A Case of Dupilumab-Induced Diffuse Alveolar Hemorrhage.

Eosinophilic pneumonia is a known side effect of dupilumab; however, diffuse alveolar hemorrhage has not yet been reported in association with dupilumab. We herein report a case of diffuse alveolar hemorrhage caused by dupilumab. A 57-year-old man with severe asthma was unable to discontinue oral steroids and thus was prescribed dupilumab. The patient was admitted to the hospital four weeks after treatment because of suspected eosinophilic pneumonia. Bronchoscopy revealed diffuse alveolar hemorrhage characterized by hemosiderin-phagocytic macrophages in the bronchoalveolar lavage fluid without eosinophils. The steroid dosage improved the respiratory status and resolved the infiltrate shadow. Dupilumab may thus cause diffuse alveolar hemorrhage, which can be differentiated using bronchoscopy.

A case of synovitis-acne-pustulosis-hyperostosis-osteitis syndrome with right pleural effusion.

A 79-year-old man presented with fatigue and right shoulder pain. Computed tomography revealed right pleural effusion and osteosclerosis of the sternoclavicular joint. There were no signs of malignancy or infection in the pleural fluid studies. His bone scintigraphy exhibited the "bull's head sign." Despite the absence of skin lesions, he was diagnosed with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. Remission was achieved after treatment with non-steroidal anti-inflammatory drugs and oral prednisolone. SAPHO syndrome causes pleural effusion, even in patients without skin lesions. Bone scintigraphy should be considered in the workup for patients with unexplained pleural effusion.

A case of successful desensitization treatment with tepotinib after tepotinib-induced rash.

Tepotinib is one of the key drugs for MET exon 14-skipping mutation-positive non-small cell lung cancer (NSCLC). The main adverse event of tepotinib treatment is edema. Rash is a rare adverse event, affecting only 0.7% of patients. We report a case of successful desensitization after skin rash caused by tepotinib. A 61-year-old male was treated with tepotinib 500 mg as second-line therapy for NSCLC with MET exon 14-skipping mutation. Treatment was discontinued on day 12 due to grade 3 erythema throughout the body. After improvement of the skin rash, he was started on 250 mg tepotinib with an oral antihistamine and topical steroid. Treatment was discontinued on day 11 due to skin rash exacerbation. One month of treatment-free follow-up showed skin rash improvement but lung carcinoma growth. Tepotinib desensitization therapy was started at a dose of 12.5 mg and gradually increased to 250 mg/day. The patient has since continued tepotinib treatment without skin rashes. Desensitization therapy may be effective for managing skin rash due to tepotinib.

Pembrolizumab in advanced NSCLC patients with poor performance status and high PD-L1 expression: OLCSG 1801.

BACKGROUND: The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear. PATIENTS AND METHODS: We conducted a phase II trial to investigate the efficacy and safety of pembrolizumab as first-line therapy for non-small-cell lung cancer (NSCLC) patients with PSs of 2-3 and programmed cell death ligand 1 (PD-L1) expression ≥ 50%. The primary endpoint of this study was the objective response rate (ORR). RESULTS: Fourteen patients treated at eight institutions were enrolled. Most patients had PS 2 (12/14; 86%) and others had PS 3 (2/14; 14%). The ORR was 57.1% (95% confidence interval 28.9-82.3%), which met the primary endpoint. The median progression-free survival (PFS) and 1-year PFS rates were 5.8 months and 20.0%, respectively. At the time of data cut-off, one patient had received treatment for more than 1 year; another patient had received treatment for more than 2 years. Nine patients had improved PS with treatment (Wilcoxon signed-rank test, p = 0.003). Two patients had immune-related adverse events ≥ grade 3: grades 5 and 3 elevation in alanine and aspartate aminotransferases. Two PS 3-stage patients were diagnosed with clinically progressive disease prior to initial computed tomography; both died within 2 months. CONCLUSION: Pembrolizumab was effective for the treatment of NSCLC patients with a poor PS and PD-L1 level ≥ 50%. However, given the poor outcomes of the PS 3 patients, the drug is not indicated for such patients. Adverse events, including liver dysfunction, should be carefully monitored. REGISTRATION ID: UMIN000030955.

Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon EGFR mutation.

In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. Afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. Dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). Afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14 months. Pemetrexed plus carboplatin followed by pemetrexed, docetaxel, atezolizumab and S-1 were performed in sequence. Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. Dacomitinib is a possible treatment option for NSCLC with uncommon mutations.

Efficacy of afatinib treatment for lung adenocarcinoma harboring exon 18 delE709_T710insD mutation.

Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient's clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.

A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202.

INTRODUCTION: S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown. METHODS: The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40mg/m2, twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40mg/m2, twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated. RESULTS: Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134days (95% CI: 79-173) and 479days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P<0.01). CONCLUSION: This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option.

Development of a cryogenic load frame for the neutron diffractometer at Takumi in Japan Proton Accelerator Research Complex.

To prepare for projects such as the Large Hadron Collider upgrade, International Thermonuclear Experimental Reactor and Demonstration reactor, it is important to form a clear understanding of stress-strain properties of the materials that make up superconducting magnets. Thus, we have been studying the mechanical properties of superconducting wires using neutron diffraction measurements. To simulate operational conditions such as temperature, stress, and strain, we developed a cryogenic load frame for stress-strain measurements of materials using a neutron diffractometer at Japan Proton Accelerator Research Complex (J-PARC) Takumi beam line. The maximum load that can be applied to a sample using an external driving machine is 50 kN. Using a Gifford-MacMahon cryocooler, samples can be measured down to temperatures below 10 K when loaded. In the present paper, we describe the details of the cryogenic load frame with its test results by using type-304 stainless steel wire.

Development of a microcalorimeter with transition edge sensor for detection of LX rays emitted by transuranium elements.

A transition edge sensor (TES) microcalorimeter has been developed for use as an energy dispersive X-ray spectrometer. The TES microcalorimeter is a thermal detector that enables one to determine the energy of an incident photon by measuring the resultant increase in temperature. In this work, a Ti/Au TES microcalorimeter was developed to measure LX rays emitted by transuranium elements. The phase transition temperature was set at ~200 mK by using a bilayer structure composed of a 110-nm-thick Au layer and a 40-nm-thick Ti layer. An Au of 5 µm thickness was deposited on the Ti/Au bilayer to achieve an absorption efficiency of 35-80 % for the energy range of LX rays (10-25 keV). The developed TES microcalorimeter was irradiated with LX rays emitted by an (241)Am source at an operating temperature of 140 mK. An energy resolution of ~80 eV (full width at the half maximum) was obtained for L(ß1)X ray of 17.75 keV.