Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres.

There is an unmet need for novel biomarkers in the diagnosis of multifactorial COPD. We applied next-generation proteomics to serum extracellular vesicles (EVs) to discover novel COPD biomarkers. EVs from 10 patients with COPD and six healthy controls were analysed by tandem mass tag-based non-targeted proteomics, and those from elastase-treated mouse models of emphysema were also analysed by non-targeted proteomics. For validation, EVs from 23 patients with COPD and 20 healthy controls were validated by targeted proteomics. Using non-targeted proteomics, we identified 406 proteins, 34 of which were significantly upregulated in patients with COPD. Of note, the EV protein signature from patients with COPD reflected inflammation and remodelling. We also identified 63 upregulated candidates from 1956 proteins by analysing EVs isolated from mouse models. Combining human and mouse biomarker candidates, we validated 45 proteins by targeted proteomics, selected reaction monitoring. Notably, levels of fibulin-3, tripeptidyl-peptidase 2, fibulin-1, and soluble scavenger receptor cysteine-rich domain-containing protein were significantly higher in patients with COPD. Moreover, six proteins; fibulin-3, tripeptidyl-peptidase 2, UTP-glucose-1-phosphate uridylyl transferase, CD81, CD177, and oncoprotein-induced transcript 3, were correlated with emphysema. Upregulation of fibulin-3 was confirmed by immunoblotting of EVs and immunohistochemistry in lungs. Strikingly, fibulin-3 knockout mice spontaneously developed emphysema with age, as evidenced by alveolar enlargement and elastin destruction. We discovered potential pathogenic biomarkers for COPD using next-generation proteomics of EVs. This is a novel strategy for biomarker discovery and precision medicine.

A case of simultaneous occurrence of hepatitis and pancreatitis during the combination immunochemotherapy for non-small cell lung carcinoma.

Immune checkpoint inhibitors (ICIs) improved the prognosis of patients with advanced lung cancers. The combination therapy of cytotoxic drugs and ICI is approved as first-line chemotherapy in non-small-cell lung cancer (NSCLC) and extensive disease small-cell lung cancer (ED-SCLC). It has been reported various immune-related adverse events (irAEs). We herein report a 65-year-old man with NSCLC who developed hepatitis and pancreatitis simultaneously during the combination immunochemotherapy. In the treatment of hepatitis and pancreatitis, the clinical course was different. In this report, the importance of accurate diagnosis through detailed examination and treatment priority depending on the severity of the symptoms is indicated.

A lung abscess caused by secondary syphilis - the utility of polymerase chain reaction techniques in transbronchial biopsy: a case report.

BACKGROUND: In Japan and other countries, the number of patients with syphilis is increasing year by year. Recently, the cases of the pulmonary involvement in patients with secondary syphilis have been reported. However, it is still undetermined how to obtain a desirable specimen for a diagnosis of the pulmonary involvement, and how to treat it if not cured. CASE PRESENTATION: A 34-year-old man presented with cough and swelling of the right inguinal nodes. A physical examination revealed erythematous papular rash over the palms, soles and abdomen. A 4 cm mass in the right lower lobe of the lung was detected on computed tomography. He was diagnosed as having secondary syphilis, because he was tested positive for the rapid plasma reagin and Treponema pallidum hemagglutination assay. Amoxycillin and probenecid were orally administered for 2 weeks. Subsequently, rash and serological markers were improved, however, the lung mass remained unchanged in size. Transbronchial biopsy (TBB) confirmed the pulmonary involvement of syphilis using polymerase chain reaction techniques (tpp47- and polA-PCR). Furthermore, following surgical resection revealed the lung mass to be an abscess. CONCLUSIONS: To our knowledge, this is the first surgically treated case of a lung abscess caused by syphilis, which was diagnosed by PCR techniques in TBB. This report could propose a useful diagnostic method for the pulmonary involvement of syphilis.

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

BACKGROUND: The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events. METHODS: To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up. RESULTS: Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response. CONCLUSIONS: Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623. FUNDING: This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).

