Tomoyuki Yano

Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice.

Chronic intermittent injection of carbon tetrachloride (CCI4) for more than 10 weeks induced liver fibrosis in mice, as evidenced by positive Azan staining and increased intrahepatic collagen content. Preceding the onset of liver fibrosis, interleukin‐6 (IL‐6) gene expression was enhanced in liver and immunoreactive IL‐6 was detected in infiltrating inflammatory cells. To delineate the role of IL‐6 in this process, we treated IL‐6‐deficient mice with CCl4 in a similar manner for 12 weeks, after which fibrotic changes were less evident and serum albumin levels were lower in IL‐6‐deficient than wild‐type mice. Moreover, CCl4‐induced expression of transforming growth factor β1 and hepatocyte growth factor genes in liver was significantly reduced in IL‐6‐deficient mice. Thus, IL‐6 may be vitally involved in fibrotic changes and maintenance of serum albumin levels, partly by modulating intrahepatic expression of these cytokines. J. Leukoc. Biol. 66: 601–608; 1999.

Interleukin-6 produced by pancreatic carcinoma cells enhances humoral immune responses against tumor cells : A possible event in tumor regression

Production of interleukin‐6 (IL‐6) by human pancreatic carcinoma cells inversely correlates with potentials for blood‐borne metastasis to the liver in nude mice. IL‐6 cDNA was transfected to PCI‐43, one of our cultured pancreatic carcinoma cell lines that does not produce IL‐6 and generates numerous metastases to the liver. An IL‐6 high‐producer clone (PCI‐43h) generated few metastases; IL‐6 production thus has a direct effect on metastasis, whereas other transfectants (PCI‐43I and PCI‐43n), which are IL‐6 low‐, and IL‐6 non‐producers, respectively, did generate metastases. Tumor‐reactive IgG, which mediated antibody‐dependent cellular cytotoxicity (ADCC) in vitro, was detected in sera from recipient nude mice inoculated with PCI‐43h but not in sera from mice given PCI‐43I, PCI‐43n or parent PCI‐43. Tumor‐reactive IgM was detected in sera from all mice, irrespective of inoculated PCI‐43 species, with a slight augmentation being noted in PCI‐43h‐inoculated nude mice. Severe combined immunodeficiency (SCID) beige mice were then used as recipients for PCI‐43 species, and tumorigeneity was examined by s.c. inoculation of a suboptimal number of PCI‐43 transfectants (1 × 106/0.1 ml). Only PCI‐43h formed palpable masses in SCID beige mice, whereas it first grew to be palpable but subsequently became not palpable in nude mice, thereby revealing a dual action of tumor‐derived IL‐6. Thus, tumor‐derived IL‐6 confers growth promotion in SCID beige mice, while the same cytokine exhibits anti‐tumorigenic functions, presumably through humoral immune responses, in nude mice. Int. J. Cancer 75:284–289, 1998.

A case of α-fetoprotein-producing pulmonary carcinoma with restricted expression of hepatocyte nuclear factor-4α in hepatoid foci : a case report with studies of previous cases

We report a case of *-fetoprotein (AFP)-producing pulmonary carcinoma with studies for messenger RNA (mRNA) expression of hepatocyte nuclear factor (HNF)-4*, which is a transcription factor that is highly expressed in the process of liver development. The patient was a 64-year-old man with a pulmonary tumor in his left lower lobe. Serum AFP was 673 ng/mL. The microscopic analysis of the surgical specimen revealed a large cell neuroendocrine carcinoma with occasional hepatoid foci. The competitive reverse transcriptase polymerase chain reaction analysis revealed that HNF-4* mRNA was expressed on the order of 10(2)- to 10(3)-fold more abundantly than control pulmonary carcinomas and normal lung tissues. In addition, AFP and HNF-4* expression was restricted in hepatoid foci. Two previously reported cases of AFP-producing pulmonary carcinoma were also positive, whereas all 18 control pulmonary carcinomas were negative for HNF-4*. These findings suggest that aberrant expression of HNF-4* is implicated in the emergence or maintenance of hepatoid foci in AFP-producing pulmonary carcinomas.

