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Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition with no established treatment. Intravenous immunoglobulin (IVIG) is a unique therapy with both anti-inflammatory and anti-infective effects. Therefore, we hypothesized that IVIG may have a positive effect on AE of interstitial pneumonia. This study aimed to determine the effect of IVIG in patients with AE of fibrotic idiopathic interstitial pneumonias (IIPs), including IPF.We retrospectively analyzed consecutive patients who were diagnosed with AE of fibrotic IIPs and treated with pulse corticosteroid therapy (methylprednisolone 500-1000 mg/day for 3 days) between April 2018 and May 2021 at Kagawa Rosai Hospital and KKR Takamatsu Hospital.This study included 52 patients with AE of fibrotic IIPs (IPF,41; fibrotic IIPs other than IPF,11). Thirteen patients received IVIG (5 g/day for 3-5 days) concurrently with pulse corticosteroid therapy. The remaining 39 patients were assigned to the control group. The survival rate on day 90 was significantly higher in the IVIG group than that in the control group (76.9% vs. 38.5%, p = 0.02). IVIG administration (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02-0.69; p = 0.02) and C- reactive protein (OR, 1.19; 95% CI, 1.06-1.33, p0.01) were independently associated with 90-day mortality.The results indicate that administration of IVIG may improve the survival of patients with AE of fibrotic IIPs. We are now conducting a prospective study to confirm the effect of IVIG on AE of IPF since May 2022 (jRCT1061220010).

Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown.We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020.After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%).Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.

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., 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. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies.

Simple 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.

The purpose of this study was to investigate the prevalence of locomotive syndrome (LS) in patients with obstructive sleep apnea syndrome (OSAS), and to compare the health-related quality of life (HRQOL) among patients with and without LS as classified by age and sex. A total of 1173 patients with OSAS (1013 males and 160 females) who were treated with continuous positive airway pressure (CPAP) therapy were enrolled in this cross-sectional study. Male participants were divided into 6 groups (30–39 years, 40–49 years, 50–59 years, 60–69 years, 70–79 years, and 80–89 years) and female participants were divided into 5 groups (40–49 years, 50–59 years, 60–69 years, 70–79 years, and 80–89 years). LS was evaluated using a “loco-check” established by the Japanese Orthopedic Association. HRQOL was evaluated using the EuroQol 5-dimensional questionnaire (EQ-5D). The prevalence of LS among the different age and sex groups was 19.6–79.4% in males and 27.0–95.5% in females and increased with age. In males aged 30–39 and 70–79 years, and in females aged 50–59 years, the EQ-5D scores were significantly lower in OSAS patients with LS than in OSAS patients without LS, even after adjusting for confounding factors. In OSAS patients, LS was closely linked to HRQOL. Preventing and improving the outcomes of LS would be beneficial for improving the HRQOL in OSAS patients.

The aim of this study was to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration using afatinib in patients with non-small-cell lung cancer (NSCLC) with a sensitive non-T790M EGFR mutation who had received cytotoxic chemotherapy after acquiring resistance to EGFR-TKIs. Eligible patients had EGFR-mutant tumors resistant to first- or second-generation EGFR-TKIs and an EGFR-TKI-free period with cytotoxic agents. Confirmation of absence of the T790M mutation was required before registration. Afatinib (40 mg/body) was administered daily. The primary endpoint was progression-free survival (PFS). We assumed estimated and threshold PFS times of 3.3 and 1 months, with an α of 0.05 and β of 0.1, respectively. Twelve patients were enrolled from December 2014 to May 2017. The objective response rate and disease control rate were 17% and 84%, respectively. The median PFS time was 4.2 months (95% confidence interval [CI] 2.0–5.8), which met the pre-defined primary endpoint. The median overall survival was 11.6 months (95% CI 9.2-not reached). Grade 3 or worse adverse events included diarrhea (25%), elevated creatinine levels (8%), and hypokalemia (8%), without any treatment-related deaths. EGFR-TKI readministration with afatinib for sensitive EGFR-mutant NSCLC without T790M after resistance to a first- or second-generation EGFR-TKI yielded modest activity with tolerable toxicity. It might be one of the treatment options in patients who do not possess T790M tumors, although further studies in this patient setting are warranted.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.

