Transforming growth factor-beta1 induced hepatocyte apoptosis--a possible mechanism for growth of colorectal liver metastasis

The mechanisms of colonization and growth of metastatic liver tumors from colorectal cancers remain obscure. Forty-three resected colorectal metastatic liver tumors with surrounding livers were evaluated for apoptotic index (AI), proliferation index (PI), and immunohistochemical expressions of TGF-beta1. TGF-beta receptor II, Fas, and Fas-ligand. All the parameters were significantly higher in the peri-tumoral livers than in the tumors with the exception of PI, which was significantly high in tumors. Enhanced TGF-beta1 expression was noticed at the interface between the metastatic tumor and the adjacent liver parenchyma. The AIs of hepatocytes in the TGF-beta1-positive areas (8.7 +/- 7.5%, n = 43) were significantly higher when compared with those in the TGF-beta1-negative areas (2.4 +/- 4.5%, n = 42) (p < 0.001). However, the same kind of correlation could not be found in metastatic tumors. The enhanced expression of TGF-beta1 and hepatocyte apoptosis in the peri-tumoral liver parenchyma may suggest that TGF-beta1 plays a substantial role in the development of colorectal liver metastasis.     

Regulation of cytokine production in carcinoembryonic antigen stimulated Kupffer cells by beta-2 adrenergic receptors: implications for hepatic metastasis

Elevated Carcinoembryonic antigen (CEA) levels in the serum indicate a poor prognosis for colorectal cancer patients. Induction of proinflammatory cytokines by CEA interaction with Kupffer cells has been proposed as a mechanism for hepatic metastasis formation. Studies show that the cytokine response in circulating and peritoneal macrophages is regulated by beta-adrenergic receptor signals, though little information is available regarding Kupffer cells. We investigated the relationship between beta-adrenergic receptor stimulation and the response of Kupffer cells to CEA. Comparisons between unstimulated and CEA stimulated rat Kupffer cells, using cDNA arrays, showed up-regulation (>4 fold) of the beta2-adrenergic receptor mRNA. Peak up-regulation occurred after 30 min with a decline at 1 h. We examined the effects of the specific beta2-adrenergic receptor agonist terbutaline on cytokine production by CEA stimulated rat Kupffer cells. Pre-treatment of Kupffer cells with terbutaline followed by CEA caused a significant increase in IL-6 and IL-10 production, but a significant reduction in TNF-alpha production (>3 fold). mRNA levels reflected those of the ELISA assays for IL-6 and IL-10 but not for TNF-alpha. For IL-6 and TNF-alpha, these changes were serum independent, while IL-10 was serum dependent. This response is different from LPS treated Kupffer cells where all three cytokines showed serum dependency. Overall, these data suggest that Kupffer cell stimulation by CEA is under beta-adrenergic receptor control and induction of the beta-receptor is an early event following CEA binding to its receptor. Control of TNF-alpha production is negatively affected by terbutaline, while that of IL-6 and IL-10 is positively controlled suggesting that very different beta-adrenergic receptor signaling pathways are involved.     

A multi-institutional survey of the effectiveness of chemotherapy combined with radiotherapy for patients with nasopharyngeal carcinoma

BACKGROUND: Previous randomized trials have shown a survival advantage of concurrent platinum-based chemoradiotherapy with or without adjuvant chemotherapy for advanced nasopharyngeal cancer. Applicability of these data to a Japanese population is an important issue which remains to be solved. METHODS: A retrospective survey of treatment of patients with nasopharyngeal cancer in 17 institutions in Japan was done with special reference to the relationship between the type of chemotherapy and survival outcome. Chemotherapy used was classified according to: (i) whether > or =2 courses of platinum plus 5-fluorouracil (FP) was given; or (ii) whether platinum was administered concurrently with radiotherapy (RT). This resulted in three groups being produced consisting of (i)/(ii) = YES/YES, other miscellaneous (MISC) and RT alone. RESULTS: Of 333 evaluable replies, 67 patients (20%) corresponded to the YES/YES, 192 (58%) to the MISC and 74 (22%) to the RT alone group. The YES/YES group achieved a better overall survival than RT alone for patients with intermediate stage (T3N0 or T1-3N1, 81.9 versus 60.7% at 5 years, P = 0.042) and advanced stage (T4 or N2/3, 56.6 versus 31.5%, P = 0.017) disease. The MISC group achieved an almost identical survival rate to that in the YES/YES group for patients with intermediate stage disease (81.9% at 5 years, P = 0.968), whereas it was not significantly different from that of the RT alone group for patients with advanced stage disease (44.0%, P = 0.261). CONCLUSION: The results of this survey mirrored the data from previous randomized trials for patients with intermediate and advanced stage nasopharyngeal cancer in Japan. However, confirmatory prospective trials are required to test the efficacy of less toxic approaches for patients with intermediate stage disease.     

