Okayama University Medical SchoolActa Medica Okayama0386-300X7712023Effect of a Cyclooxygenase-2 Inhibitor in Combination with (−)-Epigallocatechin Gallate or Polyphenon E on Cisplatin-Induced Lung Tumorigenesis in A/J Mice6570ENKenSatoDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNagioTakigawaDepartment of General Internal Medicine 4, Kawasaki Medical SchoolToshioKuboDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHidekiKatayamaDepartment of Medicine, Yamaguchi-Ube Medical CenterDaizoKishinoDepartment of Medicine, Yamaguchi-Ube Medical CenterToshiakiOkadaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkikoHisamotoDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunkoMimotoDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuakiOchiDepartment of General Internal Medicine 4, Kawasaki Medical SchoolTadashiYoshinoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiUeokaDepartment of Medicine, Yamaguchi-Ube Medical CenterMitsuneTanimotoDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshionobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOriginal Article10.18926/AMO/64363We investigated the effects of celecoxib combined with (−)-epigallocatechin-3-gallate (EGCG) or polyphenon E in a cisplatin-induced lung tumorigenesis model. Four-week-old female A/J mice were divided into seven groups: (i) Control, (ii) 150 mg/kg celecoxib (150Cel), (iii) 1,500 mg/kg celecoxib (1500Cel), (iv) EGCG+150 mg/kg celecoxib (EGCG+150Cel), (v) EGCG+1,500 mg/kg celecoxib (EGCG+1500Cel), (vi) polyphenon E+150 mg/kg celecoxib (PolyE+150Cel), and (vii) polyphenon E+1,500 mg/kg celecoxib (PolyE+1500Cel). All mice were administered cisplatin (1.62 mg/kg of body weight, i.p.) 1×/week for 10 weeks and sacrificed at week 30; the numbers of tumors on the lung surface were then determined. The tumor incidence and multiplicity (no. of tumors/mouse, mean±SD) were respectively 95% and 2.15±1.50 in Control, 95% and 2.10±1.29 in 150Cel, 86% and 1.67±1.20 in 1500Cel, 71% and 1.38±1.24 in EGCG+150Cel, 67% and 1.29±1.38 in EGCG+1500Cel, 80% and 1.95±1.36 in PolyE+150Cel, and 65% and 1.05±0.10 in PolyE+1500Cel. The combination of high-dose celecoxib with EGCG or polyphenon E significantly reduced multiplicity in cisplatin-induced lung tumors.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7152017Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease453457ENAkihikoTaniguchiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalNobuakiMiyaharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalNaohiroOdaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalDaisukeMorichikaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalIsaoOzeDivision of Epidemiology and Prevention, Aichi Cancer Center Research InstituteYasushiTanimotoNational Hospital Organization Minami-Okayama Medical CenterHirohisaIchikawaDepartment of Respiratory Medicine, KKR Takamatsu HospitalUtakoFujiiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMitsuneTanimotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalArihikoKanehiroDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalClinical Study Protocol10.18926/AMO/55446 Although recent retrospective studies suggested that the use of β-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of β-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective β-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812832016第7 回日本血液学会(IJH)国際シンポジウム報告243244ENMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812832016集学的治療により長期生存が得られた食道神経内分泌癌の2 例207212ENTatsuhiroGotodaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSeijiKawanoDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshiyasuKonoDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKouMiuraDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiromitsuKanzakiDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasayaIwamuroDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshiroKawaharaDepartment of Endoscopy, Okayama University HospitalTakehiroTanakaDepartment of Pathology, , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiYoshinoDepartment of Pathology, , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroShirakawadDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahiroTabataDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiOkadaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Esophageal neuroendocrine carcinoma (ECC) is rare and has a poor prognosis when presenting with vascular invasion and distant metastasis from an early stage. Multidisciplinary therapy with surgery, chemotherapy, and radiation therapy may prolong survival in patients with advanced ECC, but there is as yet no standard therapy for advanced ECC. We treated two patients who have achieved long-term survival (> 4 years) who underwent multidisciplinary therapy, including chemotherapy, for ECC. Our experience with these two cases suggests that multidisciplinary therapy, including chemotherapy, may be effective for treating ECC at an advanced stage.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7052016Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease429433ENTakeruAsanoDepartment of Hematology and Oncology, Okayama University HospitalKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalSatoshiIyamaDepartment of Medical Oncology and Hematology, Sapporo Medical University HospitalKazuteruOhashiHematology division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome HospitalYoshihiroInamotoDepartment of Hematopoietic Stem Cell Transplantation, National Cancer Center HospitalChikakoOhwadaDepartment of Hematology, Chiba University HospitalMakotoMurataDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineAtsushiSatakeFirst Department of Internal Medicine, Kansai Medical UniversityChikamasaYoshidaDivision of Hematology, National Hospital Organization Minami-Okayama Medical CenterKoichiNakaseDivision of Hematology, Ehime Prefectural Central HospitalYasuoMoriDepartment of Hematology and Oncology, Kyushu University HospitalMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University HospitalClinical Study Protocols10.18926/AMO/54608Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7052016An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease409412ENYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalYoshihiroInamotoDepartment of Hematopoietic Stem Cell Transplantation, National Cancer Center HospitalHirohisaNakamaeDepartment of Hematology, Osaka City University HospitalMasashiSawaDepartment of Hematology and Oncology, Anjo Kosei HospitalYasuoMoriDepartment of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical SciencesKazuteruOhashiHematology Division, Tokyo Metropolitan Cancer and Infectious Diseases CenterShin-ichiroFujiwaraDivision of Hematology, Department of Medicine, Jichi Medical UniversityMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University HospitalClinical Study Protocols10.18926/AMO/54603Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7042016Heerfordt’s Syndrome Associated with a High Fever and Elevation of TNF-α273277ENGoMakimotoDepartment of Respiratory and Allergy Medicine, Okayama University HospitalNobuakiMiyaharaDepartment of Respiratory and Allergy Medicine, Okayama University HospitalMaoYoshikawaDepartment of Respiratory and Allergy Medicine, Okayama University HospitalAkihikoTaniguchiDepartment of Respiratory and Allergy Medicine, Okayama University HospitalArihikoKanehiroDepartment of Respiratory and Allergy Medicine, Okayama University HospitalMitsuneTanimotoDepartment of Respiratory and Allergy Medicine, Okayama University HospitalKatsuyukiKiuraDepartment of Respiratory and Allergy Medicine, Okayama University HospitalCase Report10.18926/AMO/54503Heerfordtʼs syndrome is a rare manifestation of sarcoidosis and is defined as a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. We report a case of Heerfordtʼs syndrome presenting with a high fever and increased serum tumor necrosis factor alpha (TNF-α) levels. The patient had facial palsy, parotid swelling, uveitis, and swelling of the right supraclavicular and hilar lymph nodes. Corticosteroid therapy was initiated, and her symptoms soon resolved completely, in tandem with a decrease in TNF-α serum levels. No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7042016Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation243253ENMasahiroOsawaDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshioKuboDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesEikiIchiharaDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSaburoTakataDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNagioTakigawaDepartment of General Internal Medicine 4, Kawasaki Medical SchoolMinoruTakata Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto UniversityMitsuneTanimotoDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOriginal Article10.18926/AMO/54499Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, p<0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812812016第55回日本リンパ網内系学会総会報告6768ENMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.Springer-VerlagActa Medica Okayama0941-43552122013Antibiotic sensitivity of bacteria on the oral mucosa after hematopoietic cell transplantation367368ENYoshihikoSogaYoshinobuMaedaMitsuneTanimotoTakayukiEbinumaHiroshiMaedaShogoTakashibaNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6952015Pilot Analysis of Asbestos-induced Diffuse Pleural Thickening with Respiratory Compromise261266ENDaisukeNojimaNobukazuFujimotoKatsuyaKatoYasukoFuchimotoKatsuyukiKiuraTakumiKishimotoMitsuneTanimotoOriginal Article10.18926/AMO/53671We investigated the clinical features of asbestos-induced diffuse pleural thickening (DPT) with severe respiratory compromise. We conducted a retrospective study of consecutive subjects with asbestos-induced DPT. Medical data such as initial symptoms, radiological findings, respiratory function test results, and clinical course were collected and analyzed. There were 24 patients between 2003 and 2012. All were men, and the median age at the development of DPT was 74 years. The top occupational category associated with asbestos exposure was dockyard workers. The median duration of asbestos exposure was 35.0 years, and the median latency from first exposure to the onset of DPT was 49.0 years. There were no significant differences in respiratory function test results between the higher and lower Brinkman index groups or between unilateral and bilateral DPT. Thirteen patients had a history of benign asbestos pleural effusion (BAPE), and the median duration from pleural fluid accumulation to DPT with severe respiratory compromise was 28.4 months. DPT with severe respiratory compromise can develop after a long latency following occupational asbestos exposure and a history of BAPE.No potential conflict of interest relevant to this article was reported.Springer Berlin HeidelbergActa Medica Okayama0941-43552262014Distribution of oral mucosal bacteria with mecA in patients undergoing hematopoietic cell transplantation16791683ENTakayukiEbinumaYoshihikoSogaTakamaroSatoKazuyukiMatsunagaChiekoKudoHiroshiMaedaYoshinobuMaedaMitsuneTanimotoShogoTakashiba[Purpose]
We recently reported frequent detection of antibiotic-resistant bacteria on the oral mucosa during the period of hematopoietic cell transplantation (HCT) and suggested an association between oral mucositis and antibiotic-resistant bacterial infection. Methicillin-resistant Staphylococcus spp. were frequently detected, and the oral cavity may be a reservoir of the gene mediating methicillin resistance, mecA. Here, we examined the frequency of mecA carriers in patients undergoing HCT.
