Springer Science and Business Media LLCActa Medica Okayama1341-96253072025Guidance on the short hydration method for cisplatin administration12871293ENKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalKeiKunimasaDepartment of Thoracic Oncology, Osaka International Cancer InstituteYasukoKurataDepartment of Pharmacy, Okayama University HospitalYukiSatoDepartment of Respiratory Medicine, Kobe City Medical Center General HospitalYasuhitoFujisakaDepartment of Medical Oncology, Osaka Medical and Pharmaceutical UniversityHitoshiIshikawaQST Hospital, National Institutes for Quantum Science and TechnologyKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalCisplatin is currently used as the central agent in several cancer chemotherapy protocols because of its broad antitumor spectrum and potent antitumor effects; however, preventing cisplatin-induced renal damage and other adverse events is challenging. Recently, several clinical studies have shown that a short hydration method could prevent cisplatin-induced renal damage. In addition, appropriate magnesium supplementation and administration of forced diuretics have been shown to be renoprotective. The Japanese Lung Cancer Society Guidelines Committee has summarized the evidence of renal protection regarding cisplatin administration to provide optimal administration guidance for the cisplatin short hydration method.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2168-81841722025Durable Response to Nivolumab Combined With Metformin in Advanced Pancreatic Cancer: A Case Report With Seven Years of Follow-Upe79001ENRyosukeSatoDepartment of Gastroenterology and Hepatology, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalToshioKuboDepartment of Allergy and Respiratory Medicine, Okayama University HospitalShigeruHoriguchiDepartment of Gastroenterology and Hepatology, Okayama University HospitalHironariKatoDepartment of Gastroenterology, Okayama City HospitalKazuyukiMatsumotoDepartment of Gastroenterology and Hepatology, Okayama University HospitalToshiyukiKozukiDepartment of Respiratory Medicine and Allergology, Kochi Medical School, Kochi UniversityHeiichiroUdonoDepartment of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMotoyukiOtsukaDepartment of Gastroenterology and Hepatology, Okayama University HospitalWe report a case of poorly differentiated pancreatic cancer that showed an exceptional response to combination therapy with nivolumab and metformin. A 58-year-old man presented with epigastric pain and was diagnosed with locally advanced pancreatic cancer with para-aortic lymph node metastasis. After disease progression following modified FOLFIRINOX therapy (a combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin), the patient was enrolled in a phase Ib clinical trial of nivolumab (3 mg/kg biweekly) combined with metformin (750 mg/day). Post-treatment imaging showed marked tumor shrinkage with normalization of the tumor markers. During treatment, the patient was diagnosed with early-stage lung cancer and underwent successful left S1+S2 segmentectomy with temporary suspension of immunotherapy. The therapeutic response of pancreatic cancer has been sustained for seven years, with minimal residual disease. This unprecedented response duration is particularly noteworthy considering his microsatellite stability, which typically predicts a limited response to immune checkpoint inhibition.<br>
This case demonstrates an exceptional response to nivolumab and metformin combination therapy in poorly differentiated pancreatic cancer. The remarkable durability of the response suggests the need for further investigation to identify patients most likely to benefit from this therapeutic approach.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-291865112026Endotracheal and Endobronchial Metastases in Epidermal Growth Factor Receptor Exon 19 Deletion Lung Adenocarcinoma: A Case Successfully Managed with Bronchoscopic Therapy and Sequential Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors15201523ENMihoFujiwaraDepartment of Respiratory Medicine, Okayama University HospitalTakahiroBabaDepartment of Respiratory Medicine, Okayama University HospitalKotaroYamadaDepartment of Respiratory Medicine, Okayama University HospitalEriNakamuraDepartment of Respiratory Medicine, Okayama University HospitalTetsuyaTakeguchiDepartment of Respiratory Medicine, Okayama University HospitalYukiTakigawaDepartment of Respiratory Medicine, NHO Okayama Medical CenterAyakoMoritaCenter for Clinical Oncology, Okayama University HospitalNaofumiHaraDepartment of Respiratory Medicine, Okayama University HospitalHiromiWatanabeDepartment of Respiratory Medicine, NHO Okayama Medical CenterKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalKenSatoDepartment of Respiratory Medicine, NHO Okayama Medical CenterYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYosukeTogashiDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalEndotracheal and endobronchial metastases from peripheral lung adenocarcinoma are rare, and optimal clinical management remains unclear. We herein report a 60-year-old woman with epidermal growth factor receptor (EGFR) exon 19 deletion-positive early-stage lung adenocarcinoma who underwent surgical resection followed by osimertinib treatment for recurrence. She later developed oligoprogressive disease with airway metastases. Bronchoscopic tumor removal was performed, and next-generation sequencing of the resected specimen revealed an acquired EGFR C797S mutation, along with exon 19 deletion. Gefitinib treatment was initiated, which led to a partial response. This case underscores the utility of repeated molecular profiling and local intervention in managing acquired resistance in EGFR-mutant non-small-cell lung cancer.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1341-96253032025Five-year outcomes with gefitinib induction and chemoradiotherapy in EGFR-mutant stage III non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study497503ENKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalShoSaekiDepartment of Respiratory Medicine, Kumamoto University HospitalShinyaSakataDepartment of Respiratory Medicine, Kumamoto University HospitalMasafumiYamaguchiDepartment of Thoracic Oncology, NHO Kyushu Cancer CenterDaijiroHaradaDepartment of Thoracic Oncology, National Hospital Organization Shikoku Cancer CenterAkihiroBesshoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalKentaroTanakaDepartment of Respiratory Medicine, Kyushu University HospitalKojiInoueDepartment of Respiratory Medicine, Kitakyushu Municipal Medical CenterKojiInoueDepartment of Respiratory Medicine, Ehime Prefectural Central HospitalKenichiGembaDepartment of Respiratory Medicine, Chugoku Central HospitalToshioKuboDepartment of Respiratory Medicine, Okayama University HospitalAkikoSatoDepartment of Respiratory Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalHiromiWatanabeDepartment of Respiratory Medicine, Okayama University HospitalJunjiKishimotoDepartment of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu UniversityYoshiyukiShioyamaRadiation Oncology, Ion Beam Therapy Center, SAGA HIMAT FoundationKuniakiKatsuiDepartment of Radiology, Kawasaki Medical SchoolKenjiSugioDivision of Radiation Oncology, Department of Thoracic and Breast Surgery, Oita UniversityKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalBackground We previously showed the 2-year OS rate, the primary endpoint, of 90% in a phase II trial of gefitinib induction followed by chemoradiotherapy (CRT) in unresectable, stage III, EGFR-mutant, non-small-cell lung cancer (NSCLC). However, neither long-term survival data nor late-phase adverse event profiles have been presented.<br>
Patients and methods Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy for 8 weeks. After confirming no disease progression during induction therapy, cisplatin and docetaxel on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy were subsequently administered.<br>
Results In the enrolled twenty patients, the 5-year OS rate and median survival time were 70.0% [95% confidence interval: 45.1–85.3] and 5.5 years [4.91-NE], respectively, whereas 5-year PFS rate and median PFS time were 15.0% (3.7–33.5) and 1.4 years [0.69–2.29], respectively. Efficacy did not seem influenced even if radiation field was re-planed in response to the effect of gefitinib induction. As for late adverse events, pulmonary fibrosis occurred in 7 patients (35%). The median time from completion of CRT to the occurrence of the event was 245 days. All were grade 1, and there was no evidence of cavitation of the lesions or chronic infections such as Aspergillus infection during the course of the disease. One case of small cell lung cancer occurred during the period.<br>
Conclusions With longer follow-up time, we demonstrated favorable efficacy with tolerable toxicity profiles in the EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III, NSCLC.<br>
