Naohide Mori

Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection

BACKGROUND Hepatocellular carcinoma has a poor prognosis because of the high intrahepatic recurrence rate. There are technological limitations to traditional methods such as TNM staging for accurate prediction of recurrence, suggesting that new techniques are needed. METHODS We investigated mRNA expression profiles in tissue specimens from a training set, comprising 33 patients with hepatocellular carcinoma, with high-density oligonucleotide microarrays representing about 6000 genes. We used this training set in a supervised learning manner to construct a predictive system, consisting of 12 genes, with the Fisher linear classifier. We then compared the predictive performance of our system with that of a predictive system with a support vector machine (SVM-based system) on a blinded set of samples from 27 newly enrolled patients. FINDINGS Early intrahepatic recurrence within 1 year after curative surgery occurred in 12 (36%) and eight (30%) patients in the training and blinded sets, respectively. Our system correctly predicted early intrahepatic recurrence or non-recurrence in 25 (93%) of 27 samples in the blinded set and had a positive predictive value of 88% and a negative predictive value of 95%. By contrast, the SVM-based system predicted early intrahepatic recurrence or non-recurrence correctly in only 16 (60%) individuals in the blinded set, and the result yielded a positive predictive value of only 38% and a negative predictive value of 79%. INTERPRETATION Our system predicted early intrahepatic recurrence or non-recurrence for patients with hepatocellular carcinoma much more accurately than the SVM-based system, suggesting that our system could serve as a new method for characterising the metastatic potential of hepatocellular carcinoma.

Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH

To clarify the genetic aberrations involved in the development and progression of hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC), we investigated DNA copy number aberrations (DCNAs) in 19 surgically resected HCCs by conventional CGH and array CGH. Conventional CGH revealed that increases of DNA copy number were frequent at 1q (79% of the cases), 8q (37%), 6p (32%), and 10p (32%) and that decreases were frequent at 17p (79%), 16q (58%), 4q (53%), 13q (42%), 10q (37%), 1p (32%), and 8p (32%). In general, genes that showed DCNAs by array CGH were usually located in chromosomal regions with DCNAs detected by conventional CGH analysis. Increases in copy numbers of the LAMC2, TGFB2, and AKT3 genes (located on 1q) and decreases in copy numbers of FGR/SRC2 and CYLD (located on 1p and 16q, respectively) were observed in more than 30% of tumors, including small, well-differentiated carcinomas. These findings suggest that these genes are associated with the development of HCV-HCC. Increases of MOS, MYC, EXT1, and PTK2 (located on 8q) were detected exclusively in moderately and poorly differentiated tumors, suggesting that these alterations contribute to tumor progression. In conclusion, chromosomal and array CGH technologies allow identification of genes involved in the development and progression of HCV-HCC.

Differential gene expression in distinct virologic types of hepatocellular carcinoma: association with liver cirrhosis

Using oligonucleotide microarray data of 45 hepatocellular carcinoma (HCC) samples, we evaluated gene expression in hepatitis B virus-positive and hepatitis C virus-positive HCCs (HBV- and HCV-HCCs) for an association with liver cirrhosis (LC). In all, 89 genes were expressed differentially between HBV-HCCs associated with LC and those not associated with LC. Among them, tumors from LC patients showed significantly lower expression levels of 72 genes and significantly higher levels of 17 genes than the levels found in tumors from non-LC patients. The former included genes responsible for signal transduction, transcription, metabolism, and cell growth. The latter included a tumor suppressor gene and a cell-growth-related gene. Only eight genes were expressed differentially between HCV-HCCs associated with and without LC. Our findings provide as a framework for clarifying the role of LC in HBV- and HCV-related hepatocarcinogenesis.

Gene expression profile linked to p53 status in hepatitis C virus‐related hepatocellular carcinoma

To clarify the role of p53 in 22 hepatitis C virus (HCV)‐infected hepatocellular carcinomas (HCCs), we compared the gene expression profiles of HCCs with wild‐type p53 (wt‐p53) (n=17) and those with mutant‐type p53 (mt‐p53) (n=5) by oligonucleotide microarray analysis. Among 83 p53‐related genes identified by a supervised learning method, 25 were underexpressed, and 58 were overexpressed in mt‐p53 HCCs compared with wt‐p53 HCCs. With a computer search, we identified consensus p53‐binding sequences in the 3‐kb region upstream of the translation initiation site in 59 of the 83 genes, suggesting that the in vivo p53‐associated transcription system is very complicated. These data will provide additional insights into p53‐related pathogenesis in HCV‐infected HCC.

