Aomori Shi, Japan
Aomori Shi, Japan

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PubMed | Hirosaki Municipal Hospital, Saitama Cancer Center, University of Chicago, Sapporo Medical University and 12 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, endoxifen. There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving pre-operative tamoxifen monotherapy for 14-28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response and hot flushes.Ki-67 labeling index in breast cancer tissues significantly decreased after pre-operative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathological response nor hot flushes, they showed significant association with Ki-67 response after pre-operative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wildtype allele).This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer.


PubMed | Hirosaki Municipal Hospital, Yodogawa Christian Hospital, Kamiiida Daiichi General Hospital, Kobe Kaisei Hospital and 13 more.
Type: Clinical Trial, Phase II | Journal: PloS one | Year: 2015

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT).Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fishers exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fishers exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted.University Hospital Medical Information Network. UMIN000003261.


PubMed | Red Cross, Nara Prefectural Gojo Hospital, Tachikawa General Hospital, Fujiyoshida Municipal Hospital and 46 more.
Type: Journal Article | Journal: Gastroenterology research | Year: 2016

To examine the effects of percutaneous endoscopic gastrostomy (PEG) on quality of life (QOL) in patients with dementia.We retrospectively included 53 Japanese community and tertiary hospitals to investigate the relationship between the newly developed PEG and consecutive dementia patients with swallowing difficulty between Jan 1st 2006 and Dec 31st 2008. We set improvements in 1) the level of independent living, 2) pneumonia, 3) peroral intake as outcome measures of QOL and explored the factors associated with these improvements.Till October 31st 2010, 1,353 patients with Alzheimers dementia (33.1%), vascular dementia (61.7%), dementia with Lewy body disease (2.0%), Pick disease (0.6%) and others were followed-up for a median of 847 days (mean 805 542 days). A total of 509 deaths were observed (mortality 59%) in full-followed patients. After multivariate adjustments, improvement in the level of independent living was observed in milder dementia, or those who can live independently with someone, compared with advanced dementia, characterized by those who need care by someone: Odds Ratio (OR), 3.90, 95% confidence interval (95%CI), 1.59 - 9.39, P = 0.003. Similarly, improvement of peroral intake was noticed in milder dementia: OR, 2.69, 95%CI, 1.17 - 6.17, P = 0.02. Such significant associations were not observed in improvement of pneumonia.These results suggest that improvement of QOL after PEG insertion may be expected more in milder dementia than in advanced dementia.


Taira N.,Okayama University | Iwata H.,Aichi Cancer Center Hospital | Hasegawa Y.,Hirosaki Municipal Hospital | Sakai T.,Cancer Institute Hospital | And 6 more authors.
Breast Cancer Research and Treatment | Year: 2014

Trials of adjuvant endocrine therapy for breast cancer have shown that aromatase inhibitors have little impact on global health-related quality of life (HRQoL), but have significant effects on patient-reported endocrine symptoms (ESs). There are few studies of HRQoL and psychological distress during preoperative endocrine therapy performed to determine endocrine responsiveness. The NEOS trial is a multicenter, phase 3 randomized controlled trial in postmenopausal women with hormone receptor-positive breast cancer. The primary aim of the trial was to evaluate the need for adjuvant chemotherapy in patients with clinical T1c-T2N0M0, hormone receptor-positive tumors who responded to neoadjuvant letrozole (LET) administered for 24-28 weeks before surgery. The primary endpoint was disease-free survival and the secondary endpoints included adverse events, HRQoL, and cost-effectiveness. In a HRQoL sub-study, subjects were assessed at baseline and 4 and 16 weeks after starting neoadjuvant LET, using the functional assessment of cancer therapy-breast and its ES subscale, and the hospital anxiety and depression scale. HRQoL and psychosocial distress were analyzed in the uncontrolled phase during 24-28 weeks of neoadjuvant LET therapy in the NEOS trial. From May 16, 2008, to December 14, 2011, 503 patients were recruited into the HRQoL sub-study. The full analysis set included 497 patients with a mean age of 63-years old. The questionnaire response rates at enrollment and 4 and 16 weeks were 94.4, 90.7, and 89.1 %, respectively. There were no significant changes in the FACT-G or B-trial outcome index over time, but the social and family well-being score and the ES subscale deteriorated significantly, and the number of patients with clinically significant hot flush increased significantly. Anxiety, depression, and emotional well-being improved significantly after neoadjuvant LET. Neoadjuvant endocrine therapy with LET had no impact on global HRQoL, but did influence endocrine-related symptoms such as hot flush. This study is registered as UMIN000001090. © 2014 Springer Science+Business Media New York.


PubMed | Clinical Trials Research Unit, Hirosaki Municipal Hospital, University of Washington, Weston Park Hospital and 3 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response.Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC.pCRb and pCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase pCRb or pCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the pCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01-4.55) and a non-significant benefit of the pCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90-7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA.This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on pCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC.