[Purpose] This study aimed to examine the prevalence of locomotive syndrome among patients with obstructive sleep apnea syndrome (OSAS) using the "loco-check" recently developed by the Japanese Orthopedic Association, and to compare health-related quality of life (HRQOL) among patients with and without locomotive syndrome. [Subjects and Methods] This cross-sectional study evaluated 1,195 outpatients with OSAS (1,030 males and 165 females). Locomotive syndrome was evaluated using the Japanese Orthopedic Association's "loco-check". HRQOL and psychological distress were evaluated using the EuroQol 5-dimensional (EQ-5D) and 6-item Kessler questionnaires. [Results] Locomotive syndrome was detected in 578 patients (48.4%), including 398 males (38.6% of males) and 119 females (70.3% of females). Patients with OSAS and locomotive syndrome had significantly lower EQ-5D scores, compared to patients without locomotive syndrome. Multiple regression analysis revealed that HRQOL among patients with OSAS was independently associated with locomotive syndrome, age, gender, body mass index, apnea hypopnea index, the Japanese version of the Epworth Sleepiness Scale score, and exercise habits. [Conclusion] The prevalence of locomotive syndrome was thought to be comparatively high in patients with OSAS, and locomotive syndrome was associated with lower HRQOL, even after adjusting for confounding factors. Prevention or management of locomotive syndrome may be beneficial for improving HRQOL among patients with OSAS.

To investigate the impact of age on the relationship between obstructive sleep apnea syndrome (OSAS), nocturia, and other lower urinary tract symptoms (LUTSs).This was a secondary analysis study based on data derived from a previously conducted prospective observational cohort study on OSAS and nocturia. We analyzed 90 subjects who were suspected of having OSAS. Prior to polysomnography, we assessed International Prostate Symptom Score-Quality of Life scores, Overactive Bladder Symptom Scores, and International Consultation on Incontinence Modular Questionnaire-Nocturia Quality of Life scores to evaluate LUTSs. Nocturnal urine volume, night-time frequency, and night-time urine electrolyte content were measured during polysomnography. Patients were divided into groups according to age and OSAS severity determined using apnea-hypopnea index (AHI) scores. Young patients were those aged65 years and elderly patients, ≥65 years. A multiple linear regression with multiple imputations was performed to examine the association of night-time frequency with demographic, polysomnographic, and clinical characteristics.In young patients, night-time frequency was significantly associated with nocturnal urine volume, AHI score, and total IPSS. However, night-time frequency in elderly subjects was not associated with demographic and polysomnographic characteristics. In order to compare the severity of OSAS, night-time frequency and urinary sodium content significantly increased only in young patients (P = .007 and .004, respectively).OSAS is a strong candidate of causative factor for nocturia in younger individuals. When a younger patient complains nocturia without any urological disorders, OSAS should be kept in mind as a potential cause of nocturia.

Background Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline. Methods This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled. Results We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009). Conclusions We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone.

The platinum doublet is considered to be the standard cytotoxic chemotherapy for advanced lung cancer. It has been previously reported that nedaplatin and S-1 have clinical efficacy against squamous cell lung cancer. As the combination of nedaplatin and S-1 has never been studied for advanced squamous cell lung cancer, a phase I trial of this combination in the first-line setting was conducted. Patients who had not received chemotherapy previously, aged ≤75 years and with advanced squamous cell lung cancer were recruited. Nedaplatin was administered intravenously (day 1), and S-1 was orally administered (days 1-14) at a fixed dose based on the body surface area (BSA)

Objective: The purpose of this study was to investigate the risk factors linked to patient dropout from continuous positive airway pressure (CPAP) therapy for the treatment of obstructive sleep apnea syndrome (OSAS). Methods: This study included 1191 patients with OSAS at baseline assessment, who were followed for 3 years. We evaluated clinical parameters, indicators related to OSAS treatment, exercise habits and the presence of locomotive syndrome (LS). LS was evaluated by a &lsquo, loco-check&rsquo, as established by the Japanese Orthopedic Association. The OSAS patients were categorized at baseline as belonging to an &lsquo, LS group&rsquo, or a &lsquo, non-LS group&rsquo, and clinical parameters were compared. Results: Eighty-six patients (7.2%) dropped out of CPAP therapy during the 3 year follow-up period. The dropout rate of the LS group was significantly higher than that of the non-LS group. Using a Cox-proportional hazard model, the LS, old age and poor compliance were determined to be significant risk factors for dropping out of CPAP therapy. The hazard ratios (95% CI) of LS, elderly people and poor CPAP compliance were 2.11 (1.31&ndash, 3.48), 1.80 (1.11&ndash, 2.94) and 1.61 (1.04&ndash, 2.47), respectively. Conclusion: LS may be the critical risk factor for dropping out of CPAP therapy among patients with OSAS.

