Ōkawara, Japan
Ōkawara, Japan

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Soeda H.,Tohoku University | Shimodaira H.,Tohoku University | Watanabe M.,Tohoku University | Suzuki T.,Sendai Medical Center | And 6 more authors.
International Journal of Clinical Oncology | Year: 2013

Background: Anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab, and panitumumab are established as a new treatment option for metastatic colorectal cancer (mCRC). Among activating mutations downstream of EGFR, the KRAS mutation, which is present in 30-45 % of CRC patients, has shown to be a predictive biomarker of resistance to anti-EGFR antibody therapy based on Caucasian studies. Methods: Forty-three chemotherapy-refractory Japanese patients with mCRC were treated with cetuximab monotherapy or cetuximab plus irinotecan. KRAS, BRAF, and PIK3CA mutational status of tumors was assessed. The association between mutational status and treatment outcome was evaluated. Results: Of 43 tumors, KRAS, BRAF, and PIK3CA mutations were identified in 12 (27.9 %), 2 (4.7 %), and 2 (4.7 %) tumors, respectively. The wild-type KRAS subgroup showed better clinical outcomes than the mutant KRAS subgroup in terms of response rate (RR) (31.3 % vs. 0 %, P = 0.034) and progression-free survival (PFS) (5.1 vs. 3.0 months, P = 0.017). No responder to treatment was shown in 16 (37.2 %) patients with tumors harboring mutations in any one of the three genes (KRAS, BRAF, and PIK3CA). The wild-type subgroup without any mutations in KRAS, BRAF, and PIK3CA had a better RR (37.0 %) and PFS (6.4 months) than did the wild-type KRAS subgroup. Conclusion: Our data indicated that KRAS status is predictive of cetuximab response in the Japanese population. The additional analysis of BRAF and PIK3CA genes in wild-type KRAS patients could improve selection of patients who are most likely to benefit from anti-EGFR antibody therapy. © 2012 Japan Society of Clinical Oncology.


Amato P.,Oregon Health And Science University | Tachibana M.,South Miyagi Medical Center | Sparman M.,Oregon Health And Science University | Mitalipov S.,Oregon Health And Science University
Fertility and Sterility | Year: 2014

The exchange of nuclear genetic material between oocytes and embryos offers a novel reproductive option for the prevention of inherited mitochondrial diseases. Mitochondrial dysfunction has been recognized as a significant cause of a number of serious multiorgan diseases. Tissues with a high metabolic demand, such as brain, heart, muscle, and central nervous system, are often affected. Mitochondrial disease can be due to mutations in mitochondrial DNA or in nuclear genes involved in mitochondrial function. There is no curative treatment for patients with mitochondrial disease. Given the lack of treatments and the limitations of prenatal and preimplantation diagnosis, attention has focused on prevention of transmission of mitochondrial disease through germline gene replacement therapy. Because mitochondrial DNA is strictly maternally inherited, two approaches have been proposed. In the first, the nuclear genome from the pronuclear stage zygote of an affected woman is transferred to an enucleated donor zygote. A second technique involves transfer of the metaphase II spindle from the unfertilized oocyte of an affected woman to an enucleated donor oocyte. Our group recently reported successful spindle transfer between human oocytes, resulting in blastocyst development and embryonic stem cell derivation, with very low levels of heteroplasmy. In this review we summarize these novel assisted reproductive techniques and their use to prevent transmission of mitochondrial disorders. The promises and challenges are discussed, focusing on their potential clinical application. © 2014 by American Society for Reproductive Medicine.