[Methods]
Fifty-nine patients (male (M) = 37, female (F) = 22, 47.3 ± 11.0 years) receiving HCT were enrolled in this study. Buccal swab samples were obtained four times from day −7 to day +20 (once/week), and mecA was detected by PCR. Fifty-two subjects without systemic disease, who completed dental treatment, especially periodontal treatment (M = 21, F = 31, 55.4 ± 14.2 years), were also enrolled as controls and checked for mecA on the oral mucosa.
[Results]
Seventy-six percent (45/59) of the HCT patients carried mecA at least once in the study period (days −7 to +20), while no control subjects had mecA. The frequency of mecA carriers was 19.2 % from days −7 to −1, while it was significantly increased on days +7 to +13 and +14 to +20, with frequencies of 60.9 and 63.2 %, respectively (P < 0.01, ANOVA).
[Conclusions]
mecA was detected in oral mucosa of patients undergoing HCT. The high detection frequency of staphylococci resistant to penicillin and beta-lactams in our recent report was supported.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6862014Severe Case of Peripheral Leukocytosis Initially Diagnosed as Myelodysplastic Syndrome/Myeloproliferative Neoplasm, Unclassifiable, but Possibly Prefibrotic Primary Myelofibrosis363368ENSeisukeOtaYasushiHiramatsuEiseiKondoAkinoriKasaharaSaimonTakadaSachioUmenaToshioNoguchiMitsuneTanimotoTadashiMatsumuraCase Report10.18926/AMO/53025Leukocytosis is occasionally seen in patients with presumptive but undiagnosed myeloproliferative disorders (MPD). A 74-year-old woman was admitted to our hospital for tarry stools, anemia, and marked peripheral leukocytosis of 1.4×10<sup>5</sup>/μL. Gastroenteroscopy revealed an acute gastric and duodenal mucosal lesion that was treated successfully via endoscopic hemoclipping. Bone marrow aspiration revealed marked megakaryocyte proliferation with atypia of naked nuclei and marrow hypercellularity (90% cellularity). A fluorescence in situ hybridization test could not detect the BCR-ABL fusion gene. Bone marrow aspiration later revealed further abnormalities of megakaryocytes. The patient died from cerebral bleeding. The present case fulfilled 2 of the 3 major criteria of primary myelofibrosis according to the World Health Organization 2008 classification:namely, megakaryocytic hyperplasia with hypercellular marrow and granulocytic hyperplasia. However, the megakaryocytic abnormality was not strictly compatible with the criteria. Instead, we considered prefibrotic primary myelofibrosis as a possibility, although myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) was technically the correct diagnosis. The present case shows that MPN diagnosis remains difficult and suggests that other cases of peripheral leukocytosis with diagnosed MDS/MPN-U might include similar findings.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0014-482732622014Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors201209ENMasayukiYasugiNagioTakigawaNobuakiOchiKadoakiOhashiDaijiroHaradaTakashiNinomiyaToshiMurakamiYoshihiroHondaEikiIchiharaMitsuneTanimotoKatsuyukiKiuraEverolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1 mm in the everolimus-treated and control groups were 1.9 +/- 0.9 and 9.4 +/- 3.2 (t-test, p<0.001), respectively. pS6 was suppressed during everolimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0014-482732212014Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer168177ENNobuakiOchiNagioTakigawaDaijiroHaradaMasayukiYasugiEikiIchiharaKatsuyukiHottaMasahiroTabataMitsuneTanimotoKatsuyukiKiuraTo study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)1-(3-pyridy1)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0046-81774572014Low-grade B-cell lymphoma presenting primarily in the bone marrow13791387ENKayokoIwataniKatsuyoshiTakataYasuharuSatoTomokoMiyata-TakataNorikoIwakiWeiCuiSeikoSawada-KitamuraHiroshiSonobeMaikoTamuraKatsuhikoSaitoKatsuyaMiyataniRieYamasakiIchiroYamadoriNobuharuFujiiYasushiTerasakiYoshinobuMaedaMitsuneTanimotoNaoyaNakamuraTadashiYoshinoCases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma.No potential conflict of interest relevant to this article was reported.Elsevier Ireland Ltd.Acta Medica Okayama0169-50028312014Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model3036ENToshiMurakamiNagioTakigawaTakashiNinomiyaNobuakiOchiMasaakiYasugiYoshihiroHondaToshioKuboEikiIchiharaKatsuyukiHottaMitsuneTanimotoKatsuyukiKiuraObjective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation.
Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MIT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method.
Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model: Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 +/- 0.18 and 2.25 +/- 0.53 (p <0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p <0.0001).
Conclusion: AZD1480 may be effective against lung tumors driven by an activating EGER mutation.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1083-87912022014Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease183191ENHarukoSugiyamaYoshinobuMaedaHisakazuNishimoriYoshikoYamasujiKen-ichiMatsuokaNobuharuFujiiEiseiKondoKatsujiShinagawaTakehiroTanakaKengoTakeuchiTakanoriTeshimaMitsuneTanimotoChronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into OH model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with GSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1618-124710022012Histological and immunohistochemical features of gingival enlargement in a patient with AML254257ENNorihiroSonoiYoshihikoSogaHiroshiMaedaKoichiIchimuraTadashiYoshinoKazutoshiAoyamaNobuharuFujiiYoshinobuMaedaMitsuneTanimotoRichardLoganJudithRaber-DurlacherShogoTakashibaHere, we discuss the pathophysiology of leukemia-associated gingival enlargement based on a case of acute myelomonocytic leukemia (AML-M4) with typical gingival enlargement. Uniquely, this patient was well enough to allow full periodontal examination and incisional gingival biopsy to be performed both before and after chemotherapy. The patient was a 39-year-old Japanese woman with AML-M4 showing gingival enlargement. Histological and immunohistochemical features of gingiva and bacterial counts in the periodontal pockets were examined before and after chemotherapy. The results were as follows: (1) infiltration of myelomonocytic blasts in enlarged gingiva; (2) resolution of gingival enlargement with complete remission of AML by anticancer chemotherapy; and (3) the numbers of bacteria in the periodontal pockets were not high and were not altered before or after chemotherapy. In patients with AML-M4, remarkable mucosal enlargement is not generally observed in the body except in the gingiva. We hypothesized that antigens derived from periodontal bacteria, even if they are not present in large numbers, could act as chemoattractants for myelomonocytic leukemic cells.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1347-9032104112013Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model14401446ENHiromiHayakawaEikiIchiharaKadoakiOhashiTakashiNinomiyaMasayukiYasugiSaburoTakataKatsuyaSakaiKunioMatsumotoNagioTakigawaMitsuneTanimotoKatsuyukiKiuraNon-small-cell lung cancers with epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs); however, unlike cytotoxic agents, it is generally accepted that minimal doses of drugs inhibiting target molecules are sufficient when molecular-targeted agents, including EGFR-TKIs, are used. Thus, any utility of higher doses remains unclear. We compared low-dose (15mg/kg) gefitinib therapy with high-dose (50mg/kg) therapy using an EGFR-mutated lung cancer xenograft model. Both gefitinib doses induced tumor shrinkage, but tumors regrew in the low-dose group within 1month, whereas tumors in the high-dose group did not. Neither the T790M mutation nor MET amplification was apparent in regrown tumors. We also compared outcomes after two doses of gefitinib (5 and 25mg/kg) in a transgenic EGFR-mutated lung cancer mouse model. In line with the results obtained using the xenograft model, both gefitinib doses completely inhibited tumor growth, but tumors treated with the lower dose of gefitinib developed earlier drug resistance. In conclusion, a low gefitinib dose caused tumors to become drug-resistant prior to acquisition of the T790M mutation or MET amplification in EGFR-mutated models of lung cancer. This suggests that it is important to optimize the EGFR-TKI dose for treatment of EGFR mutation-associated lung cancer. Gefitinib may need to be given at a dose greater than the minimum required for inhibition of target molecules.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812622014リンパ腫・骨髄腫143150ENKyosukeSaekiYoshinobuMaedaMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812622014癌告知後の精神症状の治療に難渋したてんかん既往のある癌患者の1例133135ENDaisukeMinamiEikiIchiharaNobuyukiOkabeNaosukeYokomichiNorikoKougeMakotoKajizonoYutakaAkimotoKeisukeHoriMinoruMatsubaraJunichiroNasuMitsuneTanimotoKatsuyukiKiuraJunziMatsuoka A 58-year-old man with cervical esophageal cancer and a history of epilepsy was treated with chemoradiotherapy from May of 2013. When tube feeding was initiated due to aspiration pneumonitis, the patient showed a degree of irritability that affected routine staff work and treatment compliance. We attempted to perform supportive care for maladjustment by the notice, the fast, and the tube feeding, but there was no improvement. After we added carbamazepine, primidone, and propericiazine (which had been canceled at the initiation of the tube feeding) to the patient's intravenous phenytoin, the symptoms and treatment compliance improved significantly. We concluded that the causes of the patient's irritability were maladjustment and his epilepsy.No potential conflict of interest relevant to this article was reported.Biomed Central LtdActa Medica Okayama1465-993X142013IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in miceENEtsukoKurimotoNobuakiMiyaharaArihikoKanehiroKoichiWasedaAkihikoTaniguchiGenyoIkedaHikariKogaHisakazuNishimoriYasushiTanimotoMikioKataokaYoichiroIwakuraErwin W.GelfandMitsuneTanimotoBackground: Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it's role in the inflammatory response of elastase-induced emphysema remains unclear.
Methods: In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid.
Results: Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment.
