A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Reduction in levels of amphiphysin 1 mRNA in the hippocampus of aged rats subjected to repeated variable stress.

Various neurobiological studies of aging indicate that elevated levels of circulating glucocorticoids lead to hippocampal vulnerability to stress, though little is known about the molecular mechanism underlying stress vulnerability in the elderly. We have compared the gene expression profiles in the hippocampus of aged (20 months) and adult (3 months) rats in response to repeated variable stress (RVS) for 4 days, using a cDNA array technique and real-time quantitative PCR, to identify putative genes involved in the mechanism of stress vulnerability in the elderly. We found a significant decrease in the levels of amphiphysin 1 mRNA in aged rats subjected to RVS compared with treated and untreated adult rats or to untreated aged rats. Similarly, we found a significant decrease in hippocampal levels of amphiphysin 1 mRNA in aged rats subjected to RVS for 8 days, but not in those subjected to a single VS. These findings suggest that the decrease in the hippocampal levels of amphiphysin 1 mRNA in response to repeated stress may be involved in the stress vulnerability in the elderly, and may lead to the disturbance of learning and memory under stressful conditions in the elderly.

Diastereoselective tandem Michael-intramolecular Wittig reactions of a cyclic phosphonium ylide with 8-phenylmenthyl enoates.

The diastereoselective tandem Michael-intramolecular Wittig reactions of a five-membered cyclic phosphonium ylide 2 using 8-phenylmenthyl enoates were examined. The reaction of the phosphonium ylide with 8-phenylmenthyl cinnamate followed by the hydrolysis of the resulting enol ether 4a afforded (3R,4S)-4-(diphenylphosphinyl)-3-phenylcycloheptanone (3R,4S)-5a as the major isomer. The diastereoselectivity of the initial tandem reactions was estimated to be 94:6 from the 31P NMR of a mixture of the diastereomeric ketal derivatives 6a and 6'a which were obtained by the reaction of 5a with (2R,3R)-2,3-butanediol, and the absolute configuration of the major isomer was determined by the single-crystal X-ray analysis. Similar reactions using some 8-phenylmenthyl alkenoates were attempted. As a result, it was clarified that the corresponding trans-ketones 5b-d were obtained and that the diastereomer ratios of their ketal derivatives were 60:40-73:27.

Eosinophilic granuloma of the stomach mimicking gastric cancer, report of a case.

We report a rare case of eosinophilic granuloma of the stomach mimicking gastric cancer. A 49-year-old man was admitted to our hospital to undergo surgery for gastric tumor. Radiologic and endoscopic examination showed a protruding tumor with a deep ulcer at the anterior wall of the pylorus. Although malignant cells were not histologically confirmed in the biopsy specimens, subtotal gastrectomy with lymphadenectomy was performed because gastric cancer was strongly suspected. The gross appearance of the tumor seemed to be that of a gastric cancer, but the histological diagnosis was eosinophilic granuloma. If submucosal tumor of the stomach is suspected, eosinophilic granuloma should be considered as one of the differential diagnoses. Endoscopic removal of the tumor may be useful to make a precise diagnosis before surgery.

Orthovanadate decreases leptin secretion from isolated mouse fat pads.

When isolated mouse fat pads were incubated with orthovanadate (vanadate) or insulin for up to 4 h, the leptin secretion into the medium was decreased by vanadate and increased by insulin. Propranolol, a nonspecific antagonist of beta-adrenergic receptors, bupranorol, a specific antagonist of beta3-adrenergic receptor, and H-89, an inhibitor of cAMP-dependent protein kinase (PKA) all inhibited the decrease by vanadate to various extents. In contrast, no inhibition was observed with specific antagonists of beta1- and beta2-adrenergic receptors or with inhibitors of protein kinase C and Ca/calmodulin kinase. Short-term incubation of the fat pads with vanadate showed a transient increase in the cellular cAMP content; this increase was inhibited by propranolol and bupranolol. Vanadate had no effect on the incorporation of [3H]-leucine into proteins of the fat pads with a 4-h incubation, although insulin stimulated the incorporation. The decreasing effect of vanadate on the leptin secretion seems to be independent of the regulation of protein synthesis. These results suggest that vanadate decreases the leptin secretion through mechanisms involving the increase in cellular cAMP content via beta3-adrenergic receptor, probably leading to the activation of PKA.

