Japanese Society of Internal MedicineActa Medica Okayama0918-291864232025Remarkable Efficacy of Capmatinib in a Patient with Cancer of Unknown Primary with MET Amplification34603464ENTakaakiTanakaDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalRyoheiSumiiDepartment of General Internal Medicine, NHO Fukuyama Medical CenterRikaOmoteDepartment of Pathology, NHO Fukuyama Medical CenterYayoiAndoClinical Research Support Office, National Cancer Center HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalThis case report describes a 70-year-old female with cancer of unknown primary origin (CUP) who exhibited multiple distant lymph node metastases. Despite conventional chemotherapy (carboplatin and paclitaxel) and immunotherapy (nivolumab), disease progression was noted. Genomic profiling revealed MET amplification, leading to the administration of capmatinib, a selective MET tyrosine kinase inhibitor. The patient experienced substantial tumor reduction with dose adjustments due to adverse effects, indicating the potential efficacy of capmatinib in treating CUP with MET amplification.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-291864232025A Prompt Diagnosis of Ascites and Dramatic Effect of Alectinib for Advanced Lung Adenocarcinoma Harboring EML4-ALK Fusion34133418ENTakahiroBabaDepartment of Respiratory Medicine, Okayama University HospitalHirofumiInoueDepartment of Medical Support, Okayama University HospitalHiromiMatsuokaDepartment of Medical Support, Okayama University HospitalMioKyakunoDepartment of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of MedicineYusukeYoshinagaDepartment of Respiratory Medicine, Okayama University HospitalTetsuyaTakeguchiDepartment of Respiratory Medicine, Okayama University HospitalMihoFujiwaraDepartment of Respiratory Medicine, Okayama University HospitalKotaroYamadaDepartment of Respiratory Medicine, Okayama University HospitalEriNakamuraDepartment of Respiratory Medicine, Okayama University HospitalAyakoMoritaDepartment of Respiratory Medicine, Okayama University HospitalNaofumiHaraDepartment of Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalHisaoHigoDepartment of Respiratory Medicine, Okayama University HospitalMasanoriFujiiDepartment of Geriatric Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYosukeTogashiDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalA 75-year-old never-smoker woman presented with dyspnea and loss of appetite. A mass was identified in the left upper lobe of the lung, and the patient was referred to our hospital. Despite the diagnosis of lung adenocarcinoma via bronchoscopy, anaplastic lymphoma kinase (ALK) immunostaining was negative. Rapid weight gain and abdominal distension caused by ascites prompted fluid testing using the AmoyDx® Pan Lung Cancer PCR Panel. EML4-ALK fusion was confirmed, and alectinib therapy was initiated immediately. The tumor size had decreased significantly, and the patient was discharged on day 34. This case highlights the necessity of multiplex genetic testing even when ALK immunostaining is negative.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2045-763414152025Real‐World Data of Comprehensive Cancer Genomic Profiling Tests Performed in the Routine Clinical Setting in Sarcomae71098ENEijiNakataDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTatsunoriOsoneDepartment of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakutoItanoDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTomohiroFujiwaraDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiyukiKunisadaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNaoyukiIdaDepartment of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHidekiYamamotoDepartment of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMashuFutagawaDepartment of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTatsunoriShimoiDepartment of Medical Oncology, National Cancer Center HospitalHiroyukiYanaiDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAkiraHirasawaDepartment of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShinichiToyookaCenter for Comprehensive Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasahiroTabataCenter for Clinical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshifumiOzakiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesIntroduction: Next-generation sequencing-based comprehensive cancer genomic profiling (CGP) tests are beneficial for refining diagnosis and personalized treatment of various cancers. However, the clinical impact of CGP, as covered by public health insurance in the management of sarcomas, remains unknown. Especially, the data on the utility of the newly emerging dual DNA–RNA panel compared to the conventional DNA-only panel in clinical settings is lacking. Therefore, we evaluated the utility of CGP in routine clinical practice for sarcoma treatment.<br>
Patients and Methods: In this study, three types of DNA panel and one DNA–RNA panel, reimbursed by Japanese public health insurance, were utilized. We detected oncogenic and druggable gene mutations and genotype-matched therapies.<br>