Conclusions: These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812612014白血病および白血病類縁疾患における分子標的治療4954ENYoshinobuMaedaMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.Amer Assoc Cancer ResearchActa Medica Okayama1535-71631252013Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model589597ENTakashiNinomiyaNagioTakigawaEikiIchiharaNobuakiOchiToshiMurakamiYoshihiroHondaToshioKuboDaisukeMinamiKenichiroKudoMitsuneTanimotoKatsuyukiKiuraAn irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0046-81774492013Distinct morphologic, phenotypic, and clinical-course characteristics of indolent peripheral T-cell lymphoma19271936ENEikoHayashiKatsuyoshiTakataYasuharuSatoYukieTashiroYoshiroTachiyamaSeikoSawada-KitamuraYasushiHiramatsuShunSugiguchiSoichiroNoseMitsuyoshiHirokawaMidoriAndoLamiaAbd MaderYoshinobuMaedaMitsuneTanimotoTadashiYoshinoPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) consists of a heterogeneous group of lymphomas. Patients. generally show an aggressive clinical course and very poor outcome. Although the 2008 World Health Organization classification of PTCL-NOS includes 3 variants, low-grade lymphoma is not Included. Of 277 PTCL-NOS cases recorded in our consultation files, we examined the clinicopathologic characteristics of 10 patients with T-cell lymphomas composed of small-sized cells with slight nuclear atypia. Eight patients showed extranodal involvement (5 patients, spleen; 3 patients, thyroid), and 5 patients were at clinical stage I or II. Histologically, all samples presented diffuse infiltrate of small lymphoid cells, with few mitotic figures. Immunohistologically, all samples were positive for CD3, and CD:20 Was detected in 5 samples. All samples showed a low Ki-67 labeling index (mean, 1.05%), and 7 samples were positive for central memory T-cell markers. Clonal T-cell receptor gamma chain and/or alpha-beta chain gene rearrangements were detected in all 10 patients. Five patients received chemotherapy, whereas for 3 patients, treatment consisted only of observation following surgical resection of the spleen or thyroid. Nine patients were alive at a median follow-up time of 19.5 months, whereas 1 patient died of an unrelated disease. The present study strongly indicates that T-cell lymphoma with small-sized lymphoma cells and a low Ki-67 labeling index is a distinct variant. Recognition of this novel lymphoma subtype, which should not be defined merely as PTCL-NOS, should be seriously considered.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1262013Matrix-Embedded Osteocytes Regulate Mobilization of Hematopoietic Stem/Progenitor Cells737747ENNoboruAsadaYoshioKatayamaMariSatoKentaroMinagawaKanakoWakahashiHirokiKawanoYukoKawanoAkikoSadaKyojiIkedaToshimitsuMatsuiMitsuneTanimotoThe bone marrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC) migration out of the niche and into the circulation. Here, we demonstrate that osteocytes, the major cellular component of mature bone, are regulators of HSPC egress. Granulocyte colony-stimulating factor (G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression of the osteocytic network that precedes changes in osteoblasts. This rapid response is likely under control of the sympathetic nervous system, since osteocytes express the β2-adrenergic receptor and surgical sympathectomy prevents it. Mice with targeted ablation of osteocytes or a disrupted osteocyte network have comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF. Taken together, these results indicate that the BM/bone niche interface is critically controlled from inside of the bone matrix and establish an important physiological role for skeletal tissues in hematopoietic function.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0014-482731942013Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency417423ENHiromasaTakedaNagioTakigawaKadoakiOhashiDaisukeMinamiItaruKataokaEikiIchiharaNobuakiOchiMitsuneTanimotoKatsuyukiKiuraThe effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact FTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack FTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6752013Preparation of Enteric-coated Capsules of Beclomethasone Dipropionate for Patients with Intestinal Graft-versus-Host Disease and a Case Study319324ENKiminakaMurakawaTomoakiSatoYoshinobuMaedaYoshihisaKitamuraMitsuneTanimotoToshiakiSendoCase Report10.18926/AMO/51868Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP-EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs.No potential conflict of interest relevant to this article was reported.Biomed Central LtdActa Medica Okayama1465-993X142013Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responsesENHikariKogaNobuakiMiyaharaYasukoFuchimotoGenyoIkedaKoichiWasedaKatsuichiroOnoYasushiTanimotoMikioKataokaErwin W.GelfandMitsuneTanimotoArihikoKanehiroBackground: Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice.
Methods: BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge.
Results: Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-beta 1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice.
Conclusion: These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil-and eosinophil-dominant phases of the response to secondary allergen challenge.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812522013十二指腸濾胞性リンパ腫はAIDの発現を欠くがBACH2の発現を有しmemoryB細胞としての性質を有する103107ENKatsuyoshiTakataYasuharuSatoNaoyaNakamuraMamiTokunakaYukariMikiYara YukieKikutiKazuhikoIgarashiEtsuroItoHideoHarigaeSeiichiKatoEikoHayashiTakashiOkaYoshinobuHoshiiAkiraTariHiroyukiOkadaABD Alkader LamiaMohamadoYoshinobuMaedaMitsuneTanimotoTomohiroKinoshitaTadashiYoshinoNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1347-9032103102012JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation17951802ENDaijiroHaradaNagioTakigawaNobuakiOchiTakashiNinomiyaMasayukiYasugiToshioKuboHiromasaTakedaEikiIchiharaKadoakiOhashiSaburoTakataMitsuneTanimotoKatsuyukiKiuraEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 612 similar to months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 312 similar to h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.(Cancer Sci, doi: 10.1111/j.1349-7006.2012.02363.x, 2012)No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1347-903210412013Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy7884ENToshioKuboNagioTakigawaMasahiroOsawaDaijiroHaradaTakashiNinomiyaNobuakiOchiEikiIchiharaHiromichiYamaneMitsuneTanimotoKatsuyukiKiuraTumors are presumed to contain a small population of cancer stem cells (CSCs) that initiate tumor growth and promote tumor spreading. Multidrug resistance in CSCs is thought to allow the tumor to evade conventional therapy. This study focused on expression of CD133 and CD87 because CD133 is a putative marker of CSCs in some cancers including lung, and CD87 is associated with a stem-cell-like property in small-cell lung cancer (SCLC). Six SCLC cell lines were used. The expression levels of CD133 and CD87 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry. CD133+/- and CD87+/- cells were isolated by flow cytometry. The drug sensitivities were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Non-obese diabetic/severe combined immunodeficiency mice were used for the tumor formation assay. SBC-7 cells showed the highest expression levels of both CD133 and CD87 among the cell lines. CD133-/CD87-, CD133+/CD87-, and CD133-/CD87+ cells were isolated from SBC-7 cells; however, CD133+/CD87+ cells could not be obtained. Both CD133+/CD87- and CD133-/CD87+ subpopulations showed a higher resistance to etoposide and paclitaxel and greater re-populating ability than the CD133-/CD87- subpopulation. CD133+/CD87- cells contained more G0 quiescent cells than CD133-/CD87- cells. By contrast, CD133-/CD87- cells showed the highest tumorigenic potential. In conclusion, both CD133 and CD87 proved to be inadequate markers for CSCs; however, they might be beneficial for predicting resistance to chemotherapy. (Cancer Sci 2013; 104: 7884)No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1535-71631092011Liposomal Delivery of MicroRNA-7-Expressing Plasmid Overcomes Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistance in Lung Cancer Cells17201727ENKammeiRaiNagioTakigawaSachioItoHiromiKashiharaEikiIchiharaTatsujiYasudaKenjiShimizuMitsuneTanimotoKatsuyukiKiuraEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR-7), targeting multiple sites in the 30-untranslated region of EGFR mRNA. Two EGFR-TKI-sensitive cell lines (PC-9 and H3255) and two EGFR-TKI-resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7-expressing plasmid. After transfection of the miR-7-expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR-7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC-9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7-expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7-expressing plasmids against EGFR oncogene-addicted lung cancers including T790M resistance by liposomal delivery. Mol Cancer Ther; 10(9); 1720-7.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812512013肺癌と分子標的薬5766ENKatsuyukiKiuraMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6712013Chronic Graft-versus-Host Disease: Disease Biology and Novel Therapeutic Strategies18ENHisakazuNishimoriYoshinobuMaedaMitsuneTanimotoReview10.18926/AMO/49251Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Chronic GVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases. Standard treatment is 1-2mg/kg/day of prednisone or an equivalent dose of methylprednisolone, with continued administration of a calcineurin inhibitor for steroid sparing. However, the prognosis of steroid-refractory chronic GVHD remains poor. Classically, chronic GVHD was said to involve predominantly Th2 responses. We are now faced with a more complex picture, involving possible roles for thymic dysfunction, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), B cells and autoantibodies, and Th1/Th2/Th17 cytokines, as well as regulatory T cells (Tregs), in chronic GVHD. More detailed research on the pathophysiology of chronic GVHD may facilitate the establishment of novel strategies for its prevention and treatment.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-43551972011Bacterial substitution of coagulase-negative staphylococci for streptococci on the oral mucosa after hematopoietic cell transplantation9951000ENYoshihikoSogaYoshinobuMaedaFumihikoIshimaruMitsuneTanimotoHiroshiMaedaFusanoriNishimuraShogoTakashibaCoagulase-negative staphylococci (CoNS) are frequently isolated from blood cultures of hematopoietic cell transplantation (HCT) patients. Generally, the use of central venous catheters is recognized as a significant risk factor for CoNS infection, while the impact of CoNS infection from oral ulcerative mucositis, which occurs frequently in HCT, may be underestimated. Here, we examined the bacteria on the buccal mucosa after HCT.
Sixty-one patients were examined for bacteria on the buccal mucosa routinely once a week from 1 week before to 3 weeks after allogeneic HCT. Subjects were divided into groups with short and long periods of antibiotic use, and differences in bacterial substitution were evaluated. The relationships between type of HCT (conventional HCT or RIST) and bacterial substitution were also evaluated.
