Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660.

Evaluation of nasal mucosal swelling and microcirculation throughout nasal and bronchial provocation tests with lysine-aspirin in asthmatics with nasal polyposis.

According to the GA2LEN recommendations, nasal challenge test with lysine-aspirin should be performed only in patients with severe asthma, because the sensitivity of this test has been lower than in bronchial and oral challenge tests. The AIA patient group often have severe asthma with impaired lung function, and therefore improvement of the nasal challenge is warranted. The outcomes of this study clearly indicate that a prolonged detection time from two to three hours might improve the sensitivity of the nasal challenge as a method for diagnosing aspirin intolerance. Moreover, we found a different vascular response in the nasal mucosa in the subjects with AIA after local challenge with lysine-aspirin as compared to an ATA patient group. This puts RSM-LDF as a possible new method in addition to those previously recommended for this particular test.

Quantitative assessment of 99mTc-depreotide uptake in patients with non-small-cell lung cancer: immunohistochemical correlations.

BACKGROUND: Somatostatin receptor (SSTR) scintigraphy with (99m)Tc-depreotide is used for differential diagnosis of solitary pulmonary nodules. The method is based on SSTR expression in cancer tissue. PURPOSE: To estimate the expression of SSTRs in non-small-cell lung cancer (NSCLC) in vitro, and to determine the correlation between (99m)Tc-depreotide uptake in vivo and different tumor characteristics determined in vitro, such as tumor grade, and presence of SSTR2, MIB-1, and p53. MATERIAL AND METHODS: A total of 127 patients with lung lesions detected on computed tomography (CT) were investigated with SSTR scintigraphy after injection of 740 MBq (99m)Tc-depreotide. This study includes 19 patients with NSCLC with histologically proven diagnosis. The quantitative evaluation of (99m)Tc-depreotide was performed using region-of-interest analysis and includes tumor counts/cm(3), background counts/cm(3), and the ratio between tumor and background counts. RESULTS: 99mTc-depreotide uptake was found in all NSCLC tumors, which expressed SSTR2 defined in vitro by immunochemical methods. SSTR2 expression was negatively correlated to the degree of the tumor's differentiation (P<0.05). 99mTc-depreotide uptake in tumor cells did not correlate with tumor grade, or SSTR2, MIB-1, or p53 expression. CONCLUSION: There is an expression of SSTRs in NSCLC. The degree of tumor differentiation correlates negatively with SSTR2 measured in vitro and positively with MIB-1 expression in tumor tissue. No correlation was found between (99m)Tc-depreotide uptake and possible prognostic factors such as MIB-1 and p53 expression in tumor cells in NSCLC. Lastly, no correlation was found between (99m)Tc-depreotide uptake and tumor grade or SSTR2 expression.

Functional endoscopic sinus surgery improved asthma symptoms as well as PEFR and olfaction in patients with nasal polyposis.

BACKGROUND: Nasal polyposis is a disease known to be associated with asthma. The management is anti-inflammatory, with topical and oral corticosteroids as the first-line treatment. The effect of surgical treatment on lower airway inflammation has not been sufficiently studied. AIM: The aim of this study is to investigate the effects of functional endoscopic sinus surgery (FESS) as well as fluticasone proprionate nasal drops (FPND) 400 microg b.i.d. on nasal and lower airway parameters in asthmatics with nasal polyposis. METHODS: This was a prospective 21-week study of 68 patients with asthma and nasal polyposis, on the benefits of FESS on nasal '(butanol test, subjective olfaction, peak nasal inspiratory flow, congestion, rhinorrhoea, and polyp score)', and on the lower airway parameters (dyspnea, cough, mean daily peak expiratory flow rate (PEFR), and lung function tests). It also included a randomized, double-blind, placebo-controlled 14 weeks phase on FPND. RESULTS: Functional endoscopic sinus surgery significantly improved mean asthma symptom scores and daily PEFR and all nasal parameters including subjective and objective olfaction tests. This is the first study that shows the benefits of FESS on butanol tests in patients with nasal polyposis. We found no significant difference between topical treatment with FPND or placebo in the nasal or lower airway variables. CONCLUSION: Functional endoscopic sinus surgery improved nasal and asthma symptoms in patients with nasal polyposis. Functional endoscopic sinus surgery could be considered early in the natural course of nasal polyposis with concomitant asthma, as well as a second-line treatment in nasal polyposis patients with a reduced sense of smell. The potential benefits of FPND 400 microg b.i.d. were probably overshadowed by FESS.