Palladium-catalyzed allylic alkylation using chiral hydrazones as ligands.

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (4) with a dimethyl malonate-BSA-LiOAc system and its derivatives has been successfully carried out in the presence of a new chiral hydrazone ligands such as 2-(diphenylphosphino)benzaldehyde SAMP hydrazone (DPPBA-SAMP) (3a) in high yields with high enantioselectives.

Negative regulation of expression and function of Fc gamma RIII by CD3 zeta in murine NK cells.

Fc gamma RIII is involved in Ab-dependent cell-mediated cytotoxicity (ADCC) and cytokine production by NK cells. Signaling and expression of Fc gamma RIII are dependent on FcR gamma. Although NK cells express not only FcR gamma but also CD3 zeta, the role of CD3 zeta in NK cell function remains unclear. Here, we found that the expression of Fc gamma RIII on NK cells from CD3 zeta-deficient mice is unexpectedly up-regulated compared with that on cells from normal mice. Furthermore, ADCC and IFN-gamma production upon Fc gamma RIII-cross-linking by NK cells from CD3 zeta-deficient mice were also up-regulated. Up-regulation of the surface expression of Fc gamma RIII on CD3 zeta-deficient NK cells is not mediated by transcriptional augmentation of either Fc gamma RIII or FcR gamma gene because there was no significant difference in the expression of mRNA for Fc gamma RIII and FcR gamma. Transfection of CD3 zeta into a cell line expressing Fc gamma RIII and FcR gamma induced a decrease in the cell surface expression of Fc gamma RIII. These findings reveal a negative regulatory role of CD3 zeta in Fc gamma RIII-mediated function of murine NK cells.

[A patient with myopathy due to preclinical Cushing syndrome].

A 57 year-old man with a history of diabetes mellitus was admitted to our hospital for the complaint of slowly progressive muscle weakness involving proximal limbs and head dropping. His serum CK level was within normal range, and muscle biopsy showed no inflammatory changes. To rule out myasthenia gravis, computerized tomography was done for the detection of thymoma, and detected an adrenal tumor in stead. He was not over-weighted, and his morning plasma levels of ACTH and cortisol were within normal ranges. Additional hormonal examinations revealed daily autonomous hypersecretion of cortisol. He received diagnosis of preclinical Cushing syndrome. After resection of the tumor, muscle weakness improved and his diabetes mellitus was controlled better. The muscle symptoms seem to be related with steroid myopathy. Preclinical Cushing syndrome should be included as a differential diagnosis for myopathy of unknown etiology.

The role of thymidine phosphorylase expression in the invasiveness of gastric carcinoma.

BACKGROUND: Thymidine phosphorylase (TP) has angiogenic activity in various cancer tissues. Gastric carcinomas are classified into two histologic groups: differentiated and undifferentiated adenocarcinomas. There are differences in the modes of development and the extent of infiltration between the two groups. The purpose of the current study was to determine whether TP is involved in the invasiveness and progression of these two types of gastric carcinoma. METHODS: To investigate the expression and localization of TP and the microvessel counts, the authors examined specimens from 149 gastric carcinoma patients. The specimens were stained using monoclonal antibody against TP and polyclonal antibody against factor VIII. To determine the cell type expressing TP, immunohistochemical staining using a monoclonal antibody against CD68 that is specific for macrophages and double staining using antibodies to both TP and CD68 were performed. RESULTS: The proportion of TP positive tumors in differentiated adenocarcinomas was higher than that in undifferentiated adenocarcinomas. The TP positive differentiated adenocarcinomas invaded more deeply than the TP negative ones, but this was not the case with undifferentiated adenocarcinomas. TP was expressed mainly in the invasive edges of tumors and was expressed more frequently in macrophages than in tumor cells. TP expression was correlated with microvessel count and CD68 expression. Patients with TP positive carcinomas had a poorer prognosis than those with TP negative differentiated adenocarcinomas. CONCLUSIONS: TP expressed in macrophages may be correlated with microvessel count and play an important role in tumor invasiveness and progression in differentiated gastric adenocarcinoma.