The changes in detection frequencies of CoNS and alpha-streptococci from before to 3 weeks after HCT were significant (P < 0.05, chi (2) test): 14.5-53.3% and 92.7-53.1%, respectively. Significant bacterial substitution of CoNS for streptococci was observed in the long-term antibiotic use group (P < 0.05, chi (2) test), but also occurred in cases with short-term or no antibiotic use. No relationships between type of HCT (conventional HCT or RIST) were observed.
Bacterial substitution of CoNS for streptococci occurred frequently on the buccal mucosa after HCT. In addition to antibiotic use, environmental factors may be involved in bacterial substitution. It is important to consider the presence of oral mucositis in CoNS infection after HCT.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-43551832010Total bacterial counts on oral mucosa after using a commercial saliva substitute in patients undergoing hematopoietic cell transplantation395398ENYukoSugiuraYoshihikoSogaKokoroYamabeSoichiroTsutaniIchiroTanimotoHiroshiMaedaSusumuKokeguchiNobuharuFujiiFumihikoIshimaruMitsuneTanimotoFusanoriNishimuraShogoTakashibaThe commercial saliva substitute OralbalanceA (R) has been reported to alleviate symptoms of postradiotherapy xerostomia in head and neck cancer patients. OralbalanceA (R) may also be effective for xerostomia in patients undergoing hematopoietic cell transplantation (HCT) with high-dose chemotherapy and total-body irradiation. However, HCT patients are in a severely compromised condition, and saliva substitute must not promote infection. We reported previously that OralbalanceA (R) has antimicrobial effects against microbial species detected during HCT in vitro. This study was performed to determine the in vivo effects of OralbalanceA (R) on oral mucosal total bacterial counts in patients undergoing HCT.
A total of 18 neutropenic patients undergoing HCT were enrolled in this study. Before and after 1 week of OralbalanceA (R) use, bacterial samples were obtained from patients by wiping an area of I center dot 1 cm on the buccal mucosa with sterilized cotton swabs. Total bacterial counts of the obtained samples were examined by quantitative polymerase chain reaction amplification of the bacterial 16S ribosomal RNA gene. As controls, bacterial samples were also obtained from ten healthy subjects, and total bacterial counts were examined.
No significant increase in bacterial count was observed with use of OralbalanceA (R). None of the patients showed bacterial counts above the range found in healthy controls after using OralbalanceA (R).
In neutropenic patients undergoing HCT, OralbalanceA (R) did not increase the total counts of oral mucosal bacteria beyond the range found in healthy controls. Oral care using OralbalanceA (R) may alleviate the symptoms induced by hyposalivation without promoting infection.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-43551812010Oral mucositis in patients receiving reduced-intensity regimens for allogeneic hematopoietic cell transplantation: comparison with conventional regimen115119ENKanayoTakahashiYoshihikoSogaYumenoMurayamaMikaUdagawaHitomiNishimotoYukoSugiuraYoshinobuMaedaMitsuneTanimotoShogoTakashibaSevere oral mucositis induced by allogeneic hematopoietic cell transplantation (HCT) is associated with intolerable pain and risk of systemic bacteremia infection. Differences between conventional HCT and reduced-intensity regimens for allogeneic HCT (RIST) may influence the occurrence and severity of oral mucositis. Here, we evaluated oral mucositis in patients undergoing RIST and compared the results with those in conventional allogeneic HCT patients to facilitate predictive measures for mucositis.
A total of 127 consecutive patients undergoing HCT (conventional, 63; RIST, 64) were included in this study. Severity of oral mucositis during HCT period was evaluated daily. Differences in severity of mucositis among HCT types were analyzed. Use of morphine to control pain due to oral mucositis was evaluated in each HCT method.
The severity of oral mucositis was reduced in patients undergoing RIST. Worsening of oral mucositis was delayed in patients receiving RIST. Use of morphine to control pain due to oral mucositis was significantly decreased in patients undergoing RIST compared with those receiving conventional allogeneic HCT.
The severity of oral mucositis was reduced and the peak day of oral mucositis was delayed in RIST patients compared with those receiving conventional HCT.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-43551752009Febrile neutropenia and periodontitis: lessons from a case periodontal treatment in the intervals between chemotherapy cycles for leukemia reduced febrile neutropenia581587ENYoshihikoSogaYoshikoYamasujiChiekoKudoKaoriMatsuura-YoshimotoKokoroYamabeYukoSugiuraYoshinobuMaedaFumihikoIshimaruMitsuneTanimotoFusanoriNishimuraShogoTakashibaOral and systemic infections arising from the oral cavity are significant problems in clinical management of patients undergoing leukemia treatment. However, there is significant disparity in the reported incidences of development of periodontal infections. Evidence is limited to those showing the systemic influence of periodontal infection in neutropenic patients. This study indicated an association between febrile neutropenia (FN) and periodontitis in a case in which periodontal treatment in the intervals between chemotherapy cycles reduced FN in subsequent courses of chemotherapy and hematopoietic transplantation (HCT).
Periodontal treatment was performed in a 61-year-old man with advanced periodontitis, who received HCT following three cycles of chemotherapy. After recovery from neutropenia induced by initial chemotherapy, periodontal treatment was performed in each chemotherapy interval period. Following extraction of teeth with severe advanced periodontitis, all teeth were subjected to periodontal pocket curettage and root planning, which are common periodontal treatments to reduce periodontal pockets harboring anaerobic periodontal bacteria, before HCT.
Periodontal treatment successfully reduced periodontal pockets from 4.1 +/- 1.5 mm to 3.0 +/- 0.6 mm, which was almost within the healthy range (< 3.0 mm), before HCT. The frequency of FN decreased significantly with increasing cycles of chemotherapy, and decreases in FN corresponded to progress of periodontal treatment. Blood cultures obtained a total of 12 times throughout leukemia treatment were all negative.
The observations reported here indicate the importance of periodontal treatment in clinical management of patients undergoing leukemia treatment to prevent FN, although all blood cultures were negative.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-435516102008Evaluation of xerostomia in hematopoietic cell transplantation by a simple capacitance method device11971200ENYukoSugiuraYoshihikoSogaSachikoNishideKotoeKonoKanayoTakahashiNobuharuFujiiFumihikoIshimaruMitsuneTanimotoFusanoriNishimuraShogoTakashibaGoals Hematopoietic cell transplantation (HCT) may lead to the development of xerostomia. However, there have been few reports of xerostomia in HCT patients based on objective data. We investigated moisture in the oral mucosa in patients undergoing HCT by the capacitance method using a convenient device, Moisture Checker for Mucus (R) (MCM; Life Co., Ltd., Saitama, Japan).
Subjects and methods Thirty-six patients undergoing HCT at Okayama University Hospital of Medicine and Dentistry (Male=22, Female=14; age=41.6 +/- 16.2 years old) were enrolled in this study. Moisture in the oral mucosa was measured by MCM in accordance with the manufacturer's instructions. The results were obtained as MCM values (%), which are the weight percentage of water content in the oral mucosal epithelium. As controls, moisture of the oral mucosa was also examined in healthy volunteers (Male=27, Female=35; age=43.0 +/- 14.6 years old).
Main results Throughout the examination period, MCM values were significantly lower in patients who underwent HCT than in controls. The degree of mucosal moisture in HCT patients showed wide interindividual differences.
Conclusion The degree of mucosal moisture in HCT patients was low and showed wide interindividual differences. Evaluation of xerostomia using such a device may contribute to appropriate oral care with saliva substitute.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-43551922011Progress of oral care and reduction of oral mucositis-a pilot study in a hematopoietic stem cell transplantation ward303307ENYoshihikoSogaYukoSugiuraKanayoTakahashiHitomiNishimotoYoshinobuMaedaMitsuneTanimotoShogoTakashibaOral mucositis is a common symptomatic complication associated with hematopoietic stem cell transplantation (HCT). We use simple strategies aimed to reduce oral mucositis by keeping the oral cavity clean and moist. Here, we report on the progress of oral care and the changes in the degree of oral mucositis. The purpose of this pilot study is to evaluate the effects of our strategies on the prevalence and the severity of oral mucositis.
Fifty-three consecutive patients from 2003 to 2006 administered with conventional allogeneic HCT were enrolled in this study. The degree of oral mucositis was evaluated daily in all patients. Our oral care program was divided into two periods: "examination and trial period (2003 and 2004)" and "intensive oral care period (2005 and 2006)." In the latter, an oral care regimen was carried out systematically by a multidisciplinary team.
Using our oral care strategies, the prevalence of ulcerative oral mucositis was decreased significantly. The rate was reduced from 76% (10 of 13) of patients with ulcerative oral mucositis in 2003 to only 20% (3 of 15) in 2006.
Our pilot study suggests that oral mucositis in HCT patients can be alleviated by simple strategies aimed at keeping the oral cavity clean and moist.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0941-43551642008Antimicrobial effects of the saliva substitute, Oralbalance (R), against microorganisms from oral mucosa in the hematopoietic cell transplantation period421424ENYukoSugiuraYoshihikoSogaIchiroTanimotoSusumuKokeguchiSachikoNishideKotoeKonoKanayoTakahashiNobuharuFujiiFumihikoIshimaruMitsuneTanimotoKokoroYamabeSoichiroTsutaniFusanoriNishimuraShogoTakashibaGoals The commercially available saliva substitute Oralbalance (R) has been reported to alleviate symptoms of post-radiotherapy xerostomia in head and neck cancer patients. Oralbalance (R) may also be effective for xerostomia in patients undergoing hematopoietic cell transplantation (HCT) with high-dose chemotherapy and total-body irradiation. However, HCT patients are severely compromised, and saliva substitute must therefore not promote infection. This study was performed to determine the effects of Oralbalance (R) on microbial species identified during HCT.
