Association between skin toxicity and efficacy of necitumumab in squamous non-small-cell lung cancer: a pooled analysis of two randomized clinical trials-SQUIRE and JFCM.

BACKGROUND: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM). MATERIALS AND METHODS: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints. RESULTS: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity. CONCLUSIONS: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.

Predicting the Readmission and Mortality in Older Patients Hospitalized with Pneumonia with Preadmission Frailty.

BACKGROUND: In older people, frailty has been recognized as an important prognostic factor. However, only a few studies have focused on multidimensional frailty as a predictor of mortality and readmission among inpatients with pneumonia. OBJECTIVE: The present study aimed to assess the association between preadmission frailty and clinical outcomes after the hospitalization of older patients with pneumonia. DESIGN: Single-center, retrospective case-control study. SETTING: Acute phase hospital at Kobe, Japan. PARTICIPANTS: The present study included 654 consecutive older inpatients with pneumonia. MEASUREMENTS: Frailty status before admission was assessed using total Kihon Checklist (KCL) score, which has been used as a self-administered questionnaire to assess comprehensive frailty, including physical, social, and cognitive status. The primary outcome was a composited 6-month mortality and readmission after discharge. RESULTS: In total, 330 patients were analyzed (median age: 79 years, male: 70.4%, median total KCL score: 10 points), of which 68 were readmitted and 10 died within 6 months. After multivariate analysis, total KCL score was associated with a composited 6-month mortality and readmission (adjusted hazard ratio, 1.07; 95% confidence interval, 1.02-1.12; p = 0.006). The cutoff value for total KCL score determined by receiver operating characteristic curve analysis was 15 points (area under the curve = 0.610). The group with a total KCL score ≥ 15 points had significantly higher readmission or mortality rates than the groups with a total KCL score < 15 points (p < 0.001). CONCLUSIONS: Preadmission frailty status in older patients with pneumonia was an independent risk factor for readmission and survival after hospitalization.

Identification of patterns of factors preceding severe or life-threatening asthma exacerbations in a nationwide study.

BACKGROUND: Reducing near-fatal asthma exacerbations is a critical problem in asthma management. OBJECTIVES: To determine patterns of factors preceding asthma exacerbations in a real-world setting. METHODS: In a nationwide prospective study of 190 patients who had experienced near-fatal asthma exacerbation, cluster analysis was performed using asthma symptoms over the 2-week period before admission. RESULTS: Three distinct clusters of symptoms were defined employing the self-reporting of a visual analogue scale. Cluster A (42.1%): rapid worsening within 7.4 hours from moderate attack to admission, young to middle-aged patients with low Body mass index and tendency to depression who had stopped anti-asthma medications, smoked, and hypersensitive to environmental triggers and furred pets. Cluster B (40.0%): fairly rapid worsening within 48 hours, mostly middle-aged and older, relatively good inhaled corticosteroid (ICS) or ICS/long-acting beta-agonist (LABA) compliance, and low perception of dyspnea. Cluster C (17.9%): slow worsening over 10 days before admission, high perception of dyspnea, smokers, and chronic daily mild-moderate symptoms. There were no differences in overuse of short-acting beta-agonists, baseline asthma severity, or outcomes after admission for patients in these 3 clusters. CONCLUSION: To reduce severe or life-threatening asthma exacerbation, personalized asthma management plans should be considered for each cluster. Improvement of ICS and ICS/LABA compliance and cessation of smoking are important in cluster A. To compensate for low perception of dyspnea, asthma monitoring of peak expiratory flow rate and/or exhaled nitric oxide would be useful for patients in cluster B. Avoidance of environmental triggers, increase usual therapy, or new anti-type 2 response-targeted therapies should be considered for cluster C.

IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.

BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Severe or life-threatening asthma exacerbation: patient heterogeneity identified by cluster analysis.