A case of long survival with UFT and lentinan treatment in a patient with peritoneal metastasis of gastric carcinoma

The patient was a 50-year-old female with peritoneal metastasis of Type 4 gastric cancer. She underwent a relative curative resection with total gastrectomy and peritonectomy. Postoperative chemotherapy with 5'-DFUR following 5-FU and CDDP was performed. Thirteen months after surgery, cancer recurrence was suspected due to elevated levels of the serum tumor markers carcinoembryonic antigen (8.9 ng/ml) and alpha fetoprotein (85.8 ng/ml). She was additionally treated with UFT 300 mg/day and Lentinan 2 mg/week. The serum tumor markers decreased gradually returned to normal levels. At 5 years and 8 months after surgery, she is alive without any sign of recurrence.     

Usefulness of weekly administration of paclitaxel for advanced or recurrent gastric cancer

We report herein the efficacy and feasibility of weekly administration of paclitaxel for advanced/recurrent gastric cancer retrospectively. Eleven patients with advanced or recurrent gastric cancer who had received prior chemotherapy were treated with this regimen. Seventy mg of paclitaxel per m2 dissolved in 250 ml 5% glucose was administered by 1-hour intravenous infusion once a week for 3 weeks followed by 1 week rest. To avoid hypersensitivity reactions, the following short premedication was given to all the patients 1 hour before paclitaxel treatment: Dexamethasone 20 mg intravenously (i.v.), diphenhydramine 50 mg i.v., and ranitidine 50 mg i.v. Treatment cycle was 1 to 23 with an average cycle of 5.4. The response rate was 33% (2/6 with measurable lesions), the median time to progression was 104 days, and the median survival time was 160 days. Grade 3 neutropenia occurred in 27.2% of the patients. Weekly paclitaxel may be a promising regimen as a second-line chemotherapy for advanced/recurrent gastric cancer. However, special attention needs to be paid to the neutropenic adverse effect in gastric cancer patients with poor performance status than 2 (greater).     

A case of metastatic liver tumor from colorectal carcinoma--continued arterial infusion chemotherapy through a microcatheter located in replaced right hepatic artery

The patient was a 78-year-old male with a history of colon cancer. After surgical resection of colon cancer, he suffered a multiple liver metastasis. We treated him by arterial infusion chemotherapy with the catheter edge embedded at the common hepatic artery. For a long period, the lesions were defined as partial response on WHO-criteria, but a wide area of the common hepatic artery was shrunk. After changing the treatment to systemic intravenous chemotherapy, the metastatic lesions began to enlarge. Then, we somehow were able to put a microcatheter into the replaced right hepatic artery (rRHA), and could restart arterial infusion chemotherapy. We continued this procedure for over a year without any complication.     

Bone density in myasthenia gravis patients receiving long-term prednisolone therapy

Osteoporosis is an adverse effect of prednisolone therapy, although no study has been conducted on myasthenia gravis patients receiving high-dose prednisolone. We measured bone density in 36 patients (26 females and 10 males) who had undergone long-term prednisolone administration, and found a decrease in bone density in 31% of female patients and osteoporosis in only 11.5% (three cases). This frequency is lower than the presumptive rate of the general population in Japan (22.6%). No osteoporosis was detected in male patients. In conclusion, prednisolone-treated patients with myasthenia gravis have an acceptable risk of bone loss if prophylactic medication is administered.     

Clinical investigation of genetic contributions to childhood-onset epilepsies and epileptic syndromes

Although there have been major advances in the understanding of the molecular bases of certain inherited epilepsy syndromes, clinical studies are still needed to verify the possible genetic contributions to common epilepsies. We examined the proportions of positive family histories of epilepsy (within second-degree relatives) and consanguinity (within first-degree relatives) in 311 probands with childhood-onset epilepsy, and found that they had high family history rates of epilepsy (19.3%) and consanguinity (6.1%). A positive family history of epilepsy was found more in probands with generalized epilepsy than in ones with localization-related epilepsy, and more in probands with idiopathic/cryptogenic epilepsy than in ones with symptomatic epilepsy. However, on analysis after the symptomatic epilepsies had been divided into two categories, probands with pre- or perinatal symptomatic generalized epilepsy and ones with postnatal symptomatic localization-related epilepsy showed high positive family history rates, similar to ones with idiopathic/cryptogenic epilepsy. On the other hand, a positive family history of consanguinity was noted more in probands with generalized epilepsy than in ones with localization-related epilepsy, but there was no significant difference between probands with idiopathic/cryptogenic epilepsy and ones with symptomatic epilepsy. These findings suggest that in addition to the hereditary effect on idiopathic/cryptogenic epilepsy, a genetic susceptibility may contribute to the development of pre- or perinatal symptomatic generalized epilepsy, and to that of postnatal symptomatic localization-related epilepsy. Furthermore, a genetic predisposition seems to have an influence through consanguinity on the etiologies of both idiopathic/cryptogenic and symptomatic generalized epilepsies.