DOCK2 is involved in the host genetics and biology of severe COVID-19.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. MATERIALS AND METHODS: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. RESULTS: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). CONCLUSION: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

Asthma is a risk factor for general fatigue of long COVID in Japanese nation-wide cohort study.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. METHODS: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. CONCLUSIONS: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

Cough and sputum in long COVID are associated with severe acute COVID-19: a Japanese cohort study.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. METHODS: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan-Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. CONCLUSIONS: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

Clinical utilization of artificial intelligence-based COVID-19 pneumonia quantification using chest computed tomography - a multicenter retrospective cohort study in Japan.

BACKGROUND: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions. METHODS: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions. RESULTS: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59-19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60-8.76), IMV requirement (aOR 7.73, 95% CI 2.52-23.7), and mortality rate (aOR 6.46, 95% CI 1.87-22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36-9.52), older age (aOR 2.53, 95% CI 1.16-5.51), female sex (aOR 2.41, 95% CI 1.13-5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09-4.50) independently predicted persistent residual lung lesions. CONCLUSIONS: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19.

Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

Longitudinal Assessment of Prognostic Understanding in Patients with Advanced Lung Cancer and Its Association with Their Psychological Distress.

BACKGROUND: Accurate prognostic understanding in patients with advanced cancer is essential for shared decision making; however, patients may experience psychological burden through knowing the incurable nature of advanced cancer. It has been unclear how their prognostic understanding fluctuates and whether accurate prognostic understanding is associated with psychological distress from the time of diagnosis over time. MATERIALS AND METHODS: We longitudinally investigated prognostic understanding in 225 patients with newly diagnosed advanced lung cancer at 16 hospitals in Japan until 24 months after diagnosis. We examined associated factors with being consistently accurate in prognostic understanding, especially focusing on its association with psychological well-being. RESULTS: The proportion of patients with an inaccurate prognostic understanding remained approximately 20% over time with the presence of patients with inconsistent understanding. Patients with consistently accurate prognostic understanding showed a significantly lower Emotional Well-Being subscale score at both 3 and 6 months after diagnosis (p = .010 and p = .014, respectively). In multivariate analyses, being consistently accurate in prognostic understanding was significantly associated with female gender and higher lung cancer-specific symptom burden at 3 months (p = .008 and p = .005, respectively) and lower emotional well-being at 6 months (p = .006). CONCLUSION: Although substantial proportions of patients with advanced lung cancer had inaccurate prognostic understanding from the time of diagnosis over time, patients with consistently accurate prognostic understanding experienced greater psychological burden. Our findings highlight the importance of continuous psychological care and support for patients who understand their severe prognosis accurately. IMPLICATIONS FOR PRACTICE: This study demonstrated that approximately 20% of patients with advanced lung cancer had an inaccurate understanding about their prognosis, not only at the time of diagnosis but also at the later time points. Being consistently accurate in prognostic understanding was significantly associated with elevated levels of psychological distress. Although accurate prognostic understanding is essential for decision making for treatment and advance care planning, health care providers should be aware of psychological burdens in patients that accept their severe prognosis accurately. Appropriate care and support for such patients are warranted from diagnosis over time.

Functional dissection of the KRAS G12C mutation by comparison among multiple oncogenic driver mutations in a lung cancer cell line model.

The development of molecular targeted therapy has improved clinical outcomes in patients with life-threatening advanced lung cancers with driver oncogenes. However, selective treatment for KRAS-mutant lung cancer remains underdeveloped. We have successfully characterised specific molecular and pathological features of KRAS-mutant lung cancer utilising newly developed cell line models that can elucidate the differences in driver oncogenes among tissues with identical genetic backgrounds. Among these KRAS-mutation-associated specific features, we focused on the IGF2-IGF1R pathway, which has been implicated in the drug resistance mechanisms to AMG 510, a recently developed selective inhibitor of KRAS G12C lung cancer. Experimental data derived from our cell line model can be used as a tool for clinical treatment strategy development through understanding of the biology of lung cancer. The model developed in this paper may help understand the mechanism of anticancer drug resistance in KRAS-mutated lung cancer and help develop new targeted therapies to treat patients with this disease.

Trends of concerns from diagnosis in patients with advanced lung cancer and their family caregivers: A 2-year longitudinal study.

