Social impact of brain fog and analysis of risk factors: Long COVID in Japanese population.

OBJECTIVE: To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID-19). METHODS: We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID-19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. RESULTS: The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C-reactive protein and elevated D-dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. INTERPRETATIONS: This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

A case of community-acquired pneumonia caused by Bacillus subtilis subsp. natto in an immunocompetent patient.

A 70-year-old immunocompetent male with a history of insomnia presented with pneumonia and bacteremia caused by Bacillus subtilis. The patient took benzodiazepines and regularly consumed alcohol and natto (fermented soybeans). Initial antibiotic treatment was not effective, and bronchoalveolar lavage was performed. Bronchoalveolar lavage fluid (BALF) analysis revealed an increased lymphocytes fraction, and B. subtilis was detected in the BALF. Whole-genome sequencing confirmed the congruence of the genetic sequences between the strain in the blood culture of the patient, BALF, and strain isolated from the consumed natto, confirming B. subtilis subsp. natto as the causative pathogen of pneumonia and bacteremia. Vancomycin followed by levofloxacin and systemic corticosteroid were used to treat the condition. This case highlights community-acquired pneumonia and bacteremia caused by B. subtilis subsp. natto, particularly in individuals who consume natto.

Longitudinal long COVID symptoms in Japanese patients after COVID-19 vaccinations.

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

A case of disseminated intravascular coagulation following tumour lysis syndrome due to small cell carcinoma of the lung.

A 64-year-old man was diagnosed with small cell lung cancer (SCLC) with multiple bone and liver metastases and bone marrow metastases. Spontaneous tumour lysis syndrome (TLS) was observed before starting chemotherapy with carboplatin, etoposide, and atezolizumab. The tumour further collapsed, and the patient developed disseminated intravascular coagulation (DIC) on day 4 of chemotherapy. The patient was successfully treated with intravenous hydration and rasburicase for TLS and subcutaneous unfractionated heparin for DIC. A large amount of tissue factor may be released in TLS, which could induce DIC. However, to the best of our knowledge, this is the first report of DIC following TLS in a case of SCLC. DIC following TLS in SCLC is a rare but life-threatening oncologic complication. Therefore, clinicians should be aware of this possibility when treating patients with advanced SCLC.

A case of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung diseases developed after administration of COVID-19 vaccine and subsequent pneumococcal vaccine.

Five cases of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung diseases (anti-MDA5-positive DM-RPILD) following COVID-19 vaccination have been reported previously. We present the first case of the disease that developed following the sequence of COVID-19 infection, COVID-19 vaccination, and 23-valent pneumococcal polysaccharide vaccine (PPSV23) administration. A 75-year-old-Japanese man received the third dose of Pfizer COVID-19 vaccine 4 weeks after he had a mild COVID-19 infection. Eleven weeks after vaccination, he received PPSV23 for the first time. He developed fever, malaise, and anorexia the day after the PPSV23, rash a week later, and shortness of breath 2 weeks later. He was then admitted to a local hospital and treated with antibiotics, but his condition worsened. He was transferred to our hospital 4 weeks after the PPSV23 and was diagnosed with anti-MDA5-positive DM-RPILD. Despite intensive treatment, the patient died on the 10th hospital day.

A Prospective Observational Study on the Tolerability of Transnasal Bronchoscopy With a Surgical Mask for Aerosol Control.

Background As far as we know, there are no reports comparing the safety and cough frequency of transnasal bronchoscopy (TNB) with transoral bronchoscopy (TOB). Methods The subjects were 50 patients who underwent either TNB or TOB and completed the pain score questionnaire between May and November 2020. Complications, pain scores, and cough frequency (times per minute) were compared between the patients with TNB and TOB. A surgical mask was worn over the mouthpiece during the examination. Results Thirty-two and 18 patients underwent TNB and TOB, respectively. Between the two groups, there were no significant differences in examination time and frequency of serious complications. In pain scores, there were no significant differences in terms of anesthesia suffering, several pains during the examination, and availability of re-examination. The TNB group did not feel the prolonged examination time compared to the TOB group (p=0.04). Cough frequency was lower in the TNB group than in the TOB group (0.36 vs 0.73, p=0.027). Moreover, cough frequency in the 25 TNB patients who underwent thin bronchoscopy was significantly lower (0.19 vs 0.73, p<0.01). Conclusions TNB with a surgical mask was well tolerated and safe. Cough frequency in the transnasal thin bronchoscopy was extremely low, suggesting aerosol reduction can be expected.