Patients and methods Microbial identification of oral mucosa was performed in 28 patients undergoing HCT. The antimicrobial effects of Oralbalance (R) against bacteria and fungi detected in the HCT period were examined in vitro. Briefly, bacteria and fungi were spread on agar plates, and 0.1g of Oralbalance (R) gel was applied (about phi 1cm). After incubation at 37 degrees C for 24h, the presence of a transparent zone of inhibition around Oralbalance (R) was observed.
Main results Not only bacterial species constituting normal flora of the oral mucosa but also those not usually constituting normal flora, e.g., coagulase-negative Staphylococcus, were detected. A transparent zone was observed around Oralbalance (R) in all bacterial species examined. No transparent zone was observed for Candida albicans, but growth was inhibited in the area where Oralbalance (R) was applied.
Conclusions Oralbalance (R) does not facilitate increases in microorganisms in the HCT period. Oral care with Oralbalance (R) does not promote infection in patients undergoing HCT.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812432012EGFRチロシンキナーゼ阻害薬耐性肺癌細胞に対するmicroRNA-7発現プラスミドのリポソームを用いた導入による克服の検討207210ENKammeiRaiNagioTakigawaSachioItoHiromiKashiharaEikiIchiharaTatsujiYasudaKenjiShimizuMitsuneTanimotoKatsuyukiKiuraNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812432012合成レチノイドAm80はTh1とTh17を抑制することにより慢性移植片対宿主病を改善する197201ENHisakazuNishimoriYoshinobuMaedaMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6642012Effect of Taurine on Acinar Cell Apoptosis and Pancreatic Fibrosis in Dibutyltin Dichloride-induced Chronic Pancreatitis329334ENKokiMatsushitaTakaakiMizushimaAkinoriShirahigeHiroakiTaniokaKiminariSawaKojiOchiMitsuneTanimotoNorioKoideOriginal Article10.18926/AMO/48687The relationship between pancreatic fibrosis and apoptosis of pancreatic acinar cells has not been fully elucidated. We reported that taurine had an anti-fibrotic effect in a dibutyltin dichloride (DBTC)-chronic pancreatitis model. However, the effect of taurine on apoptosis of pancreatic acinar cells is still unclear. Therefore, we examined apoptosis in DBTC-chronic pancreatitis and in the AR42J pancreatic
acinar cell line with/without taurine. Pancreatic fibrosis was induced by a single administration
of DBTC. Rats were fed a taurine-containing diet or a normal diet and were sacrificed at day 5. The AR42J pancreatic acinar cell line was incubated with/without DBTC with taurine chloramines. Apoptosis was determined by using terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. The expression of Bad and Bcl-2 proteins in the AR42J cells lysates was detected by Western blot analysis. The apoptotic index of pancreatic acinar cells in DBTC-administered rats was significantly increased. Taurine treatment inhibited pancreatic fibrosis and apoptosis of acinar cells induced by DBTC. The number of TUNEL-positive cells in the AR42J pancreatic
acinar cell lines was significantly increased by the addition of DBTC. Incubation with taurine chloramines ameliorated these changes. In conclusion, taurine inhibits apoptosis of pancreatic acinar cells and pancreatitis in experimental chronic pancreatitis.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6632012Selective Cyclooxygenase-2 Inhibitor Prevents Cisplatin-induced Tumorigenesis in A/J Mice245251ENToshiakiOkadaNagioTakigawaDaizoKishinoHidekiKatayamaShouichiKuyamaKenSatoJunkoMimotoHiroshiUeokaMitsuneTanimotoKatsuyukiKiuraOriginal Article10.18926/AMO/48564Cisplatin is used to treat lung cancer;however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2) inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated
the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups:group 1, no treatment;group 2, low-dose celecoxib (150mg/kg);group 3, high-dose celecoxib (1,500mg/kg);group 4, cisplatin alone;group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62mg/kg, i.p.) once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p<0.05, group 4 vs. group 6). Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p<0.01, group 4 vs. group 6).No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812412012同種抗原による移植片対白血病効果減弱のメカニズム58ENShojiAsakuraDaigoHashimotoShuichiroTakashimaHarukoSugiyamaYoshinobuMaedaKoichiAkashiMitsuneTanimotoTakanoriTeshimaNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6562011Successful Extracorporeal Life Support for Life-threatening Hypercapnia with Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplantation403406ENKoichiWasedaYasushiTanimotoShingoIchibaNobuakiMiyaharaToshiMurakamiNobuakiOchiMichihisaTeradoOsamuNaganoYoshinobuMaedaArihikoKanehiroYoshihitoUjikeMitsuneTanimotoCase Report10.18926/AMO/47266Bronchiolitis obliterans (BO) is a disease with a poor prognosis, and a key factor that limits long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). We here report a case of a 31-year woman with acute lymphatic leukemia, which was treated by chemotherapy and HSCT, and consequently developed BO 2 years after HSCT. A non-tuberculous mycobacterial infection occurred and showed gradual exacerbation. She started taking anti-mycobacterial drugs, but lost appetite, felt tired and finally lost consciousness one month after beginning medication. Arterial blood gas revealed marked hypercapnia. Using extracorporeal life support (ECLS), the carbon dioxide concentration was reduced and her consciousness recovered. To our knowledge, this is the first case in which ECLS was successfully used for hypercapnia in a patient with BO.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6562011Targeting Angiogenesis in Cancer Therapy353362ENEikiIchiharaKatsuyukiKiuraMitsuneTanimotoReview10.18926/AMO/47260Angiogenesis is an essential process in tumor growth. The concept of angiogenesis, when proposed by Folksman in 1971, had a great impact on cancer research and therapy, as the survival and proliferation of cancer depend on angiogenesis, which could be a target of cancer therapy. In subsequent decades, numerous antiangiogenic agents were developed, and some of them have been applied clinically. However, angiogenesis includes a complex and multistep process that has not been sufficiently elucidated. In this review, we focus on signaling pathways related with tumor angiogenesis and several antiangiogenic agents approved by the United States Food and Drug Administration or under investigation.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812332011新型インフルエンザウイルス(A/H1N1)感染後にARDSを来たした1例221225ENAkihikoTaniguchiNobuakiMiyaharaAtsushiNakaharaSaburoTakataRyoSakugawaOsamuNaganoYasushiTanimotoArihikoKanehiroKatsuyukiKiuraYoshitoUjikeMitsuneTanimotoA 28-year-old man with a history of mental retardation was admitted to our hospital because of dyspnea, cough and high fever. His SpO(2) level at room-environmental conditions was in the eighties, and his chest radiograph showed diffuse infiltrates in both lungs. He was diagnosed as suffering from influenza A by a rapid influenza virus antigen test. The echocardiogram showed no evidence of left cardiac failure; therefore, his symptoms were consistent with acute respiratory distress syndrome (ARDS). Oseltamivir was started, and antibiotics were also given because of the possibility of secondary bacterial infection. Due to respiratory failure and low blood pressure, which suggested septic shock, intensive treatments including mechanical ventilation were performed. Corticosteroid therapy was started for ARDS and sepsis, and these therapies improved his respiratory condition. Polymerase chain reaction of his pharyngeal swab revealed that he had influenza A (H1N1). This is the first case of ARDS following infection by influenza A (H1N1) virus in Japan.No potential conflict of interest relevant to this article was reported.Elsevier Ireland Ltd.Acta Medica Okayama0169-50027412011A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 04018084ENNaoyukiNogamiKatsuyukiHottaShoichiKuyamaKatsuyukiKiuraNagioTakigawaKenichiChikamoriTakuoShibayamaDaizoKishinoShinobuHosokawaAkihikoTamaokiShingoHaritaMasahiroTabataHiroshiUeokaTetsuShinkaiMitsuneTanimotoBackgrounds: Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. Methods: Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases. Results: Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths. Conclusion: This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6542011Is Adenosine Deaminase in Pleural Fluid a Useful Marker for Differentiating Tuberculosis from Lung Cancer or Mesothelioma in Japan, a Country with Intermediate Incidence of Tuberculosis?259263ENYoshikoOgataKeisukeAoeAkioHirakiKazuoMurakamiDaizoKishinoKenichiChikamoriTadashiMaedaHiroshiUeokaKatsuyukiKiuraMitsuneTanimotoOriginal Article10.18926/AMO/46851The objective of this study was to evaluate the utility of the determination of adenosine deaminase (ADA) level in pleural fluid for the differential diagnosis between tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) in Japan, a country with intermediate incidence of tuberculosis (TB). We retrospectively reviewed the clinical records of 435 patients with pleural effusion and investigated their pleural ADA levels as determined by an auto analyzer. ROC analysis was also performed. The study included patients with MPE (n=188), TPE (n=124), benign nontuberculous pleural effusion (n=94), and pleural effusion of unknown etiology (n=29). The median ADA level in the TPE group was 70.8U/L, which was significantly higher than that in any other groups (p<0.05). The area under the curve (AUC) in ROC analysis was 0.895. With a cut-off level for ADA of 36U/L, the sensitivity, specificity, positive predictive value, and negative predictive value were 85.5%, 86.5%, 69.7%, and 93.6%, respectively. As many as 9% of patients with lung cancer and 15% of those with mesothelioma were false-positive with this ADA cutoff setting. Although the ADA activity in pleural fluid can help in the diagnosis of TPE, it should be noted that some cases of lung cancer or mesothelioma show high ADA activity in geographical regions with intermediate incidence of TB, in contrast to high prevalence areas.