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Background: P63 is a gene located in chromosome 3q27-29, which has been implicated in regulation of stem cell commitment and promotion of squamous differentiation in various tissues. The aim of this study was to investigate whether there was a correlation between p63 expression, differential diagnosis of lung carcinoma, and prognosis. Material/Methods: Immunohistochemical expression of p63 in 62 lung carcinomas was investigated and mRNA analysis using RT-PCR method was done in 6 selected cases. Results: When cases were evaluated for p63 staining, 24 of 25 (96%) squamous cell carcinomas were strongly positive. Six of 20 adenocarcinomas (25%) and 1 (100%) large cell carcinoma (except neuroendocrine carcinoma) were mildly positive. p63 staining was statistically significant in favor of squamous cell carcinoma than other tumors (p

We assessed whether single nucleotide polymorphisms (SNPs) in MDR1 gene C3435T predicted the outcome of platinum-based chemotherapies and survival in our non small cell lung cancer (NSCLC) patients. A total of 79 non-small cell lung cancer patients were enrolled to study. We determined the MDR1 C3435T single nucleotide gene polymorphisms. Median age was 60. years: 91.7% male, 8.9% female. We found that CC, CT, TT genotype and T, C allele frequencies in lung cancer patients as 24.1%, 62%, 13.9% and 44.3%, 55.7%, respectively. Patients with CT genotype had a higher response rate (11.4%) than the other genotypes. However, this difference is not statistically significant (. p=. 0.743). Cox regression analysis for overall survival showed that ECOG PS status 0 (HR PS 1 vs. 0, 5.68 . p=. 0.002; HR of PS 2 vs. 0 is 21.579, . p=. 0.001; HR of PS 3 vs. 0 is 35.35, . p=. 0.001), stage ≤. II (HR of stage III vs. I. +. II is 17.77; . p=. 0.016, HR of stage IV vs. I. +. II is 26.97, . p=. 0.006), and albumin level ≥. 3. g/dl (HR of albumin

The majority of non-small-cell lung cancer (NSCLC) patients present with locally advanced (35%) or metastatic disease (40%); in this setting, it is of the utmost importance to balance efficacy with toxicity. However, with platinum combinations, survival has reached a " plateau" , with median overall survival times of a mere 10-12 months, making it mandatory to search for new strategies and to identify more effective treatment. Molecular characteristics can be more informative than clinical features in predicting clinical benefit, and the identification of molecular markers can help define subgroups of patients who are likely to respond to different treatments, thus avoiding unnecessary toxicities and costs and providing the maximum benefit to each patient. Here we review research on biomarker assessment that was presented during the Molecular Biology Workshop held in Palma de Mallorca on 25 November 2010, during the Fifth Educational Symposium of the Spanish Lung Cancer Group. © 2011.

Introduction: Frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is different between ethnic groups; however, there is no information in Latin-American population. Methods: A total of 1150 biopsies of NSCLC patients from Latin America (Argentina, Colombia, Peru, and Mexico) were used extracting genomic DNA to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 650 samples. In Mexico, Scorpions ARMS was also used to obtain a genetic profile. Results: We report the frequency of mutations in EGFR and KRAS genes in four Latin-American countries (n = 1150). Frequency of EGFR mutations in NSCLC was 33.2% (95% confidence interval [CI] 30.5-35.9) (Argentina 19.3%, Colombia 24.8%, Mexico 31.2%, and Peru 67%). The frequency of KRAS mutations was 16.6% (95% CI 13.8-19.4). EGFR mutations were independently associated with adenocarcinoma histology, older age, nonsmokers, and absence of KRAS mutations. Overall response rate to tyrosine kinase inhibitors in EGFR-mutated patients (n = 56) was 62.5% (95% CI 50-75) with a median overall survival of 16.5 months (95% CI 12.4-20.6). Conclusions: Our findings suggest that the frequency of EGFR mutations in Latin America lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world. Copyright © 2011 by the International Association for the Study of Lung Cancer.

INTRODUCTION The identification of novel prognostic markers may help to better assess survival probability in different subgroups of patients with non-small-cell lung cancer (NSCLC) and to tailor treatment according to the molecular profile of the tumour. AIM We sought to examine whether the immunohistochemical expression of excision repair cross-complementing 1 (ERCC1), an essential component of the nucleotide excision repair pathway, may predict prognosis in NSCLC. MATERIAL AND METHOD Formalin-fixed paraffin-embedded tumour samples from 44 Turkish patients with NSCLC treated by adjuvant platinum-based chemotherapy were included in the study. Immunohistochemical expression levels of ERCC1 were correlated with clinical outcomes by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis. RESULTS A total of 29 patients had ERCC1-negative tumours while 15 had ERCC1-positive tumours. The mean progression- free survival (PFS) was significantly lower in patients with ERCC1-positive tumours (13±2 months) than in those with ERCC1-negative tumours (27±5 months, p0.05). Similarly, the mean overall survival (OS) was significantly lower in patients with ERCC1-positive tumours (20±3 months) than in those with ERCC1-negative tumours (33±5 months, p0.05). After allowance for potential confounders, Cox regression analysis demonstrated that ERCC1 expression was significantly associated with both PFS and OS (both p0.05). CONCLUSION This study provides support for the prognostic value of ERCC1 immunohistochemical expression in patients with NSCLC treated by adjuvant platinum-based chemotherapy. If independently confirmed, these findings may improve prognostic stratification in this group of patients.

Purpose: To study the phenomenon of positive urine cytology in patients with lung cancer in the absence of obvious urothelial metastases. Patients and methods: 150 patients with small (SCLC) and non-small cell lung cancer (NSCLC) of all stages and 3 control groups were prospectively studied. Immunocytochemical study (cytokeratins 7-20, TTF1) in all positive urine specimens and chemokine profile (CXCR4, CCL21) study of the primary tumor in selected positive patients was performed. In experimental study, C57Bl/6 BALB/C mice injected with LLC lung and 4T1 mammary cancer cells were used for the detection of positive urine cytology. Results: 11% of patients with NSCLC, 7% of patients with SCLC and none of the control group had positive urine cytology. In NSCLC, metastatic disease and high tumor burden positively correlated (p = 0.01 and 0.03 respectively) with the phenomenon. In SCLC, correlation with extensive disease and multiple metastatic sites (p = 0.02 and 0.04 respectively) was found. No correlation was found in either group with: age, gender, histology, performance status, line of chemotherapy, previous platinum-based chemotherapy, adrenal metastases, renal function, abnormal urinary sediment, response to chemotherapy and overall survival (p = 0.9). Distinctive chemokine expression was identified in positive patients studied and was not observed in negative patients (×2 p = 0.008). In the experimental study, only the LLC lung cancer cells were detected in the urine cytology of mice. Conclusion: This phenomenon, carrying undefined pathophysiological mechanisms, seems to characterize only patients with metastatic/extensive disease and high tumor burden. Further studies are needed to validate our preliminary chemokine expression results. © 2010 Elsevier Ireland Ltd. 73 1 51 58