Are alpha-blockers involved in lower urinary tract dysfunction in multiple system atrophy? A comparison of prazosin and moxisylyte.

Lower urinary tract dysfunction is a major cause of morbidity in patients with multiple system atrophy (MSA). alpha1-Adrenergic receptors are present in the proximal urethra where impaired relaxation may be responsible for voiding difficulty and a large amount of residual urine. An open study was designed to evaluate whether the blockade of these receptors by prazosin (a nonselective alpha1 blocker) and moxisylyte (an alpha1A-selective blocker) would improve bladder emptying in patients with MSA. Post-micturition residual volumes and clinical symptoms of 49 patients with MSA were evaluated at trial entry and after 4 weeks (prazosin; n=21 and moxisylyte; n=28). The respective means for the prazosin and moxisylyte groups were 38.1% and 35.2% reductions in residual urine volume (P<0.05), and there was lessening of urinary symptoms. Side effects due to orthostatic hypotension were seen in 23.8% of the prazosin group but in only 10.7% of the moxisylyte group. These effects were common in patients with postural hypotension of more than -30 mmHg at trial entry (P<0.05). Modulation of alpha1-receptors may function in the management of lower urinary tract dysfunction in MSA.

Risperidone treatment of neuroleptic-induced tardive extrapyramidal symptoms.

Tardive extrapyramidal symptoms (EPS) induced by neuroleptic treatment, and particularly EPS which persist after withdrawal of the drugs, are clinically serious problems. We describe a patient with four types of tardive and persistent EPS such as dystonia, dyskinesia, choreatic movement and myoclonus, induced by haloperidol. These EPS were remarkably inhibited by 3 mg/day risperidone. This is the first published case demonstrating simultaneous development of these four types of tardive EPS induced by a neuroleptic and then reduced by low-dose risperidone treatment. ( Int J Psych Clin Pract 2000; 4: 241 - 243).

Clinical and biological features of t1 ductal adenocarcinoma of the pancreas.

BACKGROUND/AIMS: The impact of tumor size on tumor development and long-term prognosis is still controversial for patients with ductal adenocarcinoma of the pancreas. We investigated the clinicopathological and biological features of ductal adenocarcinoma limited to the pancreas without direct histological extrapancreatic invasion (t1 tumor). METHODOLOGY: The clinical records of 86 patients who underwent surgery for ductal adenocarcinoma of the pancreas were reviewed to determine clinical features, histopathological findings, operative management and outcomes. Immunohistochemical staining of the p53 tumor suppressor gene (p53) was performed for the resected specimens. RESULTS: Only 10 (12%) of the 86 resected ductal adenocarcinomas of the pancreas were t1 tumors. Six of the 10 patients with t1 tumors survived for more than 5 years. The rates of nodal metastasis (10%) and neural plexus invasion (0%) in t1 tumors were significantly lower than those in non-t1 tumors, although the rates of blood-borne metastasis (30%) and p53 expression (50%) in t1 tumors were the same as those in non-t1 tumors. CONCLUSIONS: Curative resection contributes to a satisfactory long-term prognosis of patients with t1 tumor of the pancreas as a result of the low rates of both nodal metastasis and neural plexus invasion associated with this procedure. In patients with t1 tumor of the pancreas, a satisfactory long-term prognosis can be assured as a result of the low rates of both nodal metastasis and neural plexus invasion associated with curative resection.

Easy Preparation of Methyl 7-epi-Jasmonate and Four Stereoisomers of Methyl Cucurbate, and Assessment of the Stereogenic Effect of Jasmonate on Phytohormonal Activities.