Self-organizing-map-based molecular signature representing the development of hepatocellular carcinoma

Using high‐density oligonucleotide array, we comprehensively analyzed expression levels of 12 600 genes in 50 hepatocellular carcinoma (HCC) samples with positive hepatitis C virus (HCV) serology (well (G1), moderately (G2), and poorly (G3) differentiated tumors) and 11 non‐tumorous livers (L1 and L0) with and without HCV infection. We searched for discriminatory genes of transition (L0 vs. L1, L1 vs. G1, G1 vs. G2, G2 vs. G3) with a supervised learning method, and then arranged the samples by self‐organizing map (SOM) with the discriminatory gene sets. The SOM arranged the five clusters on a unique sigmoidal curve in the order L0, L1, G1, G2, and G3. The sample arrangement reproduced development‐related features of HCC such as p53 abnormality. Strikingly, G2 tumors without venous invasion were located closer to the G1 cluster, and most G2 tumors with venous invasion were located closer to the G3 cluster (P = 0.001 by Fishers exact test). Our present profiling data will serve as a framework to understand the relation between the development and dedifferentiation of HCC.

Laparoscopic resection of large leiomyomas of the gastric fundus

Two patients with a large leiomyoma arising from the gastric fundus underwent laparoscopic resection. In case 1, the tumor was located in the anterior wall of the gastric fundus. To prevent stenosis and preserve the volume of the residual stomach, intragastric resection was adopted. The tumor was markedly and resected with laparosonic coagulating shears with a 1-cm safety margin. In case 2, a large tumor was detected in the duodenal bulb. Serious hemorrhage mandated emergency resection. The tumor originated from the posterior wall of the fundus. Attempts at reduction with the forceps failed. Reduction by digital manipulation via laparoscopic port sites was successful. An endostapler was used to resect the tumor and close the anterior wall. Both patients recovered uneventfully.

Nm23-H1 gene as a molecular switch between the free-floating and adherent states of gastric cancer cells

The contribution of the nm23-H1 gene to metastasis in malignant tumors, including gastric cancer, is controversial. In this study, we compared nm23-H1 levels in two cell subtypes with different morphologies (floating and adherent states), but that were derived from the same gastric cancer cell line, KATO-III. A real-time quantitative reverse transcription-polymerase chain reaction showed that the number of nm23-H1 mRNA molecules in floating cells was significantly higher than that in adherent cells (P<0.0001). The average of the copies in floating cells was approximately 2.4-fold higher than that in adherent cells. Consistent with mRNA levels, intracellular levels of nm23-H1 protein were higher in floating cells than in adherent cells. There was no difference in cell cycle characteristics between the two subtypes. In conclusion, our present data indicate that expression of nm23-H1 by a tumor could be altered during the different steps in metastases, suggesting that nm23-H1 may act as a molecular switch between the free-floating and adherent states of cancer cells.

A Case Report of Superior Mesenteric Artery Syndrome after abdominoperineal Excision of Rectal Cancer.

上腸間膜動脈症候群 (以下, SMASと略記) は急激な体重減少を契機として発症することが多く, 原則的には保存的治療が奏効する. われわれは, 直腸癌の腹会陰式直腸切断術後にSMASを発症し, 保存的治療が無効で手術を施行した症例を経験した. 術後に小腸が小骨盤腔に落ち込み強固に癒着して腸間膜根の過緊張をきたし, 上腸間膜動脈が十二指腸水平脚を圧迫したことが原因であった. これに対して十二指腸授動術を行い, いったんは軽快したがSMASは再発した. 再手術では十二指腸空腸側々吻合術を施行した. 術後8年経過した現在に至るまで腸閉塞は起こさず, 良好に経過している.SMASの手術適応は諸家によりさまざまであるが, 上部消化管造影と超音波検査とをあわせて腸間膜根部の可動性を適切に評価することが治療方針を決定する上で重要である. 手術術式は, 十二指腸空腸側々吻合術が, 手技的にも簡単で吻合口も十分にとれ治療効果も確実な方法として推奨される

A case report of mixed type hepatocellular carcinoma with early recurrence in the form of peritoneal dissemination after hepatectomy.

症例は59歳女性で, 47歳時B型急性肝炎発症, 54歳時に肝硬変の診断を受け, 経過観察されていた. 有茎性肝細胞癌の診断にて当科紹介され, 肝部分切除を施行し, 低分化型肝細胞癌の一部に胆管細胞成分を含む混合型肝癌と診断された. 術後75日目に癌性腹膜炎にて死亡し, 剖検で高度な腹腔内播種が確認されたが, 他に肉眼的転移を認めなかった. 播種巣の組織像はごく一部に胆管細胞成分がみられたが, 原発巣と同様の低分化型肝細胞癌が優勢であった. 肝細胞癌の播種性転移の頻度は低いとされているが, 常にその可能性を念頭に置き対策を講ずる必要がある.