Underdiagnosis of COPD: The Japan COPD Real-World Data Epidemiological (CORE) Study.

Purpose: The prevalence of airflow obstruction in Japan is 3.8%-16.9%. This epidemiological study based on a large database aimed to reassess the prevalence of airflow obstruction in Japan and the diagnosis rate of chronic obstructive pulmonary disease (COPD). Patients and Methods: We used data regarding claims from the health insurance union and health checkups provided by JMDC. The present study included a subgroup of individuals aged ≥40 years who underwent health checkups involving spirometry between January and December 2019. The study endpoints were the prevalence of airflow obstruction, COPD diagnosis rate, disease stage, and respiratory function test results. Results: Among 102,190 participants, 4113 (4.0%) had airflow obstruction. The prevalence of airflow obstruction was 5.3% in men and 2.1% in women. Among the study population, 6.8% were current smokers, while 3.4% were never or former smokers. Additionally, the prevalence of COPD increased with age. Approximately 8.4% of participants with airflow obstruction were diagnosed with COPD. Regarding the COPD diagnosis status, participants with airflow obstruction who were diagnosed with COPD were at a more advanced stage than those not diagnosed. Finally, patients diagnosed with COPD had significantly lower FEV1/FVC and FEV1 (p < 0.0001; Wilcoxon rank sum test). Conclusion: The epidemiological study based on a large database determined the COPD diagnosis rate related to airflow obstruction. The COPD diagnosis rate was extremely low among individuals who underwent health checkups, indicating the need for increased awareness about this medical condition. Moreover, primary care physicians should identify patients with suspected COPD and collaborate with pulmonologists to facilitate the early detection of COPD and enhance the COPD diagnosis rate.

Participant Selection from the General Japanese Population for Pulmonary Function Tests Using a Questionnaire on Symptoms and Smoking Habits during Annual Health Checkups: The Yamagata-Takahata Study.

Objective Pulmonary function tests are essential for diagnosing respiratory diseases, such as chronic obstructive pulmonary disease (COPD), but are typically not performed in Japan during annual health checkups, which hinders the early diagnosis of respiratory diseases. Methods Individuals who agreed to participate in the Yamagata-Takahata study during medical checkups in Takahata (Yamagata Prefecture, Japan) in 2011 were examined. We interviewed 669 participants (49.0% men; mean age, 67.7 years old) regarding their respiratory symptoms and smoking habits and performed pulmonary function tests during the study. Results Based on pulmonary function test results, 141 participants had pulmonary dysfunction, and 115 had obstructive pulmonary dysfunction. The risk of respiratory dysfunction, particularly obstructive respiratory dysfunction, was examined by referring to a questionnaire tool for an early COPD diagnosis. The associations between age, the smoking history, respiratory symptoms, and obstructive respiratory dysfunction were evaluated. Obstructive respiratory dysfunction was found in 17.6% of participants ≥50 years old and 19.5% ≥60 years old, 30.3% had a smoking history, and 32.8% had respiratory symptoms. Furthermore, the participants with multiple factors had a higher probability of obstructive respiratory dysfunction. Conclusion Subjects with obstructive pulmonary dysfunction are expected to be efficiently identified by extracting individuals by age and smoking habit and through a respiratory symptom questionnaire, although pulmonary function tests cannot be performed for all individuals during health checkups.

Management goals and stable phase management of patients with chronic obstructive pulmonary disease in the Japanese respiratory society guideline for the management of chronic obstructive pulmonary disease 2022 (6th edition).

