Publications by authors named "Yoshihiro Okayama"

17 Publications

  • Page 1 of 1

Microvascular Decompression for Trigeminal Neuralgia: A Prospective, Multicenter Study.

Neurosurgery 2021 Sep;89(4):557-564

Seikei-kai Chiba Medical Center, Chiba, Japan.

Background: Microvascular decompression (MVD) is the most effective procedure for the long-term management of trigeminal neuralgia (TGN). However, retrospective and single-center studies are inherently biased, and there are currently no prospective, multicenter studies.

Objective: To evaluate the short- and long-term outcomes and complications in patients with TGN who underwent MVD at specialized Japanese institutions.

Methods: We enrolled patients with TGN who underwent MVD between April 2012 and March 2015. We recorded their facial pain grade and complications at 7 d (short term), 1 yr (mid-term), and 3 yr (long term) postoperatively.

Results: There were 166 patients, comprising 60 men and 106 women (mean age 62.7 yr). Furthermore, 105 patients were aged over 60 yr. We conducted neuromonitoring in 84.3% of the cases. The complete pain relief, mortality, and complication rates at the short-term follow-up were 78.9%, 0%, and 16.3%, respectively. Overall, 155 patients (93.4%) completed the long-term follow-up, with the complete pain relief and complication rates of 80.0% and 5.2%, respectively.

Conclusion: In the hands of experienced neurosurgeons, MVD for TGN can achieve high long-term curative effects. In addition, complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with TGN, including elderly patients.
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http://dx.doi.org/10.1093/neuros/nyab229DOI Listing
September 2021

Acute Hospital Mortality of Venous Thromboembolism in Patients With Cancer From Registry Data.

J Am Heart Assoc 2021 06 22;10(11):e019373. Epub 2021 May 22.

Department of Cardiovascular Medicine Tokushima University Hospital Tokushima Japan.

Background The prognosis of patients with cancer-venous thromboembolism (VTE) is not well known because of a lack of registry data. Moreover, there is also no knowledge on how specific types are related to prognosis. We sought to evaluate the clinical characteristics and outcomes of patients with cancer-associated VTE, compared with a matched cohort without cancer using real-world registry data of VTE. Methods and Results This study was based on the Diagnosis Procedure Combination database in the JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination). Of 5 106 151 total patients included in JROAD-DPC, we identified 49 580 patients who were first hospitalized with VTE from April 2012 to March 2017. Propensity score was estimated with a logistic regression model, with cancer as the dependent variable and 18 clinically relevant covariates. After propensity matching, there were 25 148 patients with VTE with or without cancer. On propensity score-matched analysis with 25 148 patients with VTE, patients with cancer had higher total in-hospital mortality within 7 days (1.3% versus 1.1%, odds ratio [OR], 1.66; 95% CI, 1.31-2.11; <0.0001), 14 days (2.5% versus 1.5%, OR, 2.07; 95% CI, 1.72-2.49; <0.0001), and 30 days (4.8% versus 2.0%, OR, 2.85; 95% CI, 2.45-3.31; <0.0001). On analysis for each type of cancer, in-hospital mortality in 11 types of cancer was significantly high, especially pancreas (OR, 12.96; 95% CI, 6.41-26.20), biliary tract (OR, 8.67; 95% CI, 3.00-25.03), and liver (OR, 7.31; 95% CI, 3.05-17.50). Conclusions Patients with cancer had a higher in-hospital acute mortality for VTE than those without cancer, especially in pancreatic, biliary tract, and liver cancers.
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http://dx.doi.org/10.1161/JAHA.120.019373DOI Listing
June 2021

Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals.

Nutrients 2021 Jan 23;13(2). Epub 2021 Jan 23.

Department of Cardiovascular Medicine, Tokushima University Hospital, Tokushima 770-8503, Japan.

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.
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http://dx.doi.org/10.3390/nu13020335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911510PMC
January 2021

Prospective, Multicenter Clinical Study of Microvascular Decompression for Hemifacial Spasm.