BACKGROUND: Severe or life-threatening asthma exacerbation is one of the worst outcomes of asthma because of the risk of death. To date, few studies have explored the potential heterogeneity of this condition. OBJECTIVES: To examine the clinical characteristics and heterogeneity of patients with severe or life-threatening asthma exacerbation. METHODS: This was a multicentre, prospective study of patients with severe or life-threatening asthma exacerbation and pulse oxygen saturation < 90% who were admitted to 17 institutions across Japan. Cluster analysis was performed using variables from patient- and physician-orientated structured questionnaires. RESULTS: Analysis of data from 175 patients with severe or life-threatening asthma exacerbation revealed five distinct clusters. Cluster 1 (n = 27) was younger-onset asthma with severe symptoms at baseline, including limitation of activities, a higher frequency of treatment with oral corticosteroids and short-acting beta-agonists, and a higher frequency of asthma hospitalizations in the past year. Cluster 2 (n = 35) was predominantly composed of elderly females, with the highest frequency of comorbid, chronic hyperplastic rhinosinusitis/nasal polyposis, and a long disease duration. Cluster 3 (n = 40) was allergic asthma without inhaled corticosteroid use at baseline. Patients in this cluster had a higher frequency of atopy, including allergic rhinitis and furred pet hypersensitivity, and a better prognosis during hospitalization compared with the other clusters. Cluster 4 (n = 34) was characterized by elderly males with concomitant chronic obstructive pulmonary disease (COPD). Although cluster 5 (n = 39) had very mild symptoms at baseline according to the patient questionnaires, 41% had previously been hospitalized for asthma. CONCLUSIONS & CLINICAL RELEVANCE: This study demonstrated that significant heterogeneity exists among patients with severe or life-threatening asthma exacerbation. Differences were observed in the severity of asthma symptoms and use of inhaled corticosteroids at baseline, and the presence of comorbid COPD. These findings may contribute to a deeper understanding and better management of this patient population.

Clinical Features and Outcomes of Diffuse Alveolar Hemorrhage During Antithrombotic Therapy: A Retrospective Cohort Study.

PURPOSE: Antithrombotic therapy could trigger diffuse alveolar hemorrhage (DAH), and there are several case reports of DAH that occurred during antithrombotic therapy (DAH-AT). However, little is known about the clinical features and outcomes of DAH-AT. The purpose of this study was to clarify the features and mortality of DAH-AT. METHODS: 76 consecutive patients with DAH who were admitted to our hospital between January 2003 and April 2014 were retrospectively reviewed to identify the clinical features and outcomes of DAH-AT. The primary outcome was 90-day mortality. RESULTS: Of the 76 patients with DAH, 39 patients (51 %) had DAH-AT, and 37 patients (49 %) had DAH that occurred with no antithrombotic therapy (DAH-NAT). Of the patients with DAH-AT, 25 (64 %) were taking aspirin, 14 (36 %) were taking warfarin, 5 (13 %) were taking clopidogrel sulfate, and 4 (10 %) were taking cilostazol. Pre-existing cardiac disease was present in 23 (59 %) DAH-AT cases and 5 (14 %) DAH-NAT cases. Logistic regression analysis was used to assess the effect of antithrombotic therapy on the mortality of DAH patients, and no significant difference in survival was seen with antithrombotic therapy (OR 1.18, 95 % CI 0.38-3.78). CONCLUSIONS: Antithrombotic therapies had no effect on the 90-day mortality of DAH patients.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Non-invasive ventilation in severe asthma attack, its possibilities and problems.

Asthma attack is characterized by episodic attacks of cough, dyspnea and wheeze occurring due to bronchoconstriction, airway hyperresponsiveness and mucous hypersecretion. Although nationwide clinical guidelines have been published to establish the standard care of asthma, choices in the treatment of fatal asthma attacks remain of clinical significance. Especially, in a severe asthma attack, despite the application of conventional medical treatment, respiratory management is critical. Even though non-invasive ventilation (NIV) has been shown to be effective in a wide variety of clinical settings, reports of NIV in asthmatic patients are scarce. According to a few prospective clinical trials reporting promising results in favour of the use of NIV in a severe asthma attack, a trial of NIV prior to invasive mechanical ventilation seems acceptable and may benefit patients by decreasing the need for intubation and by supporting pharmaceutical treatments. Although selecting the appropriate patients for NIV use is a key factor in successful NIV application, how to distinguish such patients is quite controversial. Larger high quality clinical trails are urgently required to confirm the benefits of NIV to patients with severe asthma attack. In this article, we focus on the body of evidence supporting the use of NIV in asthma attacks and discuss its advantages as well its problems.

[Lobectomy for local recurrence following stereotactic radiotherapy to non-small cell lung cancer].