Kudoh A.,Hirosaki Municipal Hospital
Japanese Journal of Anesthesiology | Year: 2010

Schizophrenic patients are at increased risk for perioperative complications such as hypotension and hypothermia during anesthesia, postoperative ileus, confusion and pneumonia. In addition, schizophrenic patients are predisposed to developing pulmonary thromboembolism, torsade de pointes, water intoxication and rhabdomyolysis. The increased complications are associated with physical disorders, antipsychotic agents, hazardous health behaviors, and interactions between antipsychotic agents and anesthetic drugs. Increased cortisol, norepinephrine and cytokine concentrations are considered as possible cause of postoperative confusion and ileus. Anesthesia with ketamine, propofol and fentanyl decreased the frequency of the postoperative confusion in schizophrenic patients. Epidural anesthesia with local anesthesia in schizophrenic patients undergoing abdominal surgery minimized postoperative ileus. Antipsychotic drugs administrated to schizophrenic patients should be continued before anesthesia for decreasing postoperative confusion. Thus, anesthesiologists must not only be aware of the perioperative problems of these patients but must also learn how to manage their perioperative course.


Kudoh A.,Hirosaki Municipal Hospital
Japanese Journal of Anesthesiology | Year: 2010

Depressed patients have some problems before, during and after anesthesia such as hypotension, and torsade de pointes during anesthesia, postoperative confusion, serotonin toxicity, increased intraoperative bleeding by selective serotonin reuptake inhibitors. Depressed patients treated by antidepressants have decreased plasma cortisol and interleukin-6 response to surgery and are more at risk for developing postoperative confusion, that is associated with abnormal cortisol response to surgery and more frequent in patients discontinued antidepressants 72 hours before surgery. Depressed patients treated by antidepressants have high postoperative pain score, that depend on their depressed state. A small-dose of ketamine improves postoperative depressive state and relieves postoperative pain in depressed patients and is a suitable anesthetic for depressed patients. As the anesthetic management in depressed patients is becoming increasingly, anesthesiologists should be familiar with medical illness, abnormal response to surgery in depressed patients and must learn their perioperative management.


PubMed | Hirosaki Municipal Hospital and Hirosaki University
Type: Journal Article | Journal: Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society | Year: 2016

Multiple scoring systems have been developed to predict outcomes in patients with upper gastrointestinal bleeding. We determined how well these and a newly established scoring model predict the need for therapeutic intervention, excluding transfusion, in Japanese patients with upper gastrointestinal bleeding.We reviewed data from 212 consecutive patients with upper gastrointestinal bleeding. Patients requiring endoscopic intervention, operation, or interventional radiology were allocated to the therapeutic intervention group. Firstly, we compared areas under the curve for the Glasgow-Blatchford, Clinical Rockall, and AIMS65 scores. Secondly, the scores and factors likely associated with upper gastrointestinal bleeding were analyzed with a logistic regression analysis to form a new scoring model. Thirdly, the new model and the existing model were investigated to evaluate their usefulness.Therapeutic intervention was required in 109 patients (51.4%). The Glasgow-Blatchford score was superior to both the Clinical Rockall and AIMS65 scores for predicting therapeutic intervention need (area under the curve, 0.75 [95% confidence interval, 0.69-0.81] vs 0.53 [0.46-0.61] and 0.52 [0.44-0.60], respectively). Multivariate logistic regression analysis retained seven significant predictors in the model: systolic blood pressure <100mmHg, syncope, hematemesis, hemoglobin <10g/dL, blood urea nitrogen 22.4mg/dL, estimated glomerular filtration rate 60mL/min per 1.73mWe developed a superior scoring model for identifying therapeutic intervention need in Japanese patients with upper gastrointestinal bleeding.


PubMed | Hirosaki Municipal Hospital and Hirosaki University
Type: Case Reports | Journal: Clinical journal of gastroenterology | Year: 2016

Humoral hypercalcemia due to a gastric carcinoma-secreting parathyroid hormone-related protein (PTHrP) is a rare disease associated with poor prognosis. A 61-year-old male with gastric cancer who had been receiving chemotherapy showed serum hypercalcemia and an elevated level of serum PTHrP with a suppressed intact parathyroid hormone level. Computed tomography revealed stable disease 4weeks prior, and the laboratory examination revealed no adverse effects 2weeks prior. The biopsy at the time of diagnosis was immunohistochemically positive for PTHrP later. Despite intensive care, the patient died of multiorgan failure on the 14th day after admission. In case of undifferentiated gastric cancer, the possibility of humoral hypercalcemia of malignancy caused by gastric cancer should be considered even when the patient is receiving chemotherapy.


PubMed | Yokohama Neurology Clinic, Hirosaki Municipal Hospital and Juntendo University
Type: | Journal: Journal of neural transmission (Vienna, Austria : 1996) | Year: 2016

A recessive mutation in PLA2G6, which is known to cause infantile neuroaxonal dystrophy (INAD) and neurodegeneration associated with brain iron accumulation (NBIA), has recently been shown to be responsible for PARK14-linked dystonia-parkinsonism. To study the frequency of PLA2G6 mutations, including those caused by gene rearrangement in patients with parkinsonism, we performed direct sequencing and investigated copy number variations (CNVs) of this gene in 109 Japanese patients with parkinsonism. Direct sequencing revealed a homozygous mutation (c.1495G>A; p.A499T), which is likely to be pathogenic and is already registered as rs141045127, and two compound-heterozygous mutations we have previously reported. No CNVs in PLA2G6 were detected in our subjects. Our results suggest that CNV in PLA2G6 is rare in parkinsonism, at least in the Japanese population, in contrast to the reports of its frequency in INAD. Further large studies in various populations are warranted to elucidate what causes the difference in frequencies of PLA2G6 rearrangement mutations between INAD and dystonia-parkinsonism.

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