Neurosurgery 2021 03;88(4):846-854

Seikei-kai Chiba Medical Center, Chiba, Japan.

Background: Microvascular decompression (MVD) is the most effective procedure for hemifacial spasm (HFS). MVD results from nonspecialized or low-volume institutes are not always reliable. Most studies on MVD for HFS are retrospective and single centered; to the best of our knowledge, no prospective, multicenter studies exist.

Objective: To evaluate short- and long-term outcomes and complications in patients who underwent MVD for HFS in specialized Japanese institutions, in this multicenter, prospective, cohort study.

Methods: Included patients had undergone MVD for HFS in study centers between April 2012 and March 2015. Patients' postoperative grade of involuntary movements and complications were recorded postoperatively at 7 d (short-term) and at 1 (mid-term) and 3 (long-term) yr.

Results: A total of 486 patients (150 men, 336 women; mean age 53.9 yr with 181 patients over 60 yr) were enrolled during the study period. Neuromonitoring was used in 96.3% of the cases. The complete cure rate of symptom relief, mortality rate, and complication rate at short-term follow-up were 70.6%, 0%, and 15%, respectively. The long-term follow-up was completed by 463 patients (95.3%); the complete cure rate of symptom relief and complication rate were 87.1% and 3.0%, respectively.

Conclusion: Our study revealed that under expert guidance and intraoperative neuromonitoring, the long-term curative effect rate of MVD for HFS is high, while complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with HFS, including elderly patients.
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http://dx.doi.org/10.1093/neuros/nyaa549DOI Listing
March 2021

Association between Sarcopenia/Lower Muscle Mass and Short-Term Regression of Deep Vein Thrombosis Using Direct Oral Anticoagulants.

Int Heart J 2020 Jul 18;61(4):787-794. Epub 2020 Jul 18.

Department of Cardiovascular Medicine, Tokushima University Hospital.

Advanced age, obesity, and muscle weakness are independent factors in the onset of deep vein thrombosis (DVT). Recently, an association between sarcopenia and DVT has been reported. We hypothesized that sarcopenia related factors, observed by ultrasonography, are associated with the regression effect on the thrombus following anticoagulation therapy. The present study focused on gastrocnemius muscle (GCM) thickness and the GCM's internal echogenic brightness. We examined the association with DVT regression following direct oral anticoagulants (DOACs) treatment.The prospective cohort study period was between October 2017 and August 2018. We enrolled 46 patients diagnosed with DVT by ultrasonography, who were aged >60 years old and treated with DOACs. Sarcopenia was evaluated using the Asian Working Group for Sarcopenia flowchart. The average DOACs treatment period was 94 days, and 29 patients exhibited thrombus regression. On univariate logistic regression analysis, sarcopenia, average GCM diameter index, and gastrocnemius integrated backscatter index were significantly associated with thrombus regression. In a multivariate model, only the average GCM diameter index correlated with thrombus regression.The average GCM diameter index is associated with DVT regression treated with DOACs. Considering the GCM diameter during DVT treatment can be a marker to make a decision for the treatment of DVT.
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http://dx.doi.org/10.1536/ihj.20-032DOI Listing
July 2020

Monitoring of muscle mass in critically ill patients: comparison of ultrasound and two bioelectrical impedance analysis devices.

J Intensive Care 2019 16;7:61. Epub 2019 Dec 16.

5Emergency and Disaster Medicine, Tokushima University Hospital, 2-50-1 Kuramoto, Tokushima, 770-8503 Japan.

Background: Skeletal muscle atrophy commonly occurs in critically ill patients, and decreased muscle mass is associated with worse clinical outcomes. Muscle mass can be assessed using various tools, including ultrasound and bioelectrical impedance analysis (BIA). However, the effectiveness of muscle mass monitoring is unclear in critically ill patients. This study was conducted to compare ultrasound and BIA for the monitoring of muscle mass in critically ill patients.

Methods: We recruited adult patients who were expected to undergo mechanical ventilation for > 48 h and to remain in the intensive care unit (ICU) for > 5 days. On days 1, 3, 5, 7, and 10, muscle mass was evaluated using an ultrasound and two BIA devices (Bioscan: Malton International, England; Physion: Nippon Shooter, Japan). The influence of fluid balance was also evaluated between each measurement day.

