[BRONCHOPULMONARY ASPERGILLOSIS WITH COMORBID GRANULOMATOUS POLYANGIITIS IN A PATIENT WHO PRESENTED WITH EXOPHTHALMOS: A CASE REPORT].

There have been no reports of the coexistence of allergic bronchopulmonary aspergillosis (ABPA) and granulomatosis with polyangiitis (GPA). The first case of ABPA with comorbid GPA that developed exophthalmos is reported. A 69-year-old man was referred to our hospital for exophthalmos, fever, anorexia and weight loss. The patient had been diagnosed with ABPA six years earlier, which had been repeatedly treated but recurred with oral corticosteroids with or without antifungal therapy. The laboratory data on referral showed elevations of the white blood cell count, C-reactive protein and specific immunoglobulin E against Aspergillus fumigatus, but antineutrophil cytoplasmic antibody was not positive. Urinalysis showed proteinuria. Paranasal sinus and chest computed tomography showed sinusitis with osteochondral destruction, bronchiectasis, mucus plugging, and a pulmonary nodule. Orbital magnetic resonance imaging showed swelling of the medial rectus muscle and peripheral mass. The intraorbital tissue biopsy showed a necrotic granuloma and necrotizing vasculitis. The patient was diagnosed with GPA, on the basis of the Ministry of Health, Labour and Welfare's criteria of Japan. The patient was treated with induction therapy consisting of glucocorticoids and rituximab, and his symptoms improved. Though the pathogenesis common to ABPA and GPA remains unknown, neutrophilic inflammation induced by airway Aspergillus persistent infection might be involved. Study of further cases is needed.

Efficacy of dupilumab for severe chronic rhinosinusitis with nasal polyps and asthma: A prospective study.

BACKGROUND: Dupilumab exerts clinical effects, including improved sinus opacification, olfactory function, and quality of life, in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNPs). Meanwhile, only a few studies have reported its effects on nasal airway resistance and olfactory function, particularly in the Japanese population. Predictors of response remain unclear. OBJECTIVE: To assess the comprehensive efficacy and therapeutic response to dupilumab in patients with severe CRSwNP with comorbid asthma. METHODS: In 16 adult patients with severe CRSwNP with comorbid asthma, the efficacy of 48-week dupilumab treatment, including olfactory function measured by a T&T olfactometer, nasal airway resistance measured by rhinomanometry, nasal polyp score, Lund-Mackay computed tomography score, and 22-item Sinonasal Outcome Test (SNOT-22), was assessed. Regarding asthma, the annualized rate of exacerbations, 7-item Asthma Control Questionnaire (ACQ-7), and spirometry were assessed. Treatment responsiveness was analyzed. RESULTS: With 48-week dupilumab treatment, olfactory function, nasal airway resistance, nasal polyp score, Lund-Mackay computed tomography score, and SNOT-22 scores improved significantly. Regarding comorbid asthma, the annualized rate of exacerbations decreased, and ACQ-7 scores and lung function improved significantly. According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2020/European Forum for Research and Education in Allergy and Airway Diseases criteria, 15 patients (94%) were moderate-to-excellent responders at 48 weeks of treatment. Patients with higher SNOT-22 scores, ACQ-7 scores, the rate of asthma exacerbations in the previous year, and blood eosinophil counts benefited more from the treatment. CONCLUSION: Dupilumab improved upper and lower airway outcomes especially in patients with severe CRSwNP with comorbid, poorly controlled asthma. TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000038669.

Successful treatment of simultaneous malignant pleural mesothelioma and pulmonary adenocarcinoma: A case report.

The present report described the case of a 74-year-old male patient with asbestos exposure whose chest computed tomography revealed a right lower lobe nodule and right pleural effusion. Pleural biopsy led to the diagnosis of epithelial malignant pleural mesothelioma (cT2N0M0, stage IB). Combination therapy with cisplatin + pemetrexed led to the complete remission of malignant pleural mesothelioma; however, the right lower lobe nodule grew in size over time. The patient was subsequently diagnosed with lung adenocarcinoma (cT1aN0M0, stage IA1) by computed tomography-guided biopsy performed 18 months after chemotherapy initiation and achieved remission of lung adenocarcinoma with stereotactic radiotherapy. The patient was alive without recurrence at the 12-month follow-up. The present case illustrated that multiple active regimens are currently available for malignant pleural mesothelioma and lung cancer that can aid in the treatment of complex cases.