Real-world clinical practice for advanced non-small-cell lung cancer in the very elderly: A retrospective multicenter analysis.

BACKGROUND: The optimal treatment for advanced non-small cell lung cancer (NSCLC) in very elderly patients is unclear. We aimed to evaluate their treatment in real-world clinical practice and identify suitable therapy that can improve their prognosis. MATERIALS AND METHODS: The medical records of 132 Japanese patients aged 80 years and older with advanced NSCLCs who were enrolled at a university hospital and its 9 affiliates were retrospectively analyzed. Clinical characteristics and overall survival (OS) were compared based on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) and biomarker statuses. Patients were defined as biomarker-positive if programmed death-ligand 1 tumor proportion score (PD-L1 TPS) was ≥ 50% or activating mutations were present in epidermal growth factor receptor, anaplastic lymphoma kinase, or c-ros oncogene 1. Finally, the factors contributing to better prognosis were explored in both PS 0 - 2 and PS 3 - 4 patient groups. RESULTS: The PS 0 - 2 patients showed a longer median OS than the PS 3 - 4 patients (5.5 vs. 1.6 months). PS 0 - 2 patients with positive biomarkers who received chemotherapy showed a significantly longer median OS than those without (18.1 vs. 3.7 months). Among the biomarker-negative/unknown PS 0 - 2 patients, the median OS showed no significant difference between those who received chemotherapy and those who did not (4.5 vs. 3.1 months). The multivariate analysis showed that treatment with tyrosine kinase inhibitors or immune checkpoint inhibitors was related to better prognoses in the PS 0 - 2 group. CONCLUSION: Biomarker-matched therapy is effective even in very elderly patients. Meanwhile, the effectiveness of chemotherapy for biomarker-negative/unknown PS 0 - 2 patients is questionable.

COVID-19 vaccine induced interstitial lung disease.

A 60-year-old man presented with dyspnea four days after the second dose of the coronavirus disease (COVID-19) vaccine. Imaging revealed extensive ground-glass opacification. Blood tests were notable for elevated KL-6 levels. Bronchoalveolar lavage fluid analysis showed increased lymphocyte-dominant inflammatory cells and decreased CD4/CD8 ratio. These findings were consistent with the diagnosis of drug-induced interstitial lung disease (DIILD). To the best of our knowledge, this has never been reported in previous literature. Treatment with glucocorticoids relieved his symptoms. This paper highlights that although extremely rare, COVID-19 vaccine could cause DIILD, and early diagnosis and treatment are crucial to improve patient outcomes.

A case of pulmonary foreign body granuloma formation after transcatheter arterial chemoembolization for hepatocellular carcinoma.

We experienced a case of pulmonary foreign body granuloma diagnosed by bronchoscopy in a patient with multiple lung lesions after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma. We speculate that the lesions may be caused by transarterial migration of the materials used for TACE.

Clinical Characteristics and Therapeutic Outcomes of Metastatic Peritoneal Carcinomatosis in Non-Small-Cell Lung Cancer.

BACKGROUND: Metastatic peritoneal carcinomatosis (MPC) is not common in patients with non-small cell lung cancer (NSCLC), and the clinical characteristics and treatment outcomes are still unclear. PATIENTS AND METHODS: We recruited 46 NSCLC patients with MPC at Keio University and affiliated hospitals (Keio Lung Oncology Group) between January 2011 and December 2017, then retrospectively investigated their clinical characteristics and the impact of treatment interventions on their survival. RESULTS: The profile of histological subtype was predominantly adenocarcinoma and 15 patients harbored driver oncogenes. Univariate and multivariate analysis demonstrated that performance status and the presence of a driver oncogene were significantly associated with the prolonged overall survival (OS). Regarding treatment, the median OS in the treatment group (9.3 months) was significantly longer than in the best supportive care group (1.3 months) (P < 0.0001). CONCLUSION: The prognosis of MPC in NSCLC patients who receive only the best supportive care is poor, but therapeutic intervention may improve prognosis.

Omission of Throat Anesthesia Using Jackson's Spray Prior to Bronchoscopy for Preventing Aerosol Generation: A Survey Through Patient Distress Questionnaire.