Trial registration numbers UMIN00005086. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000006047&type=summary&language=EjRCTs071180036. https://jrct.niph.go.jp/latest-detail/jRCTs071180036No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1574-78912026Stimulator of interferon genes agonist augmented antitumor immunity of osimertinib in <i>Egfr</i> ‐mutated lung cancerENJunNishimuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadahiroKuribayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJohannesBrägelmannDepartment of Translational Genomics Faculty of Medicine and University Hospital Cologne, University of Cologne GermanySachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasatakaTaokaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuntaMoriDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokaNishimuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaakiTanakaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalRyoheiKatayamaDivision of Experimental Chemotherapy, Cancer Chemotherapy Centre, Japanese Foundation for Cancer ResearchKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYosukeTogashiDepartment of Respiratory Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMartin L.SosDepartment of Translational Genomics Faculty of Medicine and University Hospital Cologne, University of Cologne GermanyKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalEpidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers (NSCLCs) lack effective immunotherapy due to a noninflamed tumor microenvironment (TME). We previously reported that EGFR tyrosine-kinase-inhibitor (TKI) induced CD8+ T-cell immunity, which was insufficient for tumor eradication. We evaluated the potential of combining EGFR-TKI with stimulator of interferon genes (STING) agonists in activating a systemic antitumor response. Using a syngeneic mouse model of genetically engineered Egfr-mutant NSCLC, we evaluated the antitumor effects of STING agonist ADU-S100, alone and combined with osimertinib. Immunohistochemistry and flow cytometry were used to assess the TME. Osimertinib alone enhanced CD8+ T-cell infiltration but not Natural Killer (NK) cell infiltration. ADU-S100 injection alone modestly suppressed tumor growth with increasing CD8+/NK cell infiltration in the TME, but lacked an abscopal effect. Combining ADU-S100 with osimertinib significantly enhanced the antitumor effects and CD8+/NK cell infiltration. Depletion of either CD8+ or NK cells reduced the combination effect. Crucially, the combination induced an abscopal effect accompanied by PD-1+/CD8+ cell infiltration. Combining osimertinib with a STING agonist augmented innate and adaptive immunity, inducing systemic antitumor responses in EGFR-mutant NSCLC.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-90322026Afatinib Overcomes Osimertinib Resistance via Egfr V804F Mutation in a Syngeneic Egfr-Mutant Lung Cancer Mouse Model117ENTakaakiTanakaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasatoFujitaniDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchMasatakaTaokaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIwaoShimomuraDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchSachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuntaMoriDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadahiroKuribayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunNishimuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokaNishimuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAyakoMoritaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityNaofumiHaraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalGoMakimotoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityHisaoHigoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityKammeiRaiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityEikiIchiharaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalYosukeTogashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityRyoheiKatayamaDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchKadoakiOhashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama UniversityOsimertinib is the standard first-line treatment for advanced EGFR-mutant non-small cell lung cancer. However, acquired resistance invariably develops, and identifying novel resistance pathways is clinically important as a substantial portion remains undefined. We used an immunocompetent syngeneic lung cancer mouse model harboring an Egfr exon 19 deletion (mDEL tumors) to establish acquired resistance. Osimertinib-resistant tumors were generated in vivo using a drug-holiday/re-challenge protocol. The resistance mechanism was identified using Sanger sequencing, receptor tyrosine kinase arrays, and western blotting. Egfr V804F knock-in cells were generated using CRISPR/Cas9, and their sensitivity to osimertinib and afatinib was assessed in vitro and in vivo. We established two distinct osimertinib-resistant tumor lines in a syngeneic lung cancer mouse model (mDEL OsiR #1/#3). The analysis revealed an on-target secondary Egfr V804F mutation (corresponding to human EGFR V802F) in both tumor lines. Importantly, Egfr V804F knock-in cells demonstrated significant osimertinib resistance, with a 5.7–10.5-fold increase in in vitro IC50 (mean, 8.2-fold), but remained highly sensitive to afatinib. Furthermore, afatinib effectively overcame osimertinib resistance in the V804F knock-in cell-derived mouse model. Consistently, afatinib treatment resulted in marked tumor shrinkage and suppression of EGFR signaling in the established mDEL OsiR #1/#3 in vivo. These findings establish secondary Egfr V804F/EGFR V802F as an on-target osimertinib resistance mechanism, providing a preclinical rationale for evaluating afatinib in biomarker-selected patients harboring this alteration.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-903211752026TGF-β Inhibitor Potentiates Osimertinib-Induced Anti-Tumor Immunity in Egfr-Mutant Lung Cancer12601272ENTadahiroKuribayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunNishimuraDepartment 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 SciencesMasatakaTaokaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuntaMoriDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaakiTanakaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokaNishimuraDepartment 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 Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalYosukeTogashiDepartment 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 HospitalImmunotherapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains challenging. We previously found that EGFR-tyrosine kinase inhibitors induced antitumor immunity but also triggered immunosuppressive cytokines, including transforming growth factor-β (TGF-β), in Egfr-mutant lung cancer. Here, we investigate whether TGF-β inhibition potentiates osimertinib-induced antitumor immunity using a syngeneic mouse model of Egfr-mutated lung cancer, with cancer cells subcutaneously transplanted into wild-type C57BL/6J mice. We evaluated the antitumor effect of the combination therapy with osimertinib and either nintedanib (an indirect TGF-β inhibitor) or vactosertib (a specific TGF-β type I receptor kinase inhibitor). Changes in the tumor microenvironment during treatment were assessed using immunohistochemical staining, western blot analysis, and flow cytometry. We found that TGF-β expression was upregulated in the tumor treated with osimertinib. Nintedanib monotherapy showed no significant antitumor effect, whereas osimertinib combined with nintedanib significantly potentiates the antitumor effect compared with osimertinib monotherapy in vivo. Crucially, no additive effect of nintedanib on osimertinib monotherapy was observed in vitro. Combination therapy with osimertinib and nintedanib significantly increased effector T cells (CD8+CD44+CD62L−) and Granzyme B+ areas and decreased CD206+ cells, while significantly decreasing TGF-β and SMAD2/3 expression. Similar effects were observed with vactosertib but not with a vascular endothelial growth factor receptor 2 inhibitor. In conclusion, combination therapy with osimertinib and TGF-β inhibitors potentiates osimertinib-induced antitumor immunity. These findings highlight a novel therapeutic strategy for EGFR-mutated NSCLC and warrant further clinical investigation.No potential conflict of interest relevant to this article was reported.Public Library of Science (PLoS)Acta Medica Okayama1932-62032162026A multicenter, randomized, parallel-group confirmatory study protocol to evaluate the efficacy of Soft Protector CPC, a novel oral mucosal protectant, in preventing oral mucositis and alleviating pain in patients with breast cancere0350803ENKazuhiroOmoriDepartment of Pathophysiology-Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKoheiFurukawaDepartment of Dentistry and Oral Surgery, Shikoku Cancer CenterMasatoshiUsubuchiDepartment of Dentistry, Miyagi Cancer CenterTomofumiHamadaDepartment of Dentistry and Oral Surgery, Sagara HospitalTadahikoShienDepartment of Breast and Endocrine Surgery, Okayama University HospitalMichihiroYoshidaCenter for Innovative Clinical Medicine, Okayama University HospitalYukiNakatsukaCenter for Innovative Clinical Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalSoichiroIbaragiDepartment of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShogoTakashibaDepartment of Pathophysiology-Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityOral mucositis is a frequent and debilitating adverse event observed in patients undergoing chemotherapy or radiotherapy. Current management strategies are limited in duration, require frequent application, and fail to address the mechanical irritation from teeth. A novel device, Soft Protector CPC, was developed to overcome these limitations. This multicenter, randomized, two-arm, open-label, confirmatory trial aims to evaluate the efficacy and safety of Soft Protector CPC in patients with breast cancer undergoing chemotherapy. A total of 154 participants will be randomly assigned in a 1:1 ratio to receive either oral care with Soft Protector CPC or oral care alone. The primary endpoint will be oral mucositis as assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 during the comparative treatment period. The secondary endpoints will include CTCAE v3.0 during the continuous treatment period, oral mucositis, pain (CTCAE v5.0), quality of life (Patient Reported Outcomes-CTCAE version 1.0 [PRO-CTCAE v1.0], the 15-item oral health questionnaire of the European Organization For Research And Treatment Of Cancer [EORTC QLQ-OH15], and the pain Numeric Rating Scale), onset and site of mucositis, completion of chemotherapy, use of rescue medications, technical feasibility, and patient preference. The safety endpoints will include adverse events, device malfunction, and laboratory tests. This trial is expected to establish the clinical utility of the Soft Protector CPC for the prevention and management of oral mucositis, with the potential to improve the patients’ quality of life and adherence to cancer therapy. This study was approved by the Clinical Research Review Board and registered with the Japan Registry of Clinical Trials, jRCTs062250005, on April 18, 2025.No potential conflict of interest relevant to this article was reported.American Association for Cancer Research (AACR)Acta Medica Okayama2767-9764622026Clinical Characteristics and Spatial Transcriptome Analysis of Non–Small Cell Lung Cancers Exhibiting Early Alectinib Resistance: A Retrospective OLCSG Study284293ENTadahiroKuribayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalHirofumiInoueCenter for Comprehensive Genomic Medicine, Okayama University HospitalToshihideYokoyamaDepartment of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central HospitalShoichiKuyamaDepartment of Respiratory Medicine, NHO Iwakuni Clinical CenterYukaKatoDepartment of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer CenterKenichiroKudoDepartment of Respiratory Medicine, National Hospital Organization Okayama Medical CenterNaokatsuHoritaDepartment of Respiratory Medicine, Kure Kyosai HospitalHiroeKayataniDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalMasaakiInoueDepartment of Chest Surgery, Shimonoseki City HospitalKeisukeSugimotoDepartment of Respiratory Medicine, Japanese Red Cross Kobe HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYosukeTogashiDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalSome anaplastic lymphoma kinase (ALK) gene rearrangement–positive lung cancers show early resistance, within 3 months, to alectinib. This study investigated the clinical and molecular characteristics of these patients. We analyzed patients with unresectable stage III/IV disease without indications for radical radiotherapy and recurrent ALK-positive lung cancer who received alectinib as the primary ALK tyrosine kinase inhibitor between 2013 and 2021 at nine hospitals. In total, 103 patients were included. The median age was 65 years; 44 were male and 22 had brain metastases. The median progression-free survival and overall survival (OS) were 28.7 and 80.6 months. Nineteen patients treated for ≤3 months and 84 treated for >3 months were categorized into the early resistance and responder groups, respectively. The early resistance group had significantly shorter OS (8.4 months vs. not estimable, P < 0.001) and was significantly more likely to have brain metastases (42% vs. 17%, P = 0.027). They also showed elevated inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR). Univariate analysis identified brain metastases and high NLR as significant predictors of early resistance. Spatial transcriptome analysis and immunohistochemical staining revealed upregulation of annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein involved in inflammation and cancer progression, in the early resistance group. Interleukin 6 stimulation, prompted by elevated inflammatory markers, increased ANXA1 expression and reduced alectinib sensitivity. Knockdown of ANXA1 improved alectinib sensitivity in alectinib-resistant cells. In conclusion, brain metastases and high NLR are associated with early resistance. ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2168-81841762025Retreatment With EGFR-Tyrosine Kinase Inhibitor After Disease Progression Following Gefitinib Induction and Chemoradiotherapy in EGFR-Mutant Stage III Non-small Lung Cancer: An Efficacy and Safety Analysis of the LOGIK0902/OLCSG0905 Studye86575ENShoSaekiDepartment of Respiratory Medicine, Kumamoto University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalShinyaSakataDepartment of Respiratory Medicine, Kumamoto University HospitalNaohiroOdaDepartment of Respiratory Medicine, Okayama University HospitalKojiInoueDepartment of Respiratory Medicine, Kitakyushu Municipal Medical CenterTomokiTamuraDepartment of Respiratory Medicine, Okayama University HospitalRyoToyozawaDepartment of Thoracic Oncology, National Hospital Organization Kyushu Cancer CenterDaijiroHaradaDepartment of Thoracic Oncology, National Hospital Organization Shikoku Cancer CenterKentaroTanakaDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu UniversityKojiInoueDepartment of Respiratory Medicine, Ehime Prefectural Central HospitalYoshiyukiShioyamaRadiation Oncology, Ion Beam Therapy Center, SAGA HIMAT FoundationKenichiGembaDepartment of Respiratory Medicine, Chugoku Central HospitalTomonariSasakiDepartment of Radiation Oncology, Iizuka HospitalAkihiroBesshoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalJunjiKishimotoCenter for Clinical and Translational Research, Kyushu University HospitalKuniakiKatsuiDepartment of Radiology, Division of Radiation Oncology, Kawasaki Medical SchoolKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalKenjiSugioThoracic and Breast Surgery, Oita UniversityBackground and objective: We had previously conducted a phase II study (LOGIK0902/OLCSG0905 study) involving the eight-week administration of gefitinib, followed by cisplatin-based chemoradiotherapy, to treat locally advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC). Despite favorable overall survival outcomes, more than half of the patients relapsed after the protocol therapy, highlighting the need to clarify the clinical significance of retreatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated the efficacy and safety of EGFR-TKI retreatment after disease progression.<br>
Materials and methods: We included 14 patients who relapsed after the protocol treatment and received any type of EGFR-TKI as post-progression treatment in this sub-analysis. We evaluated the efficacy and safety of retreatment with EGFR-TKI in these patients.<br>
Results: Among the 14 patients, 11 (78.6%) responded to the induction of gefitinib in the treatment protocol. After relapse, 9/14 patients (64.3%) received gefitinib, 3/14 (21.4%) received afatinib, and 2/14 (14.3%) received erlotinib monotherapy, respectively. The median duration of post-progression EGFR-TKI treatment was 17.9 (0.7-45.5) months. The overall response rate (ORR) and disease control rate were 64.3% [9/14 patients; 95% confidence interval (CI): 35.1%-87.2%] and 85.7% (12/14 patients; 95% CI: 57.2%-98.2%), respectively. The median progression-free survival (PFS) and median survival durations after the initiation of EGFR-TKI retreatment were 11.8 months (95% CI: 5.7-20.7 months) and 47.4 months (95% CI: 31.8 months to not estimable), respectively. Adverse events were comparable to those previously reported.<br>
Conclusions: Patients with disease progression after protocol therapy demonstrated sensitivity to retreatment with an EGFR-TKI, with acceptable safety.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1341-96253082025Phase-Ib dose-finding and pharmacokinetic trial of metformin combined with nivolumab for refractory/recurrent solid tumors15371544ENToshioKuboDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHironariKatoDepartment of Gastroenterology, Okayama University HospitalShigeruHoriguchiDepartment of Gastroenterology, Okayama University HospitalToshiyukiKozukiDepartment of Thoracic Oncology and Medicine, NHO Shikoku Cancer CenterAkinoriAsagiDepartment of Gastrointestinal Medical Oncology, NHO Shikoku Cancer CenterMichihiroYoshidaCenter for Innovative Clinical Medicine, Okayama University HospitalHeiichiroUdonoDepartment of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalBackground Our previous findings showed that the addition of metformin to nivolumab resulted in remarkable tumor regression and increased the number of tumor-infiltrating T cells in mouse models. Therefore, we conducted a phase Ib study using combination therapy with nivolumab and metformin in patients with refractory/recurrent solid tumors.<br>
Methods This study consisted of two parts: 1, evaluating the maximum tolerated dose (MTD), safety, pharmacokinetics in solid tumors, and 2, principally investigating the safety at the recommended dose limited to thoracic and pancreatic cancers. Metformin and nivolumab were administered orally at doses of 750–2,250 mg/day and biweekly at a fixed intravenous dose of 3 mg/kg, respectively. Dose-limiting toxicity was evaluated within the first 4 weeks. Both metformin and nivolumab were continued until disease progression or discontinued because of toxicity.<br>
Results In total, 17 and 24 patients were enrolled in parts 1 and 2, respectively. One patient experienced increased pancreatic enzyme levels (grade 4) and lactic acidosis (grade 3). No Grade 5 adverse events were observed. MTD was not reached up to 2,250 mg/day of metformin, 2,250 mg/day was selected for part 2. An objective response was observed in 4 of 41 patients. One-year progression-free and overall survival rates were 9.8% and 56.8%, respectively. Two patients remained alive without disease progression for more than three years.<br>
Conclusions Nivolumab and metformin combination therapy was well-tolerated and showed preliminary signals of efficacy in a subset of patients. Further verification of the underlying mechanism in cases where treatment is effective is required.<br>
Trial registration numbers UMIN registration number 000028405 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031915.No potential conflict of interest relevant to this article was reported.Oxford University Press (OUP)Acta Medica Okayama1465-36215552025Multicenter, open-label, randomized, controlled study to test the utility of electronic patient-reported outcome monitoring in patients with unresectable advanced cancers or metastatic/recurrent solid tumors547555ENNarutoTairaDepartment of Breast and Thyroid Surgery, Kawasaki Medical SchoolNaomiKiyotaDepartment of Medical Oncology and Hematology, Cancer Center, Kobe University HospitalYuichiroKikawaDepartment of Breast Surgery, Kansai Medical UniversityEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalKyokoKatoDepartment of Medical Oncology, National Hospital Organization Nagoya Medical Center KaoruKubotaDepartment of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical SchoolRyosukeTateishiDepartment of Gastroenterology, Graduate School of Medicine, The University of TokyoAkinobuNakataDepartment of Gastroenterology, Osaka Metropolitan University Graduate School of MedicineKeiichiroNakamuraDepartment of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiyaNaritaDepartment of Gastroenterology, Osaka Metropolitan University Graduate School of MedicineKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalHirojiIwataDepartment of Advanced Clinical Research and Development, Nagoya City UniversityAkihikoGemmaDepartment of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical SchoolKojiroShimozumaDepartment of Biomed Sciences, College of Life Sciences, Ritsumeikan UniversityKeiMuroDepartment of Gastroenterology, Osaka Metropolitan University Graduate School of MedicineTetsuyaIwamotoCenter for Outcomes Research and Economic Evaluation for Health, National Institute of Public HealthYukiTakumotoCenter for Outcomes Research and Economic Evaluation for Health, National Institute of Public HealthTakeruShiroiwaCenter for Outcomes Research and Economic Evaluation for Health, National Institute of Public HealthTakashiFukudaCenter for Outcomes Research and Economic Evaluation for Health, National Institute of Public HealthTakuhiroYamaguchiDivision of Biostatistics, Tohoku University Graduate School of MedicineYasuhiroHagiwaraDepartment of Biostatistics, Division of Health Sciences and Nursing, The University of Tokyo Graduate School of MedicineHironobuMinamiDivision of Medical Oncology and Hematology, Department of Medicine, Kobe University Graduate School of MedicineElectronic patient-reported outcome (ePRO) monitoring for patients undergoing cancer chemotherapy may provide qualified and early detection of adverse events or disease-related symptoms, leading to improved patient care. The aim of this study is to examine whether addition of ePRO monitoring to routine medical care contributes to improved overall survival and quality of life of cancer patients undergoing chemotherapy. Patients with unresectable advanced cancers or metastatic/recurrent solid tumors receiving systemic chemotherapy will be randomized to an ePRO monitoring group and a usual care group. The ePRO group will conduct weekly symptom monitoring using an electronic device after study enrollment until the end of the study. Monitoring results will be returned to medical personnel and used as information for patient care. The primary endpoints are overall survival and health related quality of life. The initial target sample size for the study was 1500 patients. However, due to delays in enrollment, the target was readjusted to 500 patients. Enrollment has been completed, and the study is now in the follow-up phase.