To test the stereogenic effect of jasmonate on phytohormonal activities, methyl 7-epi-jasmonate (1b) and four stereoisomers of methyl cucurbate were easily prepared in racemic form: epimerization at the C-7 position of a commercially available methyl jasmonate (2b) with a base and subsequent fractional distillation gave a 46:54 mixture of 1b and 2b, whose reduction gave a mixture of methyl cucurbates (3-6). This synthetic chemistry was supplemented by molecular modeling and an NMR study on 1b and 2b. An assessment of the inhibitory activities of the prepared jasmonates on growth of the second leaf sheath of rice and on seed germination of cress clarified that the cis-configuration of the C-3 and C-7 side chains of jasmonate was an important factor for the high activities. In inhibiting the seed germination of cress, methyl 6-epi-cucurbate (4) exhibited activity that was markedly higher than the other compounds tested, showing that the stereochemistry at C-6 as well as at C-3 and C-7 was strictly recognized by this bioassay.

Cytopathological alterations and therapeutic approaches in Binswanger's disease.

Binswanger's disease (BD) is a condition characterized by prominent brain atrophy with ventricular dilatation, diffuse white matter (WM) lesions and a scattering of lacunar infarcts. BD patients have dementia, and have vascular risk factors, focal cerebrovascular deficits and evidence of subcortical cerebral dysfunction. From our clinical studies, the most effective prophylaxis against the development of BD is to manage the hypertension, especially a high nocturnal blood pressure, in the early stage patients showing only a scattering of lacunes and/or mild WM lesions. The pathogenesis of BD is likely to be chronic cerebral ischemia due to hypertensive small artery disease with capillary collagenosis, which causes the multiple lacunes and the alterations in the glia and axons. In addition, arterial hypertension and a subsequent dysfunction of the blood-brain barrier (BBB) may cause the WM lesions. A compromised BBB will permit the entry of serum components, immunoglobulins, complements and fibrinogen into the perivascular neural parenchyma. These substances may subsequently activate both astro- and microglia and thus damage the myelin structures. Experimentally, immunosuppressants, cyclosporin A and FK 506 suppressed both the glial activation and WM changes after chronic cerebral hypoperfusion. The pro-thrombotic state of the microcirculation in BD patients may also contribute to local inflammation and the BBB dysfunction, because thrombin and prostanoids are involved in various tissue reactions including brain edema and glial activation. Therefore, novel therapeutic approaches using the administration of anti-thrombin and cyclo-oxygenase-2 inhibitors as well as immunosuppressants may be useful for preventing the progression of BD.

Blood-brain barrier dysfunction in Binswanger's disease; an immunohistochemical study.

Binswanger's disease is pathologically characterized by a combination of diffuse cerebrovascular white matter lesions and lacunar infarcts in the basal ganglia and white matter. Although a blood-brain barrier (BBB) dysfunction has been implicated in the pathogenesis of these white matter (WM) lesions, few authors have addressed this problem. In the present study, we describe BBB dysfunction and its regional differences in the brains of Binswanger's disease patients. Twelve brains from Binswanger's disease patients (group III) were examined and compared with those from five patients with non-neurological disease (group I) and five cortical infarct patients without significant WM lesions (group II). Immunohistochemistry was performed for glial fibrillary acidic protein and vimentin as astroglial cell markers, and for immunoglobulins, complements and fibrinogen as extravasated serum protein markers. The grading scores for IgG extravasation were significantly higher in group III as compared to group I, in both the periventricular WM and the subcortical WM (P < 0.01). In group III, the scores in the periventricular WM and subcortical WM were significantly higher than in the subcortical U fibers and cerebral cortex (P < 0.01 for the periventricular WM; P < 0.001 for the subcortical WM), respectively. Clasmatodendritic astroglia, which had swollen cell bodies and large cytoplasmic vacuoles with disintegrated processes, incorporated the serum components IgG, IgM, C3d, Clq and fibrinogen, both in the periventricular WM and subcortical WM in 5 out of 12 (42%) Binswanger's disease brains. These results indicate that WM lesions in Binswanger's disease are accompanied by BBB dysfunction, although it remains uncertain whether BBB dysfunction is secondary to either chronic cerebral ischemia or arterial hypertension.