Expression of hypoxia-inducible factor 1α predicts clinical outcome after preoperative hyperthermo-chemoradiotherapy for locally advanced rectal cancer

Hypoxia-inducible factor 1α (HIF-1α) is an intrinsic marker of tumor hypoxia. It has been considered that hypoxic conditions reduce radiosensitivity, but the role of HIF-1α in patients treated with preoperative therapy for rectal cancer is still unclear. The aim of this study was to evaluate the predictive value of tumor response to preoperative hyperthermo-chemoradiotherapy (HCRT) and the prognostic significance of HIF-1α expression in patients with locally advanced rectal cancer. Between 2003 and 2006, 50 patients with histologically proven rectal adenocarcinoma who underwent HCRT followed by surgery were investigated. HIF-1α expression was immunohistochemically evaluated using pre-treatment biopsies. The total radiation dose was 40-50 Gy and chemotherapy consisted of 5-FU and LV administered by continuous infusion on Day 1-5, Day 15-19, and Day 29-33 during radiotherapy. Hyperthermia treatment was performed for once a week for 2-5 sessions. The surgical operation was performed 8 weeks after HCRT and each resected specimen was graded by histological criteria of the Japanese Classification of Colorectal Carcinoma. The effects of HIF-1α on clinical outcomes were analyzed by univariate and multivariate analysis. Positive HIF-1α expression was recognized in 42.0% of samples (21/50). Resected specimens that showed pathological grades 1, 2, and 3 numbered 17, 24, and 9 cases, respectively. There were no significant differences between the HIF-1α-positive group and HIF-1α-negative group for pathological grading and pCR. Overall survival (OS) rate at 3 years in the HIF-1α-negative group was 85.2%, which was significantly better than the 60.6% in the HIF-1α-positive group. Recurrence-free survival (RFS) rate at 3 years in the HIF-1α-negative group was 82.8%, being significantly better than 47.6% in the HIF-1α-positive group. In addition, elevated HIF-1α expression was significantly correlated with recurrence-free survival and metastasis-free survival rate in multivariate analysis. HIF-1α expression might be predictive of recurrence-free survival and metastasis-free survival rate for rectal cancer patients treated with HCRT.     

Optical coherence tomographic findings of the anterior segment after nonpenetrating deep sclerectomy

PURPOSE: To evaluate the efficacy of optical coherence tomography for the analysis of anterior segment after glaucoma surgery. DESIGN: Interventional case report. METHODS: In a 79-year-old man with primary open-angle glaucoma, optical coherence tomography was performed on the left eye after nonpenetrating deep sclerectomy. RESULTS: Optical coherence tomography showed thinning of the conjunctiva over the filtering bleb, presence of a space under the scleral flap that is considered as a lake, and presence of fibrous tissue in the bleb. CONCLUSION: This case indicates that optical coherence tomography, a noninvasive, noncontact optical imaging modality, may be useful for analysis of the anterior segment after glaucoma surgery.     

Optical coherence tomography of choroidal neovascularization in high myopia

AIM: To investigate morphologic changes in the eye with choroidal neovascularization (CNV) in high myopia using optical coherence tomography (OCT). METHODS: Optical coherence tomography was performed in 35 patients (42 eyes) with myopic CNV. Myopic CNV was divided into active, scar, or atrophic stages based on funduscopic and fluorescein angiographic findings. The characteristics of OCT findings in each stage were identified. RESULTS: In the active stage (11 eyes), OCT clearly displayed a neovascular membrane as a highly reflective dome-like elevation above the retinal pigment epithelium (RPE). No apparent subretinal fluid accumulation around the CNV was identified. In the scar stage (12 eyes), only the surface of the CNV showed high reflectivity, which was markedly attenuated below the surface. In the atrophic stage (19 eyes), the CNV had become totally flat and chorioretinal atrophy around the regressed CNV showed high reflectivity. CONCLUSIONS: Optical coherence tomography demonstrated characteristic features at each stage of myopic CNV. Optical coherence tomography appears to be useful in evaluating the stage and activity of myopic CNV.     