A 78-year-old man had non-small cell lung cancer (NSCLC) in the left upper lobe (squamous cell carcinoma, cT1N0M0). He preferred less invasive treatment and undertook stereotactic radiotherapy (SRT)[48 Gy/4 Fr] because his forced expiratory volume in 1 second percent (FEV1.0%) was 53.50%. The therapeutic effect was partial response and the adverse reaction was dermatitis (grade 1). Seven months after SRT, local recurrence was detected. The tumor was growing from 3 x 5 mm to 25 x 25 mm in size. Nine months after SRT, left upper lobectomy was performed successfully unaffected by SRT. He is doing well 14 months after the operation without any signs of recurrence. This case might help develop a new strategy for the treatment of stage I NSCLC. It is that patients with stage I NSCLC have SRT as 1st line treatment, and if local recurrence is observed after SRT, lobectomy may be performed.

[Effect of fluticasone propionate at half dose of beclomethasone dipropionate divided twice daily and once daily in asthmatics inhaling beclomethasone dipropionate 800 micrograms daily or more].

We conducted a 12 weeks' single-arm prospective study comparing beclomethasone dipropionate (BDP), 1/2 doses of fluticasone propionate (FP) twice daily and the same dose of FP once daily in 47 asthmatics who had been inhaling BDP 800 mcg daily or more. Peak expiratory flow (PEF), FEV1, a symptom score and a frequency of beta 2 agonist were all significantly better in FP twice daily phase than BDP phase (329 vs. 306 L/min, 1.87 vs. 1.76 L, 3.6 vs. 6.0/week and 2.7 vs. 4.5 puffs/day, respectively). There was no significant difference in these endpoints between FP twice daily phase and FP once daily phase. FP twice daily produced better plumonary function and symptom relief than the double doses of BDP. Furthermore, FP twice daily could, at least in a short-term basis, safely be changed into the same doses of FP once daily.

A comparative analysis of ABC transporters in complete microbial genomes.

The ABC transporter is a major class of cellular translocation machinery in all bacterial species encoded in the largest set of paralogous genes. The operon structure is frequently found for the genes of three molecular components: the ATP-binding protein, the membrane protein, and the substrate-binding protein. Here, we developed an "ortholog group table" by comparison and classification of known and putative ABC transporters in the complete genomes of seven microorganisms. Our procedure was to first search and classify the most conserved ATP-binding protein components by the sequence similarity and then to classify the entire transporter units by examining the similarity of the other components and the conservation of the operon structure. The resulting 25 ortholog groups of ABC transporters were well correlated with known functions. Through the analysis, we could assign substrate specificity to hypothetical transporters, predict additional transporter operons, and identify novel types of putative transporters. The ortholog group table was also used as a reference data set for functional assignment in four additional genomes. In general, the ABC transporter operons were strongly conserved despite the extensive shuffling of gene locations in bacterial evolution. In Synechocystis, however, the tendency of forming operons was clearly diminished. Our result suggests that the ancestral ABC transporter operons may have arisen early in evolution before the speciation of bacteria and archaea.

[Eosinophil count in induced sputum samples as a marker of airway inflammation and adequacy of corticosteroid inhalation treatment in asthmatic patients].

We tried to use eosinophil counts in induced sputum samples as a marker of airway inflammation, and as a guide for reducing inhaled corticosteroids in patients with well-controlled persistent asthma. The eosinophil count in induced sputum smears was defined as follows: Eos%; eosinophil percentage of 200-400 leukocytes in properly cell-separated fields, TEC; total eosinophil counts in the 5 most eosinophil-dense high power view fields (x 400). First, the eosinophil count in induced sputum samples was compared between 29 asthmatic subjects treated with inhaled corticosteroid and 15 age- and sex-matched healthy controls. Second, inhaled corticosteroid was reduced by 50% in 20 patients with green-zone asthma (morning PEF > 80% of patient's best PEF). PEF measurements were followed prospectively for 12 weeks thereafter. Once PEF decreased below 70% of their best PEF, subjects were considered as treatment "failures". Both Eos% and TEC were significantly higher than in the controls, even in well-controlled (morning PEF > 80% of their best) asthmatic patients (p = 0.001, 0.03). The chance of treatment "failure" was significantly higher in those having more eosinophils (Eos% > 10%, TEC > 100) in their initial induced sputum sample (p = 0.03, 0.001). Airway inflammation still persists in many well-controlled chronic asthmatic patients, and induced sputum eosinophilia predicts an early decrease of PEF after reduction of inhaled corticosteroids.