Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

A New Boron-Rhodamine-Containing Carboxylic Acid as a Sugar Chemosensor.

We propose a boron-rhodamine-containing carboxylic acid (BRhoC) substance as a new sugar chemosensor. BRhoC was obtained by the Friedel-Crafts reaction of 4-formylbenzoic acid and N,N-dimethylphenylboronic acid, followed by chloranil oxidation. In an aqueous buffer solution at pH 7.4, BRhoC exhibited an absorption maximum (Absmax) at 621 nm. Its molar absorption coefficient at Absmax was calculated to be 1.4 × 105 M-1 cm-1, and it exhibited an emission maximum (Emmax) at 644 nm for the excitation at 621 nm. The quantum yield of BRhoC in CH3OH was calculated to be 0.16. The borinate group of BRhoC reacted with a diol moiety of sugar to form a cyclic ester, which induced a change in the absorbance and fluorescence spectra. An increase in the D-fructose (Fru) concentration resulted in the red shift of the Absmax (621 nm without sugar and 637 nm with 100 mM Fru) and Emmax (644 nm without sugar and 658 nm with 100 mM Fru) peaks. From the curve fitting of the plots of the fluorescence intensity ratio at 644 nm and 658 nm, the binding constants (K) were determined to be 2.3 × 102 M-1 and 3.1 M-1 for Fru and D-glucose, respectively. The sugar-binding ability and presence of a carboxyl group render BRhoC a suitable building block for the fabrication of highly advanced chemosensors.

Elderly-onset inflammatory myopathy associated with Sjögren's syndrome following SARS-CoV-2 vaccination.

As vaccination against SARS-CoV-2 has progressed, various autoimmune diseases, including inflammatory myopathies, have been reported to develop after vaccination. Sjögren's syndrome (SS) sometimes presents as extra-glandular manifestations including inflammatory myopathy. In this report, we describe a case of inflammatory myopathy associated with SS that occurred in an atypically elderly patient after receiving the first dose of the SARS-CoV-2 mRNA vaccine (BNT162b2). The inflammatory myopathy was pathologically classified into non-specific myositis and characterised by predominant infiltration of the B cell lineage in this case. Combined treatment with glucocorticoid, intravenous immunoglobulin, and immunosuppressant resulted in an improvement in swallowing function and muscle strength. While we recognise the efficacy and safety of SARS-CoV-2 vaccines, we also emphasise the importance of recognising that individuals with an immunogenetic predisposition such as positivity of anti SS-A antibody may show disease activity including inflammatory myopathy following vaccination in SS, even at an atypically old age.

Establishment of lung cancer cell lines and tumorigenesis in mice from malignant pleural effusion in patients with lung cancer.

Background: Lung cancer was often diagnosed by malignant pleural effusion (MPE). Excessive MPE is generally discarded. The establishment of cell lines and the generation of cancer mouse models have the potential to be directly linked to personalized medicine. This study aimed to establish cell lines and generate mouse models using MPE. Methods: Cells derived from 5 mL of MPE were cultured in several conditions, including 100% MPE supernatant and Roswell Park Memorial Institute-1640 supplemented with 10% fetal bovine serum (FBS) or 10% MPE supernatant. When steady cell growth was observed, fewer cells were spread and the colonies were selected to establish the cell line. Cells derived from 10 mL of MPE were inoculated subcutaneously into non-obese diabetic-severe combined immunodeficiency (NOD-scid) and NOD.Cg-Prkdcscid Il2rgtmlWjl /SzJ (NSG) mice to assess tumorigenic potential. Results: MPEs were obtained from 28 lung cancer patients, 23 of whom had adenocarcinoma. Cell lines were established from 5 patients (18%). Tumorigenesis was observed in 6 of 28 cases (21%). However, in 7 cases, the mice (7 NSG and 1 NOD-scid mice) became progressively weaker, lost their hair, and died within 12 weeks without tumorigenesis. The appearance and pathological findings were consistent with graft-versus-host disease. Cell line establishment and tumorigenesis in mice were associated with a lower response to first-line therapy and poorer prognosis of patients. Conclusions: When MPEs were simply utilized, the cell line establishment rate was 18% and the engraftment rate in mice was 21%. The prognosis of patients who underwent cell line establishment and engraftment in mice was poor.

Superior vena cava syndrome induced by lung hyperinflation in chronic obstructive pulmonary disease: a case report.

