genotype 2 patients.

Hepatic failure in pregnancy successfully treated by online hemodiafiltration: Chronic hepatitis B virus infection without viral genome mutation

A 23‐year‐old nulliparous woman, a hepatitis B virus (HBV) carrier with stable liver functions, presented with exacerbation of viral replication (HBV DNA level >9.0u2009log copies/mL) in gestational week 26. During the subsequent follow up without antiviral therapy, she was hospitalized with progression to hepatic failure in gestational week 35. Following initiation of antiviral therapy with lamivudine, emergent cesarean delivery was conducted for fetal safety. Liver atrophy and persistent hepatic encephalopathy (stage 2) necessitated artificial liver support (ALS) involving online hemodiafiltration (HDF) and plasma exchange. She regained full consciousness after the sixth online HDF session. ALS was terminated after the seventh online HDF session. On day 33 of hospitalization, she was discharged home without sequelae. Genetic analysis of the HBV strain isolated from her serum showed that this strain had genotype C. Direct full‐length sequencing identified no known mutations associated with fulminant hepatitis B. HBV‐related hepatic failure observed in the present case might have been related to perinatal changes in the host immune response.