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812322011HCV感染がRCHOP療法下でのDLBCLにおける 肝障害と予後に与える影響8589ENDaisukeEnnishiMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6532011Churg-Strauss Syndrome with Necrosis of Toe Tips215218ENKoichiWasedaYasushiTanimotoKenjiroHasegawaNobuakiMiyaharaDaisukeNojimaGenyoIkedaArihikoKanehiroChiharuOkadaYoshihiroKimataMitsuneTanimotoCase Report10.18926/AMO/46635Churg-Strauss syndrome (CSS) is a granulomatous necrotizing vasculitis of unknown etiology associated with bronchial asthma. Despite affecting small to medium-sized vessels, necrosis of the digits due to vasculitis is extremely rare. We report a case of CSS with necrosis of the toe tips. A 37-year-old woman with asthma, who had been diagnosed with CSS 2 years ago, was admitted to our hospital with an exacerbation of CSS. The patient had a high grade fever and complained of abdominal pain and numbness of the lower extremities. Blood examination revealed marked eosinophilia. The fever pattern, abdominal pain and blood eosinophilia showed improvement by combination treatment with prednisolone and cyclophosphamide. However, the color of her right toe tips changed, and necrosis finally resulted despite antithrombotic therapy. Arteriography showed narrowing of the dorsalis pedis artery and of the more peripheral arteries of her right leg. Stump plasty with negative pressure dressing therapy for the toe tips, but not amputation, was done to preserve the leg function. While numbness of the extremities remained, no recurrence of necrosis was seen. Clinicians need to be aware that rare complications of CSS, including necrosis of the digits, can occur.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812312011希少呼吸器疾患の治療・管理4952ENYasushiTanimotoMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812312011生体内におけるEGFR T790M遺伝子変異を持つ肺腺癌細胞に対するバンデタニブの効果1318ENEikiIchiharaKadoakiOhashiNagioTakigawaMasahiroOsawaAtsukoOginoMitsuneTanimotoKatsuyukiKiuraNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812232010希少疾患とそれらへの対応237242ENMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6452010Cancer of Unknown Primary Site:A Review of 28 Cases and the Efficacy of Cisplatin/Docetaxel Therapy at a Single Institute in Japan285291ENHisakazuNishimoriShunjiTakahashiKatsuyukiKiuraDaisukeEnnishiTakayukiKobayashiKojiSanoEijiShinozakiMasahiroYokoyamaYukoMishimaYasuhitoTeruiKeishoChinNobuyukiMizunumaYoshinoriItoSeiichiroNishimuraKengoTakeuchiYuichiIshikawaMasahikoOguchiMitsuneTanimotoKiyohikoHatakeOriginal Article10.18926/AMO/40503We evaluated the efficacy and toxicity of cisplatin/docetaxel (CDDP/TXT) chemotherapy and identified prognostic factors in Japanese patients with cancer of unknown primary site (CUP). Twenty-eight consecutive patients seen at a single institute were reviewed retrospectively. Sixteen patients were treated with TXT 80mg/m2, followed by CDDP 75mg/m2. The overall response rate to CDDP/TXT treatment was 62.5%, with a median survival time (MST) of 22.7 months. Common adverse reactions were myelosuppression and hyponatremia. The MST of all 28 patients with CUP was 8.3 months, and the 1-year overall survival rate was 45.6%. Univariate analysis identified 5 prognostic factors:performance status, liver involvement, bone involvement, pleural involvement, and lymph node involvement. In conclusion, CDDP/TXT chemotherapy is effective with tolerable toxicity in patients with CUP. Japanese patients with CUP might be chemosensitive and may survive longer.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6432010Interstitial Lung Disease during Trimethoprim/Sulfamethoxazole Administration181187ENSyotaYuzurioNaokatsuHoritaYutaroShiotaArihikoKanehiroMitsuneTanimotoOriginal Article10.18926/AMO/40010We studied clinical and radiographic features of interstitial lung disease (ILD) during trimethoprim/sulfamethoxazole (TMP/SMX) administration. Ten patients who had received prednisolone treatment for underlying diffuse pulmonary disease showed various ILDs after introduction of TMP/SMX. The radiographic features of the ILDs were not consistent with infectious disease or exacerbation of the underlying disease, and these diagnoses were excluded radiographically and on clinical grounds during the differential diagnosis of the ILDs. These ILDs emerged relatively early after introduction of TMP/SMX, which is consistent with the former case report of drug-induced ILD (DI-ILD) caused by TMP/SMX. Therefore DI-ILDs caused by TMP/SMX were suspected in these cases. In most of these cases, the ILDs were clinically mild and disappeared immediately although administration of TMP/SMX was continued.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6412010Triplet Chemotherapy with Cisplatin, Docetaxel, and Irinotecan for Patients with Recurrent or Refractory Non-small Cell Lung Cancer3337ENNobukazuFujimotoKatsuyukiKiuraNagioTakigawaYoshiroFujiwaraShinichiToyookaShigekiUmemuraMasahiroTabataHiroshiUeokaMitsuneTanimotoOriginal Article10.18926/AMO/32866<p>We examined the feasibility of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer (NSCLC), retrospectively. Twenty-five patients (21 men and 4 women) with NSCLC and good performance status who were <70 years old were analyzed. The median age was 58 years. Most patients had performance status 1 (16/25), stage IV disease (18/25) and adenocarcinoma-histology (16/25). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2;the cycle was repeated every 3 weeks. The objective response rate was 39.1% (95% confidence interval:18.7-59.5%). The median survival time and actual 2-, 3-, and 5-year survival rates were 14.3 months, 32%, 20%, and 8%, respectively. Of note, only 6 patients were treated with gefitinib at the recurrence after triplet chemotherapy;of these, 4 (67%) achieved a partial response, which might result in favorable survival. Grade 3/4 toxicities consisted of neutropenia (100%), neutropenic fever (56%), nausea/vomiting (40%), and diarrhea (16%);no cases of treatment-related death occurred. Triplet chemotherapy showed impressive survival data in our clinical trial, but proved too toxic for use in treating patients with NSCLC in the clinical practice.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6422010Experimental Pulmonary Granuloma Mimicking Sarcoidosis Induced by Propionibacterium acnes in Mice7583ENKoujiIioTomoe UenoIioYuheiOkuiHirohisaIchikawaYasushiTanimotoNobuakiMiyaharaArihikoKanehiroMitsuneTanimotoYasunariNakataMikioKataokaOriginal Article10.18926/AMO/32852<p>Propionibacterium acnes has been implicated as an etiologic agent of sarcoidosis since the isolation of this bacterium from sarcoid lesions. We experimentally produced a murine pulmonary granuloma model using P. acnes with several features that simulate sarcoidosis. Mice were sensitized with heat-killed P. acnes and complete Freund's adjuvant and were subsequently challenged with heat-killed P. acnes at 2-week intervals. P. acnes-challenged mice developed epitheloid cell granulomas in the lungs. These mice showed a pulmonary immune response characterized by an increased number of T-lymphocytes, especially CD4 cells, and the ratio of CD4/CD8 in bronchoalveolar lavage (BAL) fluid also increased. Furthermore, significant elevations in both angiotensin-converting enzyme (ACE) serum levels and antibody titers against P. acnes were observed. Mice sensitized with P. acnes without complete Freund's adjuvant were capable of forming pulmonary granulomas, which appeared to be caused by indigenous P. acnes. The genome of P. acnes was found in the lungs, BAL cells, hilar lymph nodes, liver, and spleen in non-sensitized mice, which were thought to be germ-free. These results suggest that the immune response against indigenous P. acnes may play an important role in the pathogenesis of granuloma formation in a murine model.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6322009Expression of thyroglobulin on follicular dendritic cells of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma7178ENMitsuruMunemasaTadashiYoshinoKeitaKobayashiTakayoshiMiyakeSumie TakaseSakugawaTomohikoMannamiKatsujiShinagawaMitsuneTanimotoTadaatsuAkagiOriginal Article10.18926/AMO/31834<p>Reportedly, thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is closely associated with Hashimoto's thyroiditis. However, it remains unknown which antigen is closely associated with thyroid MALT lymphoma. We examined whether B cell response to thyroglobulin (Tg), which is a common thyroid-specific autoantigen, is related etiologically to the pathogenesis of thyroid MALT lymphoma. Expression of human Tg antigens and Cluster of differentiation (CD) 35 was examined immunohistochemically in 15 cases of thyroid MALT lymphoma using paraffin-embedded, formalin-fixed tissue specimens. In all cases of thyroid MALT lymphoma, human Tg was detected immunohistochemically in the follicular epithelial cells and follicular dendritic cells (FDCs). These FDCs were positive by double immunostaining for anti-human Tg rabbit polyclonal antibody (Ab) and for CD35. Results showed that the Tg, a thyroid autoantigen, had immunostained the germinal center of the thyroid MALT lymphoma. The Tg was present in the FDCs, as revealed by the staining pattern of the germinal center;this fact was confirmed by double immunostaining of anti-human Tg mouse monoclonal Ab and anti-CD35 mouse monoclonal Ab. The results of our study suggest that Tg is an autoantigen that is recognized by thyroid MALT lymphoma cells.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6342009Successful voriconazole treatment of invasive pulmonary aspergillosis in a patient with acute biphenotypic leukemia213216ENKoichiroKobayashiMasahiroOgasawaraYoshioKiyamaTakayoshiMiyazonoKumikoKagawaKiyotoshiImaiTeiichiHiranoNaokiKobayashiMitsuneTanimotoMasaharuKasaiCase Report10.18926/AMO/31813<p>A 23-year old woman with acute biphenotypic leukemia (ABL) complained of chest pain with cough, high fever and hemoptysis during induction chemotherapy, although she had been treated with anti-biotics and micafungin. We made a clinical diagnosis of invasive pulmonary aspergillosis (IPA) based on a consolidation in the right upper lung field on a chest radiograph as well as a high level of serum beta-D-glucan (with no evidence of tuberculosis and candidiasis). We changed her treatment from micafungin to voriconazole. Later, we discovered an air-crescent sign by CT scan that supported the diagnosis of IPA. Following voriconazole treatment, clinical symptoms ceased and abnormal chest shadows improved gradually and concurrently with a recovery of neutrophils. IPA must be considered in immunocompromised patients with pulmonary infiltrates who do not respond to broad-spectrum antibiotics. Serological tests and CT findings can aid in early diagnosis of IPA, which, along with treatment for IPA, will improve clinical outcomes.