Kakisaka Y.,South Miyagi Medical Center | Kakisaka Y.,Tohoku University | Ohara T.,South Miyagi Medical Center | Hino-Fukuyo N.,Tohoku University | And 2 more authors.
Pediatrics | Year: 2014

Idiopathic stabbing headache (ISH) is a primary headache syndrome characterized by transient, sharp, stabbing pains located in the first division of the trigeminal nerve. Reports of pediatric ISH are rare, and extracephalic pain in pediatric ISH is extremely rare. Here we report the case of a 7-year-old male patient suffering from frequent, short, stabbing headache, which was occasionally associated with abdominal and lower back pain. Various investigations were normal. He was diagnosed with ISH, and valproic acid was administered to relieve his headache and accompanying symptoms. Our case demonstrates that abdominal and lower back pain may occur in pediatric ISH. This case may provide new evidence linking ISH and migraine by showing that extracephalic symptoms accompanying ISH are similar to those of migraine. We hypothesize that the mechanism underlying the headache and abdominal and lower back pain associated with ISH may be similar to that of a migraine headache. Accumulating additional cases by asking specific questions regarding the presence of the unusual symptoms presented in our case may help to establish a detailed clinical profile of these unfamiliar and peculiar symptoms in the pediatric ISH population. Copyright © 2014 by the American Academy of Pediatrics.


Kanno T.,Tohoku University | Iijima K.,Tohoku University | Abe Y.,Tohoku University | Koike T.,Tohoku University | And 9 more authors.
Journal of Gastroenterology | Year: 2013

Background Societal stress derived from an event that affects the whole society, e. g., a natural disaster, provides a unique, indirect way of determining the relationship between psychological stress and peptic ulcer disease in humans. In this study, we investigated the changing patterns of the incidence of peptic ulcers before and after the Great East Japan earthquake, which occurred on 11 March, 2011. Methods Clinical data of patients with peptic ulcers were retrospectively collected during the 3 months after the earthquake (2011) from 7 major hospitals in the middle of the stricken area, and were compared with the data for the same period of the previous year (2010). The eligible subjects were classified into four groups according to Helicobacter pylori infection status and intake of nonsteroidal anti-inflammatory drugs (NSAIDs). Results The incidence of all types of peptic ulcers was 1.5-fold increased after the earthquake, and in particular, the incidence of hemorrhagic ulcers was 2.2-fold increased; the gastric ulcer/duodenal ulcer ratio in hemorrhagic ulcers was also significantly increased (p<0.05). Regarding the etiology of the peptic ulcers, the proportion of non-H. pylori and non-NSAID ulcers was significantly increased, from 13 % in 2010 to 24 % in 2011 after the earthquake (p<0.05). Conclusion In addition to the increased incidence of peptic ulcers, compositional changes in the disease were observed after the Great East Japan earthquake. The significant increase in the proportion of non-H. pylori and non-NSAID ulcers after the earthquake indicated that psychological stress alone induced peptic ulcers in humans independently of H. pylori infection and NSAID intake. © Springer 2012.


Nihei M.,Tohoku University | Okazaki T.,Tohoku University | Ebihara S.,Toho University | Kobayashi M.,Tohoku University | And 9 more authors.
Journal of Pathology | Year: 2015

Chronic inflammation induces lymphangiogenesis and blood vessel remodelling. Since aged pneumonia patients often have repeated episodes of aspiration pneumonia, the pathogenesis may involve chronic inflammation. For lymphangiogenesis, VEGFR-3 and its ligand VEGF-C are key factors. No previous studies have examined chronic inflammation or vascular changes in aspiration pneumonia or its mouse models. In lung inflammation, little is known about the effect of blocking VEGFR-3 on lung lymphangiogenesis and, moreover, its effect on the disease condition. This study aimed to establish a mouse model of aspiration pneumonia, examine the presence of chronic inflammation and vascular changes in the model and in patients, and evaluate the effect of inhibiting VEGFR-3 on the lymphangiogenesis and disease condition in this model. To induce aspiration pneumonia, we repeated inoculation of pepsin at low pH and LPS into mice for 21-28 days, durations in which bronchioalveolar lavage and plasma leakage in the lung suggested the presence of exaggerated inflammation. Conventional and immunohistochemical analysis of tracheal whole mounts suggested the presence of chronic inflammation, lymphangiogenesis, and blood vessel remodelling in the model. Quantitative RT-PCR of the trachea and lung suggested the involvement of lymphangiogenic factor VEGF-C, VEGFR-3, and pro-inflammatory cytokines. In the lung, the aspiration model showed the presence of chronic inflammation and exaggerated lymphangiogenesis. Treatment with the VEGFR inhibitor axitinib or the VEGFR-3 specific inhibitor SAR131675 impaired lymphangiogenesis in the lung and improved oxygen saturation in the aspiration model. Since the lung is the main site of aspiration pneumonia, the changes were intensive in the lung and mild in the trachea. Human lung samples also showed the presence of chronic inflammation and exaggerated lymphangiogenesis, suggesting the relevance of the model to the disease. These results suggest lymphatics in the lung as a new target of analysis and therapy in aspiration pneumonia. © 2014 Pathological Society of Great Britain and Ireland.