Excision Repair Cross-Complementing Group 1 (ERCC1) is an important DNA repair gene, playing critical role in nucleotide excision repair pathway and having a significant influence on genomic instability. Some studies support that ERCC1 might be a potential predictive and prognostic marker in non-small cell lung cancer (NSCLC). ERCC1 has also been shown to be a promising biomarker in NSCLC treated with a cisplatin-based regimen. Therefore, the determination of ERCC1 expression at DNA, mRNA and protein level in different stages of NSCLC is still an important topic in the cancer. Ninety-one formalin-fixed paraffin-embedded tumor samples histopathologically diagnosed as NSCLC were examined in this study. ERCC1 expression at protein level were scored by immunohistochemistry. The gene amplification and mRNA expression levels for ERCC1 were determined by real-time quantitative PCR. There was complete concordance among the three methods in 39 tumor samples (42.9%). A strong correlation was found between DNA amplification and mRNA expression (r = 0.662) while there was no correlation between mRNA and protein assessment for ERCC1 expression (r = -0.013). ERCC1 expression at mRNA and DNA level (63.1 and 84.2%, respectively) in tumors at stage III was higher than at the other stages. In contrast, the protein expression at stage II and III (56.6 and 52.6%, respectively) of NSCLC was lower than that of tumors with stage I NSCLC. These results show that the mechanism by which ERCC1 expression might play a role in tumor behavior. This study was also confirmed that the appropriate validation and qualification in methods used for ERCC1 status were needed before its clinical application and implementation. © 2011 Springer Science+Business Media B.V.

DNA repair plays a key role in prevention of carcinogenesis and one of the most important DNA repair mechanisms is nucleotide excision repair (NER) pathway. This pathway includes a number of genes such as excision repair cross-complementing group 1 (ERCC1) gene which are responsible for the 5′ incision of damaged DNA. A reduced DNA repair capacity associated with ERCC1 mRNA level has been observed in lung carcinogenesis. Two single nucleotide polymorphisms (SNPs) in ERCC1 gene, T19007C (rs11615) and C8092A (rs3212986), reportedly predict to affect the mRNA of ERCC1 in non-small cell lung cancer (NSCLC). To examine the role of two common SNPs in ERCC1 gene further, we conducted this study where 80 cases histopatologically diagnosed as NSCLC were genotyped. Genomic DNA was extracted from formalin-fixed, paraffin embedded tissues and two SNPs were analyzed using real-time PCR. The distributions of TT, TC, and CC genotypes of the T19007C SNP were 40, 44 and 16%, respectively. Significantly increased frequency of the patients carrying at least one 19007C allele was observed in early stage compared to advanced stage (P = 0.002). And also, the frequency of TC and CC genotypes significantly increased in younger patients compared to older patients (P = 0.035). Regarding C8092A SNP, the distribution of CC, CA, and AA genotypes was 38, 51 and 11%, respectively. There was no significant difference in the genotype distribution between C8092A SNP and clinicopathological parameters. This study indicated that harboring at least one 19007C allele may have protective effect in NSCLC. © 2011 Springer Science+Business Media B.V.

Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of the tumor-related genes including DNA repair genes. The objective of this study was to determine the frequency of promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene as a DNA repair gene in nonsmall cell lung cancer (NSCLC) and to analyze the correlation with clinicopathological parameters including age, gender, smoking status, histological subtype, and clinical stage. Eighty patients with NSCLC were included in this study. The analysis of DNA methylation was performed on formalin-fixed, paraffin-embedded lung cancer tissues. Following DNA isolation and bisulfite treatment, DNA methylation was analyzed by methylation-specific real-time polymerase chain reaction. MGMT promoter methylation was detected in 51 of 80 (64%) NSCLC patients. There was a significant correlation between MGMT methylation and tumor stage (p=0.01). The frequencies of the promoter methylation of MGMT gene in smokers and older patients were higher than in their counterparts. In conclusion, the present study provides strong evidence for a higher frequency of promoter methylation of the MGMT gene in NSCLC, indicating that it is a common event during the carcinogenesis of NSCLC. © 2011 Mary Ann Liebert, Inc.

Akt/PKB is a protooncogen while PTEN is a tumor suppressor gene. Their expressions are of immense importance in the development of lung cancer. However, little is known about their relations to anti-cancer treatments. Therefore, we aimed to elucidate how are these parameters affected by the treatment. Expression of phosphorylated Akt (pAkt) and PTEN have been analysed on tissues of 32 patients (stage Ill and IV) with lung cancer. In addition, the expression of these variables in 14 out of 32 patients have furtherly been analysed in terms of their response to cisplatin-based chemotherapy in vivo. Prior to and 24 h after the treatment, tumor tissues were obtained via broncoscopy and then evaluated immunohistochemically by indirect streptavidin-biotin peroxidase method. Immunoreactivity for pAkt was detected in 29 of 32 cases (91%). pAkt was observed to localize in the nucleus of positively stained cells. However, PTEN expression was found in 27 of 32 cases (84%). In contrast to the localization of pAkt that is nucleus, PTEN was however localized in the cytoplasm of positively stained cells. pAkt and PTEN expression levels of 14 post-chemotherapy patients were compared to those before chemotherapy. There was no statistically significant differences (p>0.05). Although these results do not imply any possible roles of pAkt or PTEN in the late stage lung cancer patients as a biomarker for the prediction of early response to treatment in vivo, this conclusion needs to be analyzed further at later time points in a larger cohort.

In the past few years, accumulating evidence in the literature supports the existence of pathways of caspase-independent programmed cell death (CI-PCD). These pathways are likely to be acting as 'death backup systems' that ensure effective removal of defective cells from the organism. Similar to classical apoptosis i.e. caspase-dependent programmed cell death (CD-PCD), the mitochondrion is the main organelle orchestrating the series of events which are required for the induction of CI-PCD. In addition, the pro-apoptotic proteins Bax and Bid are also key participants in CI-PCD. However, contrary to CD-PCD, CI-PCD involves executioners other than the caspases which include the cathepsins, the calpains and serine proteases. The protein AIF may also play an important role in the induction of CI-PCD. In this review we report current knowledge on CI-PCD and provide evidence for its regulation by chemotherapeutic agents currently used in the clinic and under investigation in clinical trials. Lastly, we discuss how the study of natural and synthetic agents triggering CI-PCD may help in the pharmacological design of a new generation of more effective chemotherapeutic drugs. The use of such drugs activating both CD-PCD and CI-PCD pathways should achieve a more successful eradication of carcinogenic cells and the attainment of lower levels of tumor resistance. © 2009 Bentham Science Publishers Ltd. 9 717 728 Tradenames: azaspirane bzl 101 chm 1 cy 103 rb 110 rb 49 xyotax Cited By :47

