A case of primary malignant melanoma of the esophagus with long-term survival

Primary malignant melanoma of the esophagus is uncommon, and its prognosis is poor compared to that of cutaneous malignant melanoma. Here we describe a case of primary malignant melanoma of the esophagus with a long-term survival. A 52-year-old woman received an upper gastrointestinal endoscopy and an upper gastrointestinal series for a dull back pain and dysphagia. A pigmented polypoid tumor in the esophagus was discovered and diagnosed pathologically as a malignant melanoma on the biopsied specimen. After effective chemotherapy with cisplatin (CDDP), the patient underwent surgical operation. A subtotal esophagectomy with three-field lymph node dissection was performed through a right thoracotomy. No distant metastasis including liver and lung was found, and histopathological examination revealed no lymph node metastasis. Postoperatively, six courses of chemotherapy with CDDP were performed. The patient has been alive without any problems for more than 11 years postoperatively.     

Probucol and atorvastatin decrease urinary 8-hydroxy-2'-deoxyguanosine in patients with diabetes and hypercholesterolemia

To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total- and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 +/- 7.5 to 8.1 +/- 4.2 ng/mg/Cr in the atorvastatin group (p < 0.05) and 12.3 +/- 8.8 to 6.8 +/- 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 +/- 4.9 to 9.2 +/- 3.4 ng/mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 +/- 8.2 to 6.67 +/- 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress.     

Intra‐arterial 5‐fluorouracil/interferon combination therapy for hepatocellular carcinoma with portal vein tumor thrombosis and extrahepatic metastases

Background and Aims: We investigated the efficacy of intra‐arterial 5‐fluorouracil (5‐FU) and systemic interferon (IFN)‐α (5‐FU‐IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. Methods: We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non‐meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5‐FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. Results: For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non‐meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non‐meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P < 0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P < 0.001) and overall survival (P < 0.001). No patient died of extrahepatic HCC‐related disease. Conclusions: The efficacy of 5‐FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited.     

SAP-1 is a microvillus-specific protein tyrosine phosphatase that modulates intestinal tumorigenesis

SAP-1 (PTPRH) is a receptor-type protein tyrosine phosphatase (RPTP) with a single catalytic domain in its cytoplasmic region and fibronectin type III-like domains in its extracellular region. The cellular localization and biological functions of this RPTP have remained unknown, however. We now show that mouse SAP-1 mRNA is largely restricted to the gastrointestinal tract and that SAP-1 protein localizes to the microvilli of the brush border in gastrointestinal epithelial cells. The expression of SAP-1 in mouse intestine is minimal during embryonic development but increases markedly after birth. SAP-1-deficient mice manifested no marked changes in morphology of the intestinal epithelium. In contrast, SAP-1 ablation inhibited tumorigenesis in mice with a heterozygous mutation of the adenomatous polyposis coli gene. These results thus suggest that SAP-1 is a microvillus-specific RPTP that regulates intestinal tumorigenesis.     

Prevention by Methionine of Enhancement of Hepatocarcinogenesis by Coadministration of a Choline-deficient L-Amino Acid-defined Diet and Ethionine in Rats

The effects of methionine on hepatocarcinogenesis induced by Coadministration of a choline-deflcient L-amino acid-defined (CDAA) diet and ethionine were examined. F344 male rats were divided into 4 experimental groups. Groups 1 and 2 received the CDAA diet and a choline-supplemented L-amino acid-defined (CSAA) diet, respectively. Group 3 received the CDAA diet containing 0.05% ethionine, and group 4 the CDAA diet containing 0.05% ethionine and 0.47% methionine. Animals were killed after 12 weeks of treatment. Histologically, the CDAA diet induced intracellular fat accumulation and foci. In contrast, ethionine caused not only foci, but also hyperplastic nodules, cholangiofibrosis and the proliferation of oval cells without such fat accumulation. Methionine abolished the development of all of the liver lesions induced by Coadministration of the CDAA diet and ethionine. To investigate the effects of methionine on induction of c- myc and c-Ha- ras expression, as well as generation of 8-hydroxyguanine (8-OHGua) and 2-thiobarbituric acid-reacting substances (TBARS), by Coadministration of the CDAA diet and ethionine, subgroups of 3 to 5 animals were killed at 2, 4, 8 or 11 days after the beginning of the experiment. Coadministration of the CDAA diet and ethionine markedly enhanced the level of expression of c- myc and c-Ha- ras , 8-OHGua formation and TBARS generation as compared with the CDAA or CSAA diet within 11 days, and methionine blocked these actions. These results indicate that addition of methionine prevents the induction of c- myc and c-Ha- ras expression, 8-OHGua formation and TBARS generation, as well as hepatocellular lesions, by Coadministration of the CDAA diet and ethionine in rats, and suggest a possible involvement of oxidative stress and gene expression in hepatocarcinogenesis by these agents.     