[A Case of Mediastinal Small Cell Lung Cancer in a Patient Receiving Mechanical Ventilation Who Was Successfully Treated with Chemotherapy and Finally Extubated].

BACKGROUND: The efficacy and safety of chemotherapy for patients with lung cancer who are in need of intensive care, such as invasive mechanical ventilation, have not been established. CASE: A 59-year-old woman consulted a doctor with complaints of dyspnea.She was intubated because of acute respiratory failure and transferred to our hospital.Enhanced CT images revealed advanced stenosis of her trachea due to a bulky mediastinal tumor.Cervical lymph node biopsy was performed, and she was diagnosed with mediastinal small cell lung cancer.She received combination chemotherapy with carboplatin and etoposide along with invasive mechanical ventilation.Chemotherapy was effective, and extubation was performed under careful bronchoscopic observation.Her general condition improved gradually, and she was discharged from our hospital on foot with ambulatory chemotherapy. CONCLUSION: Even though patients with lung cancer develop respiratory failure and need invasive mechanical ventilation, they may be treated with effective chemotherapy and may be weaned from ventilation.

Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging.

Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging, but the mechanism remains unclear. Tetraspanins have emerged as key players in malignancy and inflammatory diseases. Here, we found that CD9/CD81 double knockout (DKO) mice with a COPD-like phenotype progressively developed a syndrome resembling human aging, including cataracts, hair loss, and atrophy of various organs, including thymus, muscle, and testis, resulting in shorter survival than wild-type (WT) mice. Consistent with this, DNA microarray analysis of DKO mouse lungs revealed differential expression of genes involved in cell death, inflammation, and the sirtuin-1 (SIRT1) pathway. Accordingly, expression of SIRT1 was reduced in DKO mouse lungs. Importantly, siRNA knockdown of CD9 and CD81 in lung epithelial cells additively decreased SIRT1 and Foxo3a expression, but reciprocally upregulated the expression of p21 and p53, leading to reduced cell proliferation and elevated apoptosis. Furthermore, deletion of these tetraspanins increased the expression of pro-inflammatory genes and IL-8. Hence, CD9 and CD81 might coordinately prevent senescence and inflammation, partly by maintaining SIRT1 expression. Altogether, CD9/CD81 DKO mice represent a novel model for both COPD and accelerated senescence.

Evaluation of Natriuretic Peptide in Non-small Cell Lung Cancer Patients Treated with Bevacizumab Together with Carboplatin-Paclitaxel: A Prospective Study.

AIM: To identify predictive markers for efficacy of combination bevacizumab and carboplatin-paclitaxel treatment in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty patients received carboplatin (area under the concentration-time curve (AUC) 6 mg/ml×min) and paclitaxel (200 mg/m2) with bevacizumab (15 mg/kg) on day 1 of a 21-day cycle. After four cycles of induction therapy, patients received bevacizumab maintenance therapy until disease progression or unacceptable toxicity occurred. Plasma and serum samples (baseline, day 8 and before cycle 2) were analyzed for natriuretic peptide content. RESULTS: Plasma brain natriuretic peptide (BNP) levels were significantly decreased at day 8 (20.1±4.0 pg/ml vs. 9.1±1.8 pg/ml, p=0.0002). Patients whose plasma BNP level was reduced to <50% of the baseline at day 8 had a longer progression-free survival (PFS) than those with a less decrease (9.73 versus 2.63 months, p=0.00013). In multivariate Cox analysis, decrease of plasma BNP concentration was associated with a longer PFS (p=0.0022). CONCLUSION: Decrease of plasma BNP concentration correlated with PFS after a treatment of combination bevacizumab plus carboplatin-paclitaxel.

Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: Two Case Reports.