Background and objective Due to the outbreak of coronavirus disease 2019 (COVID-19), the Japanese Society of Respiratory Endoscopy recommended the omission of throat anesthesia using Jackson's spray prior to bronchoscopy for preventing aerosol generation. In this survey, we investigated the tolerability of patients toward the omission of anesthesia using Jackson's spray before bronchoscopy. Methods Group A patients received throat anesthesia with 5 mL of 4% lidocaine using Jackson's spray prior to bronchoscopy and were then administered pethidine hydrochloride and midazolam intravenously. Group B patients did not receive anesthesia using Jackson's spray before bronchoscopy. They were administered pethidine hydrochloride and midazolam and were then administered 8% lidocaine several times into the pharynx. A patient distress questionnaire, classified as a five-graded score, was administered to each group after bronchoscopy. Results Seventy patients participated in this study: 39 patients in Group A and 31 patients in Group B. There were no significant differences in their backgrounds. In the questionnaire survey, the distress caused by pre-examination anesthesia in Group A was significantly higher than in Group B (3.03 ± 1.25 vs. 1.23 ± 0.62; p < 0.0001), and no significant differences were observed in the other questions during bronchoscopy. Conclusion This study demonstrates the tolerability of patients toward the omission of throat anesthesia using Jackson's spray prior to bronchoscopy, which is recommended for preventing infection, including COVID-19.

A Case of Guillain-Barré Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrosis Overlap After Pembrolizumab Treatment.

A 76-year-old man was admitted to our hospital with Guillain-Barré syndrome (GBS), presenting with facial palsy, dysarthria, and dysphagia as Grade 3 immune-related adverse events (irAEs) due to pembrolizumab administration for Stage IV lung adenocarcinoma. Although prednisolone (1 mg/kg) was started for GBS due to the irAE, dark erythema and skin eruptions appeared on the patient's torso. Then erosion was observed on 18% of the body surface area and skin biopsy was performed. Finally, the patient was diagnosed with Stevens-Johnson syndrome/toxic epidermal necrosis overlap. Intravenous immunoglobulin therapy was started, and the skin symptoms improved, with the erosion becoming epithelial. He died of aspiration pneumonia related to GBS, although his neurological symptoms had improved after steroid and intravenous immunoglobulin therapy. This is the first reported case of pembrolizumab-induced GBS and Stevens-Johnson syndrome/toxic epidermal necrosis overlap. It is necessary to be careful that the possibility of other severe irAEs may occur simultaneously.

Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

A case of hyperprogressive disease following atezolizumab therapy for pulmonary pleomorphic carcinoma with epidermal growth factor receptor mutation.

A 66-year old man with non-smoking history was diagnosed with pulmonary pleomorphic carcinoma of the right lower lobe. The carcinoma metastasized to the brain, lungs, pleura, and mediastinal lymph nodes. It was positive for epidermal growth factor receptor (EGFR) L858R mutation, and tumor cells highly expressed programmed death-ligand 1(PD-L1). Atezolizumab was initiated as the fourth treatment. After three days, he developed cardiac tamponade and immediately underwent pericardial drainage. Computed tomography showed bilateral ground-glass opacity (GGO), significant worsening of multiple lung metastases, and increased size of metastatic lesions. Newly developed metastasis was noted in the lung, and the patient's respiratory condition rapidly deteriorated. He died of respiratory failure on day 13 after atezolizumab administration. The autopsy showed widespread metastasis in all lobes of the bilateral lungs, cardiac tamponade due to carcinomatous pericarditis, carcinomatous lymphangiopathy, and multiple lung metastases, which were thought to be comprehensively the cause of death. These symptoms suggested hyperprogressive disease (HPD). Hence, we report the first case of HPD following atezolizumab therapy for pulmonary pleomorphic carcinoma with EGFR mutation.

Homeless Patients with Lung Cancer in Metropolitan Tokyo.