Aortic valve replacement in patients age 70 years and older: early and late results

This retrospective analysis was performed to determine the early and late outcome in patients 70 years and older undergoing aortic valve replacement (AVR). From October 1994 to May 2001, 49 patients (24 men and 25 women, age 70 to 88 years [mean 74 +/- 4.6 years]) underwent primary AVR with or without concomitant procedures. Twenty-one received mechanical valves and 28 bioprostheses. Age was different between both groups: 72 +/- 2.3 years (mechanical) and 76 +/- 5.1 years (bioprosthetic) (p = 0.0005). Aortic stenosis was present in 25 patients (51%). Follow-up was 100% complete at a mean follow-up of 2.9 years (range 0.3-6.5 years). Overall hospital mortality was 4.1% (2/49). There were no postoperative complications in 24% of patients. Postoperative hospital stay or hospital survival was 27 +/- 13 days. Survival at 3 and 5 years was 89 +/- 5% and 80 +/- 7%, respectively. Three late deaths were due to noncardiac causes and 1 each had a cardiac or valve-related cause (thromboembolism). Other valve-related complications such as anticoagulant-related hemorrhage, perivalvular leak, endocarditis, prosthetic valve failure, and reoperation were not noted in any of the 49 patients. The actuarial survival curve was similar in each group of bioprosthetic versus mechanical and septuagenarians versus octogenarians. Under the selection criteria for AVR currently applied in our hospital, geriatric patients showed a satisfactory early outcome and medium-term survival benefit.     

Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases

The phenolic active metabolites, cis-4-hydroxytamoxifen (cis-HO-TAM) and trans-4-hydroxytamoxifen (trans-HO-TAM), of the anti-breast-cancer drug, trans-tamoxifen (TAM), were geometrically selectively glucuronidated in the manner of cis>trans by microsomes and sulfated in the manner of trans>cis by cytosol from the liver of 10 human subjects (7 females and 3 males). There was a large individual difference in the microsomal glucuronidation of cis-HO-TAM, which correlated well with glucuronidation of 4-hydroxybiphenyl by human liver microsomes. However, there was only a slight correlation between the glucuronidation of cis-HO-TAM and trans-HO-TAM or 4-nitrophenol (NP). A small individual difference was observed for the human liver cytosolic sulfation of trans-HO-TAM, which correlated well with the sulfation of NP. Recombinant human UDP-glucuronosyltransferase (UGT)2B15 catalyzed the cis-selective glucuronidation of geometrical isomers of HO-TAM. UGTs1A1, 1A4, 1A9 and 2B7 had weak activity toward HO-TAMs with a much smaller cis-selectivity than did UGT2B15. UGTs1A3 and 1A6 had no detectable activity toward these substrates. Among the four known major sulfotransferases (SULTs) occurring in the human liver, SULT1A1 was strongly suggested to play the most important role in the hepatic cytosolic trans-selective sulfation of HO-TAM isomers. A good correlation was observed between the hepatic cytosolic sulfation of trans-HO-TAM and NP, a standard substrate for SULT1A1. SULT1E1 had slight activity toward the HO-TAMs. SULTs1A3 and 2A1 had no detectable activity toward HO-TAMs.