Masao Yagi

Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection

BACKGROUND/AIMS Prognostic analysis on hepatocellular carcinoma (HCC) in patients undergoing hepatectomy is necessary to determine the clinical value of hepatectomy on prognosis. METHODS Survival and disease-free survival were analyzed in 104 HCC patients undergoing hepatectomy using clinicopathologic factors by univariate and multivariate analyses. The value of the International Union Against Cancer (UICC) TNM classification on prognosis was assessed in the patients. RESULTS In multivariate analysis, portal vein invasion was the most influential factor. The difference between stage 1 and 2 or stage 3 and 4A using UICCs TNM classification was not significant with respect to survival or disease-free survival. The UICCs classification was modified as follows; stage 1, solitary tumor without vascular invasion; stage 2, solitary or multiple tumor(s) involving adjacent to vessel branch; stage 3, tumor(s) involving major vessel branch or with regional lymph nodal metastasis; and stage 4, tumor(s) with distant metastasis. The differences between each stage in the modified classification were significant with respect to disease-free survival. CONCLUSIONS The UICCs TNM classification was not of prognostic significance. Further studies on survival in patients with HCC are necessary to evaluate the value of the UICCs TNM classification; some modification may be necessary.

Hepatic resection using a water jet dissector.

A newly-designed water jet dissector was used for hepatic resections in humans. To evaluate its usefulness, the water jet dissector was compared toan ultrasonic surgical aspirator in terms of average blood loss and time of operation. In hepatectomies on patients associated with liver cirrhosis, the average blood loss during hepatic resection using the water jet dissector was significantly smaller (P<0.05) than that with the ultrasonic surgical aspirator. However, in hepatectomies on patients without cirrhosis, the average blood loss during hepatic resection did not significantly differ between the two groups. Neither did the time of operation significantly differ between the two procedures in hepatectomies on patients with and without liver cirrhosis. No serious complications attributable to the use of the water jet dissector were encountered. The water jet dissector is thus considered to be a useful new device for use in the transection of the liver during hepatic resections.

Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy.

FK506 is a powerful immunosuppressive drug currently in use that inhibits the activation of several transcription factors (nuclear factor (NF)-AT and NF-kappaB) critical for T cell activation. We show here that, contrary to the situation in T cells, FK506 activates transcription factor NF-kappaB in nonlymphoid cells such as fibroblasts and renal mesangial cells. We further show that FK506 induces NF-kappaB-regulated IL-6 production in vitro and in vivo, in particular in kidney. IL-6 has been shown previously to produce renal abnormalities in vivo, such as mesangioproliferative glomerulonephritis. Similar renal abnormalities were also observed in FK506-treated animals. These results thus suggest a causal relationship between FK506-induced NF-kappaB activation/IL-6 production and some of FK506-induced renal abnormalities.

Activation of immediate early gene, c-fos, and c-jun in the rat small intestine after ischemia/reperfusion.

BACKGROUND Activated immediate early genes (IEGs) play key roles in mediating cellular response after ischemia/reperfusion (I/R) injuries in some organs such as liver, heart and kidney. However, there is no report investigating an association between the activation of IEGs and cellular regeneration or programmed cell death after I/R in small intestine. METHODS We examined a sequential expression of c-fos and c-jun after I/R in rat small intestine using reverse transcription-polymerase chain reaction and Northern blot analysis, and compared the patterns with coexistent two parameters: (1) regeneration determined by immunohistochemical detection of proliferating cell nuclear antigen, (2) programmed cell death determined with the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling (TUNEL) method and DNA fragmentation. RESULTS The expression of c-fos and c-jun mRNA increased markedly 15 min after reperfusion and was, respectively, 6.3 and 4.4 times higher than in controls. Proliferating cell nuclear antigen expression was significantly elevated between 5 min and 4 hr, peaking at 30 min after reperfusion. Apoptosis showed a peak 60 min after reperfusion. Apoptosis after I/R was detected in the nuclei of absorptive epithelial cells by the TUNEL method, and these apoptotic signals were consistent with the expression of c-Fos and c-Jun proteins using an immunohistochemical method. CONCLUSIONS These results suggest that overexpression of c-fos and c-jun after I/R in the small intestine correlates with programmed cell death and subsequent cellular regeneration.

Hypoxia, but not reoxygenation, induces interleukin 6 gene expression through NF-κB activation

Interleukin (IL) 6 is one of major mediators of inflammation, and IL-6 gene activation during hypoxia/reoxygenation has been implicated in the pathogenesis of ischemia/reperfusion injury. However, molecular events involved in IL-6 gene expression during hypoxia/reoxygenation remain to be identified. We have previously shown that NF-kappa B plays an essential and indispensable role in the transcriptional activation of the IL-6 gene induced by various stimuli, including IL-1 and tumor necrosis factor-alpha. We show here that hypoxia, but not reoxygenation, induces the activation of NF-kappa B through the degradation of a major inhibitor of NF-kappa B, I kappa B alpha. This hypoxia-induced NF-kappa B activation resulted in the kappa B-dependent transcriptional activation of the IL-6 gene. Interestingly, the time course of hypoxia-induced NF-kappa B activation was rather slow as compared with those of NF-kappa B activation induced by other stimuli, such as IL-1: a significant NF-kappa B activation was not observed before 1 hr of hypoxia treatment and persisted for up to 7 hr of hypoxia treatment. However, hypoxia-induced NF-kappa B activation was not inhibited by cycloheximide, which indicates that hypoxia directly triggers NF-kappa B activation. Furthermore, while hypoxia is unlikely to generate reactive oxygen intermediates, pretreatment of cells with antioxidants such as N-acetyl cysteine and alpha-tocopherol inhibited NF-kappa B activation induced by hypoxia. Thus, we discuss possible implications of these results for a postulated role of reactive oxygen intermediates in NF-kappa B activation.