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.Spandidos PublicationsActa Medica Okayama2049-94502332025Association of the expression of 5‑FU biomarkers with aging and prognosis in elderly patients with lung cancer treated with S‑1 adjuvant chemotherapy: Follow‑up results of the Setouchi Lung Cancer Group Study 120179ENJunichiSohDepartment of Thoracic Surgery, Okayama University HospitalHiromasaYamamotoDepartment of Thoracic Surgery, Okayama University HospitalNorihitoOkumuraDepartment of Thoracic Surgery, Kurashiki Central HospitalHiroyukiSuzukiDepartment of Chest Surgery, Fukushima Medical University HospitalMasaoNakataDepartment of General Thoracic Surgery, Kawasaki Medical School HospitalToshiyaFujiwaraDepartment of Thoracic Surgery, Hiroshima City Hiroshima Citizens HospitalKenicehiGembaDepartment of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Hiroshima 720‑0001, Japan; 8Department of Respiratory Surgery, Japanese Red Cross Nagasaki Genbaku HospitalIsaoSanoDepartment of Respiratory Surgery, Japanese Red Cross Nagasaki Genbaku HospitalTakujiFujinagaDepartment of General Thoracic Surgery, National Hospital Organization Nagara Medical CenterMasafumiKataokaDepartment of Surgery and Respiratory Center, Okayama Saiseikai General HospitalYasuhiroTerasakiDepartment of Respiratory Surgery, Saga Medical Center KoseikanNobukazuFujimotoDepartment of Medical Oncology and Respiratory Medicine, Okayama Rosai HospitalKazuhikoKataokaDepartment of Thoracic Surgery, National Hospital Organization Iwakuni Clinical CenterShinjiKosakaDepartment of Thoracic Surgery, Shimane Prefectural Central HospitalMotohiroYamashitaDepartment of Thoracic Surgery, National Hospital Organization Shikoku Cancer CenterHidetoshiInokawaDepartment of Thoracic Surgery, National Hospital Organization Yamaguchi‑Ube Medical CenterMasaakiInoueDepartment of Thoracic Surgery, Shimonoseki City HospitalHiroshigeNakamuraDivision of General Thoracic Surgery, Tottori University HospitalYoshinoriYamashitaDepartment of Thoracic Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer CenterYutaTakahashiDepartment of Thoracic Surgery, Okayama University HospitalHidejiroTorigoeDepartment of Thoracic Surgery, Okayama University HospitalHirokiSatoDepartment of Thoracic Surgery, Okayama University HospitalShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalHiroshigeYoshiokaDepartment of Thoracic Oncology, Kansai Medical University HospitalSatoshiMoritaDepartment of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of MedicineKeitaroMatsuoDivision of Cancer Epidemiology and Prevention, Aichi Cancer Center Research InstituteJunichiSakamotoTokai Central HospitalHiroshiDateDepartment of Thoracic Surgery, Kyoto University HospitalShinichiToyookaDepartment of Thoracic Surgery, Okayama University HospitalManaging elderly patients presents several challenges because of age‑related declines; however, age should not be the sole determinant for adjuvant treatment decisions in patients with non‑small cell lung cancer (NSCLC). Moreover, age may affect the expression of 5‑fluorouracil (5‑FU) biomarkers. The present study assessed: i) The effect of age on the expression levels of 5‑FU biomarkers by analyzing a public database; and ii) the ability of these biomarkers to predict clinical outcomes in elderly patients with NSCLC who underwent complete resection in the Setouchi Lung Cancer Group Study 1201 (SCLG1201) followed by S‑1 adjuvant chemotherapy. Changes in gene expression levels across age groups were assessed by analyzing The Cancer Genome Atlas (TCGA) database. The expression of 5‑FU biomarkers, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase, epidermal growth factor receptor (EGFR) and excision repair cross‑complementation group 1 (ERCC1), were assessed via quantitative reverse‑transcription PCR assays in 89 elderly patients (≥75 years) with NSCLC who received adjuvant chemotherapy with oral fluoropyrimidine prodrug S‑1 in the SLCG1201 trial. TCGA database analysis (n=955) showed that TS expression decreased significantly with aging, especially in the age group ≥75. In the SCLG1201 trial, univariate analysis revealed that EGFR upregulation and TS downregulation were correlated with favorable recurrence‑free survival (RFS) and overall survival (OS), respectively. Multivariate analysis demonstrated that pathological stage was an independent prognostic factor for both RFS and OS. EGFR mutations were associated with upregulation of DPD and EGFR, and downregulation of TS and ERCC1. In conclusion, although pathological stage is an independent prognostic factor for survival, EGFR upregulation and TS downregulation may be a greater predictor of clinical outcomes in elderly patients with NSCLC treated with S‑1 adjuvant chemotherapy. The age‑related decrease in TS expression supports the potential benefit of 5‑FU therapies in elderly patients. Nonetheless, further research is warranted to validate these results.No potential conflict of interest relevant to this article was reported.Japan Neurosurgical SocietyActa Medica Okayama2188-4226122025Safety of Adenosine-assisted Clipping Surgery for Unruptured Cerebral Aneurysms: Interim Results of a Single-center, Single-arm Study115119ENTomohitoHISHIKAWADepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiMURAIDepartment of Neurosurgery, Kawasaki Medical SchoolMasafumiHIRAMATSUDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunHARUMADepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiEBISUDANIDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaoYASUHARADepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKenjiSUGIUDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyoshiSHIMIZUDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiNAKAGAWADepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAyaKIMURA-ONOCenter for Innovative Clinical Medicine, Okayama University HospitalKatsuyukiHOTTACenter for Innovative Clinical Medicine, Okayama University HospitalHiroshiMORIMATSUDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIsaoDATEDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe aim of this single-center, single-arm study was to evaluate the safety of adenosine-assisted clipping surgery for unruptured cerebral aneurysms. Five patients underwent aneurysmal clipping during adenosine-induced hypotension at ≤60 mmHg. The mean age of patients was 63.4±8.5 years, and the mean aneurysm size was 5.3±1.1 mm. The prevalence of patients with modified Rankin Scale scores of zero 30 days after surgery was 100%. The degree of aneurysm obliteration was complete in 4 patients and residual dome in 1 patient. The mean total dosage of adenosine was 37.4±18.8 mg. The mean duration of systolic blood pressure at ≤60 mmHg was 64.2±28.3 secs. No patients exhibited paroxysmal atrial fibrillation within 24 hours after adenosine administration or elevation of high-sensitivity cardiac troponin T on postoperative day 1. There was no reduction in either motor-evoked or somatosensory-evoked potential amplitude during surgery. Adenosine-induced hypotension is a safe procedure in clipping surgery for unruptured cerebral aneurysms.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.MDPIActa Medica Okayama2072-669416232024Frequency and Significance of Body Weight Loss During Immunochemotherapy in Patients with Advanced Non-Small Cell Lung Cancer4089ENMasatakaTaokaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalToshihideYokoyamaDepartment of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central HospitalKojiInoueDepartment of Respiratory Medicine, Ehime Prefectural Central HospitalTomokiTamuraDepartment of Respiratory Medicine, NHO Iwakuni Clinical CenterAkikoSatoDepartment of Internal Medicine, National Hospital Organization Okayama Medical CenterNaohiroOdaDepartment of Respiratory Medicine, Fukuyama City HospitalHirohisaKanoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalKayoNakamuraDepartment of Respiratory Medicine, Japanese Red Cross Himeji HospitalHaruyukiKawaiDepartment of Internal Medicine, Okayama Saiseikai General HospitalMasaakiInoueDepartment of Chest Surgery, Shimonoseki City HospitalNobuakiOchiDepartment of General Internal Medicine 4 , Kawasaki Medical SchoolNobukazuFujimotoDepartment of Respiratory Medicine, Okayama Rosai HospitalHirohisaIchikawaDepartment of Respiratory Medicine, KKR Takamatsu HospitalChihiroAndoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalIsaoOzeDivision of Cancer Information and Control, Aichi Cancer Center Research InstituteKatsuyukiKiuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalBackground: Limited data are available on the frequency and significance of body weight loss during cancer therapy. This study investigated the frequency of patients who experienced body weight loss during immune checkpoint inhibitor (ICI) plus chemotherapy for advanced non-small cell lung cancer (NSCLC) and the impact of weight loss on treatment outcomes. Methods: Using the clinical data of 370 patients with NSCLC who received a combination of ICI and chemotherapy at 13 institutions, this study investigated the frequency of body weight loss > 5% during treatment and determined the impact of body weight loss on patient outcomes. Results: Of the 370 included patients, 141 (38.1%) lost more than 5% of their body weight during ICI plus chemotherapy (WL group). The 2-month landmark analysis showed that patients who experienced body weight loss of >5% during treatment had worse overall survival (OS) and progression-free survival (PFS) than those who did not (OS 14.0 and 31.1 months in the WL non-WL groups, respectively, p < 0.001; PFS 6.8 and 10.9 months in the WL non-WL groups, respectively, p = 0.002). Furthermore, a negative impact of body weight loss on survival was observed even in those who had obesity (body mass index [BMI] >= 25.0) at the start of therapy (OS 12.8 and 25.4 months in the WL non-WL groups, respectively, p < 0.001; PFS 5.7 and 10.7 months in the WL non-WL groups, respectively, p = 0.038). Conclusions: In conclusion, weight loss of >5% during ICI plus chemotherapy negatively influenced patient outcomes. Further and broader studies should investigate the role of nutritional status, specifically weight change and nutritional support, in responsiveness to ICI plus chemotherapy.