Tracheal Glomus Tumor Complicated with Asthma Exacerbation in a Pregnant Woman.

A 34-year-old pregnant woman in the 34th week of gestation with uncontrolled asthma was admitted because of asthma exacerbation. Although she received bronchodilators and systemic corticosteroids, respiratory failure rapidly progressed. Chest computed tomography revealed a mass occluding approximately 80% of the tracheal lumen. After urgent Caesarean section, endobronchial resection was performed. The pathological findings of the resected tumor were compatible with tracheal glomus tumor. Tracheal tumors are often misdiagnosed as asthma, but its complication with asthma is rare. Even if the diagnosis of asthma is definitive, clinicians should consider coexisting diseases, including tracheal tumors, when asthma control is poor.

An autopsy case of immune-related severe colitis due to long-term use of nivolumab in a patient with non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have been developed as cornerstones of cancer therapy, but the growing use of ICIs has induced immune-related adverse effects (irAEs). Immune-related colitis, which is one of the most common irAEs, generally occurs 2-4 months after ICI treatment initiation and can be life threatening. Therefore, early diagnosis and appropriate management are required. A rare autopsy case of nivolumab-related severe colitis that occurred 34 months after the start of treatment and recurred despite temporal remission with corticosteroids and infliximab is presented. Physicians should be aware of the possibility of late-onset irAEs in patients on receiving long-term ICI treatment.

Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel.

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC50) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment.

Characteristics of the European Thoracic Society/American Thoracic Society severe asthma definition as a determinant of future use of biologics/bronchial thermoplasty.

Background: International guidelines define severe uncontrolled asthma. Biologics or bronchial thermoplasty (Bio/BT) are recommended for such patients. Objectives: To determine which definitions of severe uncontrolled asthma are associated with an additional Bio/BT treatment in patients with severe uncontrolled asthma. Methods: Consecutive 107 asthmatics (including 15 patients for whom Bio/BT was introduced within 3 months after examination), classified as treatment step 4 according to the Global Initiative for Asthma 2015 guideline, were eligible for this analysis. Patients were assessed using the European Thoracic Society/American Thoracic Society (ERS/ATS) severe uncontrolled asthma guideline as defined by these 4 characteristics: poor control (ACT < 20), frequent exacerbations (≥2/yr), admissions (≥1/yr), and airflow limitation (forced expiratory volume in 1 second < 80% of predicted), along with comorbidities, and biomarkers, including blood granulocytes, fractional nitric oxide, and capsaicin cough reflex sensitivity (C-CS). These indices were compared between patients with and without Bio/BT introduction, and multivariate logistic regression analysis was performed to determine the association of the 4 definitions with treatment needs for Bio/BT. Results: Patients who were introduced to Bio/BT had heightened C-CS, heavier smoking history, and a greater prevalence of diabetes mellitus than those without (p < 0.05). Poor asthma control (ACT < 20), frequent exacerbations (≥2/yr), and admissions (≥1/yr) were relevant to the future use of Bio/BT in the multivariate regression analysis. Type 2-related biomarkers including absolute eosinophil counts were higher in patients in the Bio introduction group than in the BT introduction group. Meanwhile, there was no significant difference of the 4 characteristics of severe uncontrolled asthma definition between patients in the Bio and those in the BT groups. Conclusion: Although multiple factors such as treatment cost and asthma phenotypes affect treatment decision-making, the definition of poor asthma control, frequent exacerbations and admission by the ERS/ATS guidelines were important factors for an additional intensive treatment for severe uncontrolled asthma. Trial Registration: UMIN Clinical Trials Registry: UMIN000024734.

Predictive role of CYFRA 21-1 for S-1 monotherapy in non-small cell lung cancer patients.