Results: One hundred and thirty-six patients were included in this study. Based on the detection of highly histology-specific translocations in the sequencing results, 2.2% of patients were re-classified. In patients with translocation-related sarcomas, a DNA–RNA panel identified more histology-specific fusion genes than DNA panels (p = 0.0035). Specifically, 86.8% and 39.0% of patients had oncogenic and druggable genomic alterations, respectively. Of these, 9.6% underwent genotype-matched therapy, with a 36.3% response rate and an 81.8% disease control rate. Patients who were administered genomically matched therapy had better overall survival (OS) than those who did not in patients with metastatic or advanced sarcoma with no prior chemotherapy (3-year OS: 83.3% vs. 48.0%, p = 0.42). Patients with TP53 and RB1 mutations had worse OS than those without. Germline findings were detected in 11.0% of the patients, one of whom had a truly germline origin.<br>
Conclusions: This study suggests that publicly reimbursed CGP tests, particularly the dual DNA–RNA panel, could be beneficial for refining diagnostic precision in selected sarcoma subtypes, treatment decisions, detecting the germline findings, and prognosis prediction in routine clinical settings for sarcoma. The implementation of genotype-matched therapies showed favorable clinical outcomes and improved the prognosis.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0941-43553342025Cancer-related alopecia and wig acquisition: how age, sex, and treatment affect patient choices283ENHidekiKatayamaDepartment of Palliative and Supportive Care, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalAyakoMoritaDepartment of Allergy and Respiratory Medicine , Okayama University HospitalGoMakimotoDepartment of Allergy and Respiratory Medicine , Okayama University HospitalShunsukeKagawaCenter for Clinical Oncology, Okayama University HospitalAyanoIshiiIntegrated Support Center for Patients and Self-Learning , Okayama University HospitalMasahiroTabataDepartment of Palliative and Supportive Care, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalPurpose This study aimed to explore the prevalence and cost of wig purchases among patients with cancer in Okayama Prefecture, Japan, and examine the relationship between wig purchases and various demographic, social, and clinical factors. The findings aim to provide insights into appearance care and support systems for patients with cancer, particularly wig subsidies.<br>
Methods A survey was conducted between July and August 2023 among 3000 patients with cancer at 13 designated cancer care hospitals in Okayama Prefecture. Data on demographics, cancer treatment status, and wig purchase details were collected. Statistical analyses, including the Mann–Whitney U test, chi-square test, and logistic regression, were performed to identify factors significantly associated with wig purchases.<br>
Results Among the 863 respondents, 31.4% (271 patients) reported purchasing wigs. Factors significantly associated with wig purchase included young age (odds ratio [OR] = 1.04), female sex (OR = 1.61), and current cancer treatment (OR = 1.16). No significant correlation was found between wig purchase and household income, although higher-income patients tended to purchase more expensive wigs.<br>
Conclusion The findings suggest that younger female patients with cancer and those undergoing treatment were more likely to purchase wigs, highlighting the importance of appearance care and the need for enhanced financial support for low-income patients.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221512025Plasma S100A8/A9 level predicts response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer2577ENTadahiroKuribayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRieKinoshitaDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKiichiroNinomiyaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalToshioKuboDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKammeiRaiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKatsuyukiHottaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMasahiroTabataDepartment of Allergy and Respiratory Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalShinichiToyookaDepartment of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasakiyoSakaguchiDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalBlood-based predictive markers for the efficacy of immune checkpoint inhibitors (ICIs) have not yet been established. We investigated the association of the plasma level of S100A8/A9 with the efficacy of immunotherapy. We evaluated patients with unresectable stage III/IV or recurrent non-small cell lung cancer (NSCLC) who were treated with ICIs at Okayama University Hospital. The pre-treatment plasma levels of S100A8/A9 were analyzed. Eighty-one eligible patients were included (median age, 69 years). Sixty-two patients were men, 54 had adenocarcinoma, 74 had performance status (PS) 0–1, and 47 received ICIs as first-line treatment. The median time to treatment failure (TTF) for ICIs was 5.7 months, and the median overall survival (OS) was 19.6 months. The TTF and OS were worse in patients with high plasma S100A8/A9 levels (≥ 2.475 µg/mL) (median TTF: 4.3 vs. 8.5 months, p = 0.009; median OS: 15.4 vs. 38.0 months, p = 0.001). Multivariate analysis revealed that PS ≥ 2, liver metastasis, and high plasma S100A8/A9 levels were significantly associated with short TTF and OS. In conclusion, plasma S100A8/A9 level may have a limited effect on ICI therapy for NSCLC.