Results: We analyzed 93 images in 21 patients. The age of the patients was 69 (interquartile range, IQR, 59-74) years, with 16 men and 5 women. The length of ICU stay was 11 days (IQR, 9-25 days). The muscle mass, monitored by ultrasound, decreased progressively by 9.2% (95% confidence interval (CI), 5.9-12.5%), 12.7% (95% CI, 9.3-16.1%), 18.2% (95% CI, 14.7-21.6%), and 21.8% (95% CI, 17.9-25.7%) on days 3, 5, 7, and 10 ( <  0.01), respectively, with no influence of fluid balance ( = 0.04,  = 0.74). The muscle mass did not decrease significantly in both the BIA devices (Bioscan,  = 0.14; Physion,  = 0.60), and an influence of fluid balance was observed (Bioscan,  = 0.37,  <  0.01; Physion,  = 0.51,  <  0.01). The muscle mass assessment at one point between ultrasound and BIA was moderately correlated (Bioscan,  = 0.51,  <  0.01; Physion,  = 0.37,  <  0.01), but the change of muscle mass in the same patient did not correlate between these two devices (Bioscan,  = - 0.05,  = 0.69; Physion,  = 0.23,  = 0.07).

Conclusions: Ultrasound is suitable for sequential monitoring of muscle atrophy in critically ill patients. Monitoring by BIA should be carefully interpreted owing to the influence of fluid change.

Trial Registration: UMIN000031316. Retrospectively registered on 15 February 2018.
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http://dx.doi.org/10.1186/s40560-019-0416-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916000PMC
December 2019

Active Cancer and Elevated D-Dimer Are Risk Factors for In-Hospital Ischemic Stroke.

Cerebrovasc Dis Extra 2019 22;9(3):129-138. Epub 2019 Nov 22.

Department of Neurosurgery, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.

Background And Purpose: Little attention has been paid to the pathogenesis of in-hospital stroke, despite poor outcomes and a longer time from stroke onset to treatment. We studied the pathophysiology and biomarkers for detecting patients who progress to in-hospital ischemic stroke (IHS).

Methods: Seventy-nine patients with IHS were sequentially recruited in the period 2011-2017. Their characteristics, care, and outcomes were compared with 933 patients who had an out-of-hospital ischemic stroke (OHS) using a prospectively collected database of the Tokushima University Stroke Registry.

Results: Active cancer and coronary artery disease were more prevalent in patients with IHS than in those with OHS (53.2 and 27.8% vs. 2.0 and 10.9%, respectively; p < 0.001), the median onset-to-evaluation time was longer (300 vs. 240 min; p = 0.015), and the undetermined etiology was significantly higher (36.7 vs. 2.4%; p < 0.001). Although there was no significant difference in stroke severity at onset between the groups, patients with IHS had higher modified Rankin Scale (mRS) scores (3-6) at discharge (67.1 vs. 50.3%; p = 0.004) and rates of death during hospitalization (16.5 vs. 2.9%; p < 0.001). D-dimer (5.8 vs. 0.8 µg/mL; p < 0.001) and fibrinogen (532 vs. 430 mg/dL; p = 0.014) plasma levels at the time of onset were significantly higher in patients with IHS after propensity score matching. Multivariate logistic regression analysis revealed that active cancer (odds ratio [OR] 2.30; 95% confidence interval [CI] 1.26-4.20), prestroke mRS scores 3-5 (OR 6.78; 95% CI 3.96-11.61), female sex (OR 1.57; 95% CI 1.19-2.08), and age ≥75 years (OR 2.36; 95% CI 1.80-3.08) were associated with poor outcomes.

Conclusions: Patients with IHS had poorer outcomes than those with OHS because of a higher prevalence of active cancer and functional dependence before stroke onset. Elevated plasma levels of D-dimer and fibrinogen, especially with active cancer, can help identify patients who are at a higher risk of progression to IHS.
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http://dx.doi.org/10.1159/000504163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940458PMC
May 2020

Importance of Managing the Water-Electrolyte Balance by Delivering the Optimal Minimum Amount of Water and Sodium After Subarachnoid Hemorrhage.