BACKGROUND: S-1, an oral fluoropyrimidine derivative, is widely used for the treatment of several solid tumors. However, there are no predictive markers for its effectiveness. METHODS: We retrospectively screened 108 patients with advanced non-small cell lung cancer (NSCLC) treated via S-1 monotherapy and investigated its relationship with cytokeratin 19 fragment (CYFRA 21-1) and CEA pretreatment levels. RESULTS: Sixty-one patients with high CYFRA 21-1 levels had a statistically significant shorter progression-free survival (PFS) and overall survival (OS) than 46 patients with normal levels (median PFS = 42 days vs. 70 days, respectively; p = 0.0014; median OS = 197 days vs. 316 days, respectively, p = 0.0239). CONCLUSIONS: Serum CYFRA 21-1 levels have predictive and prognostic roles in the management of patients with advanced NSCLC on S-1 monotherapy.

Differences in the Therapeutic Effect of Chemotherapy Regimens for Concurrent Chemoradiotherapy of Locally Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: The optimal chemotherapy for concurrent chemoradiotherapy (cCRT) of lung cancer is still unclear. PATIENTS AND METHODS: We investigated the therapeutic effect of different chemotherapy regimens for cCRT of lung cancer in 65 patients at our hospital. RESULTS: Of the 65 patients, 53 were male and 12 female. The median age was 64 years and 58 participants had a smoking history. The histological type was adenocarcinoma in 34 cases, squamous cell carcinoma in 22 cases, and others in 9 cases. Induction therapy consisted of cisplatin plus vinorelbine (CDDP+VNR) in 50 cases, and weekly carboplatin plus paclitaxel (CBDCA+PTX) in 15 cases. In all patients, the overall response rate, disease control rate, median progression survival, and median overall survival were 78.5%, 95.4%, 337 days, and 1,037 days, respectively. The median progression-free survival was 337 days in total; it was significantly longer for CDDP+VNR than CBDCA+PTX. The median overall survival was 1,037 days in total; it tended to be slightly longer for CDDP+VNR than CBDCA+PTX. CONCLUSION: Different chemotherapy regimens for cCRT possibly have different therapeutic effects.

Nasal polyp eosinophilia and FeNO may predict asthma symptoms development after endoscopic sinus surgery in CRS patients without asthma.

BACKGROUND: Asthma is a significant comorbidity of eosinophilic chronic rhinosinusitis (CRS). Type2-driven biomarkers such as sinus tissue eosinophilia and fractional nitric oxide (FeNO) may be utilized to detect high risk patients who develop asthma symptoms after endoscopic sinus surgery (ESS) in CRS patients. METHODS: Thirty-six CRS patients without asthma who agreed to undergo ESS between October 2015 and December 2017 were prospectively observed for 12 months following ESS. They were monitored for the development of typical asthma symptoms including dyspnea, wheezes, and cough which responded to anti-asthma medication. Biomarkers were compared between patients who developed asthma symptoms after ESS (asthma symptoms group) and those who did not (non-asthma group). Biomarker changes following ESS intervention were also evaluated. RESULTS: Six patients were lost to follow after ESS. Thus, 30 CRS patients [16 with nasal polyps (NPs) proved by surgery] were followed. Seven (23%) newly complained of asthma symptoms during follow-up. Levels of FeNO and the prevalence of eosinophilic NPs (eosinophils ≥ 70/high power fields) were significantly higher in the asthma symptom group than in non-asthma group [50.7 ppb vs 22.4 ppb for FeNO levels, and 100% (n = 3) vs 23% (n = 3) for eosinophilic NP prevalence, both p < 0.05]. Levels of sputum periostin decreased significantly by ESS in the non-asthma group. However, changes of biomarkers after ESS were comparable between the two groups. CONCLUSIONS: Eosinophils in NPs (≥70/high power fields) and preoperative FeNO may be significant biomarkers for predicting the development of asthma symptoms after ESS.

Eosinophilic Granulomatosis with Polyangiitis Presenting with Central Retinal Artery Occlusion During Treatment with Anti-interleukin-5 Receptor Monoclonal Antibody.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophilic cytoplasm antibody (ANCA)-associated vasculitis characterized by asthma and eosinophilia. Although EGPA involves multiple organs, ocular involvement is infrequent and often carries a poor visual prognosis. We herein report a rare case of EGPA presenting with central retinal artery occlusion (CRAO) in which visual loss developed during treatment with anti-interleukin (IL)-5 receptor monoclonal antibody, and improvement in visual outcomes was attained after treatment combining high-dose oral corticosteroids, cyclophosphamide and an anticoagulant. Physicians should consider CRAO as an ophthalmic manifestation of EGPA in patients with severe eosinophilic asthma.