Background: Gene expression profiling platforms were recently shown to accurately assign cancer of unknown primary (CUP) to a primary tissue of origin, with unknown impact on patient outcome. We examined chemotherapy activity and outcome in CUP trials and in metastatic solid tumour trials in order to screen for a distinct biological behaviour of CUP. Patients and methods: An online search for autopsy or molecular platform studies on CUP indolent primaries was followed by identification of phase II or III clinical trials enrolling at least thirty patients with poor-risk CUP from 2002 or later. Chemotherapy activity and patient survival data were narratively compared to data from phase III chemotherapy trials on patients with metastatic breast, lung, pancreatic and colon cancer, to which CUP is most commonly classified by molecular profiling. Results: Lung and pancreatic tumours were the primaries most commonly found in CUP autopsy series, whereas microarray platforms assigned CUP to breast, colon in a third and pancreatic, lung primaries in

In non-small-cell lung cancer (NSCLC), stage of the disease is still the most important prognostic factor. Other than stage, many biological markers and many other prognostic factors are studied to define their effects on prognosis of lung cancer. In this study, we aimed to evaluate the expressions of Bax and bcl-2 genes which are important in apoptosis and c-kit, which is a tyrosine kinase transmembrane receptor, as well as searched their response to treatment modalities and effects on survival. Sixty-nine NSCLC cases' pathological samples were stained with specific Bax, bcl-2 and c-kit dyes by immunohistochemical (IHC) methods. IHC evaluation was done by the semichantitative method according to the distribution and intensity of the staining. Twelve of 69 cases (17.4%) were stage I, 28 (40.5%) were stage II, 17 were (24.6%) stage IIIA, nine cases were (13.1%) stage IIIB and three cases (4.4%) were stage IV patients. Their histological subtypes were as follows: of 69 cases, 36 (52.2%) were squamous cell carcinoma, 28 (40.6%) were adenocarcinoma, five (7.2%) were adenosquamous cell carcinoma (two patients) and large-cell carcinoma (three patients). The positive immunostaining rates for Bax and bcl-2 in whole group, squamous cell carcinoma and adenocarcinoma groups were 40.6%/36.2%, 55.6/69.4% and 25.0/0.0%, respectively. The positive immune staining rates for c-kit in whole group, squamous cell carcinoma and adenocarcinoma groups were 7.2, 5.6 and 7.1%, respectively. We didn't find any correlation with Bax, bcl-2 and c-kit expressions and clinicopathological parameters such as age, tumour size, lymph node involvement, smoking, stage of the disease, response to radiotherapy and chemotherapy. Results are interpreted according to survival; bax and bcl-2 expressions were not so effective both in whole group and histologically subgrouped patients. C-kit expression was also found not related with survival in whole group whereas found as a bad prognostic factor in patients with squamous cell carcinoma. These findings could indicate that the expression of apoptotic pathway markers and c-kit may have a role in the prognosis of early stage NSCLC, especially with squamous cell carcinoma subtype. © Blackwell Publishing Ltd, 2006.

Purpose: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. Experimental Design: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. Results: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. Conclusions: The schedule B daily cisplatin-topotecan × 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Purpose: The combination of paclitaxel and carboplatin has become a widely used regimen in NSCLC due to phase II reports of moderate toxicity, reasonable activity and easy outpatient administration. Purpose of our present prospective study was to evaluate the dose-response relationship of paclitaxel. Patients and methods: Since July 1996, 198 patients with non-operable NSCLC and measurable disease without previous chemotherapy entered the trial. Ninety nine patients (group A) were randomized to receive paclitaxel 175 mg/m2 in three-hour infusion plus carboplatin dosed to an area under the concentration-time curve of 6 every 3 weeks and 99 (group B) to receive the same regimen with paclitaxel increased to 225 mg/m2. Eligibility criteria included WHO performance status 0-2, documented inoperable stage IIIA and IIIB, IV, no brain metastasis, no prior chemotherapy and adequate renal and hepatic function. Patients in both groups were well-matched with baseline disease characteristics. Results: In group A with 90 evaluable patients, the response rate was 25.6%(6 CR, 17 PR) whereas in group B with 88 evaluable patients, the response rate was 31.8% (3 CR, 25 PR), P = 0.733. Median time to progression favored the high-dose paclitaxel (4.3 vs. 6.4 months, P = 0.044). The median survival was 9.5 months for group A versus 11.4 months for group B (P = 0.16). The one-year survival was 37% for group A and 44% for group B (P = 0.35). The best prognostic factor for one-year survival was the response rate (P < 0.0001). With a relative dose intensity of paclitaxel 0.94 in both groups, neurotoxicity (P = 0.025) and leucopenia (P = 0.038) were more pronounced in group B patients. No toxic death was observed. Conclusions: Higher dose paclitaxel prolongs the median time to progression but causes more neurotoxicity and leucopenia. The better response rate, the longer overall and better one-year survival seen with the higher dose of paclitaxel are not statistically significant. 11 7 799 805

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies., LPA is funded by Fondo de Investigación Sanitaria (PI081156, PI1102688 and R12/0036/0028), Proyecto de Excelencia de la Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P08-CVI-04090), and the Roche Fellowship in 75th Anniversary, Spain. SMP is funded by Fondo de Investigación Sanitaria (CD1100153), Fundación Científica de la Asociación Española Contra el Cáncer, Consejería de Salud, Servicio Andaluz de Salud (PI-0224/2009 and PI-0046/2012), and Fundación Mutua Madrileña (2009). MDP is funded by Fondo de Investigación Sanitaria (CD0900148). RGC is funded by Fondo de Investigación Sanitaria (PI10/02164). GMB is funded by SAF2010-20175 and Madrid Regional Government (S2010/BMD-2303). AC lab was supported by grants to from the Spanish Ministry of Economy and Competitivity, ISCIII (PI12/00137, RTICC: RD12/0036/0028), Consejeria de Ciencia e Innovacion (CTS-6844) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012).

[No abstract available]

Summary Background It was recently reported that when ifosfamide was added to cisplatin and vinblastine the response rate was increased but not the survival in patients with non-small-cell lung cancer (NSCLC). The purpose of this study was to investigate the possibility of increased responses and survival with use of the combination of cisplatin, ifosfamide, etoposide (VIP-16) in comparison tothe combination of cisplatin, ifosfamide, vinblastine (VIP) in non-operable NSCLC. Patients and methods Two hundred twelve patients with histologically confirmed diagnoses of NSCLC were randomized into two groups: group A received cisplatin 100 mg/m2, vinblastine 6 mg/m2 and ifosfamide 3 mg/m2 i.v. on day 1 every 3 weeks; group B received the same regimen except that etoposide 120 mg/m2 was substituted for vinblastine on days 1, 2, and 3. Patients were well balanced for age, sex, performance status (PS), stage, grade, histology and sites of disease, and the relative dose intensity was similar in both groups. Results One hundred one patients were evaluable for response in group A and 99 in group B. The overall response rates were 29% in group A (5CR) and 25% in group B (3CR). The median time to progression was 7.51 (2–35) months for group A and 7.7(1–28) months for group B (P = 0.34). The median survival was 8.49 (0.33–37.44) months for group A and 9.38 (0.43–36.59) for group B (P = 0.39). Multivariate Cox stepwise analysis showed stage to be the only significant prognostic factor for survival (P = 0.0114). Toxicity was not remarkable and not different between the two groups except for alopecia which was much more common in the patients who received etoposide. Conclusion VIP and VIP-16 combination chemotherapies are equally active in NSCLC with acceptable toxicity. Stage proved to be the most significant prognostic factor for survival in this study.

