KRASG12C Inhibitor as a Treatment Option for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

Favorable treatment response of bevacizumab-combined chemotherapy for advanced or recurrent invasive mucinous adenocarcinoma of the lung: A retrospective observational study.

Invasive mucinous adenocarcinoma (IMA) of the lung is a rare variant of adenocarcinoma characterized by abundant intracytoplasmic mucin within the tumor. Although IMA has poor sensitivity to conventional chemotherapy regimens used for non-small cell lung cancer, we observed a better response to the bevacizumab (BEV) regimen. In this retrospective study, we aimed to investigate the response to BEV-combined regimens in patients with IMA. Among 16 consecutive patients diagnosed with IMA between January 2016 and December 2020 at our institution and treated with systemic chemotherapy, seven patients were treated with BEV-combined regimens. The overall response rate to BEV-combined regimens was 85.7%, with six patients showing a partial response. The median progression-free survival was 6.1 months. One patient experienced respiratory failure, which was improved after administration of BEV-combined regimen. BEV-combined systemic therapy may have a favorable effect on advanced or recurrent IMA of the lung.

Use of Ranibizumab for evaluating focal laser combination therapy for refractory diabetic macular edema patients: an exploratory study on the RELAND trials.

Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for diabetic macular edema (DME), but is less effective in some patients. We conducted a prospective study to determine whether laser combination therapy with anti-VEGF was more effective than Ranibizumab monotherapy in anti-VEGF-resistant DME patients. There was no significant difference in the improvement of the best-corrected visual acuity (BCVA) between the laser combination therapy and Ranibizumab monotherapy groups (3.2 letters and -7.5 letters, p = 0.165). BCVA did not significantly change between visits 1 and 7 (the laser combination group, 64.3 letters 70.3 letters, respectively, p = 0.537; the Ranibizumab monotherapy group, 72.3 letters and 64.8 letters, respectively, p = 0.554), with no significant improvements in central foveal retinal thickness (the laser combination therapy group, 9.3%: the Ranibizumab monotherapy groups, - 7.3%; p = 0.926). There was no significant difference in the number of Ranibizumab intravitreal therapy (IVT) sessions between the groups (laser combination therapy, 5.2; ranibizumab monotherapy, 6.0; p = 0.237). This study did not show that laser combination therapy was significantly more effective for anti-VEGF-resistant DME than anti-VEGF monotherapy alone. Therefore, for anti-VEGF-resistant DME, alternative therapeutic approaches beyond combined laser therapy may be considered.

Suitability of respiratory endoscopy for sampling malignant thoracic tumors for comprehensive genomic profiling.

Comprehensive genomic profiling (CGP) is implemented to detect actionable gene aberrations and design matched therapies. Although malignant thoracic tumors are commonly detected through respiratory endoscopy, it is questionable whether the small specimens obtained thereof are sufficient for CGP. Therefore, this study aimed to investigate the suitability of respiratory endoscopy for sampling primary and metastatic thoracic tumors for CGP. Patients whose specimens were collected through respiratory endoscopy and assessed by pathologists to determine their suitability for CGP at our institution between June 2019 and May 2022 were reviewed retrospectively. The suitability of each procedure as a sampling technique for CGP and, in the cases actually analyzed, the distribution of the detected gene aberration were assessed. In total, 122 patients were eligible for analysis; the median age was 61 (range, 29-86) years, and 71 (58.2%) patients were male. Primary intrathoracic tumors were found in 91 (74.6%) cases, including 84 (68.9%) primary lung cancers; the remaining thoracic metastases of extrathoracic origin included various types. The suitability rates of specimens obtained using conventional bronchoscopy with and without cryobiopsy, endobronchial ultrasound-guided transbronchial needle aspiration, and medical thoracoscopy were 82.8% (24/29), 70.4% (19/27), 72.9% (35/48), and 100% (18/18), respectively. Of the 96 cases judged suitable, 83 were subjected to CGP, and all but one were successfully analyzed. Finally, 47 (56.6%) patients had at least one actionable gene aberration and eight (9.6%) were treated with the corresponding targeted therapies. In conclusion, specimens obtained through respiratory endoscopy are suitable for CGP; medical thoracoscopy and cryobiopsy in conventional bronchoscopy are particularly useful.