Moulds and Staphylococcus aureus enterotoxins are relevant allergens to affect Type 2 inflammation and clinical outcomes in chronic rhinosinusitis patients.

BACKGROUND: Sensitisation to moulds and Staphylococcus aureus enterotoxins (SEs) is associated with the pathophysiology of both asthma and chronic rhinosinusitis (CRS). The purpose of this study was to clarify the contribution of sensitisation to these allergens to Type 2 inflammation in the blood, nose and the lower airways, and clinical outcomes in CRS patients. METHODS: We prospectively enrolled 56 CRS patients who underwent endoscopic sinus surgery (ESS) (20 with comorbid asthma) and 28 healthy controls between October 2015 and December 2017. CRS patients were followed up for 12 months after surgery. Type 2 inflammation-related biomarkers were analysed using blood, resected tissue samples and sputum. 10 allergens including Alternaria, Aspergillus and SEs were measured. Type 2 inflammation-related biomarkers and clinical outcomes were compared in the stratification with the presence or absence of allergen sensitisation. RESULTS: Sensitisation rate to moulds and SEs in asthmatic patients was increased when changing the cut-off value of specific IgE titre from 0.35 UA·mL-1 to 0.10 UA·mL-1 (1.7- and 4.5-fold, respectively). Moulds and SEs affected the prevalence of asthma and eosinophilic CRS by interacting with each other. All Type 2 inflammation-related biomarkers except for eosinophils in sinus tissue were significantly higher in patients with mould or SE (mould/SE) sensitisation (≥0.10 UA·mL-1) (n=19) than in those without (n=37) and healthy subjects (all p<0.05). Meanwhile, mould/SE sensitisation did not affect longitudinal changes in clinical outcomes after ESS. Changes in serum mould/SE-IgE levels after ESS remained unclear. CONCLUSION: Mould/SE sensitisation (≥0.10 UA·mL-1) may affect the development of Type 2 inflammation and clinical outcomes in CRS patients.

Nestin Expression Affects Resistance to Chemotherapy and Clinical Outcome in Small Cell Lung Cancer.

Objectives: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cells. Aberrant expression of nestin is linked to poor prognosis in different cancers, including non-small cell lung cancer. However, the association between nestin expression and clinicopathological feature or prognosis has remained unclear for SCLC. This study examined whether nestin expression was associated with malignant features and clinical outcomes in SCLC. Materials and Methods: Using previously established Nestin knock-down cells and a newly established Nestin-overexpressing cell line, we examined the relationship between nestin expression and cell proliferation in vitro and in vivo and chemosensitivity. We also analyzed nestin expression in three drug-resistant lung cancer cell lines. Furthermore, we examined samples from 84 SCLC patients (16 patients with surgical resection, and 68 patients with biopsy), and immunohistochemically analyzed nestin expression. Results: Nestin expression correlated positively with cell proliferation, but negatively with chemosensitivity. Nestin expression in drug-resistant cell lines was upregulated compared to their parental cells. Among the 84 SCLC patients, 24 patients (28.6%) showed nestin-positive tumor. Nestin-positive ratio tended to be higher in operated patients than in biopsied patients. Nestin-positive and -negative patients showed no significant differences in response rate (RR) or progression-free survival (PFS) following first-line chemotherapy. However, positive expression of nestin was associated with shorter PFS following second-line chemotherapy (median PFS: nestin-positive, 81 days vs. nestin-negative, 117 days; P = 0.029). Conclusions: Nestin expression may be associated with malignant phenotype and worse outcome in SCLC patients.

Value of TTF-1 expression in non-squamous non-small-cell lung cancer for assessing docetaxel monotherapy after chemotherapy failure.