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Objective: Lung cancer is an uncommon diagnosis during pregnancy. The combination of smoking in young women, increased maternal age during pregnancy, and increasing incidence of lung cancer worldwide may cause an increase of pregnancy associated lung cancer. The aim of this study was to describe all cases of lung cancer during pregnancy, registered in the international Cancer in Pregnancy registration study (CIP study; www.cancerinpregnancy.org). Materials and methods: We present nine cases, all advanced lung cancer during the course of pregnancy. Collected data included demographic features of the study patients, cancer treatment, pregnancy outcome as well as maternal and fetal outcomes. Results and conclusion: Nine pregnant patients from 4 European centres with a median age of 33 years old (range, 26-42) were included. The median gestational age at diagnosis was 17 weeks (range, 6-28). All patients presented with metastatic disease including bone, lung, brain, spinal cord, pleura, lymph nodes, adrenal and liver. Histopathology was compatible with adenocarcinoma in 4 patients, non-small cell lung cancer with unidentified subtype in 2 patients and squamous-cell, large-cell and a poorly differentiated carcinoma in 3 patients, respectively. Eight patients were treated with systemic therapy, five of them during gestation. No responses were seen. The maternal postpartum outcome was poor with less than one year survival following delivery. One patient experienced a spontaneous abortion and three pregnancies were terminated. Five infants were all born premature due to poor maternal status by cesarean section, with a median gestational age of 30 weeks (range 26-33). To summarize, lung cancer in pregnancy has a dismal maternal outcome in our series. We add nine new cases and discuss both therapeutic and prognostic results. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. Imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'-> P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. Currently, GRN163L is being investigated in several clinical trials, including a phase II human non-small cell lung cancer clinical. trial, in a maintenance setting following standard doublet chemotherapy. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo.

Mutations in the EGFR gene are critical determinants of treatment with EGFR tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) patients. DNA isolation from tumor samples usually requires surgery; therefore, we wanted to isolate DNA from circulating tumor cells by using the serum of NSCLC patients. This protocol was recently published. DNA was isolated from the serum of 52 Turkish NSCLC patients and their EGFR mutation status was examined by pyrosequencing. EGFR mutations were detected in 25 of the 52 patients (48.1%): 17 patients with delE746-A750, 2 with delE747-A750insP, and 6 with L858R. All mutations detected by pyrosequencing were confirmed by dideoxy sequencing, and the presence of the same mutations in the tumors was verified by using paraffin embedded tissues of all the patients. Mutations were detected more frequently in adenocarcinomas (24 of 36, 66.7%) than in squamous cell carcinomas (1 of 16, 6.3%) (. P < 0.001). These results confirm the utility of serum DNA and pyrosequencing for the detection of EGFR mutations in patients with advanced NSCLC. © 2013 .

Phosphates and tensin homologue deleted on chromosome 10 (PTEN) is a tumour suppressor gene which dephosphorilates phosphoinositol 3,4,5 triphosphates. Therefore PTEN can regulate PI3K/AKT pathway in cells. Because of promoter methylation or gene deletion, PTEN expression is commonly decreased or lost in non-small cell lung cancer (NSCLC) cell lines. Therefore, we hypothesized that PTEN could regulate the activity of superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx) and catalase. We first recreated PTENwt, G129R and G129E expressions in lung cell lines, in which endogenous PTEN expression was not detected. Then, we showed that PTEN could suppress AKT activity by its lipid phosphatase domain. We then examined the effect of recreated PTEN expressions in NSCLC cells. While PTENwt expression caused enhanced activity of SOD, GPx and catalase in transfected cells lines, neither G129R nor G129E expression effected enzyme activities. These results suggest that PTEN can up-regulate SOD, GPx and catalase activity by inhibition of PI3K/AKT pathway in NSCLC cell lines. © 2013 Informa UK, Ltd.

Cyclamen coum is a traditional medicinal plant in the Turkey. Its anticancer properties and whether cyclamen extract induces any cytotoxicity in solid cancer cell lines have not been thoroughly investigated previously. Therefore we examined cytotoxic effects on cervical cells; HeLa and non small cell lung cancer cell, H1299, lines; Cyclamen extract induced cellular death of both HeLa and H1299 cells in a dose dependent manner. We also analyzed the capacity of cyclamen extract to induce apoptosis by the TUNEL method. Here, for the first time we report that the extract of Cyclamen coum, an endemic plant for Turkey, Bulgaria, Georgia and the Middle East can induce cytotoxicity via apoptosis in HeLa and H1299 cells. These results imply that cyclamen extract can be further analyzed to potentially find novel anticancer compounds.

Objective: In this study we have investigated the effect of extracts obtained from well-known vegetable diets consumed commonly in Mediterranean and Aegean regions of Turkey on the expression of aromatase at protein, mRNA and activity levels in human non-small cell lung cancer cells- PC-3 and PC-14 cell lines. Method: For this purpose, cytotoxicity was determined by using crystal violet stain. In vivo and in vitro aromatase activity was determined flourometrically. The expression of aromatase in protein and mRNA levels was detected by Western blotting using anti-hCYP19 and reverse transcriptase- polymerase chain reaction using suitable primers, respectively. Result: Extracts obtained from Laurus nobilis, Mentha piperita, Crocus sativus reduced aromatase activity 32%, 44%, 36% and 42%, 32%, 56% in PC-14 and PC-3 cell lines, respectively, no significant changes were observed in protein and mRNA levels. Whereas extract obtained from Allium porrum decreased aromatase activity and mRNA level only in PC-14 cell lines by 52% and 2,5-fold, respectively, without significant influence on aromatase protein level. Conclusion: The results obtained in this study have shown that Laurus nobilis, Mentha piperita, Crocus sativus and Allium porrum do contain effective aromatase inhibitors. Therefore, further studies investigating the content of these vegetables are necessary to understand the potential role and mechanism of action of these foods in reducing the risk of non-small cell lung carcinomas. © TurkJBiochem.com.

Lung cancer causes high mortality without a declining trend and non small cell lung cancer represents 85% of all pulmonary carcinomas. MicroRNAs (miRNAs) serve as fine regulators of proliferation, migration, invasion/metastasis and angiogenesis of normal and cancer cells. Using TargetScan6.2, we predicted that the ubiquitin ligase, ?-TRCP2, could be a target for two of the constituent miRNAs of the miR-106b-25 cluster (miR-106b and miR-93). We generated a stable clone of miR-106b-25 cluster (CL) or the empty vector (EV) in H1299 (non small cell lung cancer) cells. The expression of ?-TRCP2 mRNA was significantly lower in CL than that in EV cells. Transient expression of miR-93 but not antimiR-93 decreased the expression of ?-TRCP2 mRNA in H1299 cells. ?-TRCP2-3'UTR reporter assay revealed that its activity in CL cells was only 60% of that in EV cells. Snail protein expression was higher in CL than that in EV cells and H1299 cells exhibited an increase in the expression of Snail upon transient transfection with miR-93. miR-106b-25 cluster-induced migration of CL measured by scratch assay was more than that in EV cells and no significant difference in migration was observed between antimiR-93-transfected H1299 cells and the corresponding control-oligo-transfected cells. miR-106b-25 cluster-induced migration of CL cells was again confirmed in a Boyden chamber assay without the matrigel. CL cells were more invasive than EV cells when assessed using Boyden chambers with matrigel but there were no significant changes in the cell viabilities between EV and CL cells. Colony formation assay revealed that the CL cells formed more number of colonies than EV cells but they were smaller in size than those formed by EV cells. The supernatant from CL cells was more effective than that from EV cells in inducing tube formation in endothelial cells. Taken together, our data indicate that miR-106b-25 cluster may play an important role in the metastasis of human non-small cell lung cancer cells by directly suppressing the ?-TRCP2 gene expression with a consequent increase in the expression of Snail. � 2013 Elsevier Inc.