Lipid membrane modulated control of magnetic nanoparticles within bacterial systems.

Bacterial magnetosomes synthesized by the magnetotactic bacterium Magnetospirillum magneticum are suitable for biomedical and biotechnological applications because of their high level of chemical purity of mineral with well-defined morphological features and a biocompatible lipid bilayer coating. However, utilizations of native magnetosomes are not sufficient for maximum effectiveness in many applications as the appropriate particle size differs. In this study, a method to control magnetosome particle size is developed for integration into targeted technological applications. The size and morphology of magnetosome crystals are highly regulated by the complex interactions of magnetosome synthesis-related genes; however, these interactions have not been fully elucidated. In contrast, previous studies have shown a positive correlation between vesicle and crystal sizes. Therefore, control of the magnetosome vesicle size is tuned by modifying the membrane lipid composition. Exogenous phospholipid synthesis pathways have been genetically introduced into M. magneticum. The experimental results show that these phospholipids altered the properties of the magnetosome membrane vesicles, which yielded larger magnetite crystal sizes. The genetic engineering approach presented in this study is shown to be useful for controlling magnetite crystal size without involving complex interactions of magnetosome synthesis-related genes.

An exa-scale high-performance molecular dynamics simulation program: MODYLAS.

A new version of the highly parallelized general-purpose molecular dynamics (MD) simulation program MODYLAS with high performance on the Fugaku computer was developed. A benchmark test using Fugaku indicated highly efficient communication, single instruction, multiple data (SIMD) processing, and on-cache arithmetic operations. The system's performance deteriorated only slightly, even under high parallelization. In particular, a newly developed minimum transferred data method, requiring a significantly lower amount of data transfer compared to conventional communications, showed significantly high performance. The coordinates and forces of 101 810 176 atoms and the multipole coefficients of the subcells could be distributed to the 32 768 nodes (1 572 864 cores) in 2.3 ms during one MD step calculation. The SIMD effective instruction rates for floating-point arithmetic operations in direct force and fast multipole method (FMM) calculations measured on Fugaku were 78.7% and 31.5%, respectively. The development of a data reuse algorithm enhanced the on-cache processing; the cache miss rate for direct force and FMM calculations was only 2.74% and 1.43%, respectively, on the L1 cache and 0.08% and 0.60%, respectively, on the L2 cache. The modified MODYLAS could complete one MD single time-step calculation within 8.5 ms for the aforementioned large system. Additionally, the program contains numerous functions for material research that enable free energy calculations, along with the generation of various ensembles and molecular constraints.

Adult T-cell leukemia/lymphoma complicated by Pneumocystis pneumonia in a non-endemic area.

Adult T-cell leukemia/lymphoma (ATLL) is a human T-cell leukemia virus type 1-inducing unevenly-distributed T-cell malignancy, which is often complicated by opportunistic infections. Here, we discuss the case of a 75-year-old woman presenting with Pneumocystis pneumonia (PCP) who was subsequently diagnosed with ATLL in Tokyo, a non-endemic area of ATLL. In addition to the elevated soluble interleukin-2 receptor and the detection of flower cells in the screening blood test, the high-resolution computed tomography findings, atypical of PCP, were clues to the diagnosis of ATLL. ATLL should be considered as an underlying disease when patients present with PCP, even in non-endemic areas.

Incidence of acute exacerbation in patients with interstitial lung disease after COVID-19 vaccination.