BACKGROUND: Both advanced cancer patients and their family caregivers experience distress and have a range of concerns after cancer diagnosis. However, longitudinal studies on this topic have been lacking. AIM: To investigate concerns in both patients with advanced lung cancer and their family caregivers longitudinally from diagnosis. DESIGN: A multi-center prospective questionnaire-based study. SETTING/PARTICIPANTS: We recruited patients with newly diagnosed advanced lung cancer and their family caregivers at 16 hospitals in Japan. We prospectively assessed the prevalence of their concerns using the Concerns Checklist and investigated the associations between their concerns and mental status as well as quality of life until 24 months after diagnosis. RESULTS: A total of 248 patients and their 232 family caregivers were enrolled. The prevalence of serious concerns was highest at diagnosis (patients: 68.3%, family caregivers: 65.3%). The most common serious concern was concern about the future in both groups at diagnosis (38.2% and 40.5%, respectively) and this remained high in prevalence over time, while the high prevalence of concern about lack of information improved 3 months after diagnosis in both groups. Approximately one-third of patient-family caregiver dyads had discrepant reports of serious concerns. The presence of serious concerns was significantly associated with anxiety and depression continuously in both groups. CONCLUSIONS: The majority of advanced lung cancer patients and their family caregivers have serious concerns from diagnosis, which is associated with their psychological distress. The spectrum of concerns alters over the disease trajectory, warranting efficient tailored care and support for both groups immediately after diagnosis.

Intracellular levels of reactive oxygen species correlate with ABT-263 sensitivity in non-small-cell lung cancer cells.

ABT-263 (Navitoclax) is a BH3-mimetic drugs targeting anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, thereby inducing apoptosis. In small-cell lung cancer (SCLC) cells, the response to ABT-263 is associated with the expression of myeloid cell leukemia-1 (MCL-1) protein, however the efficacy of ABT-263 in non-small-cell lung cancer (NSCLC) has not been thoroughly evaluated. There are currently no established biomarkers for predicting the efficacy of ABT-263 treatment in NSCLC. We screened a panel of different NSCLC cell lines and found that ABT-263 inhibited cell proliferation and induced apoptosis in Calu-1, Calu-3, and BID007 cells. Inconsistent with previous reports on SCLC, low levels of MCL-1 did not predict the response to ABT-263 in NSCLC cells, however we found that intracellular levels of reactive oxygen species (ROS) in cancer cells were associated with sensitivity to ABT-263 in NSCLC cells. We also showed that increasing the level of intracellular ROS could enhance the sensitivity to ABT-263 in NSCLC cells. In summary, we propose that the intracellular levels of ROS could be used as a potential novel biomarker for predicting a response to ABT-263 in NSCLC. Furthermore, we show some evidence supporting the further assessment of ABT-263 as a new therapeutic strategy in patients with NSCLC combined with agents regulating ROS levels. We believe that our findings and follow-up studies on this matter would lead to novel diagnostic and treatment strategies in patients with NSCLC.

Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma.

We identified transmembrane protease, serine 4 (TMPRSS4) as a putative, druggable target by screening surgically resected samples from 90 Japanese non-small-cell lung cancer (NSCLC) patients using cDNA microarray. TMPRSS4 has two druggable domains and was upregulated in 94.5% of the lung cancer specimens. Interestingly, we found that TMPRSS4 expression was associated with tissue factor pathway inhibitor 2 (TFPI-2) expression in these clinical samples. In contrast to TMPRSS4, TFPI-2 expression was downregulated in NSCLC samples. The in vitro induction of TFPI-2 in lung cancer cell lines decreased the expression of TMPRSS4 mRNA levels. Reporter assay showed that TFPI-2 inhibited transcription of TMPRSS4, although partially. Knockdown of TMPRSS4 reduced the proliferation rate in several lung cancer cell lines. When lung cancer cell lines were treated with 5-aza-2'-deoxycytidine or trichostatin A, their proliferation rate and TMPRSS4 mRNA expression levels were also reduced through the upregulation of TFPI-2 by decreasing its methylation in vitro. The TFPI-2 methylation level in the low TMPRSS4 group appeared to be significantly low in NSCLC samples (P = 0.02). We found a novel molecular mechanism that TFPI-2 negatively regulates cell growth by inhibiting transcription of TMPRSS4. We suggest that TMPRSS4 is upregulated by silencing of TFPI-2 through aberrant DNA methylation and contributes to oncogenesis in NSCLC.

A Phase II study of S-1 and irinotecan combination therapy in previously treated patients with advanced non-small cell lung cancer.

