Beta Blockers with Statins May Decrease All-Cause Mortality in Patients with Cardiovascular Diseases and Locally Advanced Unresectable Non-Small-Cell Lung Cancer after Chemoradiotherapy.

The study was conducted in the era when maintenance immunotherapy with durvalumab was not available in clinical practice after chemoradiotherapy (CRT) in unresectable non-small-cell lung cancer (NSCLC). The main aim of the study was to check whether the presence of cardiovascular diseases (CVD) and their pharmacotherapy affects the overall survival (OS) in such NSCLC patients undergoing sequential CRT. The group of 196 patients were analyzed: 101 patients with CVD (51.53%) and 95 patients with other reasons of qualification for sequential CRT (decreased performance status, older age, and other non-cardiovascular co-morbidities). Although patients with CVD were more often in older age, and they more often experienced cardiac and nephrological complications (p < 0.05 for all), there was a statistically nonsignificant trend for lower all-cause mortality in patients with CVD. The lowest all-cause mortality was observed in patients treated with beta-blockers and statins after two (HR = 0.31; 95%CI: 0.1-0.98; p = 0.047), three (HR = 0.33; 95%CI: 0.13-0.81; p = 0.015) and even four (HR = 0.45; 95%CI: 0.22-0.97; p = 0.027) years of follow-up. The benefit in OS remained significant in 101 patients with CVD treated with beta-blockers (HR = 0.65; 95%CI: 0.43-0.99; p = 0.045), and eventually statin, throughout the whole follow-up (log-rank p < 0.05). Further prospective studies are necessary to confirm the role of beta-blockers and statins in reduction of mortality in NSCLC patients undergoing radical CRT.

Prognostic value of synaptophysin and chromogranin a expression in patients receiving palliative chemotherapy for advanced non-small-cell lung cancer.

BACKGROUND: Chemotherapy is the principal treatment method for patients with advanced non-small-cell lung cancer (NSCLC). Treatment with platinum-based and novel chemotherapeutic regimens, compared to monotherapy, slightly increases the response rates to 20-40%. The predictive and prognostic values of molecular factors are highly variable; however, data on clinical-demographic factors are still burdened by significant limitations. OBJECTIVES: The aim of this study was to assess the prognostic value of synaptophysin and chromogranin A protein expression in patients receiving palliative chemotherapy for advanced NSCLC. METHODS: The study population consisted of 23 women and 116 men. The median age was 57.3 years. Expression of synaptophysin and chromogranin was assessed using a two-step model of immunohistochemical staining. Level 0 represented lack of activity, while level 1 represented its expression. RESULTS: Expression of synaptophysin and chromogranin A was observed in 12 (8.6%) and 5 (3.6%) patients, respectively. The risk of death was significantly lower in patients with expression of synaptophysin (p = 0.008) and chromogranin A (p = 0.014). The 12- and 24-month survival rate of patients with synaptophysin expression was 64% (95% CI 0.35-0.93), while for patients without expression it was 46% (95% CI 0.36-0.56) and 16% (95% CI 0.07-0.25), respectively. The 12- and 24-month survival rate of patients with chromogranin expression was 80% (95% CI 0.44-1.00), while for chromogranin A-negative patients it was 47% (95% CI 0.37-0.57) and 19% (95% CI 0.10-0.28), respectively. We did not observe associations between expression of synaptophysin and chromogranin A and the other typical prognostic factors. CONCLUSIONS: Expression of synaptophysin and chromogranin A was associated with a longer median overall survival and might have prognostic value. These results should be confirmed in a prospective study.

[Gefitinib in patients with advanced non-small-cell lung cancer]. / Gefitynib u chorych na niedrobnokomórkowego raka pluca w zaawansowanym stadium.

INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) have a very poor prognosis. Individualization of treatment and identification of therapeutic molecular targets may improve outcomes. Gefitinib was introduced recently among several other molecular-targeted drugs of activity in NSCLC. Gefitinib is indicated for patients diagnosed with advanced or disseminated NSCLC with an activating mutation in the EGFR (epidermal growth factor receptor) gene. The paper summarize experience with gefitinib in the Department of Lung and Thoracic Tumors of Maria Sklodowska-Curie Memorial Cancer Centre and Institute in Warsaw. MATERIAL AND METHODS: The group of 11 patients diagnosed with advanced NSCLC and activating mutations in the EGFR gene was analyzed. Patients were treated from April 2010 to April 2011. Tolerability, objective response rate (ORR) and progression free survival (PFS), which was calculated by the Kaplan-Meier method, were assessed. RESULTS: Median observation time from the start of gefitinib treatment was 14 months (range 4,8-19 months). The rate of one-year survival in this group of patients was 91% (10 patients) with 54% of patients (6 patients) surviving one year without progression of disease. The ORR rate of 82% and median PFS 11.4 months were reached. No treatment-related deaths were reported. Among the complications skin toxicity (82%) and diarrhea (45%) were most frequently observed, in most cases the Common Toxicity Criteria for Adverse Events (CTCAE) first grade. CONCLUSIONS: The results confirm the literature data on the efficacy and safety profile of gefitinib in the treatment of patients with the diagnosis of advanced NSCLC and activating mutation in the EGFR gene.

Erlotinib in salvage treatment of patients with advanced non-small cell lung cancer: results of an expanded access programme in Poland.

AIM OF THE STUDY: Erlotinib and gefitinib are reversible EGFR-TKI administered orally. Results of the phase III study JBR.21 proved the clinical efficacy of erlotinib-based regimens as second- or third-line treatment of advanced NSCLC. We analyze efficacy of treatment with erlotinib in patients suffering from advanced stage NSCLC who participated in the multicentre, international phase IV study - MO 18109 TRUST (expanded access clinical program of Tarceva™ in patients with advanced stage IIIB/IV NSCLC). Our analysis was performed based on clinical data derived from centres with the largest number of patients who received erlotinib. MATERIAL AND METHODS: Between May and November 2005, a total of 56 patients (19 women and 37 men) with histologic or cytologic diagnosis of NSCLC were included in the study. The histological diagnosis was: squamous-cell (n = 23), adenocarcinoma (n = 20), broncho-alveolar carcinoma (n = 2). In 11 patients the type of NSCLC was not specified. RESULTS: Patients received erlotinib in a single dose of 150 mg per day. Partial response (PR), stable disease (SD) or progressive disease (PD) were observed in 5 (9%), 33 (59%) and 16 (29%) patients respectively. Median PFS was 16.0 weeks. In the study population adverse events (AE) were noted in 12 (21%) patients. CONCLUSIONS: Results of the TRUST study in the Polish population confirmed the efficacy of erlotinib in advanced NSCLC after failure of prior platinum-based chemotherapy. Treatment with erlotinib was associated with longer PFS as compared to the JBR.2 study, whole TRUST study population and Italian population included in the TRUST study.

Tamoxifen-induced adduct formation and cell stress in human endometrial glands.

The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen is metabolized to an array of metabolites with estrogenic effects but also to reactive intermediates that may form protein and DNA adducts. The aim of this study was to investigate cellular [(3)H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemical analysis of glucose-regulating protein 78 (GRP78), nuclear factor kappaB (NF-kappaB), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed selective [(3)H]tamoxifen adduct formation in glandular and surface epithelia after incubation with a nontoxic concentration of [(3)H]tamoxifen (6 nM). There was also a selective expression of the endoplasmic reticulum stress chaperone GRP78 and activated caspase 3 at these sites after incubation with cytotoxic concentrations of tamoxifen (10-100 microM). The cell stress was preferentially observed in samples from women in the proliferative menstrual phase. No treatment-related expression of NF-kappaB was observed. Constitutive expression of the tamoxifen-metabolizing enzymes CYP1B1, CYP2A6, CYP2B6, CYP2C8/9/19, CYP2D6, and SULT2A1 in glandular and surface epithelia was shown, but there was a large interindividual variation. The colocalization of [(3)H]tamoxifen adducts, expression of GRP78, caspase 3, and tamoxifen-metabolizing enzymes in human glandular and surface epithelia suggest a local bioactivation of tamoxifen at these sites and that epithelial cells are early target sites for tamoxifen-induced cell stress.