World Neurosurg 2019 Sep 25;129:e352-e360. Epub 2019 May 25.

Department of Neurosurgery, Tokushima University Hospital, Tokushima, Japan.

Background: After aneurysmal subarachnoid hemorrhage (aSAH), crystalloid fluids with a relatively high sodium concentration have been used to maintain the cerebral blood flow. However, the prophylactic delivery of water and sodium by intravenous (IV) infusion will not necessarily improve the prognosis of patients after aSAH, and the excessive supply of water and sodium can negatively affect the outcome. We hypothesized that the delivery of an optimal amount of water and sodium separately might improve the outcome after aSAH.

Methods: We recruited 55 consecutive patients who had undergone clipping or endovascular coil embolization after aSAH. Group 1 (n = 33) received conventional therapy (i.e., prophylactic IV sodium and water [protocol 1]). Group 2 (n = 22) received the optimal amount of water and sodium separately (protocol 2).

Results: The median total of water and sodium chloride supplied in group 1 was significantly greater than that supplied in group 2 (P < 0.01). The modified Rankin scale score at discharge was 0-2 in 15 patients (95%) in group 2 and 23 patients (55%) in group 1 (P < 0.001). On multivariate logistic regression analysis, the odds ratio for a discharge modified Rankin scale score of 0-2 or 3-6 was significantly associated with the treatment protocol (P < 0.05) and the net fluid balance on days 4-8 (P < 0.05).

Conclusion: The separate delivery of optimal amounts of water and sodium could be a promising therapeutic strategy to improve the prognosis after aSAH.
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http://dx.doi.org/10.1016/j.wneu.2019.05.152DOI Listing
September 2019

CGRP Induces Differential Regulation of Cytokines from Satellite Glial Cells in Trigeminal Ganglia and Orofacial Nociception.

Int J Mol Sci 2019 Feb 7;20(3). Epub 2019 Feb 7.

Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan.

Neuron-glia interactions contribute to pain initiation and sustainment. Intra-ganglionic (IG) secretion of calcitonin gene-related peptide (CGRP) in the trigeminal ganglion (TG) modulates pain transmission through neuron-glia signaling, contributing to various orofacial pain conditions. The present study aimed to investigate the role of satellite glial cells (SGC) in TG in causing cytokine-related orofacial nociception in response to IG administration of CGRP. For that purpose, CGRP alone (10 μL of 10 M), Minocycline (5 μL containing 10 μg) followed by CGRP with one hour gap (Min + CGRP) were administered directly inside the TG in independent experiments. Rats were evaluated for thermal hyperalgesia at 6 and 24 h post-injection using an operant orofacial pain assessment device (OPAD) at three temperatures (37, 45 and 10 °C). Quantitative real-time PCR was performed to evaluate the mRNA expression of IL-1β, IL-6, TNF-α, IL-1 receptor antagonist (IL-1RA), sodium channel 1.7 (NaV 1.7, for assessment of neuronal activation) and glial fibrillary acidic protein (GFAP, a marker of glial activation). The cytokines released in culture media from purified glial cells were evaluated using antibody cytokine array. IG CGRP caused heat hyperalgesia between 6⁻24 h (paired- test, < 0.05). Between 1 to 6 h the mRNA and protein expressions of GFAP was increased in parallel with an increase in the mRNA expression of pro-inflammatory cytokines IL-1β and anti-inflammatory cytokine IL-1RA and NaV1.7 (one-way ANOVA followed by Dunnett's post hoc test, < 0.05). To investigate whether glial inhibition is useful to prevent nociception symptoms, Minocycline (glial inhibitor) was administered IG 1 h before CGRP injection. Minocycline reversed CGRP-induced thermal nociception, glial activity, and down-regulated IL-1β and IL-6 cytokines significantly at 6 h (-test, < 0.05). Purified glial cells in culture showed an increase in release of 20 cytokines after stimulation with CGRP. Our findings demonstrate that SGCs in the sensory ganglia contribute to the occurrence of pain via cytokine expression and that glial inhibition can effectively control the development of nociception.
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http://dx.doi.org/10.3390/ijms20030711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386987PMC
February 2019

Prevalence of Posterior Disc Displacement of the Temporomandibular Joint in Patients with Temporomandibular Disorders: Systematic Review and Meta-Analyses.