Background Homeless persons are those who carry out their activities of daily living in city parks and other facilities. Little is known about homeless patients with lung cancer in Japan. Therefore, we characterized the clinical features and outcomes of homeless people in metropolitan Tokyo. Methods Between January 2014 and August 2018, 2,068 homeless patients were admitted to the homeless patient care unit at Tokyo Saiseikai Central Hospital. Of these, 13 patients were treated for primary lung cancer. We retrospectively analyzed the patients' clinical characteristics, including their age, gender, treatment, and outcome, obtained from the hospital's electronic medical records. Results A total of 13 patients were treated for lung cancer. The median age was 66.2 (range, 51-77) years old. Twelve patients (92.3%) were smokers. All of the patients were men and had advanced lung cancer. Of these, four patients had adenocarcinoma, four had squamous carcinoma, and four had other histologies. Ten patients received chemotherapy, and 3 received chemoradiotherapy (carboplatin, n=8; cisplatin, n=2, immune check point inhibitor, n=2; other, n=1). Of the patients on first-line treatment, 58% discontinued treatment, with 71% doing so willfully. The median overall survival was 7.5 (1-44) months. During the study, nine patients died in the hospital, and four were lost to follow up. Conclusion It is difficult for homeless patients to continue chemotherapy, and they often quit therapy willfully. Therefore, it is necessary to develop an education and health insurance support system to ensure treatment continuity in a good social environment.

A Case of Intravascular Diffuse Large B-Cell Lymphoma Initially Suspected as Interstitial Pneumonia Associated With Systemic Scleroderma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL. The patient was a 71-year-old female admitted to our hospital with hypoxia. On admission, chest computed tomography revealed a ground-glass opacity. Interstitial pneumonia associated with systemic scleroderma was suspected because of positive anti-centromere antibody. Thereafter, steroid pulse therapy and plasma exchange were performed. Although ground-glass opacity improved, bilateral pleural effusion appeared, so we performed a random skin biopsy because of her elevated serum lactate dehydrogenase and soluble interleukin-2 receptor levels. The patient was diagnosed with IVLBCL with symptoms improving after 6 cycles of rituximab plus chemotherapy treatment.

A case report of aspergillosis accompanied by saccular bronchodilation after bronchial thermoplasty in a 19-year-old woman.

BACKGROUND: Fungal infections are rarely reported as a complication of bronchial thermoplasty (BT) in patients without immunosuppressive comorbidity. CASE PRESENTATION: A 19-year-old woman college student was admitted to our hospital owing to uncontrolled severe asthma despite using the maximum dose of steroid inhalation. She experienced asthmatic attacks more frequently while cheerleading, which is an extracurricular activity. She received BT because she wanted to continue cheerleading. After the second BT session, she developed more sputum and cough. During the third session, white secretion and saccular bronchodilation appeared in the left lower bronchus. Aspergillus fumigatus was detected in the culture of the bronchial lavage sample, and saccular bronchodilation in the affected bronchus was observed on computed tomography (CT). Five months after the start of oral itraconazole, her subjective symptoms as well as her CT findings improved. Her asthma condition improved enough for the patient to continue cheerleading without exacerbation. CONCLUSIONS: It is necessary to consider the possibility of respiratory tract infections including fungal infections after BT. Detailed observations of the entire bronchus and sample collection for microbial culture are highly recommended.

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.

A case of congenital bronchial atresia patient with subclinical infection who underwent lung resection.

Congenital bronchial atresia, CBA, is rare and has often asymptomatic benign condition. The CBA condition usually arose during the formation of bronchi, but the CBA patients are able to live well into adulthood. This case highlights a potential surgical intervention for a CBA patient with subclinical infection. A 55-year-old Japanese male had abnormal findings on his chest X-ray at an annual health check-up in March 2018. His chest computed tomography (CT) revealed bronchial stenosis and infiltrative shadow in the right inferior lobe. He was referred to our hospital for further investigation and was diagnosed CBA after a variety of examinations including bronchoscopy. His dilated bronchi were filled with mucus, the end of one of the bronchi had obstructive pneumonia, and subclinical infection in the CBA lesion was suspected. Also, the result of bronchoscopy disclosed intrabronchial infection with Gram-positive bacteria so we performed lobectomy onto the lower lobe. Although no protocol had been established, a surgical intervention would be necessary for this case.

A phase II trial of induction of erlotinib followed by cytotoxic chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer patients.

BACKGROUND: No consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. METHODS: In this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150 mg/day for 3 months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS). RESULTS: Twenty patients were enrolled in this study. The median age was 63 years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8-63.2), the overall RR was 55.0%, and the median PFS was 10.7 months in the intention-to-treat (ITT) population. Grade 3-4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%). CONCLUSIONS: The primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment. CLINICAL TRIALS REGISTRATION NUMBER: UMIN ID: 000013125.