Screening for anti-inflammatory activity of 12 Arnica (Asteraceae) species assessed by inhibition of NF-kappaB and release of human neutrophil elastase.

Several species in the genus Arnica have been used in traditional medicine to treat inflammatory-related disorders. Extracts of twelve Arnica species and two species closely related to arnica ( Layia hieracioides and Madia sativa) were investigated for inhibition of human neutrophil elastase release and inhibition of transcription factor NF-kappaB. Statistical analyses reveal significant differences in inhibitory capacities between extracts. Sesquiterpene lactones of the helenanolide type, of which some are known inhibitors of human neutrophil elastase release and NF-kappaB, are present in large amounts in the very active extracts of A. montana and A. chamissonis. Furthermore, A. longifolia, which has previously not been investigated, shows a high activity similar to that of A. montana and A. chamissonis in both bioassays. Sesquiterpene lactones of the xanthalongin type are present in large amounts in A. longifolia and other active extracts and would be interesting to evaluate further. COX-2:cyclooxygenase 2 EMSA:electrophoretic mobility shift assay fMLP: N-formyl-methionyl-leucyl-phenylalanine HaCaT:human keratinocyte HNE:human neutrophil elastase IkappaB:inhibitory subunit of kappaB iNOS:inducible nitric oxide synthase NF-kappaB:nuclear factor kappaB PAF:platelet activating factor STL:sesquiterpene lactone TNF-alpha:tumor necrosis factor alpha.

[Brain metabolic disorders after chemotherapy in the study by magnetic resonance spectroscopy]. / Zaburzenia metabolizmu mózgowia po chemioterapii w badaniu spektroskopii protonowej rezonansu magnetycznego.

UNLABELLED: The purpose of our study was to evaluate CNS pathology due to chemotherapy neurotoxicity, using MRI and localized proton MRS in patients with lung cancer treated with cisplatine, Vinca alkaloids and etoposide. A reduction in N-acetylaspartate was expected as a result of chemotherapy neurotoxicity. METHODS: 31 patients aged 42 to 73 years underwent the following procedures before and after chemotherapy: clinical examination; MRI of the brain (Elscint Prestige 2T), MRS (PRESS sequence, TR 1500 ms, TE 80 ms) with volumes of interest (VOI) of 8 ml localized in the semi-oval center and a cerebellar hemisphere. The analysis of each patient's NAA/Cr and Cho/Cr ratios was carried out separately for the semi-oval center and cerebellum measurements. RESULTS: None of the patients demonstrated any clinical manifestations of the CNS neuropathy. MRI of the brain did not reveal any abnormalities caused by chemotherapy. Pre-treatment NAA/Cr and Cho/Cr ratios in the semi-oval center did not differ significantly from these measured after chemotherapy. However, the analysis of the cerebellar spectra showed a significant decrease in the NAA/Cr ratio (p < 0.05) and a time-related decrease in the Cho/Cr ratio (p < 0.05) after chemotherapy. An analysis of Pearson's correlations showed a very strong linear relationship between NAA/Cr and Cho/Cr ratios (p < 0.001), both in the semi-oval center and cerebellum. CONCLUSION: The decreased NAA/Cr ratio can indicate some neuronal loss caused by chemotherapy. The decrease in the Cho/Cr ratio could be associated with some myelin damage. The MRS results suggest the presence of a sub-clinical selective cerebellar neuropathy caused by chemotherapy. The MRS revealed that reaction to chemotherapy was different at the semi-oval center than that in the cerebellum. The results allow theorizing about an alternative or two-stage brain response to the neurotoxic factor found both in the cerebrum (the semi-oval center) and cerebellum. These initial results indicate that proton MR spectroscopy is a potentially useful modality for detecting an early stage of the CNS pathology caused by neurotoxicity of chemotherapy.