Published papers

BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. RESULTS: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I-V: odds ratio, 1.12 [95% CI, 0.96-1.30]; grades III-V: odds ratio, 0.95 [95% CI, 0.78-1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I-V hypertension (I2=88.6%, P for heterogeneity=0.003). CONCLUSIONS: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, immune reconstitution inflammatory syndrome (IRIS) due to nontuberculous mycobacteria (NTM) infection is one of the most difficult types of IRIS to manage. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been suggested as a useful tool for evaluating the inflammatory status of HIV-infected patients. We present the first case of Mycobacterium avium complex (MAC)-associated IRIS (MAC-IRIS) that was successfully followed up using 18F-FDG PET/CT. CASE PRESENTATION: A 44-year-old homosexual Japanese man was referred to our hospital with fever and dyspnea. He was diagnosed with Pneumocystis jiroveci pneumonia and found to be HIV positive. After the initiation of combined antiretroviral therapy (cART), the patient's mediastinal and bilateral hilar lymphadenopathy gradually enlarged, and bilateral infiltrates appeared in the upper lung fields. 18F-FDG PET/CT was performed five months after the initiation of cART and showed intense accumulation of fluorodeoxyglucose (FDG) corresponding to the lesions of infiltration as well as the mediastinal and bilateral hilar lymphadenopathy. A bronchial wash culture and pathology findings led to a diagnosis of MAC-IRIS. Anti-mycobacterial chemotherapy with rifampicin, ethambutol, clarithromycin, and levofloxacin was started. One year after the chemotherapy was initiated, there was a significant reduction in FDG uptake in the area of the lesions except in the mediastinal lymph node. This implied incomplete resolution of the MAC-IRIS-related inflammation. Anti-mycobacterial chemotherapy was continued because of the residual lesion. To date, the patient has not experienced a recurrence of MAC-IRIS, a period of nine months. CONCLUSION: We present a case of MAC-IRIS in an HIV-infected patient whose disease activity was successfully followed up using 18F-FDG PET/CT. Our data suggest that 18F-FDG PET/CT is useful for evaluating the disease activity of NTM-IRIS and assessing the appropriate duration of anti-mycobacterial chemotherapy for NTM-IRIS in HIV-infected patients.

Background: Inconsistent diagnostic test accuracies of immunohistological staining for squamous cell carcinoma (SQC) of the lung have been frequently reported. There have been few meta-analyses of the diagnostic accuracies of the immunohistochemical markers. Methods: A systematic review and meta-analysis were performed following standard guidelines for systematic reviews of diagnostic test accuracy. Immunohistochemical markers (p40, p63, CK5/6, and DSC3) were evaluated as index tests for SQC. The diagnostic odds ratio (DOR) was obtained by the DerSimonian-Laird variate model. Summary estimates of sensitivity and specificity were calculated using a bivariate model. The protocol registration ID is UMIN000041664. Results: The meta-analysis included 85 of the 1353 first-screened articles. The total number of patients was 17,893, which consisted 6151 SQC cases and 11,742 non-squamous non-small-cell lung cancer cases. The DOR was better for p40 (377, 95% confidence interval (CI) = 213-644, I 2 = 0%) than for CK5/6 (120, 95% CI = 78-184, I 2 = 2.5%), p63 (70, 95% CI = 55-88, I 2 = 9.1%), and DSC3 (94, 95% CI = 35-250, I 2 = 3.7%). Summary estimates of sensitivity and specificity were followings: p40 sensitivity 0.92 (95% CI = 0.89-0.95), specificity 0.94 (95% CI = 0.93-0.96); p63 sensitivity 0.92 (95% CI = 0.90-0.94), specificity 0.83 (95% CI = 0.80-0.86); CK5/6 sensitivity 0.90 (95% CI = 0.87-0.93), specificity 0.91 (95% CI = 0.89-0.93); DSC3 sensitivity 0.81 (95% CI = 0.73-0.88), and specificity 0.95 (95% CI = 0.85-0.98). Conclusion: P40 had the best DOR to diagnose SQC in non-small-cell lung carcinoma. Despite its lower sensitivity, DSC3 had the best specificity among the four markers and might be useful to rule-in the diagnosis of SQC.