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.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.Elsevier BVActa Medica Okayama2212-53456252024A randomized, open-label phase II study on the preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: The OLCSG2101 study protocol897900ENNaokiNakamuraDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesGoMakimotoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalTakaakiTanakaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukaKatoCenter of Innovative Clinical Medicine, Okayama University HospitalIsaoOzeDivision of Cancer Epidemiology and Prevention, Aichi Cancer Center Research InstituteToshiyukiKozukiDepartment of Respiratory Medicine, Shikoku Cancer CenterToshihideYokoyamaDepartment of Respiratory Medicine, Kurashiki Central HospitalHirohisaIchikawaDepartment of Respiratory Medicine, KKR Takamatsu HospitalShoichiKuyamaDepartment of Respiratory Medicine, Iwakuni Clinical CenterNaofumiHaraDepartment of Respiratory Medicine, Okayama Rosai HospitalYoshinobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiHottaCenter of Innovative Clinical Medicine, Okayama University HospitalBackground: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX.<br>
Methods: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled.<br>
Discussion: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL.<br>
Ethics and dissemination: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences.<br>
Trial registration: Japan Registry of Clinical Trials (registration number jRCTs061210047).No potential conflict of interest relevant to this article was reported.Mary Ann LiebertActa Medica Okayama2689-2820512024Factors Associated with Differences in Physicians’ Attitudes toward Percutaneous Endoscopic Gastrostomy Feeding in Older Adults Receiving End-of-Life Care in Japan: A Cross-Sectional Study206214ENYokoSakamotoCenter for Innovative Clinical Medicine, Okayama University HospitalToshiharuMitsuhashiCenter for Innovative Clinical Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalBackground: Although percutaneous endoscopic gastrostomy (PEG) placement is still widely practiced in Japan, studies from Western countries report that it is less beneficial for patients in end-of-life care with cognitive decline. Decisions regarding PEG placement are largely influenced by physician judgment.<br>
Objectives: The aim of this study was to investigate the background and perceptions of Japanese physicians regarding PEG for older adults in end-of-life care and to identify the factors associated with differences in physician judgment regarding PEG.<br>
Design: The study employed a cross-sectional design.<br>
Setting/Subjects: A questionnaire on PEG for older adults in end-of-life care was sent to Japanese physicians. Logistic regression analysis was used to calculate the odds ratios (ORs) and confidence intervals (CIs) of the association between PEG recommendations and each factor.<br>
Results: PEG placement was advised for bedridden patients and older adults with cognitive decline by 26% of the physicians who responded to the survey. Differences in physician perceptions of PEG feeding were associated with the recommendation for PEG, benefits of preventing aspiration pneumonia (OR: 4.9; 95% CI: 3.1-8.2), impact on post-discharge accommodation decisions (OR: 6.1; 95% CI: 1.9-30.9), and hesitancy to recommend a PEG placement (OR: 1.9; 95% CI: 1.3-4.5). Working in a facility with PEG placement (OR: 2.0; 95% CI: 1.2-3.5) was an associated background factor.<br>
Conclusions: Differences in Japanese physicians' attitudes toward using PEG feeding for older adults in end-of-life care were significantly associated with differences in their perceptions of the impact of PEG feeding and working in a facility with PEG placement.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.Springer Science and Business Media LLCActa Medica Okayama1432-133515022024Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study89ENTadahiroKuribayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKiichiroNinomiyaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalYukariTsubataDepartment of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Faculty of Medicine, Shimane UniversityNobuhisaIshikawaDepartment of Respiratory Medicine, Hiroshima Prefectural HospitalMasahiroKodaniDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori UniversityNobuhiroKanajiDepartment of Internal Medicine, Division of Hematology, Rheumatology, and Respiratory Medicine, Faculty of Medicine, Kagawa UniversityMasahiroYamasakiDepartment of Respiratory Medicine, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors HospitalKazunoriFujitakaDepartment of Molecular and Internal Medicine, Graduate School of Biomedical and Health SciencesShoichiKuyamaDepartment of Respiratory Medicine, National Hospital Organization Iwakuni Clinical CenterNagioTakigawaDepartment of Internal Medicine 4, Kawasaki Medical SchoolNobukazuFujimotoDepartment of Medical Oncology, Okayama Rosai HospitalTetsuyaKubotaDepartment of Respiratory Medicine and Allergology, Kochi University HospitalMasaakiInoueDepartment of Chest Surgery, Shimonoseki City HospitalKeiichiFujiwaraDepartment of Respiratory Medicine, NHO Okayama Medical CenterShingoHaritaDepartment of Internal Medicine, Okayama Saiseikai General HospitalIchiroTakataInternal Medicine, Fukuyama City HospitalKenjiTakadaDepartment 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 SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalPurpose Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC.<br>
Methods We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003).<br>
Results A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046).<br>
Conclusion ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.<br>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.Public Library of ScienceActa Medica Okayama1932-62031852023Randomized phase II study of daily versus alternate-day administrations of S-1 for the elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm)-IIIA of non-small cell lung cancer: Setouchi Lung Cancer Group Study 1201e0285273ENHiromasaYamamotoDepartment of Thoracic Surgery, Okayama University HospitalJunichiSohDepartment of Surgery, Division of Thoracic Surgery, Kindai University Faculty of MedicineNorihitoOkumuraDepartment of Thoracic Surgery, Kurashiki Central HospitalHiroyukiSuzukiDepartment of Chest Surgery, Fukushima Medical University HospitalMasaoNakataDepartment of General Thoracic Surgery, Kawasaki Medical School HospitalToshiyaFujiwaraDepartment of Thoracic Surgery, Hiroshima City Hiroshima Citizens HospitalKenichiGembaDepartment of Respiratory Medicine, Chugoku Central HospitalIsaoSanoDepartment of Respiratory Surgery, Japanese Red Cross Nagasaki Genbaku HospitalTakujiFujinagaDepartment of General Thoracic Surgery, National Hospital Organization Nagara Medical CenterMasafumiKataokaDepartment of Surgery and Respiratory Center, Okayama Saiseikai General HospitalYasuhiroTerazakiDepartment of Respiratory S0urgery, Saga-Ken Medical Centre KoseikanNobukazuFujimotoDepartment of Medical Oncology and Respiratory Medicine, Okayama Rosai HospitalKazuhikoKataokaDepartment of Thoracic Surgery, National Hospital Organization Iwakuni Clinical CenterShinjiKosakaDepartment of Thoracic Surgery, Shimane Prefectural Central HospitalMotohiroYamashitaDepartment of Thoracic Surgery, National Hospital Organization Shikoku Cancer CenterHidetoshiInokawaDepartment of Thoracic Surgery, National Hospital Organization Yamaguchi-Ube Medical CenterMasaakiInoueDepartment of Chest Surgery, Shimonoseki City HospitalHiroshigeNakamuraDivision of General Thoracic Surgery, Tottori University HospitalYoshinoriYamashitaDepartment of Thoracic Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer CenterKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalHiroshigeYoshiokaDepartment of Thoracic Oncology, Kansai Medical University HospitalSatoshiMoritaDepartment of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of MedicineKeitaroMatsuoDivision of Cancer Epidemiology and Prevention, Aichi Cancer Center Research InstituteJunichiSakamotoTokai Central HospitalHiroshiDateDepartment of Thoracic Surgery, Kyoto University HospitalShinichiToyookaDepartment of Thoracic Surgery, Okayama University HospitalBackground<br>
It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC.<br>
<br>
Methods<br>
Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more.<br>
<br>
Results<br>
We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11).<br>
<br>
Conclusion<br>
Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC.No potential conflict of interest relevant to this article was reported.The Japanese Society of Internal MedicineActa Medica Okayama0918-29186292023Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy13191322ENTomokaNishimuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKiichiroNinomiyaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalMitsutakaNakashimaDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiAkagiDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadahiroKuribayashiDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHisaoHigoDepartment of Allergy and Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiItoDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalA 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus che-motherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fa-tigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulmi-nant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2072-669414242022The Effect of Pleural Effusion on Prognosis in Patients with Non-Small Cell Lung Cancer Undergoing Immunochemotherapy: A Retrospective Observational Study6184ENTomokaNishimuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalToshihideYokoyamaDepartment of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central HospitalKojiInoueDepartment of Respiratory Medicine, Ehime Prefectural Central HospitalTomokiTamuraDepartment of Respiratory Medicine, NHO Iwakuni Clinical CenterKenSatoDepartment of Respiratory Medicine, National Hospital Organization Okayama Medical CenterNaohiroOdaDepartment of Internal Medicine, Fukuyama City HospitalHirohisaKanoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalDaizoKishinoDepartment of Respiratory Medicine, Japanese Red Cross Society Himeji HospitalHaruyukiKawaiDepartment of Internal Medicine, Okayama Saiseikai General HospitalMasaakiInoueDepartment of Chest Surgery, Shimonoseki City HospitalNobuakiOchiDepartment of General Internal Medicine 4, Kawasaki Medical SchoolNobukazuFujimotoDepartment of Respiratory Medicine, Okayama Rosai HospitalHirohisaIchikawaDepartment of Respiratory Medicine, KKR Takamatsu HospitalChihiroAndoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalSimple Summary Minimal data exists on pleural effusion (PE) for non-small cell lung cancer (NSCLC) patients undergoing combined ICI and chemotherapy. We retrospectively investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival and overall survival than those without PE. In addition, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. In conclusion, PE was associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy. Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group-Immune Chemotherapy Database (OLCSG-ICD) between December 2018 and December 2020; the OLCSG-ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient's programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy.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.BMCActa Medica Okayama1465-993X2312022Identification of targetable kinases in idiopathic pulmonary fibrosis20ENHisaoHigoDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalSachiOkawaDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHiromasaYamamotoDepartment of Thoracic Surgery, Okayama University HospitalSeiichiroSugimotoOrgan Transplant Center, Okayama University HospitalSatoruSenooDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineGoMakimotoDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKiichiroNinomiyaDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineTakamasaNakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineAkihikoTaniguchiDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineToshioKuboCenter for Clinical Oncology, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalNobuakiMiyaharaDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShinichiToyookaDepartment of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalBackground Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). Methods Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). Results Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. Conclusions We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-90322021First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subsetENMiyakoSatouchiDepartment of Thoracic Oncology, Hyogo Cancer CenterKanameNosakiDepartment of Thoracic Oncology, National Hospital Organization Kyushu Cancer CenterToshiakiTakahashiDivision of Thoracic Oncology, Shizuoka Cancer CenterKazuhikoNakagawaDepartment of Medical Oncology, Faculty of Medicine, Kindai UniversityKeisukeAoeDepartment of Medical Oncology, National Hospital Organization Yamaguchi Ube Medical CenterTakayasuKurataDepartment of Thoracic Oncology, Kansai Medical University HospitalAkimasaSekineDepartment of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory CenterAtsushiHoriikeDepartment of Thoracic Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer ResearchTatsuroFukuharaMiyagi Cancer CenterShunichiSugawaraDepartment of Pulmonary Medicine, Sendai Kousei HospitalShigekiUmemuraDepartment of Thoracic Oncology, National Cancer Center Hospital EastHideoSakaDepartment of Respiratory Medicine and Medical Oncology, National Hospital Organization Nagoya Medical CenterIsamuOkamotoResearch Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu UniversityNobuyukiYamamotoInternal Medicine III, Wakayama Medical UniversityHiroshiSakaiDepartment of Thoracic Oncology, Saitama Cancer CenterKazumaKishiDepartment of Respiratory Medicine, Respiratory Center, Toranomon HospitalNobuyukiKatakamiDivision of Integrated Oncology, Institute of Biomedical Research and Innovation HospitalHidehitoHorinouchiDepartment of Thoracic Oncology, National Cancer Center HospitalToyoakiHidaDepartment of Thoracic Oncology, Aichi Cancer CenterHiroakiOkamotoDepartment of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s HospitalShinjiAtagiDepartment of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical CenterTatsuoOhiraDepartment of Surgery, Tokyo Medical UniversityShi RongHanMSD K.K.KazuoNoguchiMSD K.K.VictoriaEbianaMerck & Co., Inc.KatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalThis prespecified subanalysis of the global, randomized controlled phase Ill KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFRIALK alterations and a PD-L1 tumor proportion score of 50% or greater.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama2059-7029642021Gefitinib induction followed by chemoradiotherapy in EGFR-mutant, locally advanced non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study100191ENK.HottaCenter for Innovative Clinical Medicine, Okayama University HospitalS.SaekiDepartment of Respiratory Medicine, Kumamoto University HospitalM.YamaguchiDepartment of Thoracic Oncology, National Hospital Organization Kyushu Cancer CenterD.HaradaDepartment of Thoracic Oncology, National Hospital Organization Shikoku Cancer CenterA.BesshoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalK.TanakaDepartment of Respiratory Medicine, Kyushu University HospitalK.InoueDepartment of Respiratory Medicine, Kitakyushu Municipal Medical CenterK.GembaDepartment of Respiratory Medicine, Chugoku Central HospitalM.ShiojiriDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalY.KatoCenter for Innovative Clinical Medicine, Okayama University HospitalT.NinomiyaDepartment of Respiratory Medicine, Okayama University HospitalT.KuboDepartment of Respiratory Medicine, Okayama University HospitalJ.KishimotoCenter for Clinical and Translational Research, Kyushu University HospitalY.ShioyamaClinical Radiology, Radiology Informatics and Network, Graduate School of Medical Sciences, Kyushu UniversityK.KatsuiDepartment of Proton Beam Therapy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJ.SasakiResearch and Development Center for New Medical Frontiers, Kitasato University School of MedicineK.KiuraDepartment of Respiratory Medicine, Okayama University HospitalK.SugioDepartment of Thoracic and Breast Surgery, Oita UniversityBackground: The role of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) induction coupled with standard concurrent chemoradiotherapy (CRT) is unclear in unresectable, stage III, EGFR-mutant non-small-cell lung cancer (NSCLC). Therefore, a phase II trial was conducted to evaluate the efficacy and safety of gefitinib induction followed by CRT in this disease setting. <br>
Patients and methods: Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy (250 mg/day) for 8 weeks. Subsequently, patients without disease progression during induction therapy were administered cisplatin and docetaxel (40 mg/m(2) each) on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy. The primary endpoint was the 2-year overall survival (OS) rate, which was hypothesized to reach 85%, with a threshold of the lower limit of 60%. <br>
Results: Twenty patients (median age: 66 years; male/female: 9/11; histology: 20 adenocarcinoma; stage IIIA/IIIB: 9/11; and exon 19/21: 10/10) were enrolled. The 2-year OS rate was 90% (90% confidence interval: 71.4% to 96.8%), indicating that this trial met the primary objective. The overall response rate and 1- and 2-year progression-free survival rates were 85.0%, 58.1%, and 36.9%, respectively. Grade >= 3 adverse events (>10%) included hepatic toxicity during the induction phase and neutropenia and febrile neutropenia in the CRT phase. Radiation pneumonitis grade >= 3 or treatment-related death did not occur. <br>
Conclusions: This is the first prospective study to demonstrate the favorable efficacy and safety of EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III NSCLC. Further confirmatory studies are needed.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.Japan Neurosurgical Soc.Acta Medica Okayama0470-81056172021An Evaluation of the Safety and Feasibility of Adenosine-assisted Clipping Surgery for Unruptured Cerebral Aneurysms: Study Protocol393396ENTomohitoHishikawaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiMuraiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasafumiHiramatsuDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunHarumaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhikoNishiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiEbisudaniDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuSatoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaoYasuharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKenjiSugiuDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyoshiShimizuDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotomuKobayashiDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiNakagawaDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAyaKimura-OnoCenter for Innovative Clinical Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalHiroshiMorimatsuDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIsaoDateDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe effectiveness of adenosine-induced flow arrest in surgical clipping for the cerebral aneurysms with difficulties in temporary clip placement to the proximal main trunk has been reported. This is the first clinical trial to evaluate the safety and feasibility of adenosine-assisted clipping surgery for unruptured cerebral aneurysms (UCAs) in Japan. The inclusion criteria are as follows: patients over 20 years old, patients who agree to be enrolled in this study after providing informed consent, patients who undergo clipping surgery for UCA in our institute, and patients in whom the surgeons (T.H. or I.D.) judge that decompression of the aneurysm is effective. The primary endpoint is a modified Rankin Scale (mRS) score 30 days after surgery. We plan to enroll 10 patients in this study. The original protocol of adenosine administration was established in this trial. Herein, we present the study protocol.