Postmenopausal obesity as a breast cancer risk factor according to estrogen and progesterone receptor status (Japan)

There have been inconsistent results on the association of postmenopausal obesity with breast cancer risk according to the estrogen (ER) and/or progesterone receptor (PR) status in the breast tissue, and this requires further evaluation. This study was designed to assess whether postmenopausal obesity differs according to receptor status. Information on risk factors was obtained from 1154 breast cancer cases and 21714 controls at Aichi Cancer Center Hospital, Nagoya, Japan between 1988 and 1992. The receptor status was known for 40% of cases. Obese postmenopausal women showed an increased risk of breast cancer (odds ratio (OR) for 5 kg of current weight=1.17, 95% confidence interval (CI)=1.10-1.25; OR for 1 kg/m(2) of body mass index (BMI)=1.07, 95% CI=1.04-1.10). The elevated OR was strongest for ER-positive, as well as with PR-positive, breast cancer among postmenopausal women who had a high BMI. The risk did not differ significantly according to ER status. However, obesity indices among postmenopausal women differed with borderline significance according to PR status. These results are consistent with the hypothesis that there is a gradient of risk for postmenopausal obesity according to hormonal receptor status, at least for PR status, although this was not statistically significant.     

Locally advanced nasopharyngeal cancer

Opinion statement The Head and Neck Cancer Intergroup phase III clinical trial (Int 0099) for patients with locally advanced, squamous cell carcinomas (SCC) of the nasopharynx (or NPC) has been recently completed in the United States. The results of this study have defined the new standard of treatment for the group of patients studied. Patients with untreated, locally advanced stages III and IV NPC were randomized to a conven-tional course of radiation, or to radiation given concurrently with chemotherapy followed by three courses of combination chemotherapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 24% versus 69% (P < 0.001) and 46% versus 76% (P < 0.001) for the control and experimental groups, respectively. Recent updates of these survival figures show that they have not changed appreciably. The considerable improvement in OS versus PFS for the patient group receiving radiation alone is accounted for primarily by re-treatment with concurrent radiation-chemo-therapy, combination chemotherapy, and isolated salvage neck dissections. Highly significant differences in local control (41% vs 14%) and distant metastases (35% vs 13%) were demonstrated in favor of the chemoradiation treatment arm. The median age for these patients was 51 years, with a 2:1 male to female ratio. Although many patients had a significant history of tobacco exposure with or without alcohol use or abuse, only 24% had keratinizing or well-differentiated squamous (World Health Organization [WHO] I) type tumors. Whether these results can be extrapolated to the more common Asian variety (WHO II and III) of advanced NPC must be addressed in future clinical trials.     

A most peculiar coronary circulation in a patient with pulmonary atresia and intact ventricular septum

A patient with pulmonary atresia and intact ventricular septum was found to have a right ventricular-dependent coronary circulation. In this infant both coronary arteries lacked their normal proximal connection with the aorta, perhaps the most egregious form of this prejudicial coronary circulation. Even more interesting was a direct collateral vessel originating from the descending thoracic aorta and connecting with the coronary circulation. This patient has undergone bilateral modified Blalock-Taussig shunts, and left ventricular function seems preserved.     

Twisted atrioventricular connections in double inlet right ventricle: evaluation by magnetic resonance imaging

Twisted atrioventricular connections occur almost exclusively in the hearts with biventricular atrioventricular connections. Only one example of double inlet left ventricle has been illustrated in which the axes of the two atrioventricular valves crossed each other. We describe herein three patients, and one autopsied specimen, with double inlet right ventricle in which magnetic resonance imaging clearly demonstrated twisted atrioventricular connections.     

Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia

Although the major biochemical abnormality due to methylenetetrahydrofolate reductase (MTHFR) deficiency is hyperhomocyst(e)inemia, its pathogenicity appears to involve more than homocysteine toxicity. In patients with severe MTHFR deficiency, a metabolite(s) other than hyperhomocyst(e)inemia also appears to be associated with its clinical manifestation in cerebrovascular disease. To elucidate the specific role of the TT genotype of MTHFR in the development of cerebral infarction with and without cognitive impairment, we determined the prevalence of hyperhomocyst(e)inemia and the C677T genotypes of MTHFR in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 healthy subjects matched for age and sex. Prevalence of hyperhomocyst(e)inemia [homocyst(e)ine >/=15 micromol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively; P=0.001). In contrast, a higher frequency of MTHFR TT genotype was found only in demented patients compared with nondemented patients and healthy controls (25.2%, 9.8%, and 12.0%, respectively; P=0.01). When the study subjects were divided into normohomocyst(e)inemic and hyperhomocyst(e)inemic groups, the TT genotype was significantly associated with the risk for vascular dementia in the hyperhomocyst(e)inemic group (odds ratio 4.13, 95% CI 2.18 to 7.85; P=0.03) but not in the normohomocyst(e)inemic group. Demented patients with multiple infarcts had a higher frequency of TT genotype (odds ratio 3.13, 95% CI 2.23 to 4.39; P=0.0007), whereas those with a single infarct did not (odds ratio 2.03, P=0.15). In contrast, there was no significant association of the TT genotype with multiple infarcts in hyperhomocyst(e)inemic stroke patients. Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia. Similar to the relationship between homocystinuria due to severe MTHFR deficiency and severe cystathionine beta-synthase deficiency, the TT genotype of MTHFR in hyperhomocyst(e)inemic subjects is differentiated from the cases of the TT genotype without hyperhomocyst(e)inemia or hyperhomocyst(e)inemia without the TT genotype in the development of cerebrovascular disease.     

Chloroquine inhibits inducible nitric oxide synthase expression in murine peritoneal macrophages

Induction of inducible nitric oxide synthase in vivo or in vitro in response to stimuli is only temporary. However, chronic localized expression of inducible nitric oxide synthase in certain organs has been associated with the development of autoimmune diseases or chronic inflammatory diseases. Chloroquine is being used as an antiinflammatory drug, and its inhibitory effect on the synthesis of pro-inflammatory cytokines, such as tumour necrosis factor-alpha and interferon-gamma, has been reported. In this study, we examined whether chloroquine could inhibit nitric oxide synthesis in murine peritoneal macrophages stimulated with interferon-gamma and lipopolysaccharide. Although prolonged incubation of cells with high concentrations of chloroquine showed some cytotoxicity, the drug itself was not cytotoxic when macrophages were preincubated with chloroquine for 2 hr, washed and stimulated with interferon-gamma and lipopolysaccharide in the absence of chloroquine for another 48 hr. The nitric oxide production from stimulated macrophages was markedly reduced by chloroquine in a dose-dependent manner and induction of inducible nitric oxide synthase mRNA was also suppressed by chloroquine pretreatment. These results show that chloroquine inhibits the induction of inducible nitric oxide synthase from interferon-gamma and lipopolysaccharide-stimulated macrophages, thereby reducing nitric oxide synthesis.     

Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers

Chromosome 8p21-22 is a frequent site of allelic deletions in many types of human tumors, including non-small cell lung cancer (NSCLC). Tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) is a cell-surface receptor involved in cell death signaling. The TRAIL-R2 gene recently has been mapped to chromosome 8p21-22. To explore the possibility that the TRAIL-R2 gene might be the relevant gene to the frequent deletion of 8p21-22 in NSCLC, we have analyzed the entire coding region and all splice sites of TRAIL-R2 for the detection of the somatic mutations in a series of 104 NSCLCs. Overall, 11 tumors (10.6%) were found to have TRAIL-R2 gene mutations in the death domain known to be involved in the transduction of an apoptotic signal. Our data indicate that somatic mutation of TRAIL-R2 may play a role in the pathogenesis of some NSCLCs and that the TRAIL-R2 gene is one of the genes relevant to the frequent loss of chromosome 8p21-22 in NSCLC.     