OBJECTIVES: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors of severe coronavirus disease 2019 (COVID-19). However, limited literature exists on the effect of COPD and smoking on COVID-19 outcomes. This study examined the impact of smoking exposure in pack-years (PY) and COPD on COVID-19 outcomes among smokers in Japan. METHODS: The study included 1266 smokers enrolled by the Japan COVID-19 Task Force between February 2020 and December 2021. PY and COPD status were self-reported by patients. Patients were classified into the non-COPD (n=1151) and COPD (n=115) groups; the non-COPD group was further classified into <10 PY (n=293), 10-30 PY (n=497), and >30 PY (n=361). The study outcome was the need for invasive mechanical ventilation (IMV). RESULTS: The incidence of IMV increased with increasing PY and was highest in the COPD group (<10 PY=7.8%, 10-30 PY=12.3%, >30 PY=15.2%, COPD=26.1%; p<0.001). Significant association was found for IMV requirement in the >30 PY and COPD groups through univariate (odds ratio [OR]: >30 PY=2.11, COPD=4.14) and multivariate (OR: >30 PY=2.38; COPD=7.94) analyses. Increasing PY number was also associated with increased IMV requirement in patients aged <65 y. CONCLUSIONS: Cumulative smoking exposure was positively associated with COVID-19 outcomes in smokers.

BACKGROUND AND OBJECTIVES: Pulmonary Mycobacterium avium complex (pMAC) disease manifests as various types of lesions, such as infiltrates, nodules, cavities, and bronchiectasis. However, the important determinants for clinical parameters in lung involvement are poorly understood. The objective of this study was to obtain quantitative parameters by 3-dimensional CT, and investigate the relationship between these parameters and the pulmonary function tests (PFTs) and health-related quality of life. MATERIAL AND METHODS: Quantitative analysis using CT was performed in 67 pMAC patients. The relationship between new quantitative parameters for evaluating lung involvement using 3-dimensional CT and PFTs or St George's Respiratory Questionnaire (SGRQ) was evaluated. RESULTS: The ratio of infiltration to total lung volume showed significant correlation with the PFT results, especially the percent-predicted forced vital capacity (%FVC; ρ = -0.52), residual volume (ρ = -0.51), and total lung capacity (ρ = -0.59). The cavity volume was strongly correlated with the %FVC (ρ = -0.78) in the cavity group, while the ratio of infiltration to total lung volume was strongly correlated with the %FVC (ρ = -0.53) in the non-cavity group. The ratio of infiltration to total lung volume was significantly correlated with all SGRQ parameters (ρ = 0.41-0.52) in the non-cavity group. CONCLUSIONS: Infiltration was an important parameter for the PFTs and SGRQ in pMAC patients according to the 3-dimensional CT analysis. Moreover, cavity volume was an important parameter of the PFTs in the cavity group. Therefore, infiltration and cavity volume are key features for the management of pMAC disease.

BACKGROUND: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. METHODS: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. RESULTS: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively). CONCLUSIONS: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

BACKGROUND: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. METHODS: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. RESULTS: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11-0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43-4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. CONCLUSIONS: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

Immune checkpoint inhibitor (ICI)-related myositis is a rare, potentially fatal condition that warrants further studies. Its incidence, clinical features, and prognosis remain poorly understood. To address these gaps, we conducted a systematic review and meta-analysis to evaluate the risk of myositis associated with ICI for solid tumors by analyzing phase III randomized controlled trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4). To complement this analysis with clinical data, we evaluated published ICI case reports along with cases from our institutional registry. This registry comprised 422 patients treated with ICIs alone or in combination from September 2014 to June 2021. The analysis revealed an incidence of ICI-related myositis in 6,838 patients in 18 randomized controlled trials of 0.38% (odds ratio 1.96; 95% confidence interval 1.02-3.75) for patients receiving ICIs compared with controls. Detailed analysis of 88 cases from the literature search and our registry showed that myositis induced by PD-1 inhibitors was more frequent than that induced by anti-CTLA-4 agents, revealing a clinically diverse trend including myasthenia gravis and myocarditis. Importantly, having ptosis at the time of onset was significantly associated with the development of concomitant myocarditis (odds ratio 3.81; 95% CI 1.48-9.83), which is associated with poor prognosis. Regarding treatment, most patients received glucocorticoids, and some received immunosuppressants. Our study revealed the incidence of ICI-mediated myositis and the clinical features of myocarditis, highlighting the need for recognition and early intervention.