Docetaxel is one of the standard second/third-line treatments for non-small-cell lung cancer (NSCLC) following a failed response to prior cytotoxic chemotherapy. The predictive biomarker for the effectiveness of docetaxel therapy remains undetermined. However, thyroid transcription factor-1 (TTF-1) is known to be a good prognostic factor for a variety of chemotherapies. To investigate the association between TTF-1 expression and docetaxel monotherapy outcome, 82 patients with non-squamous NSCLC who received second/third-line docetaxel monotherapy were retrospectively screened. All backgrounds were well-balanced whether or not tumor TTF-1 was expressed, and the present clinical outcomes were similar to those reported by previous clinical studies. A better clinical outcome was indicated in TTF-1 positive compared with TTF-1 negative patients, with disease control rates of 69% vs. 42%, respectively (P=0.03) and median overall survival of 393 days vs. 221.5 days, respectively (P<0.01). Furthermore, progression free survival tended to be longer in TTF-1 positive compared with TTF-1 negative patients (median, 100 days vs. 67 days; P=0.09). Multivariate analysis revealed that TTF-1 positivity was a unique significant predictor for assessing overall survival after docetaxel monotherapy. TTF-1 positivity may be useful for predicting survival outcome in patients who received docetaxel monotherapy after failure of prior chemotherapy.

Increased Serum Periostin Levels and Eosinophils in Nasal Polyps Are Associated with the Preventive Effect of Endoscopic Sinus Surgery for Asthma Exacerbations in Chronic Rhinosinusitis Patients.

BACKGROUND: Eosinophilic nasal polyps (NPs) are associated with the presence of asthma in chronic rhinosinusitis (CRS) patients. Serum periostin has been considered a relevant biomarker for unified airway diseases. OBJECTIVE: To determine the utility of biomarkers including serum periostin that reflects reduction of exacerbations of comorbid asthma in CRS patients. METHODS: We prospectively recruited 56 CRS patients who were subjected to undergo endoscopic sinus surgery (ESS) (20 with asthma) between October 2015 and December 2017 and followed them for 1 year after ESS. Blood eosinophil count, serum periostin, and fractional nitric oxide (FeNO) were measured at enrollment. How these type 2-driven biomarkers reflect comorbid asthma was determined using receiver operating characteristic (ROC) analysis. The frequency of asthma exacerbations during 1 year was counted both before and after ESS. Associations between preoperative biomarkers including eosinophils in NPs and asthma exacerbations were evaluated. RESULTS: Blood eosinophil count, FeNO, and serum periostin levels were significantly higher in CRS patients with asthma than in those without (p < 0.01 for all) and discriminated comorbid asthma among CRS patients (p < 0.05; AUC > 0.80 for all). The increased preoperative serum periostin correlated with lower absolute number of postoperative exacerbations (ρ = -0.49, p = 0.03) and its relative reduction after ESS (ρ = 0.53, p = 0.03) in asthmatic patients. Increased eosinophils in NPs were also associated with reduced asthma exacerbations. CONCLUSION: Preoperative increased serum periostin and eosinophils in NPs are associated with the preventive effect of ESS for asthma exacerbations in CRS patients comorbid with asthma.

Variants of SLC22A16 Predict the Efficacy of Platinum Combination Chemotherapy in Advanced Non-small-cell Lung Cancer.

BACKGROUND: Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored. PATIENTS AND METHODS: This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes. RESULTS: Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model. CONCLUSION: A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.

Acute Eosinophilic Pneumonia Induced by Switching from Conventional Cigarette Smoking to Heated Tobacco Product Smoking.

Acute eosinophilic pneumonia (AEP) is an acute respiratory illness with diffuse pulmonary infiltrates and pulmonary eosinophilia. While the etiology of AEP remains unclear, a relationship between cigarette smoking and AEP onset has been suggested. The use of heated tobacco products (HTPs) has been growing, but the impact of these products on our health is not fully understood. We herein report a case of AEP that developed after switching from conventional cigarette to HTP smoking. The patient's condition improved after the cessation of HTP smoking and corticosteroid treatment initiation. In cases of AEP, physicians should consider HTPs use as a possible cause.

A novel pathophysiologic link between upper and lower airways in patients with chronic rhinosinusitis: Association of sputum periostin levels with upper airway inflammation and olfactory function.