Acute exacerbations due to COVID-19 vaccination in patients with interstitial lung disease (ILD) have been reported, but their incidence is unknown. We investigated the incidence of exacerbations of ILD and respiratory symptoms due to the mRNA COVID-19 vaccines. A questionnaire survey was conducted on adverse reactions to the mRNA COVID-19 vaccination in 545 patients with ILD attending our hospital and retrospectively examined whether the eligible patients actually developed acute exacerbations of ILD induced by the vaccine. Of the 545 patients, 17 (3.1%) patients were aware of the exacerbation of respiratory symptoms, and four (0.7%) patients developed an acute ILD exacerbation after vaccination. Of the four patients who experienced exacerbations, two had collagen vascular disease-associated ILD, one had nonspecific interstitial pneumonia, another had unclassifiable idiopathic pneumonia, and none had idiopathic pulmonary fibrosis. Four patients were treated using steroid pulse therapy with a steroid taper, and two of the four also received intravenous cyclophosphamide pulse therapy. Tacrolimus was started in one patient with myositis-associated interstitial lung disease. Eventually, all patients exhibited improvement with immunosuppressive treatment and were discharged. COVID-19 vaccination for patients with ILD should be noted for developing acute exacerbations of ILD with low incidence, although manageable with early diagnosis and treatment.

Efficacy and safety of sotrovimab for vaccinated or unvaccinated patients with mild-to-moderate COVID-19 in the omicron era.

Although sotrovimab, one of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies has been shown to be effective in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) with risk factors, their efficacy in mRNA COVID-19 vaccinated patients in omicron era is unknown. To evaluate the effectiveness of sotrovimab clinical data from both COVID-19 vaccinated and unvaccinated patients who were hospitalized and receiving sotrovimab at the Japanese Red Cross Medical Center were compared. The efficacy and adverse events were evaluated. Of the total 60 patients enrolled in this study, 45 had received the mRNA COVID-19 vaccine and 15 were unvaccinated. The clinical progression with low nasal cannula or face mask was not significantly different between groups (occurring in one patient in each group; p = 0.44), with no further progression in both groups. The duration of hospitalization was eight days for both groups (p = 0.90). Two patients in each group experienced adverse events (7%, p = 0.26). The results suggested that the efficacy and safety of sotrovimab against mild-to-moderate COVID-19 with risk factors in the omicron era might not be different regardless of the vaccination status. The results of the present study are encouraging; however, further randomized clinical studies are needed.

Pulmonary amyloidosis diagnosed via transbronchial lung cryobiopsy without surgical lung biopsy: A case series.

Pulmonary amyloidosis is a rare disease characterized by abnormal extracellular deposition of amyloid fibril in the lung tissue, and the identification of amyloid deposits is essential for its diagnosis. Surgical lung biopsy (SLB) is a standard diagnostic method for pulmonary amyloidosis. However, it has a relatively high post-procedural mortality rate. Recently, transbronchial lung cryobiopsy (TBLC) has been gradually used for diagnosing interstitial lung disease. However, its diagnostic efficacy for pulmonary amyloidosis has not yet been validated. Here, we describe two cases of pulmonary amyloidosis with deposition of amyloid light chain detected via TBLC. Since SLB is a high-risk procedure for the patients due to age and complications, TBLC was performed. Both patients presented with Congo red-positive amyloid deposits. One patient with localized pulmonary amyloidosis had a good clinical course without therapeutic intervention and was followed up. The other with systemic amyloidosis received chemotherapy and presented with a stable clinical course. TBLC can collect a larger pulmonary specimen for pulmonary amyloidosis than forceps biopsy and has fewer complications and a lower mortality rate than SLB. Thus, it can be a diagnostic method for pulmonary amyloidosis.

Comparison of Mental Health among Japanese Healthcare Workers at Two Points during the COVID-19 Pandemic.