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-291863192024A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing26552660ENHiroakiMatsuuraDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalNaohiroOdaDepartment of Respiratory Medicine, Fukuyama City HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalHisaoHigoDepartment of Respiratory Medicine, Okayama University HospitalMasanoriFujiiDepartment of Respiratory Medicine, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor.No potential conflict of interest relevant to this article was reported.American Society of Clinical Oncology (ASCO)Acta Medica Okayama2473-428482024Response to Imatinib in a Patient With Gastric Adenocarcinoma With KIT Q556_K558 In-Frame Deletion: A Case Reporte2400228ENKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University HospitalKunioOkamotoDepartment of Medical Oncology, Kagawa Prefectural Central HospitalMidoriAndoDepartment of Pathology, Kagawa Prefectural Central Hospital,SatokoNakamuraDepartment of Pathology, Kagawa Prefectural Central HospitalShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalYoshiyukiAyadaDepartment of Pathology, Okayama University HospitalGoMakimotoCenter for Clinical Oncology, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalNatsukoOkitaResearch Management Division, Clinical Research Support Office, National Cancer Center HospitalShinichiToyookaCenter for Comprehensive Genomic Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalNo potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama2213-0071512024Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy102104ENMasahiroYamashitaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHisaoHigoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalNobuharuFujiiDepartment of Hematology and Oncology, Okayama University HospitalChiakiMatsumotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalMasanoriFujiiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuakiMiyaharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalA 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-29186392024Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer12611267ENTakaakiTanakaDepartment of Respiratory Medicine, Okayama University HospitalMasatakaTaokaDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalHisaoHigoDepartment of Respiratory Medicine, Okayama University HospitalMasanoriFujiiDepartment of Respiratory Medicine, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesA 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1759-770615172024Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report13901394ENHiroakiMatsuuraDepartment of Respiratory Medicine, Okayama University HospitalHisaoHigoDepartment of Respiratory Medicine, Okayama University HospitalTadahiroKuribayashiDepartment of Respiratory Medicine, Okayama University HospitalAkihikoTamaokiOkayama Health Foundation Hospital, Okayama Health FoundationTakamasaNakasukaDepartment of Respiratory Medicine, Okayama University HospitalMariUnoDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaDepartment of Respiratory Medicine, Okayama University HospitalMasanoriFujiiDepartment of Respiratory Medicine, Okayama University HospitalKammeiRaiDepartment of Respiratory Medicine, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaDepartment of Respiratory Medicine, Okayama University HospitalNobuakiMiyaharaDepartment of Respiratory Medicine, Okayama University HospitalMasahiroTabataDepartment of Respiratory Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalThe concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.No potential conflict of interest relevant to this article was reported.AME Publishing CompanyActa Medica Okayama2218-675112102023CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancerENNaofumiHaraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHirohisaKanoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalChihiroAndoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAyakoMoritaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTatsuyaNishiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakamasaNakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAtsukoHirabaeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasayaAbeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalGoMakimotoCenter for Clinical Oncology, Okayama University HospitalMasanoriFujiiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalToshioKuboDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalBackground: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance.<br>
Methods: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC.<br>
Results: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation.<br>