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction on spirometry and symptoms such as dyspnea on exertion and chronic cough with sputum production, thus making it a significant healthcare issue worldwide. Japanese patients with COPD have unique characteristics compared to patients in Western countries, including older age and lower exacerbation frequency. The Japanese Respiratory Society (JRS) published the 6th edition of the COPD guideline in June 2022. This article introduces the management goals of COPD and describes its management during the stable phase, as outlined in the guideline. Management goals include improving the current status, such as the symptoms, quality of life (QOL), exercise tolerance, and physical activity, and reducing future risks through prevention of exacerbation and suppression of disease progression to prevent shortening of healthy life expectancy. Management plans should include avoidance of causative substances, assessment of disease severity, and personalized treatment plans. Pharmacotherapy using inhalation bronchodilators is a key component of the treatment of stable COPD. Bronchodilators, including short- and long-acting dilators, are commonly used to relieve symptoms and improve QOL. Inhaled corticosteroids (ICSs) are used in combination with long-acting bronchodilators, especially in patients with asthma and COPD overlap, or those experiencing frequent exacerbation of eosinophilia. Combination therapy with a long-acting muscarinic antagonist (LAMA), a long-acting beta 2 agonist (LABA), and ICS is expected to improve QOL and respiratory function and reduce mortality and exacerbation compared to the LAMA + LABA combination. Non-pharmacological therapies, including smoking cessation and pulmonary rehabilitation, should also be considered.

Development and external validation of the DOAT and DOATS scores: simple decision support tools to identify disease progression among nonelderly patients with mild/moderate COVID-19.

BACKGROUND: During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. METHODS: This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. RESULTS: The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. CONCLUSIONS: We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.

Secretoglobin 3A2 protects lung from developing cigarette smoke-induced pulmonary emphysema.

Secretoglobin (SCGB) 3A2 is a bioactive molecule exhibiting various functions such as improving allergic airway inflammation and pulmonary fibrosis and promoting bronchial branching and proliferation during lung development. To determine if and how SCGB3A2 is involved in chronic obstructive pulmonary disease (COPD), a multifactorial disease with both airway and emphysematous lesions, a COPD mouse model was created by exposing Scgb3a2-deficient (KO), Scgb3a2-lung-specific overexpressing (TG), and wild type (WT) mice to cigarette smoke (CS) for 6 months. The KO mice showed loss of lung structure under control condition, and CS exposure resulted in more expansion of airspace and destruction of alveolar wall than WT mouse lungs. In contrast, TG mouse lungs showed no significant changes after CS exposure. SCGB3A2 increased the expression and phosphorylation of signal transducers and activators of transcription (STAT)1 and STAT3, and the expression of α1-antitrypsin (A1AT) in mouse lung fibroblast-derived MLg cells and mouse lung epithelial-derived MLE-15 cells. In MLg cells, A1AT expression was decreased in Stat3-knockdown cells, and increased upon Stat3 overexpression. STAT3 formed a homodimer when cells were stimulated with SCGB3A2. Chromatin immunoprecipitation and reporter assays demonstrated that STAT3 binds to specific binding sites on the Serpina1a gene encoding A1AT and upregulates its transcription in lung tissues of mice. Furthermore, nuclear localization of phosphorylated STAT3 upon SCGB3A2 stimulation was detected by immunocytochemistry. These findings demonstrate that SCGB3A2 protects the lungs from the development of CS-induced emphysema by regulating A1AT expression through STAT3 signaling.

Acquired von Willebrand Syndrome in a Patient with Multiple Comorbidities, Including MALT Lymphoma with IgA Monoclonal Gammopathy and Hyperviscosity Syndrome.

Acquired von Willebrand syndrome (aVWS) develops with various underlying diseases. We herein report an individual with aVWS associated with mucosa-associated lymphoid tissue lymphoma in the lungs complicated by hyperviscosity syndrome, Sjögren's syndrome, and hypothyroidism. This patient developed life-threatening hemorrhaging during a lung biopsy despite transfusion of concentrate of plasma-derived VWF/factor VIII. The use of rituximab caused remission of the lymphoma and hyperviscosity syndrome in parallel with the resolution of aVWS. Thus, lymphoma and hyperviscosity might result in aVWS. Invasive procedures with a risk of bleeding should be avoided in individuals with aVWS.

Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema.

Hyperhomocysteinemia was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with hyperhomocysteinemia has not been fully elucidated. This study included 7- to 9-week-old C57BL6 male mice induced with hyperhomocysteinemia and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of hyperhomocysteinemia compared to that in the control group. The apoptotic A549 cells increased as homocysteine concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. In this study, we showed that hyperhomocysteinemia exacerbates CS exposure-induced emphysema in mice, suggesting that hyperhomocysteinemia and CS stimulation enhance ER stress and subsequent induced apoptosis in alveolar epithelial cells. It was suggested that there is a synergistic effect between homocysteine and CS.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic.

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.

Development of dermatomyositis after anti-transcriptional intermediary factor 1-γ antibody seroconversion during treatment for small cell lung cancer.

BACKGROUND: Inflammatory myositis, such as dermatomyositis, is sometimes complicated by cancer and is recognized as cancer-associated myositis. Although some autoimmune antibodies are considered to be involved in the development of myositis in cancer patients, the precise mechanism has not been clarified. The findings of the present case shed light on the mechanism by which anti-transcriptional intermediary factor 1 (TIF1)-γ Ab was produced and the pathogenesis of cancer-associated myositis. CASE PRESENTATION: We describe a case of dermatomyositis that developed in a 67-year-old man who had been diagnosed with small cell lung cancer of clinical T4N3M0 stage IIIB/limited disease during treatment. He received systemic chemotherapy and radiation therapy, and dermatomyositis developed along with a significant decrease in tumor size. TIF1-γ Ab, which is one of the myositis-specific antibodies, was found to be seroconverted. In addition, immunohistochemical analysis showed that cancer cells were positive for the TIF1-γ antigen. CONCLUSION: The findings of the present case suggest that transcriptional intermediary factor 1-γ, which is released from tumor cells, induces the production of TIF1-γ Ab, leading to the development of dermatomyositis.

Multiple Inflammatory Pseudotumors of the Liver Demonstrating Spontaneous Regression: A Case Report.

Inflammatory pseudotumor (IPT) of the liver is a rare benign disease. IPTs generally develop as solitary nodules, and cases with multiple lesions are uncommon. We herein report a case of multiple IPTs of the liver that spontaneously regressed. A 70-year-old woman with a 10-year history of primary biliary cholangitis and rheumatoid arthritis visited our hospital to receive a periodic medical examination. Abdominal ultrasonography revealed multiple hypoechoic lesions, with a maximum size of 33 mm, in the liver. Contrast-enhanced computed tomography revealed low-attenuation areas in the liver with mild peripheral enhancement at the arterial and portal phases. We first suspected metastatic liver tumors, but fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and contrast-enhanced ultrasonography suggested the tumors to be inconsistent with malignant nodules. A percutaneous biopsy showed shedding of liver cells and abundant fibrosis with infiltration of inflammatory cells. Given these findings, we diagnosed the multiple tumors as IPTs. After careful observation for two months, the tumors almost vanished spontaneously. Physicians should avoid a hasty diagnosis of multiple tumors based solely on a few clinical findings, and a careful assessment with various imaging modalities should be conducted.

Role of CC Chemokine Ligand 17 in Mouse Models of Chronic Obstructive Pulmonary Disease.

