New lidocaine ester derivatives with a prolonged anesthetic effect

In order to find a new long acting local anesthetic, methyl, ethyl, and butyl ester derivatives of lidocaine were synthesized in our laboratory. The topical anesthetic activity was studied with the effects on corneal reflex in rabbits, and the duration of action with those on the action potential of rabbit vagus nerve was studied in vitro. All drugs showed adequate topical anesthetic activities. The onset time to induce a complete blockage of the action potential in the excised vagus nerve was 97.1 +/- 6.3 s for lidocaine, 289.3 +/- 29.0 s for methyl ester, 186.3 +/- 18.4 s for ethyl ester, and 85.3 +/- 9.0 s for butyl ester. The mean duration of action, which was assessed as the time to recover from the complete block to 30% of control amplitude in a drug-free medium, was 32.5 +/- 3.1 min for lidocaine, 39.9 +/- 11.3 min for methyl ester, 68.2 +/- 4.2 min for ethyl ester, and 108.7 +/- 12.3 min for butyl ester. The differences in the duration of action between the ester derivatives and the original lidocaine were all statistically significant. The duration of action of all drugs studied paralleled with their protein binding capacities. These findings indicate the possibility that the ester derivatives studied, especially butyl ester, can be used as a long acting local anesthetic.     

Evaluation of esophageal bile reflux after total gastrectomy by gastrointestinal and hepatobiliary dual scintigraphy

Conducting the qualitative evaluation of reconstruction methods is difficult because of their complexity. The aim of the present study was to compare esophageal bile and food reflux by performing gastrointestinal and hepatobiliary dual scintigraphy (GHDS) after various methods of reconstruction following total gastrectomy. Of 17 patients studied, 4 had undergone Roux-en-Y anastomoses (R-Y); 6, jejunal pouch-Y anastomoses (P-Y); and 7, jejunal pouch interposition (P-I). GHDS was performed 1 year after surgery using¹¹¹In-diethylene triamine pentaacetic acid administered orally, and^99mTc-pyridoxyl-5-methyl tryptophan administered intravenously. Imaging data from a gamma camera were stored in and processed by a data analyzer. Three patients who had undergone R-Y and one who had undergone P-I complained of heartburn, while one who had undergone R-Y, two who had undergone P-Y, and three who had undergone P-I complained of a feeling of fullness. Esophageal bile reflux was confirmed by GHDS in four of the patients who had undergone R-Y, one who had undergone P-Y, and four who had undergone P-I. Moreover, GHDS demonstrated food retention in two patients who had undergone R-Y, five who had undergone P-Y, and four who had undergone P-I. Weight loss was closely related to the esophageal reflux of bile or food which can be accurately detected by GHDS. Despite the absence of heartburn, patients diagnosed as having bile reflux by GHDS showed poor recovery of body weight.     

Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro.

Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T-lymphocytes, and regardless of intensive chemotherapy, its mean survival time is less than 1 year. Nuclear factor-kappaB (NF-kappaB) activation was reported in HTLV-I associated cells, and has been implicated in oncogenesis and resistance to anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor, bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo. Bortezomib could inhibit the degradation of IkappaBalpha in ATL cells, resulting in suppression of NF-kappaB and induction of cell death in ATL cells in vitro. Susceptibilities to bortezomib were well correlated with NF-kappaB activation, suggesting that suppression of the NF-kappaB pathway was implicated in the cell death induced by bortezomib. Although the majority of the cell death was apoptosis, necrotic cell death was observed in the presence of a caspase inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective against ATL cells in vivo. These studies revealed that bortezomib is highly effective against ATL cells in vitro and in vivo by induction of apoptosis, and its clinical application might improve the prognosis of patients with this fatal disease.     

Expression of Adhesion Molecules and Cytokines on Saphenous Veins in Chronic Venous Insufficiency

The objective of this study was to assess the relationship of signaling molecules to monocyte/ macrophages as a precursor to venous valve and venous wall dysfunction in patients with varicose veins. One of the hallmarks of venous dysfunction is destruction of venous valves with subsequent reflux and elevation of distal venous pressure. We recently observed that monocytes/macrophages migrate into the venous walls and valves of patients with venous insufficiency. There, they may play a role in the pathogenesis of primary venous insufficiency. If so, an important element in their performance would be the interaction between the monocytes and the endothelium as a precursor of damage to venous valves and the venous wall. To explore this interaction, immunohistochemistry was carried out to detect adhesion molecules and cytokines in surgical specimens removed during surgical therapy. Twenty-four surgical specimens consisting of proximal saphenous vein and subterminal valve were obtained using minimally traumatic technique in 6 males and 18 females who ranged in age from 31 to 79 years. Reflux was confirmed preoperatively by duplex technique, and severity was classified by the CEAP classification of the American Venous Forum. Ten patient limbs were class 2, eight were class 3, four were class 4, and two were class 6. The venous specimens were labeled using monoclonal antibody against ICAM-1, E-selectin, IL-1alpha, and TNF-alpha. CD68 was used for detection of monocytes/macrophages. Our results indicate that not only luminal venous endothelium but also endothelium in the vasa vasora of refluxing saphenous veins is activated, as indicated by the up-regulation of ICAM-1. However, IL-1alpha and TNF-alpha were increased in only selected specimens and are mainly detected in the vein wall. The factors that serve as trigger mechanisms to activate cells in the pathogenesis of primary venous dysfunction remain to be explored.     