Alteration of β‐catenin expression in esophageal squamous‐cell carcinoma

β‐catenin regulates cadherin‐mediated cell‐cell adhesion and also functions as a signaling molecule. In this study, we examined the expression pattern of E‐cadherin, α‐catenin and β‐catenin in 22 cases of esophageal squamous‐cell carcinoma by Western‐blot analysis. Expression of E‐cadherin, α‐catenin and β‐catenin was lower in carcinomas than in normal esophageal mucosa in 4 cases (18.2%) for E‐cadherin, 6 cases (27.3%) for α‐catenin and 9 cases (40.9%) for β‐catenin. Expression of β‐catenin was not always correlated with that of E‐cadherin. Over‐expression of β‐catenin was observed in 3 cases (13.6%). Of 3 cases that presented with over‐expression of β‐catenin, 2 showed cytoplasmic staining by immunohistochemistry. Nuclear localization of β‐catenin was observed in one case that had higher β‐catenin level in tumor tissue (1.4‐fold higher than normal mucosa). The genomic DNA sequences of the β‐catenin and the APC gene were analyzed. No mutation of the β‐catenin gene was observed in any cases. Silent mutation of the APC gene was found in all the cases that showed over‐expression or nuclear localization of the β‐catenin protein. These results indicate that alterations of the cadherin‐catenin complex may play an important role in a sub‐set of esophageal carcinogenesis. Furthermore, it is suggested that β‐catenin over‐expression is not caused by genetic alteration of either the β‐catenin or the APC gene. Int. J. Cancer 85:757–761, 2000.

Activation of c-Jun N-terminal kinase during ischemia and reperfusion in mouse liver

We have generated a mouse model for hepatic ischemia in which surgical subcutaneous transposition of the spleen allows hepatic ischemia to be applied without affecting other tissues. Using this mouse model we investigated the relationship between the length of ischemic periods in the liver and subsequent liver function; furthermore, we assayed the activation of c‐Jun N‐terminal kinase (JNK) during ischemia and reperfusion. Although prior to this study only the activated form of JNK was known to be translocated to the nucleus, we found that JNK translocates to the nucleus during ischemia without activation and is then activated during reperfusion. These results suggest a novel mechanism of JNK activation.

Four cases of selenium deficiency in postoperative long-term enteral nutrition

Because selenium is seldom added to formulations for enteral nutrition (EN), postoperative patients who are supported with EN are at risk for selenium deficiency. This report describes four cases of suspected selenium deficiency in long-term EN. Two patients underwent pancreaticoduodenectomy, one underwent total gastro-pancreatectomy, and one underwent esophageal resection and reconstruction with jejunal autotransplantation. They all developed malabsorption syndrome within 2 yr after operation. Enteral nutritional support with an elemental diet was provided continuously for 7-11 yr. Over the past 1-2 yr they experienced increasing bilateral muscular pain and weakness in the legs, gait disturbance, palpitation, and shortness of breath. Investigation for possible trace element deficiency revealed very low levels of selenium in the blood. After 10-20 d of supplementation with daily intravenous administration of selenious acid 0.16 mg/d (100 micrograms/d of selenium), their blood levels of selenium rose and their symptoms resolved. They were then continued on a maintenance regimen of oral sodium selenite 0.13 mg/d (60 micrograms/d of selenium).

Regeneration of Small Intestinal Mucosa After Acute Ischemia–Reperfusion Injury

To determine whether c-Fos and c-Jun are involved in the repair of small intestinal mucosa after ischemia–reperfusion (I/R), we investigated the mechanism of regeneration following acute I/R injury in rats by evaluating changes in DNA synthesis, fractional synthesis rate (FSR) of proteins, and alkaline phosphatase (ALP) activity. Furthermore, we examined the sequential expression of c-Fos and c-Jun using western blot analysis and immunohistochemical staining. Proliferating cell nuclear antigen (PCNA) labeling index (LI) demonstrated that the LI of the I/R group at 2 and 6 hr after reperfusion was significantly higher than that of the controls. Statistically significant differences were found between the FSRs of the I/R group and the corresponding conventional group at 2, 6, and 12 hr. The expression of c-Fos and c-Jun proteins increased markedly after I/R and these proteins decreased with time. The levels of ALP in the I/R group were significantly decreased at 2 and 6 hr after reperfusion compared to controls. These results indicate that c-Fos and c-Jun play a central role in the repair process that results in complete restoration of intestinal mucosal function after I/R.

A case of pheochromocytoma with severe paralytic ileus

We report herein a rare case of a 26 year old woman with pheochromocytoma complicated by paralytic ileus. She presented with remarkable abdominal distension and respiratory difficulty but was effectively treated by surgical removal of the tumor with preoperative and operative management using α and β adrenergic blocking agents. An excessive and persistent catecholamine production from large tumors or massive metastases characterizes this rare complication, and a review of the English and Japanese literature is given following this report.