OBJECTIVE: This Phase II study was conducted to evaluate the efficacy and safety of S-1 and irinotecan combination therapy as a second-line treatment in patients with advanced non-small cell lung cancer. METHODS: Irinotecan was administered at 60 mg/m(2) on Days 1 and 8. Oral S-1 was administered on Days 1-14 every 3 weeks at 80 mg/day for patients with a body surface area of <1.25 m(2), 100 mg/day for patients with a body surface area of 1.25-1.5 m(2) and 120 mg/day for patients with a body surface area of >1.5 m(2). The primary endpoint was response rate, while the secondary endpoints were progression-free survival, overall survival and safety. RESULTS: Thirty-one patients were enrolled in this study. The response and disease control rates were 6.5 and 58.1%, respectively. Progression-free survival and median survival time were 2.8 and 12.6 months, respectively. Grade 3-4 adverse events were reported for 29.0% of the patients. Hematological toxicities of Grade 3 or 4 included leukopenia (9.7%), neutropenia (9.7%), febrile neutropenia (3.2%), thrombopenia (3.2%) and anemia (6.5%). Non-hematological toxicities of Grade 3 or 4 included pneumonitis (6.5%), diarrhea, colitis, dyspnea, rash, oral mucositis, anorexia and pulmonary thromboembolism/deep vein thrombosis (3.2% each). CONCLUSIONS: S-1 and irinotecan combination therapy at the present dose and schedule exhibited only modest efficacy with mild toxicities in previously treated patients with non-small cell lung cancer. No further clinical investigation with current dose and schedules is warranted for patients with non-small cell lung cancer who failed first-line platinum-based doublet chemotherapy.

Calcium channel blockers may reduce the development of long COVID in females.

With the rising numbers of patients infected with severe acute respiratory syndrome coronavirus 2, long coronavirus disease 2019 (COVID-19)-a sequelae of COVID-19-has become a major problem. Different sexes and age groups develop different long COVID symptoms, and the risk factors for long COVID remain unclear. Therefore, we performed subgroup analyses of patients with COVID-19, classifying them into different groups. In this multicenter cohort study, using an original questionnaire, we examined patients (≥18 years old) diagnosed with COVID-19 from November 2020 to March 2022 and hospitalized at participating medical facilities. In total, 1066 patients were registered (361 female, 620 male). Hypertension was the most common comorbidity (n = 344; 32.5%). Females with hypertension were significantly less likely to develop long COVID symptoms than those without hypertension (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.27-0.98; p = 0.043). In females, Ca channel blocker administration, rather than having hypertension, was significantly associated with reductions in the frequency of alopecia (OR 0.14, 95% CI 0.03-0.67, p = 0.015), memory impairment (OR 0.14, 95% CI 0.02-0.82, p = 0.029), sleeping disorders (OR 0.17, 95% CI 0.04-0.67, p = 0.012), tinnitus (OR 0.23, 95% CI 0.05-0.98, p = 0.047), sputum (OR 0.31, 95% CI 0.10-0.92, p = 0.035), and fever (OR 0.33, 95% CI 0.12-0.93, p = 0.036). Several long COVID symptoms, including alopecia, were significantly negatively associated with Ca channel-blocker administration in female patients with long COVID. Calcium channel blockers may reduce the development of long COVID in females.

Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data.

BACKGROUND: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. AIMS: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. MATERIALS AND METHODS: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. RESULTS: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). CONCLUSION: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

Cluster analysis of long COVID in Japan and association of its trajectory of symptoms and quality of life.

BACKGROUND: Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL). METHODS: This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis. RESULTS: Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year. CONCLUSIONS: We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID. TRIAL REGISTRATION NUMBER: The study protocol is registered at UMIN clinical trials registry (UMIN000042299).

Integrated assessment of computed tomography density in pectoralis and erector spinae muscles as a prognostic biomarker for coronavirus disease 2019.

BACKGROUND ＆ AIMS: Muscle quantification using chest computed tomography (CT) is a useful prognostic biomarker for coronavirus disease 2019 (COVID-19). However, no studies have evaluated the clinical course through comprehensive assessment of the pectoralis and erector spinae muscles. Therefore, we compared the impact of the areas and densities of these muscles on COVID-19 infection outcome. METHODS: This multicenter retrospective cohort study was conducted by the COVID-19 Task Force. A total of 1410 patients with COVID-19 were included, and data on the area and density of the pectoralis and erector spinae muscles on chest CT were collected. The impact of each muscle parameter on the clinical outcome of COVID-19 was stratified according to sex. The primary outcome was the percentage of patients with severe disease, including those requiring oxygen supplementation and those who died. Additionally, 167 patients were followed up for changes in muscle parameters at three months and for the clinical characteristics in case of reduced CT density. RESULTS: For both muscles, low density rather than muscle area was associated with COVID-19 severity. Regardless of sex, lower erector spinae muscle density was associated with more severe disease than pectoralis muscle density. The muscles were divided into two groups using the receiver operating characteristic curve of CT density, and the population was classified into four (Group A: high CT density for both muscles, Group B: low CT density for pectoralis and high for erector spinae muscle. Group C: high CT density for pectoralis and low for erector spinae muscle, Group D: low CT density for both muscles). In univariate analysis, Group D patients exhibited worse outcomes than Group A (OR: 2.96, 95% CI: 2.03-4.34 in men; OR: 3.02, 95% CI: 2.66-10.4 in women). Multivariate analysis revealed that men in Group D had a significantly more severe prognosis than those in Group A (OR: 1.82, 95% CI: 1.16-2.87). Moreover, Group D patients tended to have the highest incidence of other complications due to secondary infections and acute kidney injury during the clinical course. Longitudinal analysis of both muscle densities over three months revealed that patients with decreased muscle density over time were more likely to have severe cases than those who did not. CONCLUSIONS: Muscle density, rather than muscle area, predicts the clinical outcomes of COVID-19. Integrated assessment of pectoralis and erector spinae muscle densities demonstrated higher accuracy in predicting the clinical course of COVID-19 than individual assessments.