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5632002Comparison of chemosensitivity tests: clonogenic assay versus MTT assay.129134ENKazuhikoKawadaToshiroYoneiHiroshiUeokaKatsuyukiKiuraMasahiroTabataNagioTakigawaMineHaradaMitsuneTanimotoArticle10.18926/AMO/31714<p>When the development of chemotherapeutic agents reaches the clinical trial stage, it is necessary to perform drug sensitivity tests quickly in order to select the most promising agents for the treatment of cancer. In order to assess the possibility of using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as a substitute for the human tumor clonogenic assay (HTCA), we evaluated the correlation between the results obtained by these 2 assays in 5 human lung cancer cell lines. The correlation coefficient between the results of the HTCA and the MTT assay was 0.673, indicating a relatively good correlation. The correlation was most prominent in platinum analogues (r = 0.939) and good in anthracyclines/anthracenedione (r = 0.611). However, no significant correlation was observed in vinca alkaloids, etoposide, irinotecan, SN-38 (an active metabolite of irinotecan), and rhizoxin. The results of the MTT assay showed a high degree of correlation with those of the HTCA in predicting the sensitivity of cancer cell lines to platinum analogues, and anthracyclines/anthracenedione. These results suggest that the MTT assay may be more convenient and quickly performed than the HTCA and can replace HTCA in evaluating the effects of anticancer agents, especially the platinum analogues and anthracyclines/anthracenedione.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5652002Camptothecin induces urokinase-type plasminogen activator gene-expression in human RC-K8 malignant lymphoma and H69 small cell lung cancer cells.223227ENMisakoShibakuraKenjiNiiyaToruKiguchiYasunariNakataMitsuneTanimotoArticle10.18926/AMO/31706<p>We previously reported that anthracyclines, which could generate reactive oxygen species (ROS), could induce the urokinase-type plasminogen activator (uPA) gene expression in human RC-K8 malignant lymphoma cells and in H69 small cell lung cancer (SCLC) cells. In screening other uPA-inducible anti-cancer agents, we found that camptothecin (CPT) and its derivative, SN38, could induce uPA in RC-K8 and H69 cells. CPT and SN38, which are also used for the treatment of lymphoma and SCLC, significantly increased the uPA accumulation in the conditioned media of both cells in a dose-dependent manner. The maximum induction of uPA mRNA levels was observed 24 h after stimulation. Pretreatment with pyrrolidine dithiocarbamate (PDTC), an anti-oxidant, inhibited the CPT-induced uPA mRNA expression. Thus, CPT induces uPA through gene expression, and, therefore, CPT may influence the tumor-cell biology by up-regulating the uPA/plasmin system.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5652002Daily low-dose cisplatin and concurrent thoracic irradiation for poor-risk patients with unresectable non-small-cell lung cancer.261266ENIchiroTakataHiroshiUeokaKatsuyukiKiuraMasahiroTabataNagioTakigawaHidekiKatayamaMitsuhiroTakemotoYoshioHirakiMineHaradaMitsuneTanimotoArticle10.18926/AMO/31705<p>A pilot study was conducted to assess the efficacy and feasibility of daily low-dose cisplatin with concurrent thoracic irradiation for clinically unresectable non-small-cell lung cancer (NSCLC). Patients with inoperable NSCLC who had poor risk factors such as advanced age, poor performance status, poor lung function, or concomitant active malignancy were entered into the study. Low-dose cisplatin (6 mg/m2) was administered daily before concurrent thoracic irradiation (2 Gy/day; total dose of 60 Gy) was given. Twenty-five patients were registered. The majority of the patients had either stage IIIA (24.0%) or stage IIIB (60.0%) disease. Fifteen patients (60.0%) completed the planned treatment. Both chemotherapy and radiotherapy were stopped in 3 patients (12.0%) due to poor response, and 7 patients (28.0%) partly received radiotherapy alone as a result of their toxicity response. The proportion of total administered dose to planned dose was 90.9% for chemotherapy and 99.3% for radiotherapy, which were comparable to those in previous studies for LA-NSCLC patients without poor risk factors. Grade 3 leukopenia and neutropenia developed in 14 patients (56.0%) and 10 patients (40.0%), respectively, but grade 4 toxicity was not encountered. Grade 3 pneumonitis and esophagitis were observed in 4 patients (16.0%) and 2 patients (8.0%), respectively. The overall response rate was 60.0%. The median survival time was 22 months, and the 2-year survival rate was 50.3%. Daily low-dose cisplatin and concurrent thoracic irradiation were well tolerated even by poor-risk patients with NSCLC, and showed a therapeutic efficacy similar to that for good-risk patients.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6032006Recent improvement in lung cancer screening: a comparison of the results carried out in two different time periods.173179ENTakujiKitajimaKenjiNishiiHiroshiUeokaTakuoShibayamaKenichiGembaTsuyoshiKodaniKatsuyukiKiuraMasahiroTabataKatsuyukiHottaMitsuneTanimotoTomotakaSobueArticle10.18926/AMO/30751<p>To evaluate recent improvements in lung cancer screening, we compared the results of recently conducted lung cancer screening with those of a previous screening. This study compared the survival of lung cancer patients detected by lung cancer screening conducted between 1976 and 1984 (early period) with that conducted between 1989 and 1997 (late period). Two hundred seventy-six patients with lung cancer were detected in the early period and 541 patients with lung cancer were detected in the late period. The median survival time (late : 49.8 vs. early : 27.8 months) and the 5-year survival rate (late : 47.8 vs. early : 34.8%) of the patients with lung cancer detected in the late period were significantly better than those in the early period (p = 0.0054). Among patients undergoing resection, the proportion of pathological stage I patients in the late period was significantly higher than that in the early period (late : 60.8 vs. early : 54.9%, p = 0.005). Multivariate analysis showed that the screening time period was a significant prognostic factor (hazard ratio = 0.685, 95% confidence interval : 0.563-0.832, p = 0.0002). These results were consistent with the findings of case-control studies of lung cancer screening programs in the late period recently conducted in Japan, which also showed a greater efficacy for screening than for previous case-control studies in the early period.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6052006Severe Interstitial Pneumonia Induced by Paclitaxel in a Patient with Adenocarcinoma of the Lung295298ENNoriyukiSuzakiAkioHirakiNagioTakigawaHiroshiUeokaYasushiTanimotoToshiyukiKozukiMasahiroTabataArihikoKanehiroKatsuyukiKiuraMitsuneTanimotoArticle10.18926/AMO/30737A 71-year-old Japanese man with adenocarcinoma of the lung developed interstitial pneumonia after treatment with paclitaxel. The patient had acute chills and fever on the fourth day after the second exposure to paclitaxel, rapidly got worse despite empiric therapies, and developed prolonged respiratory failure requiring mechanical ventilation. Four months later, he died of respiratory failure due to progression of both interstitial pneumonia and lung cancer. This is the first case developing fatal paclitaxel-induced pulmonary toxicity to date. Interstitial pneumonia should be considered one of the possible life-threatening complications during treatment with paclitaxel.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812132009多角的アプローチにより癌性疼痛のコントロールを得ることができた非小細胞肺癌の一例173175ENEikiIchiharaJunjiMatsuokaNagioTakigawaTakashiMatsuzakiKuniakiKatsuiKatsuyukiKiuraMitsuneTanimotoWe report a case of cancer-related pain relieved by a polyhedral approach. A woman in her late 30s with advanced non small cell lung cancer suffered from back pain caused by the cancer invasion to a thoracic vertebra. She could not take a sufficient dose of opioid due to its adverse effects. A supplementary analgesic was not found to be effective. Palliative radiation was considered desirable, but she could not maintain a dorsal position for irradiation due to back pain. Continuous epidural anesthesia was then introduced. Epidural anesthesia allowed her to lie in a spine position for radiation therapy. After completion of radiation therapy, her back pain was relieved with a low dose of transdermal fentanyl without epidural anesthesia.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812112009中国四国広域プロ養成プログラム ―チーム医療を担うがん専門医療人の育成―www.chushiganpro.jp2933ENJunjiMatsuokaYoshioNaomotoMasahiroTabataYasuhiroShirakawaKatsuyukiHottaMitsuneTanimotoNoriakiTanakaNo potential conflict of interest relevant to this article was reported.岡山大学医学部附属病院三朝医療センターActa Medica Okayama0918-7839722002腰痛症患者における腰椎MRI画像所見の検討6670ENShingoTakataTadashiYokoiNorikazuNishidaMakotoOkamotoHirofumiTsugenoKozoAshidaYasuhiroHosakiTakashiMifuneFumihiroMitsunobuYoshiroTanizakiKenjiNiiyaMitsuneTanimoto10.18926/14842(目的) MRlは腰痛をきたす疾患の診断に必須な検査法である。腰痛と腰椎MRl所見との関係を明らかにすることを目的として検討した。(対象と方法)腰痛を訴えた30例を対象とし、腰椎MRl所見の頻度を調査した。全例に温泉療法を施行した。
(結果)全症例において腰椎MRl上異常所見を認めた。少なくとも1つ以上の椎間板の変性病変をもつ症例は30例中27例(90% )で、椎間板変性はL4/5levelで最も多く認められた(30例中18例)。椎間板ヘルニア
を示す症例は30例中10例(33.3% )であった。神経根圧迫を持つ症例は30例中8例(26.7% )であった。腰椎圧迫骨折を持つ症例は30例中6例(20% )であった。温泉療法により腰痛が改善した症例は30例中17例(56.7% )であった。
(結論)腰痛症患者は腰椎MR止異常所見を有した。温泉療法により腰痛の改善を認めたので、MRL上で認めた形態学的異常は必ずしも機能的異常や症状に直結しないと思われた。No potential conflict of interest relevant to this article was reported.岡山大学医学部附属病院三朝医療センターActa Medica Okayama0918-7839722002Effects of alpha -linolenic acid-rich supplementationon leukotriene generation by leucocytes in patientswith asthma associated with lipometabolism4554ENMakotoOkamotoFumihiroMitsunobuKozoAshidaYasuhiroHosakiHirofumiTsugenoNorikazuNishidaTadashiYokoiShingoTakataYoshiroTanizakiMitsuneTanimoto10.18926/14839Dietary sources of a -linolenic acid, such as perilla seed oil, may have the capacity to inhibit the generation of leukotrienes (LTs) by leucocytes in patients with
asthma, as has been reported with the consumption of other long - chain n- 3 fatty a-cids.