RATIONALE: Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases. Osimertinib is a third-generation oral, potent, and irreversible EGFR-TKI. It can bind to EGFRs with high affinity even when the EGFR T790M mutation exists in addition to the sensitizing mutations. Its clinical efficacy for NSCLC patients harboring the T790M mutation has already been shown; however, the evidence of osimertinib on brain metastases has not been documented well, especially in terms of the appropriate timing for treatment and its response evaluation. PATIENT CONCERNS, DIAGNOSES, AND INTERVENTIONS: We experienced 2 NSCLC patients with the EGFR T790M mutation; a 67-year-old woman with symptomatic multiple brain metastases administered osimertinib as seventh-line chemotherapy, and a 76-year old man with an asymptomatic single brain metastasis administered osimertinib as fifth-line chemotherapy. OUTCOMES: These patients showed great response to osimertinib within 2 weeks without radiation therapy. LESSONS: These are the first reports to reveal the rapid response of the brain metastases to osimertinib within 2 weeks. These cases suggest the possibility that preemptive administration of osimertinib may help patients to postpone or avoid radiation exposures. In addition, rapid reassessment of the effect of osimertinib on brain metastases could prevent patients from being too late to receive essential radiotherapy.

Successful treatment with gefitinib after Stevens-Johnson syndrome associated with afatinib therapy in a patient with adenocarcinoma of the lung.

We report a case of a 65-year-old woman with stage IV lung adenocarcinoma who experienced Stevens-Johnson syndrome (SJS) during afatinib therapy. The patient received afatinib as the first-line therapy after the confirmation of harboring an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene. The patient presented with multiple erythematous papules mainly on the body trunk and thigh 32 days after afatinib administration. Subsequently, diffuse erosions of oral mucosa and purpuric macules with flat atypical targets emerged. Skin biopsy specimen showed the histology compatible with epidermal necrosis and the patient was diagnosed as having SJS. The symptoms of SJS were recovered by systemic steroid and immunoglobulin treatment. Gefitinib was administered as the third-line therapy after the second-line therapy with carboplatin plus pemetrexed had failed. Tumor shrinkage was obtained shortly and has been maintained without the recurrence of SJS. Rechallenge of tyrosine kinase inhibitor by gefitinib could be an alternative treatment option in patients who experienced SJS by afatinib.

Exogenous lipoid pneumonia caused by repeated sesame oil pulling: a report of two cases.

BACKGROUND: Exogenous lipoid pneumonia is a rare disease caused by aspiration or inhalation of oily substances. CASE PRESENTATION: A 66-year-old male with dry cough (Case 1) and a 38-year-old female with shortness of breath (Case 2) demonstrated ground-glass opacities on chest computed tomography and were diagnosed with lipoid pneumonia based on the confirmation of lipid-laden alveolar macrophages. Both patients habitually performed sesame oil pulling via nasal or mouth washing for several months prior to the diagnosis. CONCLUSION: Steroid therapy and bronchoalveolar lavage resulted in improvement in Case 1, and no intensive therapy was required for Case 2. Sesame oil pulling has been rarely been reported to cause lipoid pneumonia.

Nuclear survivin expression in small cell lung cancer.

BACKGROUND/AIM: Little evidence exists regarding a relationship between survivin expression and prognosis in small cell lung cancer (SCLC). We investigated the relationship between survivin expression, clinical characteristics and prognosis in SCLC patients. MATERIALS AND METHODS: We retrospectively reviewed medical records of study patients and analyzed their tumor sections using nuclear survivin labeling index (LI). RESULTS: A significant correlation between nuclear survivin LI and clinical stage was found (p=0.012). In multivariate analysis, a significant association was found between survival and clinical stage (hazard ratio (HR)=2.09; 95 % confidence interval (CI)=1.08-4.31; p=0.027) but not between survival and nuclear survivin LI (HR=0.96; 95 % CI=0.91-1.02; p=0.2). CONCLUSION: We did not find any positive relationship between nuclear survivin expression and survival in SCLC patients. Conversely, we found a positive relationship between clinical stage and nuclear survivin LI, which is considered to be useful in deciding treatment strategies.