Role of scintigraphy with technetium-99m depreotide in the diagnosis and management of patients with suspected lung cancer.

BACKGROUND: In Sweden, there are over 3000 new lung cancer cases every year. There are still numerous patients with undetermined lesions after routine diagnostic evaluation by clinical examination, chest radiography, computed tomography (CT) of the thorax, and bronchoscopy. An appropriate method for further diagnostic workup is therefore needed. PURPOSE: To evaluate the diagnostic value of the somatostatin analogue depreotide in patients with suspected lung cancer, and to determine in which clinical settings it would be beneficial to use 99mTc-depreotide scintigraphy. MATERIAL AND METHODS: We included 99 consecutive patients referred to our hospital with suspected lung cancer. A clinical examination, bronchoscopy, chest radiography, CT of the thorax and upper abdomen, and scintigraphy were done. Scintigraphy was performed after injection of 740 MBq (99m)Tc depreotide with tomographical imaging of the thorax and whole-body scanning. The diagnostic outcome of the scintigrams was compared to CT, using morphology or clinical outcome as the endpoint. RESULTS: 99mTc-depreotide uptake was found in 62 out of 66 malignancies, including 57 of 58 primary lung cancer cases. Two cases of lung metastasis (one from a colon cancer and one from an adenoid cystic carcinoma originating in the palate) and one rib chondrosarcoma did not show depreotide uptake. There were 33 patients with benign lesions, of whom 16 displayed false-positive 99mTc-depreotide uptake, whereof 11 were pneumonias. Tc-99m-depreotide uptake was absent in 17 patients with benign lesions, including all 10 hamartomas. The sensitivity in detecting malignancy was 94%, and in detecting lung cancer 98%. The specificity was calculated based on two sets of data. When all cases were used, the specificity was 52%. If the 12 pneumonias are excluded, the specificity was 77%. CONCLUSION: 99mTc-depreotide scintigraphy has a high sensitivity in detecting lung cancer. The method is useful in decision-making with respect to surgery.

Somatostatin receptor scintigraphy with 99mTc-Depreotide (NeoSpect) in discriminating between malignant and benign lesions in the diagnosis of lung cancer: a pilot study.

PURPOSE: To evaluate the diagnostic value of a new somatostatin analog, 99mTc-Depreotide, in differentiating benign from malignant lesions in patients with pulmonary nodules or masses. MATERIAL AND METHODS: A pilot study was performed on 28 patients referred to our Lung Department on suspicion of lung cancer. A chest X-ray, computed tomography (CT) of the thorax and upper abdomen, and scintigraphy were done--scintigraphy following the administration of 740 MBq 99mTc-Depreotide. Planar and tomographical imaging of the thorax and whole-body scanning with a gamma camera were done, and diagnostic outcome of the scintigrams was compared to CT, pathology, and clinical outcome. RESULTS: Of 21 patients who had a focal high uptake of Depreotide, 17 were malignancies. One patient had two lesions with high Depreotide uptake, lung cancer, and pneumonia in the contralateral lung. Two patients with sarcoidosis and one with bilateral round atelectasis also had high Depreotide uptake bilaterally. Seven of the 8 patients with no uptake were true negative: 5 hamartomas and 2 round atelectases. One small lung cancer in the pleura sinus did not have Depreotide uptake. CONCLUSION: The somatostatin analog Depreotide is promising for discriminating between malignant and benign lung lesions.