BACKGROUND: The prolonged pandemic of coronavirus disease 2019 (COVID-19) has resulted in mental burden among healthcare workers (HCWs). This study aimed to conduct a repeated study to assess changes in psychological concerns among Japanese HCWs. METHODS: This study is the second survey involving HCWs at the Japanese Red Cross Medical Center conducted between November 20, 2020 and December 4, 2020. The degree of symptoms of anxiety, depression, and resilience was assessed using the Japanese versions of the 7-item Generalized Anxiety Disorder Scale, Center for Epidemiologic Studies Depression Scale, and 10-item Connor-Davidson Resilience Scale, respectively. RESULTS: The survey included 594 HCWs, comprising 95 physicians, 261 nurses, 150 other co-medical staff, and 88 office workers. Among them, 46 (7.7%) and 152 (25.6%) developed moderate-to-severe symptoms of anxiety and depression, respectively. Compared with those in the initial survey conducted 6 months earlier, the resilience score did not change, whereas the anxiety and depression scores improved significantly (P < 0.001, P = 0.033, respectively). However, the frequency of HCWs developing moderate-to-severe symptoms of anxiety or depression did not significantly improve. Multivariable logistic regression analysis showed that having higher anxiety symptoms was a risk factor for depression symptoms, while older HCWs and those with higher resilience were less likely to develop depression symptoms. CONCLUSIONS: Many HCWs still suffer from psychological concerns during the COVID-19 pandemic.

An autopsy case of idiopathic pulmonary fibrosis with remarkable honeycomb cyst expansion.

Herein, we report an autopsy case of idiopathic pulmonary fibrosis (IPF) in which remarkable honeycomb cyst expansion appeared in the clinical course. Radiological findings initially showed subpleural predominant reticulation that had progressed to usual interstitial pneumonia with honeycomb cysts, along with a restrictive pattern in the pulmonary function tests. The diameter of honeycomb cysts had gradually increased, and some cysts had abruptly expanded at the end stage. Based on pathological findings of autopsy specimens, bronchiectasis, alveolar collapse due to inflammation, and check-valve mechanism caused by a slit-like orifice of the cysts could have contributed to honeycomb cyst expansion.

Three-dimensional free-energy landscape of hydrogen and oxygen molecules in polymer electrolyte membranes: Insight into diffusion paths.

Polymer electrolyte membranes, for example, the Nafion™ membranes, used in the fuel cells are responsible for separating reactive gas molecules as well as for the efficient exchange of protons. Although control of the permeation of the gases is important to enhance the fuel cell performance, the mechanism by which hydrogen and oxygen molecules permeate through the membranes remains unclear. To clarify the mechanism, we investigated the three-dimensional free-energy landscape of hydrogen and oxygen molecules in Nafion membranes with various water contents focusing on relevant diffusion paths. Low-free-energy paths are found mainly in the polymer phase and the interfacial region between the polymer and water phases. Thus, the path of the transportation may be attributed to the polymer phase and interfacial phases. However, the free-energy value in the aqueous phase is only slightly higher (∼1-2 kBT) than that in the other two phases, which indicates that a secondary contribution from the aqueous phase is expected. The free-energy landscape in the polymer and interfacial phases was found rugged, while it is comparatively flat in the water phase. We also found that an increase in water content brings about a smoother free-energy landscape in the polymer and interfacial phases. The decreased ruggedness may facilitate the gas diffusivity. These observations help understand the molecular mechanism of the gas diffusion in the membranes.