Conclusions: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama2213-0071382022Massive hemoptysis in a post-operative patient with recurrent lung cancer successfully treated by the combination therapy of Endobronchial Watanabe Spigot and bronchial artery embolization101669ENMasatakaTaokaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalNoriyukiUmakoshiDepartment of Radiology, Okayama University HospitalKiichiroNinomiyaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHisaoHigoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalYukaKatoCenter for Innovative Clinical Medicine, Okayama University HospitalMasanoriFujiiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalA 76-year-old woman who was treated with lorlatinib for postoperative recurrent anaplastic lymphoma kinase-positive lung adenocarcinoma visited our hospital with massive hemoptysis. Chest computed tomography showed massive bleeding from the right upper lobe; however, the cause of bleeding was unclear. After bronchial artery embolization (BAE), bronchial occlusion was performed using an Endobronchial Watanabe Spigot (EWS) that was easily placed because BAE had reduced the bleeding volume. Treatment with BAE alone was inadequate; however, additional therapy with EWS after BAE successfully controlled the massive hemoptysis, especially in this patient who underwent lobectomy to prevent respiratory dysfunction.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-9032114112023Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer43434354ENChihiroAndoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalTatsuyaNishiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAyakoMoritaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNaofumiHaraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKenjiTakadaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakamasaNakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiromiWatanabeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHirohisaKanoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesGoMakimotoCenter for Clinical Oncology, Okayama University HospitalTakumiKondoDepartment of Hematology and Oncology, Okayama University HospitalKiichiroNinomiyaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMasanoriFujiiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalToshioKuboDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKen-IchiMatsuokaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory MedicineKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalGilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0169-50021782023PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer110ENTakamasaNakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsukoHirabaeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNahokoTomonobuDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKenjiTakadaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChihiroAndoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiromiWatanabeDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of MedicineMasanoriFujiiDepartment of Respiratory Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalHiromiKumonInnovation Center Okayama for Nanobio-targeted Therapy, Okayama UniversityYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalObjectives: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored.<br>
Materials and methods: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined.<br>
Results: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity.<br>
Conclusion: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.No potential conflict of interest relevant to this article was reported.KargerActa Medica Okayama1662-65751522022Successful and Prompt Treatment with Tepotinib for Lung Adenocarcinoma Harboring MET Exon 14 Skipping Mutation Combined with Lung Abscess Formation: A Case Report494498ENGoMakimotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalAtsushiShimonishiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHisaoHigoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalYukaKatoCenter for Innovative Clinical Medicine, Okayama University HospitalMasanoriFujiiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalTepotinib, the novel MET-tyrosine kinase inhibitor, shows an antitumor effect for patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. In January 2022, the AmoyDx (R) Pan Lung Cancer polymerase chain reaction Panel (AmoyDx (R) panel), which had a shorter turnaround time than the conventional test, was launched in Japan as a tepotinib companion test. We report a patient with an advanced MET-mutant NSCLC promptly diagnosed using the AmoyDx (R) panel and successfully treated with tepotinib. Although the patient's performance status (PS) worsened due to the rapid tumor progression and lung abscess formation, the tumor shrank immediately after tepotinib treatment with marked PS improvement.No potential conflict of interest relevant to this article was reported.JAPAN SOC INTERNAL MEDICINEActa Medica Okayama0918-29186132022Pulmonary Aspergilloma and Allergic Bronchopulmonary Aspergillosis Following the 2018 Heavy Rain Event in Western Japan379383ENEriAndoCenter for Graduate Medical Education, Okayama University HospitalTakamasaNakasukaAllergy and Respiratory Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalAkihikoTaniguchiAllergy and Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaHematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukaKatoAllergy and Respiratory Medicine, Okayama University HospitalEikiIchiharaAllergy and Respiratory Medicine, Okayama University HospitalKadoakiOhashiAllergy and Respiratory Medicine, Okayama University HospitalKammeiRaiAllergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaAllergy and Respiratory Medicine, Okayama University