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.ElsevierActa Medica Okayama26663643212021Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations100107ENKiichiroNinomiyaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeTeraokaInternal Medicine III, Wakayama Medical UniversityYoshitakaZenkeDepartment of Thoracic Oncology, National Cancer Center Hospital EastHirotsuguKenmotsuDivision of Thoracic Oncology, Shizuoka Cancer CenterYukikoNakamuraDepartment of Respiratory Medicine, Yokohama Municipal Citizen’s HospitalYusukeOkumaDepartment of Thoracic Oncology, National Cancer Center HospitalAkihiroTamiyaDepartment of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical CenterKanameNosakiDepartment of Thoracic Oncology, National Cancer Center Hospital EastMasahiroMoriseDepartment of Respiratory Medicine, Nagoya University Graduate School of MedicineKeijuAokageDepartment of Thoracic Surgery, National Cancer Center Hospital EastYukoOyaDepartment of Thoracic Oncology, Aichi Cancer Center HospitalToshiyukiKozukiDepartment of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer CenterTomohiroSakamotoDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Tottori UniversityKentaroTanakaResearch Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu UniversityHisashiTanakaDepartment of Respiratory Medicine, Hirosaki University Graduate School of MedicineJunkoTanizakiDepartment of Medical Oncology, Kishiwada City HospitalSatoruMiuraDepartment of Internal Medicine, Niigata Cancer Center HospitalHideakiMizutaniDepartment of Thoracic Oncology, Saitama Cancer CenterEisakuMiyauchiDepartment of Respiratory Medicine, Tohoku University HospitalOuYamaguchiDepartment of Respiratory Medicine, Comprehensive Cancer Center, Saitama Medical University International Medical CenterNoriyukiEbiDepartment of Respiratory Oncology, Iizuka HospitalYasushiGotoDepartment of Thoracic Oncology, National Cancer Center HospitalTakaakiSasakiRespiratory Center, Asahikawa Medical UniversityHarukoDagaDepartment of Medical Oncology, Osaka City General HospitalSatoshiMoritaDepartment of Biomedical Statistics and Bioinformatics, Graduate School of Medicine Kyoto UniversityTakeharuYamanakaDepartment of Biostatistics, Yokohama City University School of MedicineShinsukeAmanoJapan Federation of Cancer Patient GroupsKazuoHasegawaJapan Lung Cancer AllianceChiyo K.ImamuraAdvanced Cancer Translational Research Institute, Showa UniversityKenichiSuzukiDivision of Applied Pharmaceutical Education and Research, Hoshi UniversityKazukoNakajimaDepartment of Nursing and The Division of Stem Cell Transplantation, Shizuoka Cancer CenterHitomiNishimotoDepartment of Nursing, Okayama University HospitalSatoshiOizumiDepartment of Respiratory Medicine, National Hospital Organization Hokkaido Cancer CenterToyoakiHidaDepartment of Thoracic Oncology, Aichi Cancer Center HospitalKatsuyukiHottaCenter for Clinical Oncology, Okayama University HospitalYuichiTakiguchiDepartment of Medical Oncology, Chiba University HospitalPatients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1759-77061252021Crizotinib for recurring non-small-cell lung cancer with EML4-ALK fusion genes previously treated with alectinib: A phase II trial643649ENDaijiroHaradaDepartment of Thoracic Oncology, National Hospital Organization Shikoku Cancer CenterHidekoIsozakiDepartment of Clinical Pharmaceutics, Okayama University HospitalToshiyukiKozukiDepartment of Thoracic Oncology, National Hospital Organization Shikoku Cancer CenterToshihideYokoyamaDepartment of Respiratory Medicine, Kurashiki Central HospitalHiroshigeYoshiokaDepartment of Respiratory Medicine, Kurashiki Central HospitalAkihiroBesshoDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalShinobuHosokawaDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalIchiroTakataDepartment of Internal Medicine, Fukuyama City HospitalNagioTakigawaKatsuyukiHottaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalOkayama Lung Cancer Study GroupBackground</br>
The efficacy of crizotinib treatment for recurring EML4‐ALK‐positive non‐small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib‐refractory, EML4‐ALK‐positive NSCLC. </br>
Methods</br>
Patients with ALK‐rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest. </br>
Results</br>
Nine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20–433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8–65.5 and 95% CI: 7.5–70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression‐free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment‐related deaths occurred.</br>
Conclusions</br>
Although the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1759-77061252021Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol725731ENKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasaakiInoueShimonoseki City HospitalHidetoObataYamaguchi-ken Saiseikai Shimonoseki General HospitalYutakaUedaKagawa Prefectural Central HospitalToshiyukiKozukiNational Hospital Organization Shikoku Cancer CenterMasahiroYamasakiHiroshima Red Cross Hospital & Atomic-Bomb Survivors HospitalTomonoriMoritakaEhime Prefectural Central HospitalYoshikazuAwayaMiyoshi Central HospitalKeisukeSugimotoJapanese Red Cross Kobe HospitalKenichiGembaChugoku Central HospitalShoichiKuyamaNational Hospital Organization Iwakuni Clinical CenterHirohisaIchikawaKKR Takamatsu HospitalTakuoShibayamaNational Hospital Organization Okayama Medical CenterTetsuyaKubotaDepartment of Respiratory Medicine and Allergology, Kochi Medical School, Kochi UniversityMasahiroKodaniDivision of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori UniversityDaizoKishinoJapanese Red Cross Society Himeji HospitalNobukazuFujimotoOkayama Rosai HospitalNobuhisaIshikawaHiroshima Prefectural HospitalYukariTsubataDivision of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of MedicineTomoyaIshiiDepartment of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of MedicineKazunoriFujitakaDepartment of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityKatsuyukiHottaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalIntroduction</br>
Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice.</br>
Methods</br>
We constructed an umbrella‐type lung cancer patient registry (CS‐Lung‐003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS‐Lung‐003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017.</br>
Discussion</br>
We successfully launched the umbrella‐type CS‐Lung‐003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment.</br>
Key points</br>
CS‐Lung‐003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.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.ElsevierActa Medica Okayama0169-50021492020Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study4652ENJonathan W.GoldmanDavid Geffen School of Medicine at UCLAMarina ChiaraGarassinoFondazione IRCCS Istituto Nazionale dei TumoriYuanbinChenCancer & Hematology Centers of Western MichiganMustafaÖzgüroğluIstanbul University–Cerrahpaşa, Cerrahpaşa School of MedicineMikhailDvorkinBHI of Omsk Region Clinical Oncology DispensaryDmytroTrukhinOdessa National Medical UniversityGalinaStatsenkoOmsk Regional Cancer Center,KatsuyukiHottaOkayama University HospitalJun HoJiSamsung Changwon Hospital, Sungkyunkwan University School of MedicineMaximilian J.HochmairKarl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik FloridsdorfOleksandrVoitkoKyiv City Clinical Oncological CentreLiborHavelThomayer Hospital, First Faculty of Medicine, Charles UniversityArtemPoltoratskiyPetrov Research Institute of OncologyGyörgyLosonczySemmelweis UniversityNielsReinmuthAsklepios Lung ClinicNikunjPatelAstraZenecaPeter J.LaudStatistical Services Unit, University of SheffieldNorahShireAstraZenecaHaiyiJiangAstraZenecaLuisPaz-AresHospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and CiberoncObjectives</br>
In the phase III CASPIAN study, first-line durvalumab plus etoposide in combination with either cisplatin or carboplatin (EP) significantly improved overall survival (primary endpoint) versus EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) at the interim analysis. Here we report patient-reported outcomes (PROs).</br>
Materials and methods</br>
Treatment-naïve patients with ES-SCLC received 4 cycles of durvalumab plus EP every 3 weeks followed by maintenance durvalumab every 4 weeks until progression, or up to 6 cycles of EP every 3 weeks. PROs, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), were prespecified secondary endpoints. Changes from baseline to disease progression or 12 months in prespecified key disease-related symptoms (cough, dyspnea, chest pain, fatigue, appetite loss) were analyzed with a mixed model for repeated measures. Time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization was analyzed.</br>
Results</br>
In the durvalumab plus EP and EP arms, 261 and 260 patients were PRO-evaluable. Patients in both arms experienced numerically reduced symptom burden over 12 months or until progression for key symptoms. For the improvements from baseline in appetite loss, the between-arm difference was statistically significant, favoring durvalumab plus EP (difference, −4.5; 99% CI: −9.04, −0.04; nominal p = 0.009). Patients experienced longer TTD with durvalumab plus EP versus EP for all symptoms (hazard ratio [95% CI] for key symptoms: cough 0.78 [0.600‒1.026]; dyspnea 0.79 [0.625‒1.006]; chest pain 0.76 [0.575‒0.996]; fatigue 0.82 [0.653‒1.027]; appetite loss 0.70 [0.542‒0.899]), functioning, and global health status/QoL.</br>
Conclusion</br>