Drug-induced hypersensitivity syndrome caused by minodronic acid hydrate.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important adverse reaction caused by a few drugs. Reactivation of human herpesvirus 6 (HHV-6) is known to be associated with its pathogenesis. DIHS occasionally manifests as pulmonary lesions with a variety of imaging findings. CASE PRESENTATION: An 83-year-old woman started taking minodronic acid hydrate 5 years before admission. She noticed a generalized skin rash 44 days before admission and started oral betamethasone-d-chlorpheniramine maleate combination tablets for allergic dermatitis. She developed a fever and cough in addition to the rash, and was referred to our hospital. Laboratory data showed a high level of eosinophils and liver and biliary enzymes. Computed tomography (CT) studies revealed bilateral diffuse ground-glass opacities with ill-defined centrilobular nodules from the central to peripheral regions of the lungs. Transbronchial lung cryobiopsy specimens showed that lymphocyte infiltration was observed in the alveolar walls and fibrinous exudates and floating macrophages in the alveolar lumina. Immunohistochemistry of biopsy specimens showed more CD4+ lymphocytes than CD8+ lymphocytes, while few Foxp3+ lymphocytes were recognized. The serum anti-HHV-6 immunoglobulin G titer increased at 3 weeks after the first test. Based on these findings, we diagnosed her with DIHS. We continued care without using corticosteroids since there was no worsening of breathing or skin condition. Eventually, her clinical symptoms chest CT had improved. Minodronic acid hydrate was identified as the culprit drug based on the positive results of the patch test and drug-induced lymphocyte stimulation test. CONCLUSIONS: We described the first case of DIHS caused by minodronic acid hydrate. Lung lesions in DIHS can present with bilateral diffuse ground-glass opacities and ill-defined centrilobular nodules on a CT scan during the recovery phase. Clinicians should be aware of DIHS, even if patients are not involved with typical DIHS/DRESS-causing drugs.

All-atom molecular dynamics study of hepatitis B virus containing pregenome RNA in solution.

Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analog drugs, which are triphosphorylated and negatively charged in the cell, approach the capsid via diffusion and are absorbed into it. In this study, we performed a long-time molecular dynamics calculation of the entire HBV capsid containing pregenome RNA to investigate the interactions between the capsid and negatively charged substances. Electric field analysis demonstrated that negatively charged substances can approach the HBV capsid by thermal motion, avoiding spikes. The substances then migrate all over the floor of the HBV capsid. Finally, they find pores through which they can pass through the HBV capsid shell. Free energy profiles were calculated along these pores for small ions to understand their permeability through the pores. Anions (Cl-) showed higher free energy barriers than cations (Na+ and K+) through all pores, and the permeation rate of Cl- was eight times slower than that of K+ or Na+. Furthermore, the ions were more stable in the capsid than in the bulk water. Thus, the HBV capsid exerts ion selectivity for uptake and provides an environment for ions, such as nucleotides and nucleotide analog drugs, to be stabilized within the capsid.

Predictive model for the development of critical coronavirus disease 2019 and its risk factors among patients in Japan.

BACKGROUND: This study aimed to examine risk factors associated with critical coronavirus disease 19 (COVID-19) and to establish a risk predictive model for Japanese patients. METHODS: We retrospectively assessed adult Japanese patients diagnosed with COVID-19 at the Japanese Red Cross Medical Center, Tokyo, Japan between February 1, 2020 and March 10, 2021. The patients were divided into critical and non-critical groups based on their condition during the clinical courses. Univariate and multivariate logistic regression analyses were performed to investigate the relationship between clinical characteristics and critical illness. Based on the results, we established a predictive model for the development of critical COVID-19. RESULTS: In total, 300 patients were enrolled in this study. Among them, 86 were included in the critical group. Analyses revealed that age ≥65 y, hemodialysis, need for O2 supplementation upon diagnosis, and an initial serum C-reactive protein level of ≥6.5 mg/dL were independently associated with the development of critical COVID-19. Next, a predictive model for the development of critical COVID-19 was created, and this included the following variables: age ≥65 y, male sex, diabetes, hemodialysis, need for O2 supplementation upon diagnosis, and an initial serum C-reactive protein level of ≥6.5 mg/dL. The area under the receiver operating characteristic curve of the model was 0.86 (95% confidence interval, 0.81-0.90). Using a cutoff score of 12, the positive and negative predictive values of 74.0% and 80.4% were obtained, respectively. CONCLUSIONS: Upon diagnosis, the predictive model can be used to identify adult Japanese patients with COVID-19 who will require intensive treatment.

A case of pulmonary sclerosing pneumocytoma diagnosed preoperatively using transbronchial cryobiopsy.