The Role of Sialylated Lewis Antigens on Hematogeneous Metastases of Human Pancreas Carcinoma Cell Lines in vivo

Previous studies have shown that sialyl Lewis a (SLea) and sialyl Lewis x (SLex) correlated to hematogenous metastasis of human cancers. Although SLea/SLex and E-selectin act as a set of adhesion molecules in vitro, it is not clear whether the in vivo correlation is exclusively mediated by the adhesion function. To address this issue, we investigated whether or not the role of SLea/SLex antigens on hematogenous metastasis to the liver in SCID mice was exclusively mediated by adhesion by using antibodies for these antigens and SLea/SLEx-negative, human pancreas adenocarcinoma cell line PCI-6. The absence of SLea/SLex expression was supported by the absent flow cytometric detection of the antigens as well as by the absent attachment augmentation to activated endothelial cells. PCI-6 cells are xenotransplantable to nude and SCID mice and produce vascular endothelial cell growth factor (VEGF) in a significant amount. PCI-6 cells, 1 x 10(6), were injected into the spleens of SCID mice, and resultant liver metastases were evaluated six weeks later. We observed an inhibitory effect on the establishment and growth of metastatic colonies when anti-SLea or anti-SLex antibody was administered. This indicates that SLea/x antigens have an important in vivo role, even in the metastasis of SLea/SLex-negative tumor cells. This implies that there may be an in vivo function of SLea/x antigens other than that of the attachment between tumor and endothelial cells.

Laparoscopic pancreaticoduodenectomy combined with minilaparotomy

Laparoscopic pancreatic surgery is evolving rapidly; however, the surgical treatment of periampullary tumors is still fraught with challenges, such as technical difficulty and the appropriateness of oncologic treatment for these patients. We describe how we performed laparoscopic pancreaticoduodenectomy (LPD) combined with minilaparotomy successfully in six consecutive patients. This procedure consisted of two surgical phases: safe laparoscopic surgery, including the Kocher maneuver, tunneling behind the pancreatic neck, and dissecting along the uncinate process with magnified vision; and a secure open approach with complete skeletonization of the hepatoduodenal ligament and alimentary tract reconstruction, performed similarly to conventional pancreaticoduodenectomy, under direct visualization through the minilaparotomy. By performing this procedure, we combined a safe and secure minilaparotomy approach under direct vision with a less invasive laparoscopic approach providing a magnified image. Our experience demonstrates that LPD combined with minilaparotomy is technically feasible for selected patients with periampullary tumors.

Further evidence of hepatic transdifferentiation in hepatoid adenocarcinomas of the stomach: quantitative analysis of mRNA for albumin and hepatocyte nuclear factor-4α

Aim: To assess the production of a liver‐specific protein, albumin, and of a master transcriptional factor, hepatocyte nuclear factor (HNF)‐4α, in hepatoid adenocarcinoma tissue. Methods: Standard and quantitative RT‐PCR, using five cases of hepatoid and three cases of non‐hepatoid gastric adenocarcinoma. Results: Hepatoid adenocarcinomas expressed similarly large amounts of albumin mRNA as those expressed in hepatocellular carcinoma and normal liver tissues. The observed amounts were several hundred times more than those in non‐hepatoid adenocarcinoma and normal stomach tissues. HNF‐4α mRNA was expressed in all stomach samples examined, and the levels of expression did not quantitatively differ between hepatoid and non‐hepatoid adenocarcinomas of the stomach. Conclusions: These results provide further support of a relationship between hepatic transdifferentiation in hepatoid adenocarcinomas and albumin mRNA expression. Furthermore, transdifferentiation to the hepatocytic phenotype in hepatoid adenocarcinoma tissue was not directly associated with HNF‐4α expression, thus suggesting that transdifferentiation proceeds by a complicated mechanism.

