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Abstract Introduction Studies have shown the antitumor efficacy of immune checkpoint inhibitors (ICI) in patients with non‐small cell lung cancer (NSCLC) and brain metastases (BM). However, it is unclear whether the efficacy of ICI is similar between patients with and without BM. It is yet unclear whether the efficacy of ICI in patients with BM increases with higher levels of programmed cell death‐ligand 1 (PD‐L1) expression, as observed in patients without BM. Methods We compared the outcomes of ICI treatment between patients with and without BM using a cohort containing 1741 prospectively enrolled patients with lung cancer. We investigated whether there were differences in the outcomes of ICI based on PD‐L1 expression levels between these patients. Results We enrolled 240 patients with NSCLC with or without BM who were treated with ICI or both chemotherapy and ICI. There were no significant differences in overall survival (OS) between all patients with or without BM (p = 0.489). However, OS was significantly shorter in patients with BM than in those without in the PD‐L1 ≥ 50% group (16.5 M vs. 30.6 M, p = 0.003) but not in the PD‐L1 ≥ 1% or negative group. BM was an independent poor prognostic factor for OS (hazard ratio: [95% confidence interval], 2.045; [1.058–3.953], p = 0.033) in the PD‐L1 ≥ 50% group. Conclusion Our study indicated that the outcomes of patients with or without BM treated with ICI were not significantly different. The efficacy of ICI in patients with PD‐L1 expression ≥50% would be lower in patients with BM than in those without.

Abstract Ramucirumab (RAM) has been approved for the treatment of non‐small cell lung cancer (NSCLC). Here, we report two cases of RAM‐induced ascites with epidermal growth factor receptor‐mutant NSCLC. Patient 1, a 72‐year‐old man, developed ascites 20 months after erlotinib (ERL) and RAM administration, which resolved after their discontinuation and performing paracentesis. Patient 2, an 83‐year‐old woman, developed ascites 9 months after ERL and RAM administration, which resolved after RAM discontinuation and furosemide administration. Ramucirumab administration can cause ascites due to increased hepatic sinusoidal pressure. Clinicians should be aware of RAM‐induced ascites in patients with NSCLC and should appropriately manage it.

Abstract Background 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.

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.

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 74-year-old woman with squamous cell lung cancer (cT3N1M0, c-stage IIIA) was treated with durvalumab after chemoradiotherapy. At the beginning of the fourth treatment, Grade 2 (Common Terminology Criteria for Adverse Events ver5.0) radiotherapy-induced pneumonitis occurred, followed by sudden thrombocytopenia of Grade 4 (14,000/μL) a month later, and two weeks later, platelet and white blood cell counts decreased to 1,000/μL and 1,110/μL, respectively. Bone marrow biopsy showed markedly hypoplastic marrow without dysplasia, and we diagnosed aplastic anemia secondary to durvalumab. The patient required frequent granulocyte colony-stimulating factor (G-CSF) injections and platelet transfusions. From the beginning of treatment, the patient responded poorly to platelet transfusions, and anti-human leukocyte antigen (HLA) antibodies were detected. After multidisciplinary treatment, including the use of HLA-matched platelet transfusions, platelets and white blood cells gradually recovered from platelet transfusion dependence approximately two months after the onset of aplastic anemia. Here, we report the first case of durvalumab-induced aplastic anemia.

Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition.

Abstract Introduction 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. Methods 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. Discussion 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. Key points 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.

Immunoglobulin G4 (IgG4)-related pleurisy is a rare type of IgG4-related disease. We present the case of a 69-year-old woman with left pleural effusion and elevated adenosine deaminase levels. Initially, tuberculous pleuritis was suspected; however, the bacterial cultures and polymerase chain reaction test results for tuberculosis were negative. Thoracoscopic pleural biopsy revealed dense lymphocytic infiltrates with large numbers of IgG4-positive plasma cells. The ratio of IgG4-positive to IgG-positive plasma cells exceeded 40%. The patient was diagnosed with IgG4-related disease.

Pyrroloquinoline quinone (PQQ) is contained in fruits and vegetables and in human breast milk. It has been reported that PQQ has high reactivity and changes to an imidazole structure (imidazole pyrroloquinoline) by a reaction with an amino acid at a high ratio in nature. A comparative study was conducted to clarify physiological effects including neuroprotective effects, growth-promoting effect, antioxidative effects and a stimulatory effect on mitochondriogensis of PQQ and imidazole pyrroloquinoline (IPQ) using a human neuroblastoma cell line and a hepatocellular carcinoma cell line. We also compared the expression levels of human cytochrome c oxidase subunit IV isoform Ⅰ (COX4/1), which is an index of the amount of mitochondria in the cells that had been exposed to PQQ, PQQH2 and IPQ. The results of the comparison showed that IPQ had almost the same biological activities as those of PQQ except for anti-oxidative activity. It was also shown that PQQ and IPQ improve the memory learning ability of aged mice and that BioPQQ® improves brain function in the language field in humans.

Axillary lymphadenitis caused by non-tuberculous mycobacteria is rare and has been reported in immunocompromised hosts. Herein, we report the case of a 67-year-old man without immunodeficiency who developed right axillary lymphadenitis caused by Mycobacterium intracellulare and showed a small nodular shadow in the left pulmonary apex. Biopsy of the right axillary lymph node revealed several epithelioid granulomas, and the culture of the lymph node aspirate yielded Mycobacterium intracellulare. The lymph node lesion and left lung apex shadow resolved spontaneously after careful outpatient monitoring. This case suggests that axillary lymphadenitis could be caused by Mycobacterium intracellulare in an immunocompetent patient. Keywords: Axillary lymphadenitis, Mycobacterium avium complex infection, Mycobacterium intracellulare

A 64-year-old woman presented with dizziness, after two weeks of experiencing symptoms. Chest computed tomography revealed a peripheral nodule in her left upper lobe, and brain magnetic resonance imaging (MRI) demonstrated the presence of multiple brain masses. The patient underwent whole-brain radiotherapy based on a tentative diagnosis of lung cancer with multiple brain metastases. The diagnosis was confirmed by endobronchial biopsy as T4N3M1b, stage IV lung adenocarcinoma with an epidermal growth factor receptor mutation. On the 31st day of hospitalization, the patient developed severe headache. Subsequent magnetic resonance venography revealed defects in the superior sagittal, right sigmoid, and right transverse venous sinuses and the right internal jugular vein. Anticoagulation therapy with unfractionated heparin and warfarin was immediately administered following diagnosis of cerebral venous sinus thrombosis (CVST). Brain MRI demonstrated leptomeningeal gadolinium enhancement in front of the pons and medulla. Positive cerebrospinal fluid tumor cytology confirmed the diagnosis of leptomeningeal carcinomatosis. Following four weeks of antithrombotic therapy, complete thrombolysis was confirmed by magnetic resonance venography. Effective treatment with gefitinib was administered, and the patient survived for 10 months after the diagnosis of CVST and leptomeningeal carcinomatosis. Adequate early diagnosis and treatment of CVST enabled an excellent survival rate for the patient, despite leptomeningeal carcinomatosis. Following the development of headaches in patients with lung cancer, CVST, although rare, should be considered. Furthermore, following a diagnosis of CVST, leptomeningeal carcinomatosis should be investigated as an underlying cause. [ABSTRACT FROM AUTHOR]