J Oral Facial Pain Headache Summer 2018;32(3):277–286. Epub 2018 Apr 25.

Aims: To assess the prevalence of posterior disc displacement (PDD) in patients with temporomandibular disorders (TMD) through a systematic review of the literature and meta-analysis, as well as to assess features associated with PDD such as chief complaint, signs and symptoms, morphologic condyle and disc alterations, and PDD management.

Methods: A systematic literature search was performed in the US National Library of Medicine's PubMed/MEDLINE and Cochrane Library databases to identify all peer-reviewed, English-language manuscripts related to PDD. A critical appraisal checklist provided by the Joanna Briggs Institute for studies reporting prevalence data was used to assess the quality of the included manuscripts. A meta-analysis was conducted using software MetaXL 5.3 (EpiGear International Pty Ltd) add-in for Microsoft Excel. Pooled prevalence and 95% confidence intervals (CIs) were calculated using the software. Heterogeneity of the included studies was assessed using the Higgins I test and Cochran's Q (with P value; < .05 was considered significant).

Results: A total of 21 articles were selected for qualitative data synthesis: 2 case reports, 14 observational studies, and 5 studies that reported PDD in various conditions. Quantitative data analysis was performed for the 14 observational studies, of which 13 reported prevalence with respect to the number of joints affected and 9 reported prevalence with respect to the number of patients affected. The overall pooled prevalence of PDD for the number of joints affected was 0.7% (95% CI: 0.005 to 0.008). The pooled prevalence of PDD for the number of patients was 0.9% (95% CI: 0.007 to 0.011). PDD was found to be associated with osseous changes, including changes in the morphology of the condyle, disc, and articular eminence; osseous abnormalities (erosion, osteophytes); and joint effusion.

Conclusion: This meta-analysis showed a very low prevalence rate of PDD in TMD patients. The limited literature did not allow conclusions to be drawn about the PDD-related features.
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http://dx.doi.org/10.11607/ofph.1924DOI Listing
November 2018

Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study.

J Stroke Cerebrovasc Dis 2018 Aug 2;27(8):2134-2140. Epub 2018 Apr 2.

Department of Neurosurgery, Institute of Biomedical Biosciences, Tokushima University Graduate School, Tokushima, Japan.

Background: Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients.

Methods: Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms.

Results: Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%.

Conclusion: Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.03.008DOI Listing
August 2018

Combination of O6-methylguanine-DNA methyltransferase and thymidylate synthase for the prediction of fluoropyrimidine efficacy.

Eur J Cancer 2008 Feb 18;44(3):400-7. Epub 2007 Dec 18.

Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.

We investigated the correlation between the response to fluoropyrimidines as first-line therapy and the expressions of genes in patients with primary colorectal cancer (CRC). The study group comprised 92 patients with metastatic CRC. Total RNA was isolated from laser-captured tumour cells in surgically resected primary lesions, and gene expression was quantitatively evaluated by real-time RT-PCR assay. Low thymidylate synthase (TS), low gamma-glutamyl hydrolase, high reduced folate carrier 1, high O6-methylguanine-DNA methyltransferase (MGMT) and low cyclin E expressions were associated with a good response (P=0.0030, 0.0250, 0.0120, 0.0030 and 0.0020, respectively) on univariate analysis. On multivariate logistic regression analysis, TS and MGMT remained independent predictors of the response. The clinical response rates were 63.2% in the low TS or high MGMT group and 14.3% in high TS and low MGMT group (P<0.0001). The combination of high TS and low MGMT expression is a significant predictor of a poor response to fluoropyrimidine treatment.
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http://dx.doi.org/10.1016/j.ejca.2007.11.010DOI Listing
February 2008

Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity.