Addition of durvalumab to first-line EP maintained QoL and delayed worsening of patient-reported symptoms, functioning, and global health status/QoL compared with EP.No potential conflict of interest relevant to this article was reported. WileyActa Medica Okayama1347-9032111122020First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset44804489ENMiyakoSatouchiDepartment of Thoracic Oncology, Hyogo Cancer CenterKanameNosakiDepartment of Thoracic Oncology, National Hospital Organization Kyushu Cancer CenterToshiakiTakahashiDivision of Thoracic Oncology, Shizuoka Cancer CenterKazuhikoNakagawaDepartment of Medical Oncology, Kindai University Faculty of MedicineKeisukeAoeDepartment of Medical Oncology, National Hospital Organization Yamaguchi Ube Medical CenterTakayasuKurataDepartment of Thoracic Oncology, Kansai Medical UniversityAkimasaSekineDepartment of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory CenterAtsushiHoriikeDepartment of Thoracic Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer ResearchTatsuroFukuharaDepartment of Respiratory Medicine, Miyagi Cancer CenterShunichiSugawaraDepartment of Pulmonary Medicine, Sendai Kousei HospitalShigekiUmemuraDepartment of Thoracic Oncology, National Cancer Center Hospital EastHideoSakaDepartment of Respiratory Medicine and Medical Oncology, National Hospital Organization Nagoya Medical CenterIsamuOkamotoResearch Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu UniversityNobuyukiYamamotoInternal Medicine III, Wakayama Medical UniversityHiroshiSakaiDepartment of Thoracic Oncology, Saitama Cancer CenterKazumaKishiDepartment of Respiratory Medicine, Respiratory Center, Totanomon HospitalNobuyukiKatakamiDivision of Integrated Oncology, Institute of Biomedical Research and Innovation HospitalHidehitoHorinouchiDepartment of Thoracic Oncology, National Cancer Center HospitalToyoakiHidaDepartment of Thoracic Oncology, Aichi Cancer CenterHiroakiOkamotoDepartment of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s HospitalShinjiAtagiDepartment of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical CenterTatsuoOhiraDepartment of Surgery, Tokyo Medical UniversityShi RongHanMSD, K.K.KazuoNoguchiMSD, K.K.VictoriaEbianaMerck & Co., Inc.KatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalThis prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-9032111102020Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status37393746ENHirohisaKanoDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalDaijiroHaradaDepartment of Thoracic Oncology, National Hospital Organization Shikoku Cancer CenterKojiInoueDepartment of Respiratory Medicine, Ehime Prefectural Central HospitalHiroeKayataniDepartment of Respiratory Medicine, National Hospital Organization Okayama Medical CenterShinobuHosokawaDepartment of Respiratory Medicine, Japanese Red Cross Okayama HospitalDaizoKishinoDepartment of Respiratory Medicine, Himeji Red Cross HospitalKazuhikoWatanabeDepartment of Internal Medicine, Okayama Saiseikai General HospitalNobuakiOchiDepartment of General Internal Medicine 4, Kawasaki Medical SchoolNaohiroOdaDepartment of Internal Medicine, Fukuyama City HospitalNaofumiHaraDepartment 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 SciencesKatsuyukiHottaCenter for Innovative Clinical 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 HospitalMost clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months;P < .001 and median OS, 17.4 vs 4.0 months;P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.No potential conflict of interest relevant to this article was reported.The Japanese Society of Internal MedicineActa Medica Okayama0918-29185962020Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review823828ENJunkoItanoDepartment of Respiratory Medicine, Okayama University HospitalHisaoHigoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment 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 SciencesKatsuyukiHottaDepartment of Respiratory Medicine, Okayama University HospitalNobuakiMiyaharaDepartment 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 Hospital Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama1556086414112019Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden20092018ENGoMakimotoDepartment 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 SciencesShutaTomidaOkayama University Hospital Biobank, Okayama University HospitalKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakehiroMatsubaraOkayama University Hospital Biobank, Okayama University HospitalHiroeKayataniDepartment 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 Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkikoSatoDepartment of Respiratory Medicine, Okayama University HospitalHiromiWatanabeDepartment 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 SciencesTakashiNinomiyaDepartment of Respiratory Medicine, Okayama University HospitalToshioKuboCenter for Clinical Oncology, Okayama University HospitalKammeiRaiDepartment of Respiratory Medicine, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter of Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalShinichiToyookaOkayama University Hospital Biobank, Okayama University HospitalMinoruTakataLaboratory of DNA Damage Signaling, Department of Late Effects Studies, Graduate School of Biostudies, Radiation Biology Center, Kyoto UniversityYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiKiuraDepartment of Respiratory Medicine, Okayama University HospitalIntroduction<br/>
The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. <br/>
Methods<br/>
Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. <br/>Results<br/>
ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. <br/>Conclusions<br/>
High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7042016Study about the Efficacy of Metformin to Immune Function in Cancer Patients327330ENMototsuguWatanabeDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiromasaYamamotoDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShingoEikawaDepartment of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhikoShienDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadahikoShienDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunichiSohDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShiroHinotsuCenter for Innovative Clinical Medicine, Okayama University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, 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 SciencesHiroyoshiDoiharaDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinichiroMiyoshiDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHeiichiroUdonoDepartment of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinichiToyookaDepartment of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesClinical Study Protocols10.18926/AMO/54514A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8＋ T cells, which produce multiple cytokines. No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7042016A Phase II Clinical Trial Evaluating the Preventive Effectiveness of Lactobacillus Vaginal Suppositories in Patients with Recurrent Cystitis299302ENKoichiroWadaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinyaUeharaDepartment of Urology, Kawasaki Hospital, Kawasaki Medical SchoolAyanoIshiiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakuyaSadahiraDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasumiYamamotoDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRitsukoMitsuhataDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsushiTakamoto Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotooArakiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuyukiKobayashiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasamiWatanabeDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToyohikoWatanabeDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiHottaCenter for innovative Clinical Medicine, Okayama University HospitalYasutomoNasuDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesClinical Study Protocols10.18926/AMO/54508Urinary tract infections (UTIs) are the most common bacterial infections in women, and many patients experience frequent recurrence. The aim of this report is to introduce an on-going prospective phase II clinical trial performed to evaluate the preventive effectiveness of Lactobacillus vaginal suppositories for prevention of recurrent cystitis. Patients enrolled in this study are administered vaginal suppositories containing the GAI 98322 strain of Lactobacillus crispatus every 2 days or 3 times a week for one year. The primary endpoint is recurrence of cystitis and the secondary endpoints are adverse events. Recruitment began in December 2013 and target sample size is 20 participants.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7042016The Efficacy of Rituximab in High-risk Renal Transplant Recipients295297ENMotooArakiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoichiroWadaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYosukeMitsuiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRisaKubotaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakashiYoshiokaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuichiAriyoshiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuyukiKobayashiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiKitagawaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiTanabeDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiSugiyamaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasamiWatanabeCenter for Innovative Clinical Medicine, Okayama University HospitalToyohikoWatanabeDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalYasutomoNasuDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesClinical Study Protocols10.18926/AMO/54507Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.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 Okayama0169-50028312014Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model3036ENToshiMurakamiNagioTakigawaTakashiNinomiyaNobuakiOchiMasaakiYasugiYoshihiroHondaToshioKuboEikiIchiharaKatsuyukiHottaMitsuneTanimotoKatsuyukiKiuraObjective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation.
Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MIT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method.
Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model: Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 +/- 0.18 and 2.25 +/- 0.53 (p <0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p <0.0001).
Conclusion: AZD1480 may be effective against lung tumors driven by an activating EGER mutation.No potential conflict of interest relevant to this article was reported.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.