Vaccination Effect of Interleukin‐6‐producing Pancreatic Cancer Cells in Nude Mice: A Model of Tumor Prevention and Treatment in Immune‐compromised Patients

In an effort to explore properties important in hematogenous metastasis of pancreatic adenocarcinoma, we previously demonstrated that tumor‐derived interleukin (IL)‐6 is a crucial factor that conveys resistance to liver metastasis. Here we extend the study to examine a possible vaccination effect of tumor‐derived IL‐6 in T‐cell‐deficient nude mice, as a model for predicting the effect in immune‐compromised patients. We used a pair of IL‐6‐nonproducing and highly producing pancreatic adenocarcinoma cell lines, PCI‐43 and PCI‐43h, respectively. The reaction intensity of anti‐PCI IgG antibodies in host nude mice was maximal 28 days after inoculation of PCI‐43h cells, and remained high thereafter. A fraction of the pancreatic carcinoma cell lines, namely, PCI‐6, ‐10, and ‐43, expressed surface antigenic determinant(s) reactive with the IgG; but the others, PCI‐19, ‐24, ‐55, ‐64, ‐66, ‐68, ‐72, and ‐79, did not. Inoculation of PCI‐43h but not PCI‐43 suppressed growth of simultaneously inoculated PCI‐43, but not PCI‐24 xenografts. In addition, administration of PCI‐43h, but not PCI‐43 suppressed the growth of PCI‐43 that was xenografted 4 weeks later, thus revealing a vaccination effect of IL‐6‐producing PCI‐43h, but not IL‐6‐nonproducing PCI‐43. These data, obtained from T‐cell‐deficient nude mice, suggest an in vivo role for IL‐6 in inducing IgG‐mediated, pancreatic carcinoma‐specific vaccination against a thymus‐independent antigen.

Single incision laparoscopic approach for esophageal achalasia: A case report

INTRODUCTION Esophageal achalasia is an uncommon, benign, neurodegenerative disease that induces a transit disorder characterized by incomplete lower esophageal sphincter relaxation. PRESENTATION OF CASE A 56-year-old woman with dysphagia was admitted to our hospital. An esophagography revealed flask-type achalasia. Endoscopy revealed a dilated esophagus and some resistance at the esophagogastric junction. We used a capped wound protector, common straight forceps, and hook-type electrocautery to perform transumbilical single incision laparoscopic Heller myotomy with Dor fundoplication (SILHD). The left liver lobe and cardia were pulled by a thread. A 6-cm Heller myotomy of the esophagus was performed with an additional 2-cm myotomy of the gastric wall. Dor fundoplication was performed to cover the exposed submucosa. Intraoperative endoscopy confirmed the adequacy of the myotomy and Dor fundoplication. There were no postoperative complications. An esophagography and an endoscopic examination did not reveal stenosis or reflux at 1-year follow-up, and the patient has been satisfactorily symptom free. DISCUSSION LHD is the most accepted surgical treatment for achalasia and has low invasiveness and long-term efficacy. SILHD for achalasia is a new approach and may provide improved cosmetics and less invasiveness compared with those by conventional LHD. The 1-year follow-up results in the present case are the longest reported to date. The evaluation of long-term results in a large-scale study is necessary in future. CONCLUSION SILHD can be safe, widely accepted, mid-term minimal invasive and cosmetically superior surgical procedure for achalasia.

A Case of Portal Vein Gas Which was Treated Conservatively and was Potentially Related to the Behcet's Disease

最近の画像診断技術の進歩により, 臨床の現場で門脈ガス血症に出会う機会が増え, その報告数も増加してきている. かつて門脈ガス血症は予後不良の兆候として報告され, 死亡率が75%とも言われていたが, 最近では治癒しえた, 救命しえたという報告が多い. さらに門脈ガス血症を認めたら, 即開腹手術であるという報告に警鐘を鳴らすような報告もなされている. 今回我々は, 保存的に治癒しえた門脈ガス血症の1例を経験したので報告する. なお, 患者は退院3年後にベーチェット病と診断されており, 今回の事例と何らかの因果関係が示唆された.