Biochem Biophys Res Commun 2008 Jan 21;365(4):801-7. Epub 2007 Nov 21.

Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan.

Although 5-fluorouracil (5-FU) plus leucovorin (LV) is a standard chemotherapy regimen for colorectal cancer, the factors that determine the LV-mediated enhancement of the antitumor activity of 5-FU have remained unknown. We investigated the roles of folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH), which are the main enzymes involved in folate metabolism, in the effect of LV. LV enhanced the anticancer activity of 5-FU and the level of reduced folate in human colon cancer cells. Small-interfering RNA (siRNA) transfected into DLD-1 cells to downregulate FPGS reduced the basal level of reduced folate, the folate level after LV treatment, and the enhancement of 5-fluoro-2'-deoxyuridine (FdUrd)-induced cytotoxicity elicited by LV. By contrast, the downregulation of GGH by siRNA increased cellular sensitivity to FdUrd combined with LV. These results suggest that FPGS and GGH expression levels in tumors are determinants of the efficacy of LV in enhancing the antitumor activity of 5-FU.
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http://dx.doi.org/10.1016/j.bbrc.2007.11.043DOI Listing
January 2008

Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

Cancer Sci 2007 Apr;98(4):577-83

Personalized Medicine Research Laboratory, Taiho Pharmaceutical Co., 224-2 Ebisuno, Hiraishi, Kawauchi-cho Tokushima, 711-0194, Japan.

Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.
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http://dx.doi.org/10.1111/j.1349-7006.2007.00424.xDOI Listing
April 2007

Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray.

Clin Cancer Res 2007 Jan;13(2 Pt 1):415-20

Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.

Purpose: Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients.

Experimental Design: Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group).

Results: By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor-related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively.

Conclusions: These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-0753DOI Listing
January 2007

Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers.

Cancer Res 2006 Oct;66(20):9804-8

Department of Surgery, Teikyo University School of Medicine, Tokyo 173-8605, Japan.

Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-06-1163DOI Listing
October 2006

Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs.

Cancer Sci 2006 Jun;97(6):510-22

Optimal Medication Research Laboratory, Taiho Pharmaceutical Company, 224-2 Ebisuno, Hiraishi, Tokushima, 771-0194, Japan.

The development of a diagnostic method for predicting the therapeutic efficacy or toxicity of anticancer drugs is a critical issue. We carried out a gene expression analysis to identify genes whose expression profiles were correlated with the sensitivity of 30 human tumor xenografts to 5-fluorouracil (5-FU)-based drugs (tegafur + uracil [UFT], tegafur + gimeracil + oteracil [S-1], 5'-deoxy-5-fluorouridine [5'-DFUR], and N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine [capecitabine]), as well as three other drugs (cisplatin [CDDP], irinotecan hydrochloride [CPT-11], and paclitaxel) that have different modes of action. In the present study, we focused especially on the fluoropyrimidines. The efficacy of all anticancer drugs was assayed using human tumor xenografts in nude mice. The mRNA expression profile of each of these xenografts was analyzed using a Human Focus array. Correlation analysis between the gene expression profiles and the chemosensitivities of seven drugs identified 39 genes whose expression levels were correlated significantly with multidrug sensitivity, and we suggest that the angiogenic pathway plays a pivotal role in resistance to fluoropyrimidines. Furthermore, many genes showing specific correlations with each drug were also identified. Among the candidate genes associated with 5-FU resistance, the dihydropyrimidine dehydrogenase mRNA expression profiles of the tumors showed a significant negative correlation with chemosensitivity to all of the 5-FU based drugs except for S-1. Therefore, the administration of S-1 might be an effective strategy for the treatment of high dihydropyrimidine dehydrogenase-expressing tumors. The results of the present study may enhance the prediction of tumor response to anticancer drugs and contribute to the development of tailor-made chemotherapy.
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http://dx.doi.org/10.1111/j.1349-7006.2006.00204.xDOI Listing
June 2006
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