Thyroid hormone stimulates cell proliferation of several types of cancers and stimulates cancer-relevant angiogenesis. In the present study, we investigated the proliferative effect of thyroid hormone and the anti-proliferative and anti-angiogenic action of its nano-derivative, tetrac-NP, on human non-small cell lung cancer (NSCLC) H1299 cells in vitro and in xenografts. The anti-proliferative activity of unmodified tetrac and tetrac-NP against human H1299 cells was determined in three models: (a) cultured H1299 cells in vitro, (b) tumor cell implants in the fertilized chick chorioallantoic membrane (CAM) system and (c) xenografts in the nude mouse. An integrin alpha v beta 3 antibody inhibited thyroid hormone-induced cell proliferation in vitro, as did unmodified tetrac and tetrac-NP. Pharmacologic inhibition of the mitogen-activated protein kinase pathway also blocked NSCLC cell proliferation in response to thyroid hormone. Tetrac and tetrac-NP arrested tumor growth and tumor-related angiogenesis in H1299 cells grown in the CAM model and both agents prevented chick embryo mortality. Xenografts of H1299 cells were established in nude mice (n = 8, treatment and control groups) and when tumor volumes reached 250-300 mm(3), tetrac (1 mg/kg) or tetrac-NP (1 mg tetrac as the nanoparticle/kg) were administered intraperitoneally every 2 days. Tetrac and tetrac-NP significantly suppressed tumor growth and angiogenesis. Thus, both tetrac and tetrac-NP effectively arrest human NSCLC tumor cell proliferation in vitro and in the CAM assay and in murine xenograft models. Pharmaceutical Research Institute Charitable Leadership Foundation (CLF)

Aim: The purpose of this study was to compare two single agents paclitaxel (intravenous) versus vinorelbine (oral) in non-small cell lung cancer (NSCLC) patients with performance status (PS):2. Patients and Methods: The patients were randomized to receive either oral vinorelbine 60 mg/m 2 on days I, 8, 15 every 4 weeks for 4 cycles (group A) or paclitaxel 90 mg/m 2 intravenously for 1 h on days 1, 8, 15 every 4 weeks for a total of 4 cycles (group B). Results: Among the 74 eligible patients (36 in arm A and 38 in arm B) in arm A, two (6%) had a partial response (95% Cl, 0.7-18.7) and 5 (14%) had stable disease (95% CI, 4.7-29.5). In arm B, five (13%) had a partial response (95% CI, 4.4-28.1) and 7 (18%) had stable disease (95% CI, 7.7-34.3). No significant difference was found in terms of clinical benefit between the two groups after two cycles of treatment except for appetite in favour of paclitaxel (p=0.01). Median survival was 3.1 months (95% CI, 2.2-4.0) for arm A and 5.1 months (95% CI, 2.7-7.6) for arm B (p=0.95). Toxicity was mild and only alopecia was more profound in the patients of arm B (p=0.008). Conclusion: No significant difference was found in clinical benefit between PS:2 NSCLC patients treated with either vinorelbine or paclitaxel. 32 1 175 181

In a multicentre trial of the EORTC ECTG we have treated 43 non-pretreated patients with advanced non-small-cell lung cancer (NSCLC) with the new semisynthetic taxoid docetaxel (Taxotere). Six patients were ineligible; of the 37 eligible patients, ten had prior radiotherapy and 18 prior surgery. They received 100 mg m-2 in 1 h i.v. every 3 weeks, usually in an outpatient setting. Prophylactic steroids, antihistaminics or antiemetics were not routinely given. Two patients were not evaluable because they withdrew from the study because of a hypersensitivity reaction after the second cycle. The main toxicity was neutropenia (80% of cycles), although infections were rare (4%). One patient died from sepsis during neutropenia. Hypersensitivity reactions necessitating interruption of docetaxel (Taxotere) infusions were found in only 10% of cycles. The overall response rate was 23% with one complete response, and seven partial responses. Stable disease was found in 16 patients. The median duration of response was 36 weeks, and the median survival of all patients was 11 months. Docetaxel (Taxotere) is among the most active drugs for treatment of NSCLC. © Macmillan Press Ltd., 1994. 70 2 384 387

The antitumor activities of type III interferon (IFN) (interleukin (IL)-28 and IL-29) and the combination between type III IFN and type I IFN (IFN-α) were evaluated in in vitro and in vivo studies using human non-small cell lung cancer (NSCLC). The expression of IL-28 receptor (IL-28R) and IL-10R? was detected in NSCLC lines. IL-29 significantly inhibited the in vitro growth of a wide range of NSCLC lines in a dose-dependent fashion. To a lesser degree, IL-28A also displayed the growth inhibitory activity. Cell cycle analysis revealed that IL-29 induced cell cycle arrest at the G1 phase and no significant apoptotic cell death. IL-29 up-regulated cyclin-dependent kinase inhibitor p21Waf1/Cip1 in IL-29-sensitive, but not in IL-29-insensitive cells, and knockdown of p21 with small interfering RNA largely attenuated the antiproliferative effect. Intratumoral and systemic administration of IL-29 inhibited NSCLC tumor growth in SCID mice in a dose-dependent manner. Immunohistochemical analyses demonstrated a marked up-regulated p21 expression in NSCLC tumors treated with IL-29. Furthermore, the cytokine combination between IL-29 and IFN-α displayed a more powerful antiproliferative effect in vitro, and a more increased p21 expression than each reagent alone. Additionally, the cytokine combination therapy suppressed the in vivo NSCLC growth more effectively than each reagent alone. These findings demonstrate that type III IFN can enhance type I IFN-mediated antitumor activities, and suggest the possibility that type III IFN may improve the efficacy and reduce the side effects of type I IFN therapy of cancer., This Article is Author's Pre-print ed. Title: Type III interferon enhances the direct antitumor activity of type I interferon. Author: Hitomi Fujie, Toshiaki Tanaka, Masatoshi Tagawa, Takashi Suzuki, Naomi Kitamura and Muneo Numasaki. 34p.