BACKGROUND: Superior vena cava syndrome is rarely attributed to chronic obstructive pulmonary disease. CASE PRESENTATION: We present the case of an 82-year-old Japanese man who experienced gradually progressive dyspnea on exertion. His physical examination revealed small vascular dilatations on his chest and upper abdominal skin characterized by blood flow from head to leg, indicating superior vena cava syndrome. Radiographic findings included lung hyperinflation with a drop-like heart on chest X-ray, and emphysematous changes on computed tomography. The superior vena cava appeared extremely narrow and slit-like, with no adjacent mass or giant bulla. Pulmonary function testing indicated a forced expiratory volume in 1 second of 0.82L (44.4% of predicted value) and a forced expiratory volume in 1 second/forced vital capacity of 31.29%. A diagnosis of chronic obstructive pulmonary disease was made. We discuss how longitudinal forces can narrow the superior vena cava, particularly when it protrudes toward the lung field due to its anatomical location in the upper mediastinum. The absence of mediastinal adipose tissue may render the superior vena cava susceptible to compression, resulting in a loss of its typical columnar structure. The protrusion of the superior vena cava toward the lung field may be a contributing factor to superior vena cava narrowing in chronic obstructive pulmonary disease. CONCLUSION: This case represents the first reported instance of superior vena cava syndrome associated with chronic obstructive pulmonary disease, characterized by lung hyperinflation, in the absence of a giant bulla.

Autopsy Findings of Severe COVID-19 Pneumonia Combined with Pulmonary Aspergillosis, Pneumothorax, and Pulmonary Thromboembolisms.

BACKGROUND COVID-19-associated pulmonary aspergillosis (CAPA), acute respiratory distress syndrome (ARDS), pulmonary thromboembolism (PTE), and pneumothorax are complications in severe COVID-19 patients. CASE REPORT A 64-year-old Japanese man was diagnosed with COVID-19. His past medical history included uncontrolled diabetes mellitus. He had no vaccination for COVID-19. Despite oxygen inhalation, remdesivir, dexamethasone (6.6 mg per day), and baricitinib (4 mg per day for 12 days), the disease progressed. The patient was supported with mechanical ventilation. Dexamethasone was switched to methylprednisolone (1000 mg per day for 3 days, and then reduced by half every 3 days), and intravenous heparin was initiated. Voriconazole (800 mg on the first day and then 400 mg per day for 14 days) was also started because Aspergillus fumigatus was detected in intratracheal sputum. However, he died of respiratory failure. Pathological findings of autopsy showed: (1) diffuse alveolar damage in a wide area of the lungs, which is consistent with ARDS due to COVID-19 pneumonia, (2) PTEs in peripheral pulmonary arteries, (3) CAPA, and (4) pneumothorax induced by CAPA. These conditions were all active states, suggesting that the treatments were insufficient. CONCLUSIONS Autopsy revealed active findings of ARDS, PTEs, and CAPA in a severe COVID-19 patient despite heavy treatment for each condition. CAPA can be a cause of pneumothorax. It is not easy to improve these conditions simultaneously because their treatments can induce antagonizing biological actions. To prevent severe COVID-19, it is important to reduce risk factors, such as by vaccination and appropriate blood glucose control.

Structural basis for two-way communication between dynein and microtubules.

The movements of cytoplasmic dynein on microtubule (MT) tracks is achieved by two-way communication between the microtubule-binding domain (MTBD) and the ATPase domain via a coiled-coil stalk, but the structural basis of this communication remains elusive. Here, we regulate MTBD either in high-affinity or low-affinity states by introducing a disulfide bond to the stalk and analyze the resulting structures by NMR and cryo-EM. In the MT-unbound state, the affinity changes of MTBD are achieved by sliding of the stalk α-helix by a half-turn, which suggests that structural changes propagate from the ATPase-domain to MTBD. In addition, MT binding induces further sliding of the stalk α-helix even without the disulfide bond, suggesting how the MT-induced conformational changes propagate toward the ATPase domain. Based on differences in the MT-binding surface between the high- and low-affinity states, we propose a potential mechanism for the directional bias of dynein movement on MT tracks.

[Investigation on patient satisfaction at community pharmacies: analyzing questionnaire survey by structural equation modeling and multiple regression analysis].

Separation of the dispensing function and the prescribing function, Iyaku Bungyo, has been progressing in Japan. We are now witnessing the advent of a new society where patients select pharmacists and their satisfaction is recognized as one of the healthcare outcome indicators. It is necessary to clarify which factors affect patients' satisfaction with the services provided at community pharmacies and how they do so. A survey was conducted among 104 community pharmacies and their patients around the Tokyo metropolitan area in Japan. The questionnaire comprised 11 items (observed variables), each with a five-grade scale. With the transformed data-oriented pharmacy, the percentage of being not unsatisfactory was examined in two multivariate analyses of the relation and structure of patient satisfaction with a community pharmacy. Structural equation modeling (SEM) with factor analysis (FA) was performed using the observed variables and latent factors. Multiple regression analysis was performed with comprehensive satisfaction as an independent variable, examining the factors that affect comprehensive satisfaction with the pharmacy. The result of the FA indicated three latent factors of instruction on the use of drugs, quality of staff, and environment, based on which SEM model was constructed with a relatively high goodness of fit index. The result of multiple regression analyses indicated almost all variables such as satisfaction with reception by the pharmacist affected the comprehensive satisfaction, but privacy did not show a significant effect. These results, notably the relationship between each variables and latent factors, suggested the importance of higher skills of pharmacists, service qualities at pharmacies, and their functions adjusted to the community.