HospitalMasaomiYamaneDepartments of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuakiMiyaharaAllergy and Respiratory Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaHematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraAllergy and Respiratory Medicine, Okayama University HospitalA 16-year-old boy with asthma participated in recovery volunteer work following the 2018 heavy rains in Japan. One month later, he experienced chest pain and dyspnea. Chest computed tomography revealed a cavity with a fungal ball, and Aspergillus fumigatus was detected in his bronchoalveolar lavage fluid. He was treated with voriconazole, but new consolidations appeared rapidly. He also experienced allergic bronchopulmonary aspergillosis. After prednisolone prescription, the consolidations improved; however, his asthma worsened. He underwent partial lung resection to avoid allergens, and his symptoms improved. We must recognize cases of infection after a disaster, especially in patients with chronic respiratory diseases.No potential conflict of interest relevant to this article was reported.The Japanese Society of Internal MedicineActa Medica Okayama0918-291860182021Dramatic Response to Carboplatin Plus Paclitaxel in Pancreatic Mucinous Cystadenocarcinoma with Liver Metastasis29672971ENNaohiroOdaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalMasatoshiUnoDepartment of Internal Medicine, Kaneda HospitalYuzoUmedaDepartment of Hepato-Biliary-Pancreatic Surgery, Okayama University HospitalHironariKatoDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshioKuboCenter for Clinical Oncology, Okayama University HospitalSatoruSenooDepartment of Allergy and Respiratory Medicine, Okayama University HospitalTakahitoYagiDepartment of Hepato-Biliary-Pancreatic Surgery, Okayama University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA+PTX). CBDCA+PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma.No potential conflict of interest relevant to this article was reported.The Japanese Society of Internal MedicineActa Medica Okayama0918-291860172021Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease28312837ENSachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKammeiRaiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuharuFujiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukaGionDivision of Pathophysiology, Okayama University Graduate School of Health SciencesKiichiroNinomiyaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukaKatoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkihikoTaniguchiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshioKuboDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesEikiIchiharaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuakiMiyaharaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiHottaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahiroTabataDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuMaedaDepartment 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 SciencesA 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy.No potential conflict of interest relevant to this article was reported.Spandidos PublicationsActa Medica Okayama1792-10742232021Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1α/TGF‑α expression639ENKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalHiromiWatanabeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesGoMakimotoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakamasaNakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisaoHigoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKiichiroNinomiyaDepartment of Respiratory Medicine, Okayama University HospitalYukaKatoCenter for Innovative Clinical Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalKammeiRaiDepartment of Respiratory Medicine, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalOsimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression‑free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia‑inducible factor‑1α (HIF‑1α) and transforming growth factor‑α (TGF‑α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF‑α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF‑1α/TGF‑α.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-90322021VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancersENHiromiWatanabeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHiroeKayataniDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesGoMakimotoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKiichiroNinomiyaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHisaoHigoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesChihiroAndoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakamasaNakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHirohisaKanoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNaofumiHaraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAtsukoHirabaeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYukaKatoCenter for Innovative Clinical Medicine, Okayama University HospitalTakashiNinomiyaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshioKuboCenter for Clinical Oncology, Okayama University HospitalKammeiRaiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMolecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama0941-4355292020Demand for weekend outpatient chemotherapy among patients with cancer in Japan12871297ENHidekiKatayamaDepartment of Palliative and Supportive Care, Okayama University HospitalMasahiroTabataDepartment of Palliative and Supportive Care, Okayama University HospitalToshioKuboDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalJunjiMatsuokaDepartment of Palliative and Supportive Care, Okayama University HospitalYoshinobuMaedaDepartment of Palliative and Supportive Care, Okayama University HospitalBackground</br>