[EN] Background: Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies including lung cancer. A soluble fragment of the EGFR extracellular domain (sEGFR) can be detected in the blood of patients who have Non-small-cell lung cancer (NSCLC), but its clinical/ prognostic role must be further elucidated. Methods: sEGFR concentration was retrospectively determined by enzyme-linked immunosorbent assay in plasma samples from 308 advanced NSCLC patients (before treatment) and 109 healthy controls and correlated with clinico-pathological variables. Results: The concentration of sEGFR was lower in NSCLC patients than in controls (P, This work was sponsored in part by a grant from the Spanish Society of Medical Oncology (SEOM) and by a grant (RD06/0020/1024) from Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III (ISCIII), the Spanish Ministry of Science and Innovation and the European Regional Development Fund (ERDF) "Una manera de hacer Europa." The authors declare no conflicts of interest or any financial disclosure.

[EN] Background: In advanced-stage (IIIB or IV) non-small-cell lung cancer (NSCLC), combination chemotherapy has demonstrated response rates of 20% and a 1-year survival rate of 30%. We conducted a multicentre, open-label, nonrandomised phase II trial to determine the efficacy and tolerability of sequential monotherapy with gemcitabine followed by paclitaxel in chemotherapy-naïve patients with advanced NSCLC. Materials and methods: Between December 2002 and July 2004, the Spanish Lung Cancer Group (SLCG) conducted a study in which 34 patients with advanced (stage IIIB or IV) NSCLC received 1200 mg/m2 of i.v. gemcitabine on days 1, 8 and 15 of each 28-day cycle for a total of 3 cycles followed by 100 mg/m2 of weekly i.v. paclitaxel for a maximum of 8 weeks. If objective response or stable disease was achieved, 70 mg/m2 of weekly i.v. paclitaxel was maintained until disease progression was evident or toxic effects were intolerable. Lung Cancer Symptom Scale (LCSS) analysis was performed. Baseline levels of serum VEGF, EGFR, telomerase reverse transcriptase (hTERT) and K-ras mutations were analysed. The primary endpoint was the objective response rate. Results: The median age of the 34 patients who were enrolled was 67 years (range 46-77), but later 8 patients were excluded; 78.8% were men, 81.8% had performance status 1 and also 81.8% had metastatic disease at diagnosis. The objective response rate was 28% (95% CI, 14.2-47.8); the median overall survival was 7.2 months (95% CI, 2.1-12.3) and the median time to progression (TTP) was 3.1 months (95% CI, 2.5-5.3). Grade 3 or 4 drug-related haematological toxicities were observed in 6 patients. Patients with lower baseline serum VEGF levels had significantly longer survival. Conclusions: Sequential therapy with gemcitabine followed by paclitaxel was well tolerated with a low proportion of grade 3 or 4 adverse events, the absence of unexpected toxicity and with an improvement in quality of life. Unfortunately, the response rate did not meet the minimally required rate of 20% and the study was prematurely closed. VEGF was identified as a poor prognostic factor for TTP and survival. © 2011 Feseo.

Purpose Treatment for lung cancer is still far from satisfying rates. Therefore, there is a need for novel anticancer agents. For this purpose, novel platinum and palladium complexes {[Pd(sac)(terpy)](sac).4H(2)O (Complex 1), [Pt(sac)(terpy)] (sac).5H(2)O (Complex 2), [PdCl(terpy)](sac).2H(2)O (Complex 3), [PtCl(terpy)](sac).2H(2)O (Complex 4)} have been tested against three different non-small cell lung cancer cell lines (A549, H1299, PC-3). Methods Growth-inhibiting effcts have been tested by the MTT and ATP viability assays. Apoptosis has been detected by the caspase-cleaved cytokeratin 18 (M30-antigen) assay. Necrosis has been detected by staining the cells with fluorescent dyes. Mitotic index has been calculated by counting the mitotic figures after staining with hematoxylin. Results The complex 3 exhibited significant anti-growth effects, and its anti-growth effect was more powerful than that of cisplatin that is a standard chemotherapeutic agent for this type of cancer. The complexes did not induce apoptosis, while necrosis clearly took place. Conclusions Novel Pd(II) complex ([PdCl(terpy)] (sac).2H(2)O) seems to represent a potentially active drug against non-small cell lung cancer cell lines, and further studies in vivo are warranted.

Objective: Inflammatory response associated with radiation-induced lung injury (RILI) results in an increased 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT). In this study, we aimed to analyze the degree of FDG uptake within specific isodose regions (IR) of the irradiated lung using standardized uptake value (SUV) measurements, and to correlate posttreatment FDG uptake with radiotherapy (RT) dose parameters, patient characteristics and the imaging time interval after RT completion. Material and Methods: Data from 30 patients with non-small cell lung cancer (NSCLC) who underwent FDG PET/CT imaging at least 12 weeks (72-668 days) after completion of RT were evaluated. In each patient, side-by-side visual registration of the treatment planning CT slices including IR curves with the corresponding PET/CT slices was performed. Using SUV measurements, FDG uptake levels were analyzed within specific IRs of the irradiated lung. The statistical difference between SUVmax of each IR was determined. The RT dose parameters, patient characteristics and time interval between RT and PET/CT were tested for correlation with SUVmax of IRs. Results: The mean SUVmax in the IRs of the lung that received 2000-4000cGy was 1.51 +/- 0.66 (mean +/- SD) (mm-max: 0.69-2.84), 4000-6000cGy was 2.67 +/- 1.16 (min-max: 0.71-6.0), and >6000Gy was 3.55 +/- 1.09 (min-max: 1.2-5.72). We found statistically significant differences between the SUVmax values of all IRs (SUV2000 vs. SUV4000, p = 0.001; SUV2000 vs. 6000, p = 0.002; SUV4000 vs. 6000, p = 0.001). No statistically significant correlation was found between SUVmax and the other variables. Conclusion: The findings of this study showed that, although some overlap occurs between IRs, the degree of radiation-related parenchymal FDG uptake gets higher with increasing dose levels. Persistent high FDG uptake levels may be observed in radiation fibrosis areas on PET/CT even several months after RT. Amaç: Radyasyona bağlı akciğer hasarı (RBAH) ile ilişkili inflamatuvar yanıt pozitron emisyon tomografisi/bilgisayarlı tomografide (PET/BT) artmış 18F-florodeoksiglukoz (FDG) tutulumu ile sonuçlanır. Bu çalışmada, standardize tutulum değeri (standard uptake value; SUV) ölçümlerini kullanarak ışınlanmış akciğerin belirli izodoz alanlarında (İA) FDG tutulumunun derecesini incelemeyi ve tedavi sonrası FDG tutulumu ile radyoterapi (RT) doz parametreleri, hasta özellikleri ve RT tamamlandıktan sonra görüntüleme zamanı aralığı arasında bağıntı kurmayı amaçladık. Gereç ve Yöntemler: RT tamamlandıktan en az 12 hafta (72-668 gün) sonra FDG PET/BT yapılan küçük hücreli dışı akciğer kanserli (KHDAK) 30 hastanın verileri değerlendirildi. Her hastada, PET/BT kesitlerine karşılık gelen ve İA eğrilerini içeren tedavi planlama BT kesitlerinin yan yana görsel kaydı yapıldı. SUV ölçümleri kullanılarak, ışınlanmış akciğerin belirli İA içindeki FDG tutulum düzeyleri incelendi. Her ışınlanmış bölgenin SUVmax arasındaki istatistiksel fark belirlendi. İAnın SUVmax ile korelasyonu için RT doz parametreleri, hasta özellikleri ve RT ile PET/BT arasındaki zaman aralığı istatistiksel olarak test edildi. Bulgular: 2000-4000 cGy alan akciğer İAdaki ortalama SUVmax 1.51 ± 0.66 (mean ± SS) (min-max: 0.69-2.84) idi, 4000-6000 cGy ve >6000 alanlarda sırasıyla 2.67 ± 1.16 (min-max: 0.71-6.0) ve 3.55 ± 1.09 (min-max: 1.2-5.72) idi. Tüm İAnın SUVmax değerleri arasında istatistiksel olarak anlamlı farklar bulduk (SUV2000 ile SUV4000, p= 0.001; SUV2000 ile SUV6000, p= 0.002; SUV4000 ile SUV6000, p=0.001). SUVmax ve diğer değişkenler arasında istatistiksel olarak anlamlı ilişki bulunmadı. Sonuç: Bu çalışmanın sonuçları, izodoz alanları arasında bir miktar çakışma olmakla birlikte, radyasyonla ilişkili parankimal FDG tutulumunun derecesinin artan dozlarla arttığını göstermiştir. RT bitiminden aylar sonra bile, radyasyona bağlı fibrozis gelişen alanlarda yüksek düzeylerde FDG tutulumunun sebat ettiği görülebilmektedir.