BACKGROUND: Chronic rhinosinusitis (CRS) and asthma are collectively called unified airway diseases. Periostin has been implicated in the pathophysiologic link of these conditions but only by serum measurements. We sought to investigate sputum levels of periostin and their association with upper airway inflammation and olfactory function in CRS patients. METHODS: We prospectively recruited 56 CRS patients who underwent endoscopic sinus surgery (20 with and 36 without comorbid asthma), and 28 healthy controls between October 2015 and December 2017. Lower and upper airway indices such as sputum periostin levels and eosinophil and neutrophil counts, exhaled fractional nitric oxide (FeNO) levels, and olfactory function were evaluated in the three groups. Radiological severity of CT images and tissue eosinophilia of surgical specimens were also assessed in the CRS patients. RESULTS: Sputum periostin levels were highest, and olfactory function was most impaired, in the CRS patients with comorbid asthma, followed by those without asthma and controls in this order. CRS with asthma group showed higher sputum eosinophils and FeNO levels than the other two groups, while CRS patients without asthma showed significantly higher neutrophils in sputum than the other two groups. When confined to CRS patients, olfactory dysfunction was correlated with sputum eosinophil counts. Eosinophil counts of nasal polyps showed a significant positive correlation with sputum periostin and FeNO levels. Radiological severity of CRS was correlated with sputum eosinophil counts and FeNO levels. CONCLUSIONS: Periostin levels and inflammatory cells such as eosinophils and neutrophils in the lower airways are increased in patients with CRS, suggesting the presence of mutual interactions between upper and lower airways even if asthma does not coexist. Olfactory dysfunction and eosinophilic nasal polyps may be potential indicators of Th2-driven inflammation in the lower airways. TRIAL REGISTRATION: This study was registered on the UMIN Clinical Trials Registry (Registry ID UMIN000018672).

A case of non-small cell lung cancer with long-term response after re-challenge with nivolumab.

A 76-year-old man was admitted to our hospital with cough and dyspnea. He was diagnosed with advanced lung cancer. Nivolumab was given as second-line treatment, cytotoxic chemotherapy was given as third-line treatment, and nivolumab re-challenge was given as fourth-line treatment. Thereafter, 41 chemotherapy courses were administered over 2 years. Currently, he is being followed with no recurrence at least 10 months after treatment. Thus, the case of a patient with advanced lung cancer who was previously unsuccessfully treated with nivolumab and then demonstrated a long-term clinical response to a re-challenge with nivolumab after cytotoxic chemotherapy and radiation therapy is presented.

Increased Capsaicin Sensitivity in Patients with Severe Asthma Is Associated with Worse Clinical Outcome.

Rationale: Capsaicin cough reflex sensitivity (C-CS) is associated with poorly controlled asthma, although its association with severe asthma remains unknown.Objectives: To determine the clinical impact of C-CS on severe asthma.Methods: We prospectively enrolled 157 patients with asthma (including 122 patients with severe asthma who were in step 4 or 5 according to the Global Initiative for Asthma 2015 guidelines) between November 2016 and October 2019. A capsaicin cough challenge was performed along with spirometry and assessment of biomarkers. The concentration required to induce at least five coughs by capsaicin was adopted as an index of C-CS. An Asthma Control Test and comorbidities were also evaluated. Associations of biomarkers with four clinical features of severe asthma made by the European Respiratory Society/American Thoracic Society guidelines (poor control [Asthma Control Test < 20; n = 58], frequent exacerbations [≥2/yr; n = 28], admissions [≥1/yr; n = 17], and airflow limitation [FEV1% predicted < 80%; n = 30]) were assessed.Measurements and Main Results: Heightened C-CS was associated with poor asthma control, frequent exacerbations, and admissions, particularly in patients without atopy (n = 54). Meanwhile, C-CS was not related to airflow limitation. Multivariate regression analysis has revealed that heightened C-CS (at least five coughs by capsaicin ≤ 2.44 µM) was a significant risk for poor asthma control and frequent exacerbations. Regarding general factors and comorbidities, ex-smoking status, diabetes mellitus, and chronic rhinosinusitis were associated with clinical features of severe asthma (all P < 0.05).Conclusions: Heightened C-CS is a risk factor for severe asthma. The present study suggests the association of airway neuronal dysfunction with the pathophysiology of non-type 2 severe asthma.