Advanced cancer therapeutics have improved patient survival, leading to an increase in the number of patients who require long-term outpatient chemotherapy. However, the available schedule options for chemotherapy are generally limited to traditional business hours.</br>
Method</br>
In 2017, we surveyed 721 patients with cancer in Okayama, Japan, regarding their preferences for evening and weekend (Friday evening, Saturday, and Sunday) chemotherapy appointments.</br>
Results</br>
A preference for evening and weekend appointment options was indicated by 37% of the respondents. Patients who requested weekend chemotherapy were younger, female, with no spouse or partner, living alone, employed, and currently receiving treatment. Among these factors, age and employment status were significantly associated with a preference for weekend chemotherapy, according to multivariate analysis.</br>
Conclusion</br>
Our findings reveal a demand for evening and weekend outpatient chemotherapy, especially among young, employed patients.No potential conflict of interest relevant to this article was reported.Spandidos PublicationsActa Medica Okayama1792-10742062020Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction393ENKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalTomokiTamuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKiichiroNinomiyaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakehiroMatsubaraOkayama University Hospital BiobankSatoruSenooDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirohisaKanoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiromiWatanabeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaohiroOdaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesGoMakimotoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisaoHigoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukaKatoCenter for Innovative Clinical Medicine, Okayama University HospitalTakashiNinomiyaDepartment of Respiratory Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalHiromasa YamamotoDepartment of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShutaTomidaOkayama University Hospital BiobankKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Innovative Clinical Medicine, Okayama University HospitalShinichiToyookaDepartment of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalThe detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non‑small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC‑ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54‑81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post‑operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC‑ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC‑ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC‑ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.No 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 Okayama0386-300X7052016A Phase I Trial of 100mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer425427ENTomokiTamuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalTaizoHirataDepartment of Medical Oncology, National Hospital Organization Kure Medical CenterMasahiroTabataDepartment of Allergy and Respiratory Medicine, Okayama University HospitalShiroHinotsuCenter for Innovative Clinical Medicine, Okayama University HospitalAkinobuHamadaDivision of Clinical Pharmacology & Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterTakayukiMotokiDepartment of Breast and Endocrinological Surgery, Okayama University HospitalTakayukiIwamotoDepartment of Breast and Endocrinological Surgery, Okayama University HospitalTaekoMizooDepartment of Breast and Endocrinological Surgery, Okayama University HospitalTomohiroNogamiDepartment of Breast and Endocrinological Surgery, Okayama University HospitalTadahikoShienDepartment of Breast and Endocrinological Surgery, Okayama University HospitalNarutoTairaDepartment of Breast and Endocrinological Surgery, Okayama University HospitalJunjiMatsuokaDepartment of Breast and Endocrinological Surgery, Okayama University HospitalHiroyoshiDoiharaDepartment of Breast and Endocrinological Surgery, Okayama University HospitalClinical Study Protocols10.18926/AMO/54607Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age ≥20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812722015HER2異常等の低頻度の分子異常を有する非小細胞肺癌の臨床病理学的特徴を明らかにするための前向き観察研究（HER2-CS Study）と標準化学療法後再発・増悪または標準化学療法不応性のHER2陽性非小細胞肺癌患者を対象としたトラスツズマブエムタンシン（遺伝子組換え）の第2相試験127132ENKatsuyukiKiuraKatsuyukiHottaAkikoSatoKadoakiOhashiTakashiNinomiyaDaisukeMinnamiMasahiroTabataToshioKuboYukaKatoTaizoHirataNo 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.