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.

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.

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.

[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.

Is Baker's cyst a risk factor for pulmonary embolism?

We encountered a 73-year-old man with acute pulmonary embolism (PE) and Baker's cyst. Venography revealed that the right popliteal vein was compressed by Baker's cyst and deep venous thrombosis (DVT) had developed. DVT associated with Baker's cyst is rather common and these two conditions are thought to be causally related. Baker's cyst is the most frequent mass lesion in the popliteal region. We suggest that Baker's cyst is a risk factor for PE as well as surgery and trauma.

[Dermatomyositis complicated by sarcoidosis].

We encountered a patient with dermatomyositis complicated by sarcoidosis. A 57-year-old woman was admitted to our hospital because of fever dry cough, and myalgias. There were reticular shadows on her chest X-ray film. Although the typical skin rash and myositis suggested the diagnosis of dermatomyositis biopsy specimens from a salivary gland, muscle, and lung revealed noncaseating granulomas as well. Uveitis was also noted. These findings suggested the coexistence of sarcoidosis with dermatomyositis. Examination of the lung-biopsy specimens showed interstitial pneumonia compatible with dermatomyositis, except for the granuloma. The typical rash of dermatomyositis and pathological findings of the lung specimen were inconsistent with sarcoidosis. Therefore we concluded that this patient had both dermatomyositis and sarcoidosis. This case sheds new light on the importance of pathological examinations.

[A case of lung cancer with choroidal metastasis].

A 72-year-old woman was admitted to our hospital because of a mass shadow in the left upper lobe on chest roentgenograms. She had noticed floaters in both visual fields 2 months before admission. Percutaneous aspiration of the lung lesion was done, and revealed poorly differentiated squamous cell carcinoma. Metastatic tumors were noted in the choroid of both eyes and in both kidneys. These lesions responded partially to systemic chemotherapy and the floaters disappeared. There have been few reports of metastatic choroidal tumors, but most cite the lung and the breast as the primary sites. We should pay attention to ophthalmologic findings because lung cancer may metastasize to the choroid.

[Clinicopathological study of methicillin-resistant Staphylococcus aureus detected by pulmonary microbial culture in autopsied cases].

Microbial culture of lung specimens from 569 autopsied cases from 1986 to 1989 revealed methicillin-resistant Staphylococcus aureus (MRSA) in 28 cases, which were subsequently analyzed clinicopathologically. The number of MRSA positive cases has markedly increased in recent years (2 cases in 1986, 2 in 1987, 6 in 1988, 18 in 1989). The most frequent underlying disease was neoplasm, which was seen in 17 cases. Of non-neoplastic diseases, liver cirrhosis and diffuse panbronchiolitis were prevalent. Twenty-four cases had received a course of antibiotic therapy. Antibiotics frequently administered were third-generation Cephem and Imipenem/cilastatin sodium (used in 20 cases). Antibiotics o which MRSA was sensitive were administered in only one case (minocycline). Sputum culture was performed in only 10 cases, 5 of which were MRSA positive. MRSA had acquired resistance to fosfomycin and ofloxacin. Histological examination revealed complication by pneumonia in 19 cases. In 7 of these 19 cases, MRSA was the only pathogen detected. Pulmonary MRSA infection detected at autopsy is frequently seen in patients with terminal stage cancer, but it is frequently not diagnosed and is undertreated. This may be a factor responsible for the recent marked increase in the proportion of MRSA in pathogens causing infection within medical institutions.

[Etiological examination of idiopathic interstitial pneumonia and lung cancer in autopsy cases].