Lung function deterioration is significantly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). We previously reported that CC chemokine ligand 17/thymus and activation-regulated chemokine (CCL17/TARC) could be a predictive factor of lung function decline in patients with COPD. However, the role of CCL17 in the pathogenesis of COPD is unclear. Here we examined the role of CCL17 in lung inflammation using mouse COPD models. Exposure to cigarette smoking induced CCL17 production in bronchial epithelial cells and accumulation of alveolar macrophages in the lungs. Intranasal administration of recombinant CCL17 further enhanced cigarette smoke-induced macrophage accumulation and also aggravated elastase-induced pulmonary emphysema. We confirmed that cigarette smoke (CS) extract as well as hydrogen peroxide upregulated CCL17 in BAES-2B cells. Of note, macrophages of both M1 and M2 surface markers were accumulated by cigarette smoke. Both alveolar macrophage accumulation via exposure to cigarette smoking and emphysematous changes induced by elastase administration were significantly reduced in CCL17-deficient mice. We further demonstrated that CCL17 strongly induced the expression of CC chemokine ligand 2 (CCL2), a chemoattractant for macrophages, in RAW264.7 cells, and its production was inhibited by knockdown of CCR4, the receptor of CCL17. Collectively, the present results demonstrate that CCL17 is produced by lung epithelial cells upon CS exposure. Furthermore, CCL17 is involved in CS-induced accumulation of alveolar macrophages and development of elastase-induced pulmonary emphysema, possibly through CCL17-induced production of CCL2 by macrophages. Our findings may provide a new insight into the pathogenesis of COPD.

The Incidence and Risk Analysis of Lung Cancer Development in Patients with Chronic Obstructive Pulmonary Disease: Possible Effectiveness of Annual CT-Screening.

PURPOSE: Lung cancer is a serious complication in patients with chronic obstructive pulmonary disease (COPD) and accounts for approximately 15% of deaths in patients with COPD. However, with the exception of emphysema, few reports to date have been published on the factors that predict lung cancer development in COPD patients. It has been reported that patients with COPD develop lung cancer at a rate of 0.8% - 1.7%/year, but the incidence may be higher in the Japanese population. Therefore, we investigated the incidence of lung cancer and the lung cancer mortality rate in Japanese COPD patients, as well as factors that are associated with the development of lung cancer in COPD patients. PATIENTS AND METHODS: We followed up 224 patients with stable COPD and performed CT examinations at least once per year. The incidence of lung cancer was recorded and data at enrollment were compared with data of the group that did not develop lung cancer. RESULTS: Over a median follow-up period of 4.58 years, lung cancer was newly diagnosed in 19 patients; the incidence of lung cancer in this population was 1.85%/year. Patients who developed lung cancer had more severe emphysema assessed by CT and GOLD classification and were more likely to be current smokers than those who did not develop lung cancer. No other significant differences were observed between these two groups. Mortality was significantly increased in patients who developed lung cancer compared with those who did not. CONCLUSION: In COPD patients, the incidence of lung cancer is higher and the development of lung cancer worsens the prognosis; however, lung cancer development is unpredictable and attention should be paid to all patients. Annual CT screening is important for early detection of lung cancer.

The Japanese respiratory society guidelines for the management of cough and sputum (digest edition).

Cough and sputum are common complaints at outpatient visits. In this digest version, we provide a general overview of these two symptoms and discuss the management of acute (up to three weeks) and prolonged/chronic cough (longer than three weeks). Flowcharts are provided, along with a step-by-step explanation of their diagnosis and management. Most cases of acute cough are due to an infection. In chronic respiratory illness, a cough could be a symptom of a respiratory infection such as pulmonary tuberculosis, malignancy such as a pulmonary tumor, asthma, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, drug-induced lung injury, heart failure, nasal sinus disease, sinobronchial syndrome, eosinophilic sinusitis, cough variant asthma (CVA), atopic cough, chronic laryngeal allergy, gastroesophageal reflux (GER), and post-infectious cough. Antibiotics should not be prescribed for over-peak cough but can be considered for atypical infections. The exploration of a single/major cause is recommended for persistent/chronic cough. When sputum is present, a sputum smear/culture (general bacteria, mycobacteria), cytology, cell differentiation, chest computed tomography (CT), and sinus X-ray or CT should be performed. There are two types of rhinosinusitis. Conventional sinusitis and eosinophilic rhinosinusitis present primarily with neutrophilic inflammation and eosinophilic inflammation, respectively. The most common causes of dry cough include CVA, atopic cough/laryngeal allergy (chronic), GER, and post-infectious cough. In the last chapter, future challenges and perspectives are discussed. We hope that the clarification of the pathology of cough hypersensitivity syndrome will lead to further development of "pathology-specific non-specific therapeutic drugs" and provide benefits to patients with chronic refractory cough.