Alterations of Fas (Apo-1/CD95) gene in non-small cell lung cancer.

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The key role of the Fas system in negative growth regulation has been studied mostly within the immune system, and somatic mutations of Fas gene in cancer patients have been described solely in lymphoid-lineage malignancies. However, many non-lymphoid tumor cells have been found to be resistant to Fas-mediated apoptosis, which suggests that Fas mutations, one of the possible mechanisms for Fas-resistance, may be involved in the pathogenesis of non-lymphoid malignancies as well. In this study, we have analysed the entire coding region and all splice sites of the Fas gene for the detection of the gene mutations in 65 human non-small cell lung cancers by polymerase chain reaction, single strand conformation polymorphism and DNA sequencing. Overall, five tumors (7.7%) were found to have the Fas mutations, which were all missense mutations. Four of the five mutations identified were located in the cytoplasmic region (death domain) known to be involved in the transduction of an apoptotic signal and one mutation was located in the transmembrane domain. This is the first report on the Fas gene mutations in non-lymphoid malignancies, and the data presented here suggests that alterations of the Fas gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human lung cancers.     

Pharmacokinetic/pharmacodynamic evaluation of a novel potassium channel opener, SKP-450, in healthy volunteers

To evaluate the pharmacokinetic/pharmacodynamic characteristics of SKP-450, a novel K+ channel opener, a single blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 28 healthy volunteers. The volunteers were randomly allocated to dosage groups of 50 micrograms, 100 micrograms, 200 micrograms, and 300 micrograms. Single doses of SKP-450 were administered orally, after overnight fasting, and serial blood sampling and pharmacodynamic measurements were performed up to 48 hours after the drug was administered. The 200 micrograms group was further studied for food interactions in a crossover fashion. Drug concentrations in plasma were determined by HPLC. Hemodynamic changes after drug administration were evaluated by serial measurements of blood pressure (BP), pulse rate (PR), cardiac index (CI), and total peripheral resistance (TPR), using computerized impedance cardiography. Changes in plasma renin activity (PRA) and aldosterone concentrations (PAC) were determined 4 and 24 hours after drug administration. Both SKP-450 and SKP-818, an active metabolite, showed linear pharmacokinetic characteristics, and food intake did not significantly affect the pharmacokinetic characteristics of either compound. Dose-related pharmacological effects were obvious for both the 200 micrograms and 300 micrograms groups. Hemodynamic parameters related to vasodilation and reflex tachycardia, such as maximum changes in diastolic BP, PR, CI, and TPR, showed significant dose-dependent changes. The area under the time-effect curve (AUEC) of the parameters also showed a similar dose-dependent pattern. The PRA and PAC exhibited significant changes 4 hours after drug administration in the 300 micrograms group. Adverse effects, such as headaches, were more frequently observed at the higher dose levels. SKP-450 was generally well tolerated by these normotensive subjects. The antihypertensive efficacy of SKP-450 needs to be evaluated in hypertensive patients after multiple dosing.     

Factors influencing the protein binding of a new phosphodiesterase V inhibitor, DA-8159, using an equilibrium dialysis technique

Various factors influencing the protein binding of DA-8159 to 4% human serum albumin (HSA) were evaluated using an equilibrium dialysis technique at an initial DA-8159 concentration of 5 microg/mL. It took approximately 8 h incubation to reach an equilibrium between 4% HSA and an isotonic phosphate buffer of pH 7.4 containing 3% of dextran ('the buffer') using a Spectra/Por 2 membrane (mol. wt. cut-off: 12,000--14,000) in a water bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. The extent of binding was dependent on DA-8159 concentrations, HSA concentrations, incubation temperature, buffer pH, and alpha-1-acid glycoprotein (AAG) concentrations. The binding of DA-8159 in heparinized human plasma (93.9%) was significantly higher than in rats (81.4%), rabbits (80.4%), and dogs (82.2%), and this could be due to differences in AAG concentrations in plasma.