Inoue A.,Tohoku University | Sugawara S.,Sendai Kousei Hospital | Harada M.,Hokkaido Cancer Center | Kobayashi K.,Saitama University | And 8 more authors.
Journal of Thoracic Oncology | Year: 2014

Background: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combination of amrubicin (AMR), a new anthracycline agent, and carboplatin (CBDCA) in patients with advanced thymic malignancies. Methods: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m2, days 1-3) and CBDCA (area under the curve 4.0, day 1) every 3 weeks. Patients who had received previous chemotherapy were treated with a reduced dose of AMR (30 mg/m2). The primary end point was objective response rate (ORR), and secondary endpoints were progression-free survival, overall survival, and toxicity profile. Results: From December 2008 to October 2012, 51 patients (33 TC and 18 IT) were enrolled. The median number of treatment cycles was four in each group. The ORR and progression-free survival were 30% (95% confidence interval, 14-46) and 7.6 months in the TC group, and 17% (95% confidence interval, 0-34) and 7.6 months in the IT group, respectively. The ORR of TC patients without previous chemotherapy (n = 19) was 42%. Although grade 3 or 4 hematological toxicities were common including neutropenia (82%) and febrile neutropenia (22%), these were transient and manageable. Nonhematological toxicities were moderate and no treatment-related death was observed. Conclusions: The combination of AMR with CBDCA was active for TC with acceptable toxicity, although it was not effective for IT. Further investigation of this regimen for advanced TC is warranted. Copyright © 2014 by the International Association for the Study of Lung Cancer.


Higashi F.,Higashi Clinic | Kubo H.,Tohoku University | Yasuda H.,Yaotome Ekimae Clinic of Internal Medicine and Pediatrics | Nukiwa T.,South Miyagi Medical Center | Yamaya M.,Tohoku University
Respiratory Investigation | Year: 2014

Background: Influenza virus infection-induced inflammatory responses are associated with fever and other symptoms. Although macrolide antibiotics (macrolides) provide anti-inflammatory effects, these effects have not been well studied in influenza patients. Methods: We examined the effects of clarithromycin on influenza symptoms. A randomized, prospective, and open-label study was performed between December 2010 and March 2011 and between December 2012 and March 2013 in patients with pandemic A/H1 2009 influenza or seasonal influenza virus infections. Patients aged >15 years received either neuraminidase inhibitors (control group) or clarithromycin plus neuraminidase inhibitors (clarithromycin group). Body temperature and other symptoms were recorded for 5 days after initiating treatment. Serum interleukin (IL)-6 and IL-8 levels were also measured. Results: Herein, 79 patients were enrolled over the two influenza seasons, and data from 63 patients were analyzed. All patients showed fever and other symptoms, including rhinorrhea (n=38), cough (n=50), sore throat (n=39), arthralgia or myalgia (n=46), and general malaise (n=50). Fever duration was approximately 42% shorter in patients with temperatures ≥38.5 °C (p=0.02), decreasing from 42. h to 24. h. Among patients with pandemic influenza infections (n=20), the rhinorrhea improvement rate was higher in the clarithromycin group (p=0.03; 88% vs. 20%). Serum IL-6 levels decreased 5 days after treatment, but no differences between the two groups were detected. Conclusions: Clarithromycin may have the additional clinical benefit of improving fever, the main symptom of influenza, in patients treated with neuraminidase inhibitors. © 2014 The Japanese Respiratory Society.