Management of diabetic macular edema in Japan: a review and expert opinion

Diabetic retinopathy is a frequent cause of visual impairment in working-age adults (≥ 30 years) and in Japan is most commonly observed in those aged 50–69 years. Diabetic macular edema (DME) is one of the main causes of vision disturbance in diabetic retinopathy, which is a clinically significant microvascular complication of diabetes. Anti-vascular endothelial growth factor (VEGF) therapy is becoming the mainstay of treatment for DME. However, to achieve sustained long-term improvement in visual acuity, conventional laser photocoagulation, vitrectomy and steroid therapy are also expected to play a role in the treatment of DME. This review summarizes the epidemiology and pathology of diabetic retinopathy and DME, evaluates the findings regarding the diagnosis and treatment of DME, and underscores the importance of systemic management of the disease in the context of the current health care situation in Japan. Finally, the unmet needs of patients with DME and prospects for research are discussed. The weight of evidence suggests that it is important to establish a multipronged treatment strategy centered on anti-VEGF therapy.     

A comparison of smoking habits between nursing school and nursing college students]

This study was conducted through anonymous questionnaires in order to compare the smoking habits of nursing school students with those of nursing college students, and to identify factors that might possibly indicate causes of smoking habits, among students of two major courses (a 3-year nursing school course and a 4-year nursing college course) for becoming nurses. The subjects were students in two nursing schools and two nursing colleges in the Tokyo Metropolitan area. The results showed that the smoking prevalence among nursing school students in the first to the third grades was 26%, and that among nursing college students of the same grades was 12%. As to factors related to smoking habits of the students the smoking patterns of mothers and friends were shown to largely influence those of the nursing students. Among nursing college students, 21% agreed to a smoking ban in their schools, compared with 14% of the nursing school students.     

A new binding assay of von Willebrand factor and glycoprotein Ib using solid-phase biotinylated platelets

To obtain compounds that inhibit the interaction of von Willebrand factor (vWF) and glycoprotein (GP) Ib, a novel binding assay was established. The binding of fixed platelets to vWF-R497 mutant was quantified by a solid phase assay. In this assay, fixed platelets bound to the vWF-R497 mutant, carrying the deletion of Glu497-Tyr508 and the missense mutation of Arg545 to Ala, without binding modulators such as ristocetin. The K(d) value of the binding was 2.8 nM, which was consistent with the result from liquid binding assay. The binding was inhibited by aurin tricarboxylic acid (ATA) and an anti GPIb antibody, AK2. Using this binding assay, we screened our library compounds and obtained D74-3736. This compound also inhibited ristocetin-induced platelet aggregation in the human platelet-rich plasma.     

Population estimation regarding the effects of cytochrome P450 2C19 and 3A5 polymorphisms on zonisamide clearance

We aimed to evaluate the effects of cytochrome P450 (CYP) 2C19 and CYP3A5 polymorphisms on zonisamide (ZNS) clearance. The pharmacokinetics of the 282 ZNS concentrations at a steady state obtained from 99 Japanese epileptic patients was performed with a nonlinear mixed-effect modeling program, using a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight, gender, ZNS daily dose, CYP2C19 and CYP3A5 genotypes, and the coadministered antiepileptic drugs. The final model of ZNS apparent clearance was as follows: CL = 1.22 x (BW/44)0.77 x DOSE(-0.17 x 0.84CYP2C19 hetero EM x 0.70CYP2C19 PM x 1.24CBZ x 1.28PHT x 1.29PB x eetaCL where CL is the apparent oral clearance of ZNS, DOSE is ZNS daily dose, and CYP2C19 heterozygous extensive metabolizer (EM) or CYP2C19 poor metabolizer (PM) is equal to 1 if one or two CYP2C19-defective alleles are carried, respectively; otherwise, it is 0. Carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) is equal to 1 if carbamazepine, phenytoin, or phenobarbital is coadministered, respectively; otherwise, it is 0. etaCL is the independent random error distributed normally with the mean zero and variance equal to omegaCL. The CL of ZNS was lower in the CYP2C19 heterozygous extensive metabolizers and poor metabolizers than in the homozygous extensive metabolizers by 16% and 30%, respectively (P < 0.001). An effect of CYP3A5 polymorphisms was not identified. The coadministration of carbamazepine, phenytoin, or phenobarbital increased the CL of ZNS by 24% to 29%. This report demonstrates that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects. The clinical relevance of these changes remains to be explored in future studies.     

Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion

1. The aim of the present study was to determine the critical timing of Akt activation and its interaction with the mitochondrial permeability transition pore (mPTP) in the mechanism of infarct size limitation by erythropoietin (Epo). 2. In an isolated, buffer-perfused preparation, rabbit hearts were subjected to 30 min ischaemia/2 h reperfusion. Infusion of Epo (1 unit/mL) before ischaemia reduced infarct size from 36.6 +/- 2.6% of the risk area to 15.4 +/- 3.2%, whereas a 10-fold higher dose of Epo infused for 65 min commencing 5 min before reperfusion failed to afford significant cardioprotection. The protection afforded by Epo pretreatment was abolished by coinfusion of 5 micromol/L LY294002, a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Infusion of Epo induced phosphorylation of Akt, extracellular signal-regulated kinase, glycogen synthase kinase 3beta and p70s6 kinase before ischaemia and tended to enhance reperfusion-induced phosphorylation of these protein kinases. Erythropoietin increased phospho-Akt in the mitochondria and induced complex formation of Akt with adenine nucleotide translocase (ANT), a major subunit of mPTP, upon reperfusion. 3. In another series of experiments, cardiomyocytes were isolated from rat hearts and loaded with Rhod-2 to determine mitochondrial Ca(2+) levels. Increases in mitochondrial Ca(2+) levels following exposure to 1 mmol/L ouabain for 30 min were similar in untreated and Epo-pretreated cells. However, ouabain-induced hypercontracture was significantly suppressed from 45.1 +/- 1.6 to 39.2 +/- 1.9% by Epo. 4. In conclusion, activation of PI3-K-Akt signalling before ischaemia is crucial for Epo-induced myocardial protection and this protection may be achieved by complex formation of activated Akt with mPTP components upon reperfusion, leading to elevation of the threshold for opening of mPTP.     

Usefulness of soluble dietary fiber for the treatment of diarrhea during enteral nutrition in elderly patients

OBJECTIVES: We investigated the clinical usefulness of soluble dietary fiber (SDF) for the treatment of diarrhea during enteral nutrition in elderly patients. METHODS: This study included 10 men and 10 women (mean age +/- standard deviation: 79.3 +/- 5.1 y) who had diarrhea during long-term nutrition management. When administering SDF, the initial dose was 7 g and thereafter gradually increased at 1-wk intervals. After 4 wk, the administration was discontinued for 2 wk to confirm the effects of SDF. RESULTS: After the administration of SDF, serum diamine oxidase activity significantly increased (P < 0.001): The water content of the feces decreased significantly after the administration of fiber (P < 0.01). The frequency of daily bowel movements also decreased significantly (P < 0.05). Simultaneously, the fecal features improved. Concerning intestinal flora, there were no significant changes in the total number of bacteria or the number of anaerobic bacteria. The fecal pH decreased significantly 4 wk after the administration of fiber (P < 0.05). The total level of short-chain fatty acids increased significantly 4 wk after the administration of fiber (P < 0.05). There were no significant changes in the various nutritional indices. CONCLUSIONS: The administration of SDF is useful for controlling spontaneous, favorable bowel movement by improving symptoms of small intestinal mucosal atrophy and normalizing the intestinal flora.     

Phase II study of irinotecan and carboplatin in patients with the refractory or relapsed small cell lung cancer

We examined the safety and efficacy of the combination of irinotecan plus carboplatin in patients with refractory or relapsed small cell lung cancer (SCLC). Patients with previously treated SCLC were eligible. Patients were treated every 3 weeks with carboplatin (with a target area under the concentration versus time curve of 5 mg min/ml using the Calvert formula on day 1) plus irinotecan (50 mg/m² on days 1 and 8). From May 2000 to January 2002, 24 patients were eligible. None of the 22 patients achieved a complete response, but 15 achieved a partial response with an overall response rate of 68.2% (95% confidence interval, 45.1–86.1%). In 13 patients with sensitive disease, the response rate was 92.3% (95% confidence interval, 64.0–99.8%). The median survival time (MST) was 194 days (range 27–605 days). The MST did not differ significantly between patients with sensitive disease (245 days) and those with refractory disease (194 days, P=0.88). One patient died of treatment-related sepsis. Grade 3–4 hematologic toxicities included leukopenia in 58% of patients, neutropenia in 63%, thrombocytopenia in 58%, and anemia in 67%. Grade 3 diarrhea developed in 21% of patients and grade 3–4 infection in 13%. No patients had grade 4 diarrhea or grade 3–4 nausea and vomiting. This regimen is effective and well tolerated in patients with relapsed or refractory SCLC. However, the search for even more active regimens should be continued.