CT-derived vertebral bone mineral density is a useful biomarker to predict COVID-19 outcome.

The low vertebral bone computed tomography (CT) Hounsfield unit values measured on CT scans reflect low bone mineral density (BMD) and are known as diagnostic indicators for osteoporosis. The potential prognostic significance of low BMD defined by vertebral bone CT values for the coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to assess the impact of BMD on the clinical outcome in Japanese patients with COVID-19 and evaluate the association between BMD and critical outcomes, such as high-flow nasal cannula, non-invasive and invasive positive pressure ventilation, extracorporeal membrane oxygenation, or death. We examined the effects of COVID-19 severity on the change of BMD over time. This multicenter retrospective cohort study enrolled 1132 inpatients with COVID-19 from the Japan COVID-19 Task Force database between February 2020 and September 2022. The bone CT values of the 4th, 7th, and 10th thoracic vertebrae were measured from chest CT images. The average of these values was defined as BMD. Furthermore, a comparative analysis was conducted between the BMD on admission and its value 3 months later. The low BMD group had a higher proportion of critical outcomes than did the high BMD group. In a subanalysis stratifying patients by epidemic wave according to onset time, critical outcomes were higher in the low BMD group in the 1st-4th waves. Multivariable logistic analysis of previously reported factors associated with COVID-19 severity revealed that low BMD, chronic kidney disease, and diabetes were independently associated with critical outcomes. At 3 months post-infection, patients with oxygen demand during hospitalization showed markedly decreased BMD than did those on admission. Low BMD in patients with COVID-19 may help predict severe disease after the disease onset. BMD may decrease over time in patients with severe COVID-19, and the impact on sequelae symptoms should be investigated in the future.

Epicardial adipose tissue measured from analysis of adipose tissue area using chest CT imaging is the best potential predictor of COVID-19 severity.

BACKGROUND: Computed tomography (CT) imaging is widely used for diagnosing and determining the severity of coronavirus disease 2019 (COVID-19). Chest CT imaging can be used to calculate the epicardial adipose tissue (EAT) and upper abdominal visceral adipose tissue (Abd-VAT) areas. The EAT is the main source of inflammatory cytokines involved in chest inflammatory diseases; thus, the EAT area might be a more useful severity predictor than the Abd-VAT area for COVID-19. However, to the best of our knowledge, there are no large-scale reports that sufficiently consider this issue. In addition, there are no reports on the characteristics of patients with normal body mass index (BMI) and high adipose tissue. AIM: The purpose of this study was to analyze whether the EAT area, among various adipose tissues, was the most associated factor with COVID-19 severity. Using a multicenter COVID-19 patient database, we analyzed the associations of chest subcutaneous, chest visceral, abdominal subcutaneous, and Abd-VAT areas with COVID-19 outcomes. In addition, the clinical significance of central obesity, commonly disregarded by BMI, was examined. METHODS: This retrospective cohort study evaluated patients with COVID-19 aged ≥18 years In Japan. Data including from chest CT images collected between February 2020 and October 2022 in four hospitals of the Japan COVID-19 Task Force were analyzed. Patient characteristics and COVID-19 severity were compared according to the adipose tissue areas (chest and abdominal subcutaneous adipose tissue [Chest-SAT and Abd-SAT], EAT, and Abd-VAT) calculated from chest CT images. RESULTS: We included 1077 patients in the analysis. Patients with risk factors of severe COVID-19 such as old age, male sex, and comorbidities had significantly higher areas of EAT and Abd-VAT. High EAT area but not high Abd-VAT area was significantly associated with COVID-19 severity (adjusted odds ratio (aOR): 2.66, 95 % confidence interval [CI]: 1.19-5.93). There was no strong correlation between BMI and VAT. Patients with high VAT area accounted for 40.7 % of the non-obesity population (BMI < 25 kg/m2). High EAT area was also significantly associated with COVID-19 severity in the non-obesity population (aOR: 2.50, 95 % CI: 1.17-5.34). CONCLUSIONS: Our study indicated that VAT is significantly associated with COVID-19 severity and that EAT is the best potential predictor for risk stratification in COVID-19 among adipose tissue areas. Body composition assessment using EAT is an appropriate marker for identifying obesity patients overlooked by BMI. Considering the next pandemic of the global health crisis, our findings open new avenues for implementing appropriate body composition assessments based on CT imaging.