Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles.

BACKGROUND: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases. METHODS: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort. RESULTS: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80). CONCLUSIONS: Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab.

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.

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.

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 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.

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.

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.

The first case of micropapillary adenocarcinoma associated with cystic airspace in a non-smoking man.

Lung cancers associated with cystic airspaces are attracting increasing attention because of delayed diagnosis. The cancers that usually occur in smokers comprise lepidic, papillary, and/or acinar adenocarcinoma, but a micropapillary type has not been described to date. Pulmonary micropapillary adenocarcinoma was added to the 2015 World Health Organization (WHO) classification system as a new subtype with a notably poor prognosis. We describe the first micropapillary adenocarcinoma of the lung associated with cystic airspaces in a 79-year-old non-smoking man.

A case of central neurogenic hyperventilation without tachypnoea.

Central neurogenic hyperventilation (CNH) is a rare condition, with 37 cases reported in the literature to date. The underlying mechanisms remain unclear. Primary central nervous system lymphoma (PCNSL) is the most common cause of CNH, with 17 cases reported so far. Among these, CNH was usually accompanied by tachypnoea. Only two cases, including the present case, showed CNH with normal respiratory rate. Here, we present a case of PCNSL-induced CNH in a 60-year-old man. Magnetic resonance imaging of the brain demonstrated hyperintensity of the left cerebral cortex, basal ganglia, corona radiata, midbrain, and ventral pons on fluid-attenuated inversion recovery. The patient complained of dyspnoea and showed hyperventilation without tachypnoea on admission or during hospitalization. Examining CNH cases without tachypnoea and comparing those cases to cases of CNH with tachypnoea might provide new insights into the mechanisms of CNH. Moreover, it should be remembered that CNH can occur without tachypnoea.

Gastric perforation related to concurrent use of nintedanib and ramucirumab.

The prevalence of lung cancer in idiopathic pulmonary fibrosis (IPF) patients ranges from 9.8 to 38%. Nintedanib, a small molecule receptor tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR), has been approved for IPF after phase III INPULSIS trials in 2014. Ramucirumab, a monoclonal antibody for VEGFR-2, combined with docetaxcel, has been approved for advanced non-small cell lung cancer (NSCLC) after the phase III REVEL trail in 2014. Physicians will have more IPF patients being treated with nintedanib, who subsequently develop NSCLC, and therefore will likely be treated with ramucirumab plus docetaxel. We report the first case of 70-year-old man taking nintedanib for his IPF and treated with ramucirumab plus docetaxel as a seventh-line therapy for his pulmonary adenocarcinoma. On day 15 of his chemotherapy treatment cycle 2, after taking nintedanib for nine days, he developed gastric perforation.

Interactions between salivary Bifidobacterium adolescentis and other oral bacteria: in vitro coaggregation and coadhesion assays.

Coaggregation assays were performed to investigate interactions between oral Bifidobacterium adolescentis and other oral bacterial species. Bifidobacterium adolescentis OLB6410 isolated from the saliva of healthy humans did not coaggregate with Actinomyces naeslundii JCM8350, Streptococcus mitis OLS3293, Streptococcus sanguinis JCM5708, Veillonella parvula ATCC17745 or Porphyromonas gingivalis OB7124, but it did coaggregate with Fusobacterium nucleatum JCM8532. Subsequent examination of biofilm formation on saliva-coated hydroxyapatite discs using FISH revealed that B. adolescentis OLB6410 could not directly adhere to the coated discs. It did, however, adhere to biofilms of A. naeslundii, V. parvula, and F. nucleatum, although it did not coaggregate with A. naeslundii nor with V. parvula. These results suggest that the adhesion of B. adolescentis to tooth surfaces is mediated by other oral bacteria. Heat- or proteinase K-treated F. nucleatum could not coaggregate with B. adolescentis. Similarly, the coaggregation and coadhesion of proteinase K-treated B. adolescentis were strongly inhibited. It is therefore probable that proteinaceous factors on the cellular surface of B. adolescentis and F. nucleatum are involved in their interaction. The data presented in this study add to our understanding of bifidobacterial colonization in the human oral cavity.

Heme oxygenase-1 inhibits cytokine production by activated mast cells.

Heme oxygenase-1 (HO-1) is thought to contribute to host defense reactions against various stresses. In addition, recent reports have suggested that HO-1 modulates immunocyte activation and functions. HO-1 suppresses mast cell degranulation, but whether HO-1 suppresses cytokine synthesis as well is not yet known. We examined whether rat HO-1 cDNA transfected rat basophilic leukemia (RBL)-2H3 cells have altered cytokine production in response to stimulation with anti-ovalbumin (OA) serum/OA compared to Mock transfected RBL-2H3 cells. HO-1 inhibited anti-OA serum/OA-induced IL-3 and TNF-alpha production. Inhibition of HO-1 activity by Zn (II) protoporphyrin IX, a specific HO-1 inhibitor, prevented the suppression of TNF-alpha production. The cytokine inhibition by HO-1 was associated with selective suppression of the DNA-binding activity of AP-1 transcription factors. The suppression of mast cell cytokine production by HO-1 may be an important aspect of the processes that lead to resolution of allergic inflammation.