Miura M.,Tohoku University | Sakata Y.,Tohoku University | Nochioka K.,Tohoku University | Takahashi J.,Tohoku University | And 7 more authors.
Circulation Journal | Year: 2013

Background: Elevated blood urea nitrogen (BUN) observed in patients hospitalized for acute heart failure syndrome (AHFS) may represent increased neurohumoral activation. The purpose of this study was to examine the prognostic impact of BUN changes during hospitalization on the long-term prognosis of AHFS patients. Methods and Results: The Tohoku Acute Heart Failure Registry (n=497) is a multicenter retrospective cohort study enrolling AHFS patients who were admitted in 2007. The 337 survivors (mean age, 76 years; 52% male) were divided into 3 groups according to tertiles of BUN change during hospitalization: Decreased (D-BUN, ΔBUN (BUN level at discharge-BUN level at hospitalization) ≤-1.63 mg/dl, n=112); Unchanged (U-BUN, ΔBUN -1.64 to 5.73 mg/dl, n=113); Increased (I-BUN, ΔBUN >5.73 mg/dl, n=112). The D-BUN group had higher prevalence of lowest glomerular filtration rate during hospitalization, whereas the I-BUN group had higher systolic blood pressure. During a median follow-up period of 2.3 years after discharge, the Kaplan-Meier curve showed that D-BUN and I-BUN had worse prognosis compared with U-BUN. Multivariable logistic model showed that all-cause death was more frequent in I-BUN (hazard ratio, 2.94; 95% confidence interval, 1.51-5.73; P<0.001). Subgroup analysis revealed that BUN increase during hospitalization was associated with all-cause death, regardless of renal function. Conclusions: AHFS patients with a BUN increase during hospitalization have worse long-term prognosis, independent of renal function.


Watanuki Z.,South Miyagi Medical Center
The Tohoku journal of experimental medicine | Year: 2012

Interstitial lung diseases (ILDs) represent a large group of different diseases, with a large part comprising idiopathic interstitial pneumonias. Differentiating hypersensitivity pneumonitis (HP), especially its chronic form and other ILDs, is difficult because of similarities in radiological manifestation and clinical course, and the difficulty of identifying causative antigens. We recently experienced a patient with Cladosporium-induced chronic HP that developed in a household environment, but the cause had been misdiagnosed as idiopathic interstitial pneumonia for several years. This case highlighted the need for measures differentiating HP from idiopathic interstitial pneumonia. In this study, we examined fungal exposure in ILDs using an antibody titer in serum to identify possible fungus-related HP. We measured the antibody titer to Cladosporium spp. in 34 patients with various ILDs, 17 patients with bronchial asthma, and 21 control subjects using an immunofluorescence assay. ILDs included HP (5 patients), idiopathic interstitial pneumonias (21 patients), and ILDs with collagen vascular diseases (8 patients). Results showed a significantly higher tendency for high anti-Cladosporium antibody titers in ILD groups (12 patients out of 34 patients), compared to patients with bronchial asthma (0/17) or control subjects (0/21). This increase in antibody titers was observed not only in patients with HP, but also in those with idiopathic interstitial pneumonias and those exhibiting collagen vascular diseases with ILDs. This report highlights the pathogenic role of fungal antigens in various ILDs. In conclusion, fungi commonly observed in our living environment such as Cladosporium could be involved in the development of ILDs.


Kakisaka Y.,South Miyagi Medical Center
Journal of child neurology | Year: 2013

The symptoms and prevalence of migraine headaches are widely recognized; however, less is known about migraine-related spontaneous body pain, or migrainous corpalgia. Only a few reports have described it. The case of a 13-year-old boy with onset of migrainous corpalgia at the age of 12 years is presented. He suffered from pulsatile headaches and bilateral lower back pain, which would appear either with the headache or as an isolated symptom. Various medical examinations showed no abnormalities. He was diagnosed as having migraine without aura and successfully treated with valproic acid. It is unique for this patient to have lower back pain as a symptom of migrainous corpalgia. It would be important for physicians to understand the variety of pain symptoms in migraine patients, as shown here, for better and comprehensive understanding of migraine and its related condition.

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