Background: Circulating DNA is observed at higher concentrations in patients with lung cancer than in controls. Qualitative and quantitative analysis of circulating DNA is a promising noninvasive tool. Our aim was to prospectively study the association between the catalytic subunit of telomerase (human telomerase reverse transcriptase [hTERT]) in plasma and clinical variables and survival in a large-scale non-small cell lung cancer (NSCLC) study. Methods: Four hundred forty-six patients with stages IIIB and IV NSCLC with a median follow-up of 9.7 months (range, 0.5-45) were analyzed. Blood samples were collected before therapy start (cisplatin/docetaxel). Quantification of baseline circulating DNA was determined as the amount of free hTERT in plasma, by using real-time quantitative polymerase chain reaction. Results: Patients with hTERT ¿49.8 ng/ml (median value) had a median time to progression (TTP) of 6.3 months compared with 4.9 for hTERT more than 49.8 ng/ml (p = 0.001). Overall survival (OS) was significantly higher (10.9 versus 9.3 months) at lower hTERT levels (p = 0.012). When calculations were done using hTERT as continuous variable, we did not observe independent significant differences. Thus, there is an apparent discrepancy in p values when hTERT is considered as a continuous versus dichotomized variable. There was a tendency to differentiate median hTERT levels with respect to response rates (complete response + partial response: 33.1 versus stable disease + progressive disease: 50.7 ng/ml, p = 0.12), but other clinical variables such as age, gender, performance status, stage, histology, and number of metastatic locations were not associated with hTERT. In multivariate analysis, hTERT was an independent prognostic variable for both TTP (hazard ratio: 1.44, p < 0.001) and OS (hazard ratio: 1.33, p = 0.007). Conclusions: In advanced NSCLC, high pretreatment circulating hTERT level is an independent poor prognostic marker for TTP and OS. Circulating DNA is a noninvasive marker, which may help to improve the prognostic profile of these patients. Copyright © 2011 by the International Association for the Study of Lung Cancer., Supported, in part, by the Spanish Society of Medical Oncology (SEOM).

[EN] In addition to malignant neoplastic cells, cancer tissues also include immune cells, fibroblasts, and endothelial cells, including an abundant collection of growth factors, proangiogenic mediators, cytokines, chemokines, and components of the extracellular matrix. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. Between immune cells and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has both tumor-promoting and-inhibiting roles. In non-small cell lung cancer (NSCLC), there is a marked infiltration of different types of immune cells, and the distribution, tissue localization, and cell types are significantly associated with progression and survival. Cancer immunotherapy has seen a significant progress during the last decade. An increased understanding of the mechanisms by which lung cancer cells escape the immune system, and the recognition of the key tumor antigens and immune system components in tumor ignorance have led to the development of several lung cancer vaccines. As the NSCLC prognosis in general is dismal, one may hope that future immunotherapy may be an effective adjunct to standard therapy, reversing immunologic tolerance in the tumor microenvironment. This review reports on the tumor stroma and in particular tumor-suppressing and-promoting roles of the immune system. Furthermore, it presents recent literature on relevant immune cell-related research in NSCLC. Copyright © 2011 by the International Association for the Study of Lung Cancer.

Introduction: The vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFR) play an important role in tumor angiogenesis. Increased expression of angiogenic factors in tumors or in blood is associated with poor prognosis. The aim of this study was to investigate the role of VEGF-A and soluble VEGFR-2 (sVEGFR-2) as biomarkers in advanced non-small-cell lung cancer (NSCLC). Methods: We studied 432 patients with advanced NSCLC (stages IIIB-IV) treated with cisplatin and docetaxel and 89 healthy age-matched controls. Blood samples were collected before chemotherapy, and VEGF-A and sVEGFR-2 levels were determined by ELISA. Results: VEGF-A and sVEGFR-2 levels were higher in NSCLC patients than in the controls, but VEGF-A behaves as a better diagnostic biomarker. There were no significant associations between VEGF-A and sVEGFR-2 concentrations and clinical characteristics, such as ECOG-PS, gender, stage, histology, metastases, and treatment response. A patient subgroup characterized by a combination of high VEGF-A and low sVEGFR-2 levels exhibited the worst patient prognoses in terms of TTP and OS. Conclusions: VEGF-A and sVEGFR-2 levels were significantly higher in patients than in the controls. A combination of VEGF-A and sVEGFR-2 can be used as an independent prognostic biomarker in advanced NSCLC. © 2011 Elsevier Ireland Ltd., This work was supported in part, by a grant [PI06/104] from Instituto de Salud Carlos III and a grant [RD06/0020/1024] from Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation and European Regional Development Fund (ERDF) "Una manera de hacer Europa".