Uncoupled regulation of leukotriene C4 synthase in platelets from aspirin-intolerant asthmatics and healthy volunteers after aspirin treatment.

BACKGROUND: We have reported that thromboxane A2 induces suppression of leukotriene (LT) C4 synthase activity in human platelets. AIM: In the present study, we describe a mechanism whereby aspirin treatment can lead to increased formation of LTC4, which is a potent bronchoconstrictor and inflammatory mediator. This mechanism is also demonstrated to be present in platelets from aspirin-intolerant asthmatics (AIA). METHODS: The effect of arachidonic acid or platelet agonists on LTC4 synthase activity was investigated in platelets obtained from healthy volunteers, aspirin-intolerant asthmatics or aspirin-tolerant asthmatics after in vivo treatment or in vitro pre-incubation with aspirin. RESULTS: Incubation of normal platelets with arachidonic acid or collagen provoked approximately 50% reduction of platelet LTC4 synthase activity, as determined by the conversion of LTA4 to LTC4. However, the inhibitory effect of arachidonic acid or collagen was not observed after oral administration of aspirin prior to collection of the platelets. Arachidonic acid-induced inhibition of LTC4 synthase activity was totally abolished in platelets collected from peripheral blood already 30 min after aspirin ingestion but was fully restored in platelets collected 3 to 7 days after the administration of aspirin. Treatment of platelet suspensions with aspirin in vitro dose-dependently counteracted the suppressive effect of arachidonic acid on LTC4 formation, with total reversal at approximately 40 microm. In contrast, the major aspirin metabolite, salicylic acid did not alter arachidonic acid-induced reduction of LTC4 synthase activity. Similarly, LTC4 synthase activity in platelets from AIA and aspirin-tolerant asthmatics (ATA) was reduced by approximately 50% after pre-treatment with arachidonic acid in vitro. Again the inhibitory effect was abolished when platelets were pre-incubated in the presence of aspirin. CONCLUSION: The results indicate that oral aspirin administration can lead to uncoupling of thromboxane A2-dependent negative feedback mechanisms, which may normally restrict the production of cysteinyl leukotrienes. This mechanism can be of potential interest in aspirin-induced asthma.

Airway reactivity and exhaled NO following swine dust exposure in healthy volunteers.

Short-time exposure to swine dust causes an intense inflammation of upper and lower airways and induces increased bronchial responsiveness to methacholine in previously non-exposed healthy volunteers. The objective to this study was to investigate the nasal inflammatory response and mucosal reactivity to swine dust exposure and whether nitric oxide metabolism is involved in the inflammatory process. Nitric oxide in expired air, nasal histamine test (NH), nasal lavage (NAL) and bronchial histamine challenges were studied before and after a 3 h exposure to swine dust in a swine confinement building in 17 non-smoking healthy subjects not previously exposed to farm dust. To detect any interference between NAL and NH, the subjects were divided into two groups: in group 1, NAL was performed after NH and in group 2, NAL preceded NH. Nasal histamine response increased significantly in group 1, but not in group 2 (P=0.012). Albumin levels in NAL were higher before as well as after dust exposure in group 1 compared to group 2 (P=0.036 and 0.015 respectively). Bronchial histamine responsiveness increased following exposure (P= 0.045). Nitric oxide in expired air decreased following bronchial histamine challenge at baseline (P=0.013) but was otherwise unaltered. Short-time exposure to swine dust increases non-specific reactivity of both nose and bronchi. Nasal lavage procedure interferes with nasal histamine test when performed with connection to each other. The inflammatory reaction may involve NO metabolism.

Nasal and bronchial histamine reactivity in patients with allergic rhinitis out of season.