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 Okayama0386-300X6412010Triplet 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 Okayama0386-300X5632002Comparison 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 Okayama0386-300X5652002Daily 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 Okayama0386-300X5321999Establishment of a Drug Sensitivity Panel Using Human Lung Cancer Cell Lines6775ENAkioMatsushitaMasahiroTabataHiroshiUeokaKatsuyukiKiuraTakuoShibayamaKeisukeAoeHiroyukiKoharaMineHaradaArticle10.18926/AMO/31626<p>We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X4731993Establishment of an Adriamycin-Resistant Subline of Human Small Cell Lung Cancer Showing Multifactorial Mechanisms of Resistance191197ENKatsuyukiKiuraTaisukeOhnoshiMasahiroTabataTakuoShibayamaIkuroKimuraArticle10.18926/AMO/31598A subline highly resistant to Adriamycin (SBC-3/ADM100) was isolated in vitro from the human small cell lung cancer cell line, SBC-3, by culturing in progressively higher concentrations of Adriamycin. The SBC-3/ADM100 cells were 106-fold more resistant to the drug than the parent cells in an inhibitory concentration of 50% determined by the MTT assay. The population-doubling time was much longer in SBC-3/ADM100 than in the parent cells. Northern blot hybridization revealed marked overexpression of the MDR1 mRNA in the resistant cells. P-glycoprotein overexpression and a decrease in intracellular accumulation of Adriamycin were demonstrated in SBC-3/ADM100, indicating that outward drug transport was the major mechanism of resistance in this subline. Additionally, a significant elevation of the intracellular glutathione content coupled with the glutathione S-transferase (GST) pi level and a decrease in DNA topoisomerase II (Topo II) activity were noted in this resistant subline. These results indicate that the mechanism of resistance to Adriamycin is multifactorial; involving altered growth characteristics, an enhanced outward transport, enhanced drug detoxification process, and decreased target enzyme activity. The resistant subline will serve as a useful tool in the search for ways to overcome drug resistance.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X4731993Immunohistochemical detection of P-glycoprotein and carcinoembryonic antigen in small cell lung cancer: with reference to predictability of response to chemotherapy.181189ENYoshihikoSegawaTaisukeOhnoshiShunkichiHirakiHiroshiUeokaKatsuyukiKiuraHaruhitoKameiMasahiroTabataTakuoShibayamaKazuyoMiyatakeken-ichiGendaTadashiMatsumuraIkuroKimuraArticle10.18926/AMO/31590<p>In an attempt to elucidate the tumor properties relating to responsiveness to chemotherapy, we examined immunohistochemically the expression of P-glycoprotein (P-gp) and carcinoembryonic antigen (CEA) in small cell lung cancer (SCLC) tumors. Tumor specimens from 33 patients were obtained at the time of diagnosis and relapse. Four patients expressed P-gp in their initial tumors, and 7 others did in recurrent tumors. The overall response rate to chemotherapy of the initial tumors was 75% for P-gp-positive initial tumors and 86% for P-gp-negative tumors, whereas the disease-free and overall survival times were significantly shorter in the former than the latter. Three patients showed CEA in their initial tumors, and 5 others did in recurrent tumors. The patients with CEA-positive initial tumors tended to relapse earlier than those with CEA-negative tumors. In addition, recurrent tumors expressing CEA were resistant to salvage chemotherapy. A clear correlation between CEA expression by tumors and the CEA level in the serum was observed at diagnosis as well as at relapse. These findings indicate that P-gp and/or CEA expression by a tumor and elevated CEA level in the serum may predict refractoriness of the tumor to chemotherapy.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X4741993MDR1 gene expression and treatment outcome in small cell lung cancer: MDR1 gene expression as an independent prognostic factor.243248ENMasahiroTabataTaisukeOhnoshiHiroshiUeokaKatsuyukiKiuraIkuroKimuraArticle10.18926/AMO/31553<p>We report a preliminary study to determine whether MDR1 gene expression level in small cell lung cancer (SCLC) tumors is a useful predictor of tumor response to chemotherapy and patient survival in association with myc amplification in the tumor. We analyzed 18 patients with SCLC receiving adriamycin and etoposide combination chemotherapy between August 1989 and November 1991; 16 males and 2 females, median age of 68 years, and 7 with limited disease and 11 with extensive disease. MDR1 mRNA expression level and myc family gene amplification were simultaneously determined by polymerase chain reaction using transbronchial biopsy specimens which were obtained at diagnosis. Patients with tumors expressing low MDR1 mRNA responded more favorably to chemotherapy than those with tumors expressing high MDRI mRNA, however, the difference in tumor response was statistically not significant (84.6% versus 40%). The overall survival was significantly shorter in the latter than in the former (7.2 months versus 11.7 months; p = 0.023). The survival of the 4 patients with tumor showing myc family gene amplification was almost identical to that of patients with tumors showing no amplification of the gene (8.2 months versus 8.8 months; p = 0.73). Multivariate Cox's regression analysis supports the notion that MDR1 may be a useful independent prognostic factor.