BACKGROUND: The preoperative diagnosis of pulmonary sclerosing pneumocytoma (PSP) is complicated since PSP has several histological structural patterns in the same neoplasm; hence, it is sometimes pathologically misdiagnosed as adenocarcinoma or carcinoid. In recent years, with the prevalence of transbronchial cryobiopsy (TBLC), we are able to obtain larger specimens than previously. However, to date, there have been no reports describing PSP diagnosed using TBLC. CASE REPORTS: A 43-year-old man was referred to our hospital for an abnormal lesion in the left lung discovered on routine health examination. A computed tomography scan of the chest revealed a 14-mm heterogeneous round nodule with surrounding ground-glass opacity in the left lower lobe. The tumor size increased to 18 mm in three weeks, and he developed bloody sputum. TBLC was performed using radial endobronchial ultrasonography and fluoroscopy. An occlusion balloon and prophylactic epinephrine were used to prevent severe bleeding. Histologically, epithelioid cells with solid proliferation, various papillary lesions, and hemosiderin-laden histiocytes were observed. Immunohistochemical staining revealed the histiocytes positive for thyroid transcription factor-1 and vimentin, and the type II pneumocyte-like-cells positive for cytokeratin 7. The tumor was preoperatively diagnosed as a PSP; the patient underwent left basal segmentectomy and consequently, a final diagnosed of PSP was formulated. CONCLUSION: We report the first case of PSP preoperatively diagnosed using TBLC. Therefore, cryobiopsy could be beneficial in the preoperative diagnosis of PSP.

Clinical impact of combination therapy with baricitinib, remdesivir, and dexamethasone in patients with severe COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide and is also an important disease in Japan. Thus, the optimal treatment strategy for severe COVID-19 should be established urgently. The effects of combination treatment with baricitinib-a Janus kinase inhibitor, remdesivir, and dexamethasone (BRD) are unknown. METHODS: Patients who received combination therapy with BRD at the Japanese Red Cross Medical Center were enrolled in the study. All patients received baricitinib (≤14 d), remdesivir (≤10 d), and dexamethasone (≤10 d). The efficacy and adverse events were evaluated. RESULTS: In total, 44 patients with severe COVID-19 were enrolled in this study. The 28-d mortality rate was low at 2.3% (1/44 patients). The need for invasive mechanical ventilation was avoided in most patients (90%, 17/19 patients). Patients who received BRD therapy had a median hospitalization duration of 11 d, time to recovery of 9 d, duration of intensive care unit stay of 6 d, duration of invasive mechanical ventilation of 5 d, and duration of supplemental oxygen therapy of 5 d. Adverse events occurred in 15 patients (34%). Liver dysfunction, thrombosis, iliopsoas hematoma, renal dysfunction, ventilator-associated pneumonia, infective endocarditis, and herpes zoster occurred in 11%, 11%, 2%, 2%, 2%, 2%, and 2% of patients, respectively. CONCLUSIONS: Combination therapy with BRD was effective in treating severe COVID-19, and the incidence rate of adverse events was low. The results of the present study are encouraging; however, further randomized clinical studies are needed.

Momentum removal to obtain the position-dependent diffusion constant in constrained molecular dynamics simulation.

The position-dependent diffusion coefficient along with free energy profile are important parameters needed to study mass transport in heterogeneous systems such as biological and polymer membranes, and molecular dynamics (MD) calculation is a popular tool to obtain them. Among many methodologies, the Marrink-Berendsen (MB) method is often employed to calculate the position-dependent diffusion coefficient, in which the autocorrelation function of the force on a fixed molecule is related to the friction on the molecule. However, the diffusion coefficient is shown to be affected by the period of the removal of the center-of-mass velocity, τv0 , which is necessary when performing MD calculations using the Ewald method for Coulombic interaction. We have clarified theoretically in this study how this operation affects the diffusion coefficient calculated by the MB method, and the theoretical predictions are proven by MD calculations. Therefore, we succeeded in providing guidance on how to select an appropriate τv0 value in estimating the position-dependent diffusion coefficient by the MB method. This guideline is applicable also to the Woolf-Roux method.