In order to investigate the etiology of usual interstitial pneumonia (UIP) and UIP with lung cancer (LC), autopsy findings in 18 cases of UIP with LC and 11 cases of uncomplicated UIP were clinicopathologically compared with the environmental factors of smoking habits and occupation. UIP with LC was highly correlated with smoking, especially heavy smoking and with occupations in which dust is inhaled, such as electrical installation and ceramic production, indicating that these environmental factors are important background factors in the complication of UIP with IC. Pathologic examination of cases of UIP with LC (6 squamous cell carcinomas, 5 small cell carcinomas, 4 adenocarcinomas, and 3 large cell carcinomas, 2 of which showed pulmonary double carcinoma revealing a slight correlation between fibrosis and primary site of LC and a slightly greater correlation of squamous cell carcinoma and small cell carcinoma to smoking habits and inhalation of dust. In terms of the correlation between UIP and LC among autopsy cases, the environmental factors proved to be more significant than the fibrotic findings. These environmental factors are thought to merit consideration as common predisposing factors in the development of LC and its complication with UIP.

[Clinicopathological features of metastatic pulmonary calcinosis with malignant neoplasm].

Metastatic pulmonary calcinosis is a rare complication seen in malignancies accompanied by hypercalcemia, or chronic renal failure. We reviewed the clinicopathological findings of 8 cases of metastatic pulmonary calcinosis accompanied malignancy revealed at autopsy. The underlying diseases were malignant lymphoma in 3 cases (adult T cell lymphoma in 2 cases), multiple myeloma in 2, lung cancer in 2, and acute myelocytic leukemia in 1, all cases were complicated by hypercalcemia and renal failure. Chest X-ray revealed almost normal findings in 2 cases, bilateral diffuse infiltrates in 4, bilateral infiltrates in the apex in 1, and right atelectasis in 1. Bone scintigraphy was performed in 4 cases, and revealed warm pulmonary uptake in 1 patient with multiple myeloma and 1 with lung cancer, but normal findings in the 2 other cases. Histopathological examination revealed diffuse alveolar septal edema and fibrosis due to calcium deposition, which were considered to be the cause of respiratory failure. Metastatic pulmonary calcinosis is a rare but a serious complication in malignancies accompanied by hypercalcemia and renal failure, and bone scintigraphy seems to be a useful method for its diagnosis.

[Cellular interstitial pneumonia and follicular bronchiolitis diagnosed by open lung biopsy in a patient with rheumatoid arthritis].

A 54-year-old woman under treatment for rheumatoid arthritis was admitted because of aggravation of dyspnea on effort and restrictive pulmonary dysfunction. Although chest X-ray revealed no marked change, the symptoms progressively worsened, necessitating open lung biopsy for diagnosis and treatment. Based on the histopathological findings of the biopsied tissue, the patient was diagnosed as having active rheumatoid lung complicated with cellular interstitial pneumonia and follicular bronchiolitis. The patient responded well to adrenocorticosteroid and immunosuppressor therapy, and is now being followed up as an outpatient. Rheumatoid arthritis can be complicated by diverse lung diseases. Among them one important disease is interstitial pneumonia, which serves as a prognostic factor. When cellular interstitial pneumonia is treated with adrenocorticosteroid therapy, it responds well and its prognosis is good. Therefore, its early detection and appropriate adrenocortical therapy are essential. Patients with rheumatoid arthritis presenting with dyspnea on effort and pulmonary dysfunction should be examined for cellular interstitial pneumonia, follicular bronchiolitis and other lung diseases, even when no marked change is visible on chest X-ray films.

[Old pulmonary embolism causing intrabronchial bleeding].

A 51-year-old man was admitted because of hemoptysis. Physical examinations and chest XP revealed no abnormal findings. Fiberoptic bronchoscopy showed pulsatile bleeding at the orifice of right B6. Right bronchial arteriography showed a markedly dilated and tortous bronchial artery and shunting to the pulmonary arterial system in the middle and lower lobes. Pulmonary arteriography showed complete obstruction of the right middle lobar and lower lobe segmental arteries (A6, 9, 10). The hemoptysis was thought to be due to increased blood flow of the right bronchial artery, which compensated for reduced right pulmonary arterial flow. Right middle and lower lobe resection was done to prevent further hemoptysis. The resected specimen revealed old thromboemboli in the right middle and lower lobe pulmonary arteries. In this case old pulmonary embolism should be considered as a cause of intrabronchial bleeding.