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X4741993Antitumor activity of platinum analogs against human lung cancer cell lines and tumor specimens.233241ENToshiroYoneiTaisukeOhnoshiShunkichiHirakiHiroshiUeokaKatsuyukiKiuraTomonoriMoritakaTakuoShibayamaMasahiroTabataYoshihikoSegawaNagioTakigawaIkuroKimuraArticle10.18926/AMO/31552<p>Antitumor activities of five platinum analogs, including cisplatin, carboplatin, 254-S, DWA2114R, and NK121, were compared using five human lung cancer cell lines and 19 tumor specimens obtained from lung cancer patients. The antitumor activity was evaluated by determining the ratio of the maximum tolerated dose of each drug to the 70% tumor growth inhibitory concentration in a colony assay. Cisplatin was the most potent agent, followed by 254-S and carboplatin. DWA2114R and NK121 were less potent than cisplatin and 254-S. Cross-resistance to adriamycin was also investigated using an adriamycin-resistant small cell lung cancer subline, SBC -3/ADM30. SBC-3/ADM30 was 1.7- to 4.0-fold more resistant to cisplatin, carboplatin, NK121, and DWA2114R, than was the parent line, SBC-3, and the subline was 2.0-fold more sensitive to 254-S. Using SBC-3, in vitro combination effects of etoposide and cisplatin, carboplatin, or 254-S were evaluated by the median-effect principle. Synergism was noted when cisplatin and etoposide were combined at a fixed molar ratio of 1:1. Combination of carboplatin and etoposide showed an additive effect. The combination of 254-S and etoposide was antagonistic at low concentrations, but was markedly synergistic at higher concentrations. These data suggested the efficacy of 254-S in the treatment of lung cancer.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5221998Prognostic factors of small-cell lung cancer in Okayama Lung Cancer Study Group Trials.105111ENMakotoTamuraHiroshiUeokaKatsuyukiKiuraMasahiroTabataTakuoShibayamaKazuyoMiyatakeKenichiGenbaShunkichiHirakiMineharadaArticle10.18926/AMO/31310<p>In order to elucidate factors influencing the prognosis of small-cell lung cancer (SCLC), we reviewed the records of 253 patients with SCLC and evaluated 20 pretreatment prognostic factors by univariate analysis and Cox's multiple regression analysis. Recursive partitioning and amalgamation (RPA) was employed to identify subgroups with similar survival rates. Cox's multiple regression analysis identified five significant factors: extent of disease, number of metastatic sites, serum albumin, serum lactate dehydrogenase, and presence of weight loss. Among these, extent of disease was the most influential factor. RPA analysis revealed three subgroups predicting significantly different prognoses. The median survival time and 3-year survival rate were 18.4 months and 20.6%, respectively for the good-risk group (limited disease without weight loss), 13.5 months and 9.1%, respectively for the intermediate-risk group (limited disease with weight loss or extensive disease with less than two metastatic sites), and 9.2 months and 0%, respectively for the poor-risk group (extensive disease with two or more metastatic sites). These results will be useful for development of new staging system or subsequent stratification for randomized trials.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5131997Growth inhibitory effects of antifolates against an adriamycin-resistant human small cell lung cancer cell line121127ENKeisukeMatsuoKatsuyukiKiuraHiroshiUeokaMasahiroTabataTakuoShibayamaTadashiMatsumuraNagioTakigawaShunkichiHirakiMineHaradaArticle10.18926/AMO/30795<p>We have established an Adriamycin (ADM) -resistant small cell lung cancer (SCLC) cell line, SBC-3/ADM100, which shows multifactorial mechanisms of resistance to ADM, such as overexpression of P-glycoprotein, an enhanced detoxifying system and a decrease in topoisomerase II activity. In the present study, we confirmed that SBC-3/ADM 100 showed collateral sensitivity to methotrexate and TNP-351, a new antifolate, though this cell line showed a typical multidrug resistance (MDR) pattern. We also demonstrated a faster uptake and higher accumulation (1.3-fold) of TNP-351 in the SBC-3/ADM100 cells than those in the parent SBC-3 cells. These results explain one of the mechanisms for collateral sensitivity in the resistant cells. Furthermore, this cell line was found to have no cross-resistance to edatrexate and minimal cross-resistance to trimetrexate, 254-S (cisplatin analog), 5-fluorouracil and 4-hydroperoxyifosfamide. These drugs will have clinical importance in patients with SCLC who were previously treated with an ADM-containing regimen. Thus, antifolates, especially TNP-351 and edatrexate, can be expected to eradicate residual multidrug resistant SCLC cells selected by ADM.</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 Okayama0030-155812112009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 Okayama0030155811912007II がん登録制度6972ENAkiraGochiHisakoSenamiNaomiOharaMasahiroTabataNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030155811912007I がん診療連携拠点病院体制と岡山大学病院腫瘍センター6167ENMasahiroTabataNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1993MDRl Gene Expression and Treatment Outcome in Small Cell Lung Cancer ; MDR1 Gene Expression as an Independent Prognostic FactorENNo potential conflict of interest relevant to this article was reported.