Noriyoshi Kusano

Percutaneous Radiofrequency Ablation Therapy for Patients with Hepatocellular Carcinoma during Occlusion of Hepatic Blood Flow Comparison with Standard Percutaneous Radiofrequency Ablation Therapy

The therapeutic efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is limited by the small volume of coagulation necrosis obtained at each activation of the RF system and the sometimes irregular burn shape due to the proximity of large vessels that have a cooling effect. To improve the efficacy of RFA, the authors designed RFA with balloon occlusion of the hepatic artery (balloon‐occluded RFA). In this study, we investigated the efficacy of balloon‐occluded RFA and compared the coagulation diameters obtained with balloon‐occluded RFA and standard RFA.

Percutaneous radiofrequency ablation therapy with combined angiography and computed tomography assistance for patients with hepatocellular carcinoma

Radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC) has been reported previously. This technique is superior to percutaneous microwave coagulation therapy (PMCT) for the enlargement of the necrotic area. Therefore, a few treatment sessions of RFA for patients with small HCC lesions measuring < 3 cm in greatest dimension can achieve complete necrosis. To achieve this with a one‐treatment RFA session, the authors designed the technique of RFA with angiography combined with computed tomography (angio‐CT) assistance. The advantages of this technique are that it is possible to detect small satellite nodules and to evaluate the real‐time therapeutic effect immediately after RFA.

Examination of oncogene amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with comparative genomic hybridization analysis

To identify amplified oncogenes involved in hepatocellular carcinomas (HCC), we applied a genomic DNA microarray spotted with 57 oncogenes to 20 HCCs. Aberrations in DNA copy number also were analyzed by comparative genomic hybridization (CGH) using an aliquot of DNA samples. In 5 of 20 HCCs, only 6 oncogenes (CCND1, FGF3/FGF4, SAS/CDK4, TERC, MET, and MYC) were amplified, whereas in the remaining 15 tumors no oncogenes were amplified. A comparison of DNA microarray and conventional CGH analyses showed that, although 5 of 6 amplified oncogenes shown by microarray were located in chromosomal regions shown by CGH to have increased DNA copy numbers, not all genes located in such chromosomal regions were affected. One of the amplified oncogenes (SAS/CDK4) was found in a chromosomal region that was undetected by CGH. We, therefore, conclude that amplification of the oncogenes examined in this series is not directly implicated in hepatocellular carcinogenesis.

A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas.

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.

Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers

In order to elucidate cytogenetic changes characteristic of biliary tract cancer, we examined the genetic imbalances in 18 biliary tract cancers using comparative genomic hybridization (CGH). The most common sites of increases in copy number, in order of frequency, were 17q (33% of the cases), 5p (28%), 3q (22%), 7p (22%), 8q (22%), and 12p (22%), whereas copy number decreases of 6q (28%), 18q (28%), 4q (22%), 5q (22%), and 9p (22%) were frequent. The average number of chromosomal aberrations was significantly greater in stage IV than in stage III tumors (7.9 vs. 2.2/tumor, p < 0.05). The frequent aberrations detected in this study may be related to the development and/or progression of biliary tract cancers. This is the first report on CGH of biliary tract cancers.

Detection of genetic alterations in pancreatic cancers by comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction

The aim of this study was to elucidate cytogenetic changes in pancreatic cancers (PCs) and to examine their clinical implications. We screened for genetic alterations in 32 primary PCs including 4 cases with distant organ metastasis using comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR). The present study revealed frequent gains of chromosomes 13q and 15q and a loss of Xq in addition to a high prevalence of chromosomal imbalances. The average number of total genetic alterations and gains tended to be higher in N1 tumors (TNM classification) than in N0 tumors. The average number of amplifications was significantly higher in M1 tumors than in M0 tumors (p = 0.024). Gain/amplification of 20q was more frequently observed in M1 tumors than in M0 tumors (p = 0.016), and this change was also detected in all of 4 distant metastatic lesions. Losses of 6q, 8p, 9p, 17p, and 18q were recurrent in N0 and M0 tumors, and these alterations were also retained in N1 and M1 tumors. These observations suggest that these genetic losses contribute to the development of PCs and that increases in the DNA copy number confer an aggressive character on cancer cells. Especially, gain/amplification of 20q was associated with the potential of distant organ metastasis of tumor cells.

Novel arterial infusion chemotherapy using cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma

Advanced hepatocelluar carcinoma (HCC) has a poor prognosis. In this study, the authors evaluated the efficacy of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), and leucovorin (LV), comparing our regimen with chemotherapy using CDDP and 5-FU. Nineteen patients with advanced HCC were treated by arterial infusion of a chemotherapeutic agent via a subcutaneously implanted injection port. In Group A (n=9), one course of chemotherapy consisted of the daily administration of CDDP (10 mg/1 h, on 5 days) and LV (12 mg/10 min, on 5 days) followed by 5-FU (250 mg/5 h, on 5 days). In Group B (n=10), except for the administration of LV, the same regimen was employed. This course was repeated each week for 4 weeks. In Group A, two patients showed a complete response (CR), and the other three showed a partial response (PR). In Group B, two patients showed PR. The response rate (CR+PR/all cases) in Group A was significantly higher than that in Group B (56 vs. 20%; P=0.022). The 1- and 2-year survival rates of Group A (66.7, 44.4%) were significantly higher than those of Group B (10, 0%) (P=0.033). These results suggest that our regimen may be useful in treating patients with advanced HCC.

Evaluation of the Reliability of Chromosomal Imbalances Detected by Combined Use of Universal DNA Amplification and Comparative Genomic Hybridization

Comparative genomic hybridization (CGH) analysis of microscopic tumor samples is allowed by universal DNA amplification using degenerate oligonucleotide primed‐PCR (DOP‐PCR). To evaluate the reliablity of DOP‐PCR CGH, we performed DOP‐PCR CGH and standard CGH in parallel using DNAs extracted from 10 malignant tumors of the hepatobiliary tract and pancreas. Similar results were obtained by both methods with a few exceptions, indicating that DOP‐PCR CGH provides cytogenetic information equivalent to that obtained from standard CGH. We also investigated the sensitivity of DOP‐PCR CGH using sequential dilutions of DNA from microdissected tumor cells. DOP‐PCR using 100 to 800 pg of template DNA yielded successful CGH results. However, less than 50 pg of template DNA was not suitable because of the small amount of generated DNA. These findings suggest that DOP‐PCR CGH is applicable for CGH analysis of tiny specimens which are too small for standard CGH. Accordingly, DOP‐PCR CGH analysis may become a useful method in clinical laboratory examination.

Fulminant hepatitis complicated by small intestine infection and massive hemorrhage

Abstract: A 34-year-old man diagnosed with fulminant hepatitis, caused by hepatitis B virus, and acute renal failure was referred to our hospital. After admission to the intensive care unit, the liver and renal failure were ameliorated. Melena requiring transfusion occurred during the course of his illness. Endoscopic examination demonstrated pseudomembranes, erosions, ulcers, and hemorrhage in the duodenum, the upper jejunum, and the terminal ileum, suggesting widespread lesions throughout the small intestine. Pseudomonas putida, Xanthomonas maltophilia, and Candida glabrata were cultured from ileal fluid. Candida glabrata was also detected in sputum, feces, and on an intravenous catheter tip. The patient was treated with amphotericin B and miconazole. The melena was ameliorated, but inflammation of the small intestine persisted. Although we had difficulty in treating the enteritis, the patient survived, and 1 year later colonoscopic examination demonstrated no abnormalities. The small intestine is a difficult site to examine, but endoscopic examination of this site is important when massive hemorrhage develops.