BACKGROUND: The correlation between non-specific hyperreactivity of upper and lower airways in pathologic conditions has not been studied extensively. OBJECTIVE: To investigate the occurrence of nasal and bronchial hyperreactivity in patients with allergic rhinitis studied out-of-season. METHODS: From patients admitted to the Allergy Unit at Stockholm Söder Hospital, 12 individuals with allergic rhinitis due to grass or birch pollen were selected. The nasal mucosa was exposed to increasing concentrations of histamine chloride and the response was recorded by rhinostereometry, an optical method that exclusively measures changes in nasal congestion. Bronchial histamine challenge was performed in connection with the nasal tests, but on different days. RESULTS: The nasal histamine response was significantly greater than in a reference group of healthy volunteers (P < .01). Nasal hyperreactivity was demonstrated in 9 of 12 patients. No clear relation between the magnitude of nasal and bronchial histamine responses was seen in the study group. CONCLUSIONS: In allergic rhinitis studied out-of-season, airway hyperreactivity is common in both upper and lower airways, but does not necessarily occur together in the same individual.

Sonochemically produced fluorocarbon microspheres: a new class of magnetic resonance imaging agent.

With the intent of increasing the signal-to-noise ratio (SNR) of fluorine magnetic resonance imaging and enabling new applications, we have developed a novel class of agents based on protein encapsulation of fluorocarbons. Microspheres formed by high-intensity ultrasound have a gaussian size distribution with an average diameter of 2.5 microns. As with conventional emulsions, these microspheres target the reticuloendothelial system. However, our sonochemically produced microspheres, because of a high encapsulation efficiency, show increases in the SNR of up to 300% compared to commercially available emulsions. We also demonstrate an increase in the circulation lifetime of the microspheres with the bloodstream by more than 30-fold with a chemical modification of the outer surface of the microsphere. Finally, by encapsulating mixtures of fluorocarbons that undergo solid/liquid phase transitions, we can map temperature in the reticuloendothelial system, with signal changes of approximately 20-fold over a 5 degrees C range.

In-vivo NMR thermometry with liposomes containing 59Co complexes.

The ability to make localized temperature measurements in tissue during hyperthermia treatment of cancer is an essential factor in optimizing its efficacy. To this end we have developed and evaluated the complex tris(ethylenediamine) cobalt(III) trichloride as a temperature sensor by determining the temperature dependence of it 59Co nuclear magnetic resonance chemical shift. Encapsulating this complex within liposomes targets the agent to the reticuloendothelial system. Temperature changes of the order of 0.1 degrees C have been measured in vivo on rats, and the half-life of the complex within the body determined by plasma emission spectroscopy.

Airway reactivity of nose and bronchi in patients with nasal polyps.

The aim of the study was to determine whether patients with nasal polyps have a hyperreactive nasal mucosa and/or bronchi and whether there is any correlation between nasal and bronchial hyperreactivity. Twenty-six healthy volunteers and 10 consecutive patients with nasal polyps participated in the study. They were challenged with increasing concentrations of histamine. The nasal mucosa response was studied with rhinostereometry and the bronchial response was estimated by peak flow. One of the patients was mildly hyperreactive in the nose and 6 patients were hyperreactive in the bronchi. There was no correlation between nasal and bronchial hyperreactivity. Patients with nasal polyps do not have a hyperreactive nasal mucosa but there seems to be a high incidence of bronchial hyperreactivity in patients with nasal polyps.

[Comparative study of the detection of E. coli after time in seawater with partially modified standard media]. / Vergleichende Untersuchung zum Nachweis von E. coli nach Aufenthalt in Meerwasser mit partiell modifizierten Standardmedien.

Fecal coliform bacteria (E. coli) are the most important parameter when monitoring the hygienic quality of bathing water according to EC guidelines. Among other things the number of E. coli is clearly dependent on the length of exposure of the bacteria to marine water as well as the media used to establish the number. In a seven-day salt water stress experiment the best rate of recultivation was achieved on average with DEV lactose peptone broth. The Brila-MUG medium produced a slightly lower rate of recultivation and the fluorocult-lauryl-sulfate-broth the lowest rate of recultivation. After a shorter exposure of bacteria to marine water conditions (up to 24 h) the DEV-lactose-broth produced slightly lower rates of recultivation. An alteration of the standard components of the media did not lead to an improvement in the rate of recultivation.