Objective To evaluate the effect of continuous positive airway pressure (CPAP) treatment on nocturnal urine volume, night-time urine frequency, and quality of life (QOL) in patients with obstructive sleep apnea syndrome (OSAS). Methods Ninety-eight participants with suspicious diagnosis of OSAS were prospectively enrolled in this study. Before polysomnography, measurement of the International Prostate Symptom Score–QOL score, the Overactive Bladder Symptom score (OABSS), the International Consultation on Incontinence Modular Questionnaire–Nocturia QOL were carried out to evaluate the lower urinary tract symptoms. During polysomnography, nocturnal urine volume and night-time urine frequency were recorded, and the concentrations of electrolytes in urine were determined. OSAS was confirmed in 92 patients, and 63 patients started to undergo CPAP treatment. Change in lower urinary tract symptoms–related QOL was assessed 1 month after CPAP treatment in 51 patients. Additionally, urine was collected at the time of CPAP titration in 25 patients. Results CPAP treatment significantly improved night-time frequency, which resulted in the improvement of total IPSS and QOL score. The night-time frequency questionnaire in OABSS similarly decreased, although total OABSS scores were not significantly improved. The International Consultation on Incontinence Modular Questionnaire–Nocturia QOL showed no significant changes after CPAP treatment. In addition to the night-time frequency, nocturnal urine volume and urine electrolyte contents significantly decreased after CPAP treatment. Conclusion CPAP treatment decreases night-time urine frequency by reducing nocturnal urine volume and improves QOL in OSAS patients.

Naohiro Oda,1 Nobuaki Miyahara,1,2 Hirohisa Ichikawa,3 Yasushi Tanimoto,4 Kazuhiro Kajimoto,5 Makoto Sakugawa,6 Haruyuki Kawai,7 Akihiko Taniguchi,1 Daisuke Morichika,1 Mitsune Tanimoto,1 Arihiko Kanehiro,1 Katsuyuki Kiura1 1Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, 3Department of Respiratory Medicine, KKR Takamatsu Hospital, Takamatsu, 4Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center, Okayama, 5Department of Respiratory Medicine, Kobe Red Cross Hospital, Kobe, 6Department of Respiratory Medicine, Okayama Red Cross Hospital, 7Department of Respiratory Medicine, Okayama Saiseikai Hospital, Okayama, Japan Background: Some recent studies have suggested that beta-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations. However, the long-term effects of beta-blocker use on lung function of COPD patients have hardly been evaluated. Patients and methods: We retrospectively reviewed 31 Japanese COPD patients taking beta-blockers for >1 year and 72 patients not taking them. The association between beta-blocker use and the annual change in forced expiratory volume in 1 second (FEV1) was assessed. Results: At baseline, patient demographic characteristics were as follows: 97 males (mean age 67.0±8.2 years); 32 current smokers; and Global Initiative for Chronic Obstructive Lung disease (GOLD) stages I: n=26, II: n=52, III: n=19, and IV: n=6. Patients taking beta-blockers exhibited a significantly lower forced vital capacity (FVC), FEV1, and %FVC, and a more advanced GOLD stage. The mean duration of beta-blocker administration was 2.8±1.7 years. There were no differences in the annual change in FEV1 between patients who did and did not use beta-blockers (-7.6±93.5 mL/year vs -4.7±118.9 mL/year, P=0.671). After controlling for relevant confounders in multivariate analyses, it was found that beta-blocker use was not significantly associated with the annual decline in FEV1 (β=-0.019; 95% confidence interval: -0.073 to 0.036; P=0.503). Conclusion: Long-term beta-blocker use in Japanese COPD patients might not affect the FEV1, one of the most important parameters of lung function in COPD patients. Keywords: chronic obstructive pulmonary disease, beta-blocker, lung function, spirometry, forced expiratory volume in 1 second, long-term

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK+ non-small-cell lung cancer even in the alectinib-refractory setting.

症例は70歳,男性.糖尿病治療のため入院し,入院時腹部超音波検査にて4×3cm大の右副腎腫瘤を指摘され, CTでは内部は不均一に造影された. I131-MIBGシンチグラムでも同部に集積を認め,血・尿中カテコールアミンおよびその代謝産物の上昇を認めたことから,褐色細胞腫の臨床診断のもとに右副腎摘出術を施行した.病理組織学的診断は褐色細胞腫-神経芽腫群腫瘍混合腫瘍Mixed neuroendocrine-neural tumor (MNNT)であった.