Subjective and functional results after total gastrectomy: prospective study for longterm comparison of reconstruction procedures

Background: Many reconstruction procedures have been developed in efforts to resolve patients' complaints after total gastrectomy. However, there have been few reports of longterm comparisons between reconstruction procedures, especially with regard to the prevention of duodenal food passage. This study was undertaken to compare the longterm subjective and functional results among Roux-en-Y esophagojejunostomy (R-Y), R-Y with pouch (P-Y), and jejunal interposition with pouch (P-I) after total gastrectomy. Methods: Consecutive patients requiring curative total gastrectomy were enrolled in this prospective study by the envelope method. Results: Hospital stay was longer following a P-I than an R-Y or a P-Y. Over 50% of R-Y patients complained of heartburn, and 20% of R-Y patients showed dumping syndrome throughout the postoperative period, with this rate being significantly different from rates in the other two groups. P-Y patients complained of early satiety in the late postoperative period, while P-I patients complained of early satiety in the early postoperative period. The nutritional index in P-I patients was higher than those in patients with the other two procedures. Gastrointestinal and hepatobiliary dual scintigraphy (GHDS) showed that the rate of bile reflux with an R-Y was relatively high after surgery. Food reflux with a P-Y was increased (9.4% to 11.1%), but with a P-I food reflux was decreased at 3 years after surgery (13.3% to 9.9%). Patients with a P-Y had a faster recovery of body, weight in the early postoperative period; however, at 5 years after operation, body weight recovery with a P-I was greatest. Conclusion: Reconstruction should be performed with pouch formation after total gastrectomy with curative intent. Received: March 7, 2002 / Accepted: September 26, 2002 Acknowledgments This study was partly supported by the University of Tsukuba Research Project. Offprint requests to: S. Adachi     

Prognostic significance of loss of heterozygosity on chromosome 9p21–22 in human esophageal cancer

Background Deletions involving chromosome 9p21, on which the tumor suppressor genep16/MTS1 is located, have been noted in esophageal cancer. We investigated the relationship between the deletion of chromosome 9p21–22 and the clinical features of esophageal cancer. Methods We examined the loss of heterozygosity (LOH) on chromosome 9p21–22 in 56 esophageal cancers using polymerase chain reaction (PCR) analysis and 2 microsatellite markers (RPS6 and IFNA). Results In 18 out of 50 informative cases (36%), LOH had occurred at 1 or 2 loci on chromosome 9p21–22. We found no relationship between LOH on chromosome 9p21–22 and patient sex, age tumor length, location, histologic differentiation, depth of tumor invasion, the extent of lymph node metastasis, histologic stage, or curability. Among 35 patients without an absolute noncurative resection, the mean survival of 11 patients with LOH on chromosome 9p21–22 was 19.3 months, compared with 42.3 months for 24 patients with a normal allele; thus, the survival rate of those with LOH was significantly lower than that of patients without LOH on chromosome 9p21–22 (log-rank test;P=0.03). Conclusion These data suggest that LOH on chromosome 9p21–22, on which the cell-cycle regulatorp16/MTS1 gene is located, may be related to cancer development, and probably can serve as a clinical marker for evaluating a patient's prognosis.     

Longer-term diabetic patients have a more frequent incidence of nosocomial infections after elective gastrectomy

Diabetes mellitus (DM) is one of the risk factors for the development of postoperative nosocomial infections in surgical patients. We conducted this retrospective study to elucidate the perioperative risk factors for postoperative nosocomial infections in diabetic patients undergoing elective gastrectomy. Chart review was performed on diabetic and nondiabetic patients undergoing elective gastrectomy for gastric malignancy from January 1992 through April 1999. Fourteen of the 83 diabetic patients, and 23 of the 284 nondiabetic patients developed postoperative nosocomial infections. Statistical comparisons of multiple variables were made between patients with and without postoperative nosocomial infections. In diabetic patients, univariate analysis showed that longer-term DM (especially longer than 10 yr) was associated with a significantly increased risk for postoperative nosocomial infections. Multiple logistic regression analysis showed that DM lasting longer than 10 yr was an independent risk factor for postoperative nosocomial infections (odds ratio, 6.8; 95% confidence interval, 1.7 to 27.1). In nondiabetic patients, similar analysis showed that age was an independent risk factor for postoperative nosocomial infections. We conclude that patients with longer-term DM had a significantly greater incidence of postoperative nosocomial infections after elective gastrectomy. Implications: Postoperative nosocomial infection is one of the major problems in diabetic patients. This study demonstrated that postoperative nosocomial infections were more common in patients undergoing elective gastrectomy if they had diabetes mellitus longer than 10 yr.     

Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers.

Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of alpha-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, alpha-OHTAM, and either 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of alpha-hydroxylated TAM and its metabolites.     

A case of primary gastric small cell carcinoma with a rare pattern of lymph node metastasis

We report a very rare case of primary gastric small cell carcinoma (GSCC) that was accompanied with gastric tubular adenocarcinoma. A male in his 60s had an elevated tumor with a central ulceration in the middle stomach. The patient underwent a distal gastrectomy with lymph node dissection. The pathological examination showed two separated lesions of the stomach, which contained the components of primary GSCC and primary gastric tubular adenocarcinoma. Immunohistochemical (IHC) examination demonstrated that the tumor cells in the small cell carcinoma stained positive for synaptophysin, chromogranin A, and neural cell adhesion molecule (NCAM). GSCC cells and adenocarcinoma cells independently metastasized to each regional lymph node. Further studies on the biological behavior of individual tumors may allow the development of new treatment strategies for GSCC.