The factors affecting the suppression of leukotriene (LT) C4 generation by leucocytes were examined by comparing the clinical features of patients with asthma who had been given dietary perilla seed oil (n - 3 fatty acids). Group A consisted of patients in whom the leucocyte generation of dietary perilla seed oil LTC4 was suppressed by this procedure. Group B consisted of those in whom LTC4 generation was not suppressed. LTC4 generation by leucocytes significantly decreased in group A for two (P<0.05) and four weeks (P<O. OS), conversely, significantly increased in group B for four weeks (p<O. OS). The two study groups differed significantly in LTC4 generation by leucocytes after four weeks of dietary supplementation (P<0.05). Ventilatory parameters such as peak expiratory flow (PEF) , forced vital capacity (FVC) and forced expiratory volume in one second (FEV(1.O)) increased significantly after four weeks of dietary supplementation in group A (P<0.05). Values of PEF, FVC, FEV(1.O) and V(25) between groups A and B significantly differed prior to dietary supplementation. Serum levels of total cholesterol, LDL- cholesterol and phospholipid were significantly decreased by dietary supplementation in group A after four weeks. Serum levels of total-choles
terol, triglyceride, HDL-Cholesterol, LDL-Cholesterol and phospholipid values between the two study groups differed significantly prior to dietary supplementation. Serum
levels of triglyceride and LDL- cholesterol differed significantly between the two study groups after four weeks of dietary supplementation.
The effects of dietary supplementation with perilla seed oil to patients with asthma by suppressing the generation of LTC4 is associated with clinical features such as respiratory function and lipometabolism.No potential conflict of interest relevant to this article was reported.岡山大学医学部附属病院三朝医療センターActa Medica Okayama1348-1258732003早期診断にて軽快したMPO-ANCA関連血管炎の一例8892ENHirohisaIchikawaKozoAshidaKatsuichiroOnoShingoTakataTadashiYokoiTakuyaNagataMakotoOkamotoHirohumiTsugenoNorikazuNishidaYasuhiroHosakiFumihiroMitsunobuYoshiroTanizakiYoshinoriNoguchiMitsuneTanimoto10.18926/14775症例は76歳男性03年前肺気腫と診断された。今回呼吸器リハビリテーション目的で当院に入院の運びとなった。入院時より37-38'Cの発熱を認め,下気道感染を疑い抗生剤で加療したが改善しなかった.入院時の検尿検査で蛋白・潜血陽性であり,血清MPO-ANCAが307U/mlと高値を示した。血清クレアチニン値も徐々に上昇してきたため,MPO-ANCA関連血管炎と診断した.プレドニゾロン投与を開始したところ,症状及び検査所見は速やかに改善した.No potential conflict of interest relevant to this article was reported.岡山大学医学部附属病院三朝医療センターActa Medica Okayama1348-1258732003Bromocriptineにより白血球減少症及び血小板減少症をきたしたパーキンソン病の1例8487ENShingoTakataTakashiMifuneFumihiroMitsunobuMakotoOkamotoNorikazuNishidaHirofumiTsugenoKozoAshidaYasuhiroHosakiTadashiYokoiYoshiroTanizakiKenjiNiiyaMitsuneTanimoto10.18926/14774症例は67歳,女性。以前からパーキンソン病にて加療されていたが,リハビリテーション目的で当院入院した.入院時白血球数,血小板数正常であったが,bromocriptine投与開始後白血球減少,血小板減少を認めた.薬剤性白血球減少症及び血小板減少症を疑い, bromocriptine投与中止するとともにfilgrastim投与により,白血球減少,血小板減少は改善した。誘発試験施行し白血球減少を認めた。Bromocriptineによる白血球減少症,血小板減少症の報告は少なく,我々の検索しえた範円内では本症例を含めて2例のみであった。Bromocriptineには安全性や神経保護作用に関して多くのデータの蓄積があるが,安全性に十分な注意が必要であると考えられた。No potential conflict of interest relevant to this article was reported.岡山大学医学部附属病院三朝医療センターActa Medica Okayama1348-1258732003Effects of spa therapy combined with dietary supplementation with alpha -linolenic acids on bronchial asthma5563ENMakotoOkamotoKozoAshidaFumihiroMitsunobuYasuhiroHosakiHirofumiTsugenoNorikazuNishidaTakuyaNagataTadashiYokoiShingoTakataYoshiroTanizakiMitsuneTnimoto10.18926/14768N-3 fatty acids are reportedly effective for asthma. In addition, spa therapy has been reported to be effective for patients with asthma. In the present study, the effects of spa therapy combined with perilla seed oil- rich diet (rich in n-3 fatty acid)were examined on asthma. A total of 14 asthmatic patients had a complex spa therapy and consumed a perilla seed oil- rich diet - rich in a -linolenic acid (alpha-LNA) for 8 weeks. Generation of leukotriene (LT) C4 by leucocytes, respiratory function were analyzed. The generation of LTC4 by leucocytes decreased significantly for 2, 4 and 8 weeks (P<O.05). Peak expiratory flow (PEF) values increased significantly for 2,4, 6 and 8 weeks (P<O.05). The values of ventilatory parameters [forced vital capacity (FVC) , forced expiratory volume in one second (FEV(1)) forced expiratory flow after
25% of expired FVC (FEF(25)), forced expiratory flow after 75% of expired FVC (FEF (75)) • mean expiratory flow during the middle half of the FVC (FEF(25-75)) ] revealed a significant increase after 4 and 8 weeks of the modified diet (P<O.05). The results suggest that spa therapy combined with a perilla seed oil- rich diet are effective in the treatment of asthma in terms of its ability to suppress LTC4 generation by leucocytes, and in inducing an improvement of pulmonary function.No potential conflict of interest relevant to this article was reported.岡山大学医学部附属病院三朝医療センターActa Medica Okayama1348-1258732003Influence of long-term cigarette smoking on changes of lung density by high-resolution computed tomography in asthmatics--4 years follow-up study1018ENFumihiroMitsunobuKozoAshidaYasuhiroHosakiHirofumiTsugenoMakotoOkamotoNorikazuNishidaTakuyaNagataShingoTakataTadashiYokoiMutsuoNakaiYoshiroTanizakiMitsuneTanimoto10.18926/14750Background-The influence of cigarette smoking on the pathogenesis of asthma in the elderly remains controversial. This study attempts to estimate longitudinal changes in HRCT (high resolution computed tomography) parameters and pulmonary function parameters obtained for ex-smokers and never-smokers in asthmatics during 4-yr follow-up period. Methods-Fourteen asthmatics (6 ex-smokers and 8 never-smokers) were studied to determine the influence of aging and cigarette smoking on pulmonary function, and mean lung density (MLD) and the relative area of the lung showing attenuation values less than -950 HU (RA950) on HRCT scans. Results-The values of FVC and FEV1, were significantly more decreased in asthmatics without a smoking history during 4-yr follow-up period. The values of FVC, FEV1, FEV1/FVC and DLco/VA were significantly decreased and RV/TLC were significantly increased in asthmatics with a smoking history over 4 years, and annual decline in FEV1 ex-smokers was larger than that in never-smokers. In the upper lung field, inspiratory MLD was observed to shift in a negative direction and inspiratory RA950 was found to increase during 4-yr observation period in ex-smokers, but not in never-smokers. In the middle lung field, inspiratory RA950 was significantly enhanced in both two groups. Although expiratory MLD, expiratory RA950 and exp RA950/ins RA950 were observed to change significantly during the observation period in ex-smokers, no changes were observed in never-smokers. Conclusion-These results suggest that aging augments airspace enlargement predominantly in the middle lung field, while long term cigarette smoking further worsens emphysematous alterations in the upper lung field.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155811332001抗体による血液腫瘍の治療235239ENNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155811512005重度急性呼吸器症候群SARS6368ENNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155811632005多剤耐性結核と肺非結核性抗酸菌症287292ENNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030155811932008II 肺癌の内科的治療285292ENKatsuyukiKiuraNagioTakigawaIsaoOzeMasayukiYasugiNobuakiOchiDaijiroHaradaMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030155812012008マイクロ RNA9596ENMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030155812012008母子間免疫寛容理論に基づく同種造血幹細胞移植2328ENKen-ichiMatsuokaKazutoshiAoyamaMotokoKoyamaDaigoHashimotoShojiAsakuraTatsuoIchinoheMitsuneTanimotoTakanoriTeshimaNo potential conflict of interest relevant to this article was reported.