[EN] Background: Platinum doublets are standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether neutropenia is: (1) an indicator for treatment efficacy, or (2) associated with specific polymorphisms. Patients and Methods: Four hundred ninety-four patients, treated with cisplatin-docetaxel were retrospectively analyzed. Relative dose intensity (RDI) was assessed for both drugs. Neutrophil counts were assessed only on Day 21 of each cycle. Genotyping was performed for 4 different polymorphisms in ERCC1, XRCC3, XPD-23, and XPD-10. Results: The median overall survival was 9 months. The mean RDI was 0.94 for cisplatin and 0.93 for docetaxel. Four hundred three patients received ¿ 3 cycles of chemotherapy, and 239 received ¿ 6 cycles. Thirty-one percent developed neutropenia, and 19% had Grade (G)3-4 neutropenia. RDI was lower in patients with neutropenia (G1-4; 0.87-0.93) when compared with those without (G0; 0.94-0.95; P

Qualitative analysis of circulating DNA in the blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of KRAS mutations at codon 12 and several clinical variables in advanced non-small cell lung cancer (NSCLC) patients. Methods: We examined 308 stage IIIB and IV NSCLC patients who were treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. The KRAS mutational status was determined by an RT-PCR method that is based on allelic discrimination. Results: The median age of the patients was 60 years [31-80], 84% were male, 98% had a performance status of 0-1 and 84% of the patients were in stage IV. The histological subtypes were as follows: 30% squamous cell carcinoma (SCC), 51% adenocarcinoma (ADC) and 19% others. Of the 277 response-evaluated patients, 1% achieved a complete response (CR), 26% achieved a partial response (PR), 34% had stable disease (SD) and 39% had progressive disease (PD). Additionally, 27 (8.8%) patients had KRAS mutations; 26 had a KRAS codon 12 TGT mutation, and 1 had a codon 12 GTT mutation. Plasmatic KRAS mutations were found in patients presenting SCC or ADC. Patients with KRAS mutations in plasma DNA had a median progression free survival (PFS) of 5.77 months [3.39-8.14], whereas for patients with wild-type (wt) KRAS, the PFS was 5.43 months [4.65-6.22] (p = 0.277). The median overall survival (OS) in KRAS-mutated patients was 9.07 months [4.43-13.70] vs 10.03 months [8.80-11.26] in wt patients (p = 0.514). Conclusions: In advanced NSCLC patients, there were no significant differences between patients with or without KRAS mutations in plasma-free DNA with respect to the baseline characteristics, response rates, PFS or OS. © 2010 Elsevier Ireland Ltd., This work was sponsored in part by a grant from the Spanish Society of Medical Oncology (SEOM) and by a grant (RD06/0020/1024) from Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation & European Regional Development Fund (ERDF) "Una manera de hacer Europa". None of the funding agencies were involved in the design, data management, data analysis, manuscript preparation and review, or decision to submit.

Lung cancer in pregnancy is a rare situation; however, it is increasingly reported in the past two decades. The association might be more encountered in the coming years due to the rising trends of cigarette smoking among young women and tendency to delay pregnancy to later in life. We performed a literature search without any date or language restriction and identified 44 cases diagnosed and/or treated for lung cancer during the course of pregnancy. Patients had poor post-partum outcome with less than one-forth alive at 1 year following delivery. There was a high incidence of metastases to the products of conception reaching 26%. Eight patients were treated with systemic therapies during the course of gestation with normal fetal outcome and no evidence of fetal or placental metastases. Counseling of these patients is very important. Apart from the clinical conflict they pose, some ethical aspects should be taken in consideration. The poor maternal prognosis should be discussed and the patient's autonomy should be respected to decide whether she wants to keep the pregnancy or not. © 2009 Elsevier Ireland Ltd. All rights reserved. 67 3 251 256

Background: Our aim in the present study was to describe the quality of life (QOL), evaluate pulmonary function, and compare demographic and clinical characteristics with QOL in long-term survivors of non-small cell lung cancer treated with radical or postoperative radiotherapy. Methods: Twenty-eight patients were recruited in the study. QOL was evaluated using The European Organization for Research and Treatment of Cancer, Quality of Life Core Questionnaire (EORTC QLQ-C30, v.3). Statistical analysis was performed by SPSS 14. Results: Patients' files were reviewed in October 2006. Median duration of follow-up was 46 months (range: 25-125 months). Seven of 9 scales were found to meet the minimal reliability limit (Cronbach's alpha >0.70). The lowest and highest reliability coefficients were 0.56 and 0.93 for social and role functioning, respectively. All interscale correlations were statistically significant (P < 0.01). The strongest positive correlation was found between physical functioning and, role and cognitive functioning (r = 0.59, r = 0.37 or P = 0.01, P = 0.05, respectively). The highest correlation of EORTC QLQ-C30 and the Katnofsky performance scale (KPS) during the questionnaire was found to be with physical functioning and constipation (r = 0.41. r = 0.44 or P = 0.02, P = 0.01, respectively). When the effect of various demographic and clinical parameters on QOL was evaluated; initial KPS, age, educational level, health insurance status, stage, chemotherapy, comorbid disease, and passive smoking were determined as significant factors influencing QOL. Physical, role, cognitive, and emotional functions were found to be significantly lower in the presence of dyspnea (r = 0.42, r = 0.58, r = 0.50, r = 0.63 or P = 0.02, P < 0.01, P < 0.01, P < 0.05, respectively). Regarding the symptom scales, dyspnea was found to be correlated with increasing of fatigue, pain, insomnia, and appetite loss (r = 0.52, r = 0.40, r = 0.64, r = 0.38 or P < 0.01, P = 0.03, P < 0.05, P = 0.04, respectively). The parameters of pulmonary function tests (FEV1, FVC, and FEV1/FVC) did not show any significant relation with any scale of QOL. Conclusion: Overall, we found that QOL of our patients who survived at least 2 years after radiotherapy, was good. The Turkish version of the EORTC QLQ-C30, v.3 is a valid and reliable instrument for Turkish lung cancer patients and can be used in clinical studies. We believe further studies are needed to have a better understanding of patients' pretreatment and posttreatment .

The treatment for patients with unknown primary carcinoma, particularly those with unfavorable prognosis factors, has changed in the last decade, and continues to evolve. Empiric chemotherapy trials reported since 2000 with the newer drugs have improved the overall survival compared to retrospective historical data and prospective clinical trials reported from 1967 to 2000. Long-term survival (1, 2, 3 years and beyond) has been documented for a small minority of patients by several recent clinical trials. The survival of patients with a number of other advanced adenocarcinomas of known primary sites (colon, rectum, lung, pancreas) has been improved by the use of chemotherapy alone or combined with targeted drugs (bevacizumab, erlotinib), and about 60% of the patients with unknown primary adenocarcinomas harbor occult lesions of the colon, rectum, lung, or pancreas. Many of these patients have benefited from the newer broad-spectrum chemotherapy regimens. Several of these regimens appear about the same and currently represent the treatment of choice for the majority of these patients. Improvements in diagnostic pathology and molecular characterization of these carcinomas are likely to soon help select more appropriate and tailored therapies for many of these patients. © 2009 Elsevier Inc. All rights reserved. 36 1 65 74

The clinical manifestation of disseminated intravascular coagulation (DIC) as paraneoplastic phenomenon is common in patients with lung cancer (especially in those with non small cell lung cancer).Surprisingly, only few data have been published on the prevalence of this phenomenon. Herein we present the case of a patient with metastatic giant-cell carcinoma of the lung complicated by DIC leading the patient to death. We also review the literature regarding the incidence, the pathogenesis and the therapy of DIC in NSCLC. As more effective therapy for lung cancer becomes available and patients live longer, DIC can be expected to be encountered more frequently. Because of this fact clinicians should be alert to the occurrence of such clotting disorders and should be familiar with their diagnosis and management. © 2008 Elsevier Ireland Ltd. All rights reserved. 64 2 247 249