A New Ultrasonographic "Fluttering Sign" for Hepatic Hemangioma.

The aim of the study described here was to clarify the diagnostic value of the fluttering sign, a new sign that characterizes hepatic hemangiomas in gray-scale ultrasonography (US). It refers to a phenomenon in which the speckled echogenicity inside the hemangioma changes continuously and seems to be moving. A total of 172 hemangiomas diagnosed with contrast-enhanced US were evaluated. The fluttering sign was found in 123 of 172 hemangiomas (71.5%). Its prevalence was significantly higher than that of the marginal strong echo (89/172, 51.7%, p < 0.001), posterior acoustic enhancement (103/172, 59.9%, p = 0.031) and chameleon sign (100/172, 58.1%, p = 0.013). In addition, the fluttering sign was observed significantly more frequently in mixed or hypo-echoic tumors than in hyper-echoic tumors (p < 0.001), relatively large tumors (p < 0.001) and tumors that were less than 5 cm from the body surface (p = 0.015). The fluttering sign in gray-scale US has great potential to be a new complementary sign for the diagnosis of hemangioma.

Severe Coronavirus Disease 2019 That Recovered from Respiratory Failure by Treatment That Included High-dose Intravenous Immunoglobulin.

We herein report a case of severe coronavirus disease 2019 (COVID-19) in which high-dose intravenous immunoglobulin (IVIg) treatment achieved significant clinical improvement of deterioration of pulmonary inflammation after temporary clinical improvement. In the present case, clinical and radiological deterioration occurred despite a decrease in viral load, suggesting that deterioration was caused by reactivation of proinflammatory factors, such as tumor necrosis factor-α and interleukin-6, rather than direct viral effects. IVIg treatment may provide not only immunosuppressive effects but also inhibition of proinflammatory cytokines, indicating that treatment including IVIg may be effective by inhibiting cytokine storm in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection.

Prognostic value of morphological characteristics assessed by CT scan in patients with non-small cell lung cancer treated with nivolumab.

BACKGROUND: Nivolumab is known to demonstrate superior overall survival compared with docetaxel in pretreated non-small cell lung cancer (NSCLC) patients. Programmed death-ligand 1 (PD-L1) expression is reported to predict the outcome of treatment by nivolumab in lung cancer patients. However, the significance of the morphological characteristics of chest computed tomography (CT) as predictors of nivolumab efficacy for advanced NSCLC patients remains unknown. METHODS: We performed a multicenter retrospective trial from April 2013 to March 2017, to assess the significance of CT morphological characteristics as predictors of nivolumab efficacy for advanced NSCLC patients. A total of 78 NSCLC patients pretreated with nivolumab were enrolled. A chest radiologist used chest CT to assess the following morphological characteristics of each patient's main tumor and intrathoracic status prior to nivolumab treatment; interstitial septal thickening, peritumoral ground-glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node, and accumulation of small lymph nodes. Logistic regression and Cox proportional hazards regression models were used to analyze outcomes. RESULTS: A total of 60 (77%) patients were male and 72 (92%) had a performance status (PS) of 0 or 1. The objective response rates of male patients and heavy smokers were significantly higher than those of female patients and light or never smokers, respectively. Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS). CONCLUSIONS: Interstitial septal thickening was a significant and independent predictor of PFS in NSCLC patients treated with nivolumab. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Interstitial septal thickening is an independent predictor of progression free survival in non-small lung cancer patients treated with nivolumab. WHAT THIS STUDY ADDS: The current study reveals the significance of morphological characteristics obtained via chest computed tomography as a predictor of nivolumab efficacy for advanced non-small cell lung cancer patients.

Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.

Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses. Here we describe the isolation and characterization of a high affinity antibody (C0021158) that inhibits ARG2 enzymatic function completely, effectively restoring T-cell proliferation in vitro. Enzyme kinetic studies confirmed that C0021158 exhibits a noncompetitive mechanism of action, inhibiting ARG2 independently of L-arginine concentrations. To elucidate C0021158's inhibitory mechanism at a structural level, the co-crystal structure of the Fab in complex with trimeric ARG2 was solved. C0021158's epitope was consequently mapped to an area some distance from the enzyme's substrate binding cleft, indicating an allosteric mechanism was being employed. Following C0021158 binding, distinct regions of ARG2 undergo major conformational changes. Notably, the backbone structure of a surface-exposed loop is completely rearranged, leading to the formation of a new short helix structure at the Fab-ARG2 interface. Moreover, this large-scale structural remodeling at ARG2's epitope translates into more subtle changes within the enzyme's active site. An arginine residue at position 39 is reoriented inwards, sterically impeding the binding of L-arginine. Arg39 is also predicted to alter the pKA of a key catalytic histidine residue at position 160, further attenuating ARG2's enzymatic function. In silico molecular docking simulations predict that L-arginine is unable to bind effectively when antibody is bound, a prediction supported by isothermal calorimetry experiments using an L-arginine mimetic. Specifically, targeting ARG2 in the tumor microenvironment through the application of C0021158, potentially in combination with standard chemotherapy regimens or alternate immunotherapies, represents a potential new strategy to target immune cold tumors.

Efficacy and safety of S-1 monotherapy in previously treated elderly patients (aged ≥75 years) with non-small cell lung cancer: A retrospective analysis.

BACKGROUND: S-1 monotherapy is effective and feasible for previously treated patients with advanced non-small cell lung cancer (NSCLC). However, it is not clear whether its effectiveness and tolerability in elderly patients are equivalent to those in younger patients. Hence, this study aimed to evaluate the efficacy and feasibility of S-1 monotherapy in elderly patients with NSCLC who had previously received other treatments. METHODS: We included 96 elderly patients (aged ≥75 years) with advanced NSCLC treated with S-1 alone as a subsequent-line treatment at 12 medical facilities between January 2005 and March 2018 in this study. The baseline characteristics of the patients, response to S-1 monotherapy, and adverse events (AEs) were investigated, retrospectively. RESULTS: A total of 68 male and 28 female patients (median age, 78 [range: 75-86] years) were analyzed. In elderly patients who were treated with S-1 monotherapy as a subsequent-line treatment, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 8.3%, 43.8%, 3.4 months, and 9.6 months, respectively. Observed AEs included anorexia, anemia, nausea, fatigue, reduced platelet count, and skin hyperpigmentation. Treatment-related death was observed in one patient because of pneumonitis. In patients who experienced no progressive disease, subsequent-line S-1 alone was associated with longer PFS and OS. CONCLUSIONS: S-1 monotherapy is effective and feasible as a subsequent-line treatment in elderly patients who were previously treated for NSCLC, and it produces results. S-1 monotherapy could be one of the treatment choices for elderly patients with previously treated NSCLC.

Monomorphic Epitheliotropic Intestinal T-cell Lymphoma Involving the Lung and Brain: A Rare Case Study.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma and other organ involvement is very rare. A rare case of MEITL involving the lung and brain is herein reported. The patient developed panperitonitis with a small intestinal perforation, and emergency surgery was performed. The pathological findings from the surgical specimens demonstrated atypical lymphoid cells which were positive for CD3, CD8, and CD56. Moreover, the pathological findings of lung specimens taken by bronchoscopy were consistent with those of the small intestine. It is therefore important to include the possibility of MEITL in the differential diagnosis of cancer patients.