Cancer Res 2006 May 15; 66(10): 5346-53 (Read article online)

Ueda S, Basaki Y, Yoshie M, Ogawa K, Sakisaka S, Kuwano M, Ono M

Hepatocellular carcinoma (HCC) is one of the most common tumor-related causes of death worldwide for which there is still no satisfactory treatment. We previously reported the antiangiogenic effect of gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been used successfully to treat lung cancer. In this study, we investigated the effects of gefitinib on tumor-induced angiogenesis by using HCC cell lines (HCC3, CBO12C3, and AD3) in vitro as well as in vivo. Oral administration of gefitinib inhibited angiogenesis induced by HCC3 and CBO12C3, but not by AD3 in the mouse dorsal air sac model. Production of both vascular endothelial growth factor (VEGF) and chemokine C-X-C motif ligand 1 (CXCL1) by EGF-stimulated HCC was more markedly inhibited by gefitinib in HCC3 and CBO12C3 cells than in AD3 cells. EGF stimulated the phosphorylation of EGFR, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) in HCC3 and CBO12C3 cells, whereas EGF stimulated phosphorylation of EGFR and ERK1/2, but not Akt in AD3 cells. In fact, Akt was constitutively activated in the absence of EGF in AD3 cells. Gefitinib inhibited Akt phosphorylation in all three cell lines, but it was about five times less effective in AD3 cells. The concentration of PTEN in AD3 cells was about a half that in HCC3 and CBO12C3 cells. Transfection of HCC3 cells with PTEN small interfering RNA reduced their sensitivity to gefitinib in terms of its inhibitory effect on both Akt phosphorylation and the production of VEGF and CXCL1. In conclusion, effect of gefitinib on HCC-induced angiogenesis depends on its inhibition of the production of angiogenic factors, probably involving a PTEN/Akt signaling pathway. (Cancer Res 2006; 66(10): 5346-53).

Clin Cancer Res 2006 May 15; 12(10): 3193-9 (Read article online)

Yuan ZP, Chen LJ, Fan LY, Tang MH, Yang GL, Yang HS, Du XB, Wang GQ, Yao WX, Zhao QM, Ye B, Wang R, Diao P, Zhang W, Wu HB, Zhao X, Wei YQ

PURPOSE: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. EXPERIMENTAL DESIGN: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues. RESULTS: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis. CONCLUSIONS: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.

Cancer Res 2006 May 15; 66(10): 5330-5337 (Read article online)

Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, Tsao MS, Penn LZ

The product of the MYC oncogene is widely deregulated in cancer and functions as a regulator of gene transcription. Despite an extensive profile of regulated genes, the transcriptional targets of c-Myc essential for transformation remain unclear. In this study, we show that c-Myc significantly induces the expression of the H19 noncoding RNA in diverse cell types, including breast epithelial, glioblastoma, and fibroblast cells. c-Myc binds to evolutionarily conserved E-boxes near the imprinting control region to facilitate histone acetylation and transcriptional initiation of the H19 promoter. In addition, c-Myc down-regulates the expression of insulin-like growth factor 2 (IGF2), the reciprocally imprinted gene at the H19/IGF2 locus. We show that c-Myc regulates these two genes independently and does not affect H19 imprinting. Indeed, allele-specific chromatin immunoprecipitation and expression analyses indicate that c-Myc binds and drives the expression of only the maternal H19 allele. The role of H19 in transformation is addressed using a knockdown approach and shows that down-regulation of H19 significantly decreases breast and lung cancer cell clonogenicity and anchorage-independent growth. In addition, c-Myc and H19 expression shows strong association in primary breast and lung carcinomas. This work indicates that c-Myc induction of the H19 gene product holds an important role in transformation. (Cancer Res 2006; 66(10): 5330-7).

J Clin Oncol 2006 May 20; 24(15): 2245-2251 (Read article online)

Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Thirugnanam A, Tan EH

PURPOSE Tobacco smoke is a definite causative agent for lung cancer. It is increasingly being recognized that never-smokers can be afflicted with non-small-cell lung cancer (NSCLC). We aim to assess survival differences between smokers and never-smokers with NSCLC. PATIENTS AND METHODS We analyzed 975 NSCLC patients who presented from January 1999 to December 2002. Clinical characteristics among current-, former- and never-smokers were tested using chi(2) or Kruskal-Wallis test. The hazard ratio (HR) for death and its 95% CI were calculated by Cox regression. Results Of 975 patients, 59 had no smoking history and 33 had no quit time recorded. Of 883 patients analyzed, 286 patients (32.4%) were never-smokers. One hundred ninety-six never-smokers (68.5%) were females compared with 12% among current- and 13% among former-smokers (P < .001). There was a significant difference in histologic subtype between never-smokers and smokers: 69.9% with adenocarcinoma versus 39.9% (current-smokers) versus 47.3% (former-smokers); 5.9% with squamous cell carcinoma versus 35.7% (current-smokers) versus 28% (former-smokers; P < .001). Smokers had significantly poorer performance status (P = .002) and higher median age at diagnosis (P < .001) while more never-smokers presented with advanced disease (P = .002). Eight hundred and five patients (82.6%) died by May 30, 2005. The HR for smokers was significantly higher on both univariate and multivariate analysis (HR, 1.297; 95% CI, 1.040 to 1.619). CONCLUSION Never-smokers comprised a high proportion of NSCLC patients in Singapore. Definite epidemiologic differences exist between never-smokers and smokers. Differences in survival outcome further suggest that the biology underlying the pathogenesis and behavior of the disease may be different for never-smokers.

Cancer Gene Ther 2006 May 19; (Read article online)

Oshikiri T, Miyamoto M, Hiraoka K, Shichinohe T, Kawarada Y, Kato K, Suzuoki M, Nakakubo Y, Kondo S, Dosaka-Akita H, Kasahara N, Katoh H

Squamous cell carcinoma antigens SCCA1 and SCCA2 are highly homologous serine proteinase inhibitors which have been widely utilized as serological markers for squamous cell cancers, but it has recently been demonstrated that only SCCA2 is truly specific for certain forms of lung cancer. Using a construct containing the 5'-flanking region of the SCCA2 gene between -460 and +0 bp and the luciferase reporter gene, SCCA2 promoter activity was detected in SCCA2-producing SCC cell lines (LK-2, LC-1), but not in SCCA2-nonproducing lung adenocarcinoma cell lines (A549, ABC-1, and RERF-LC-MS) or normal cells (WI-38, SAEC, and NHEK-Adult). Infection with a recombinant adenovirus vector, Ad-SCCA2-DsRed, resulted in cell-specific expression of the SCCA2 promoter-driven DsRed marker gene only in LK-2 and LC-1 cells. The same strategy was used for SCCA2-driven expression of a proapoptotic gene, (KLAKLAK)2, which can cause mitochondrial disruption by triggering mitochondrial permeabilization and swelling, resulting in the release of cytochrome c and induction of apoptosis. Infection with Ad-SCCA2-KLAKLAK2 specifically reduced the growth of the two human lung SCC cell lines compared to the SCCA2 nonproducing cell lines both in vitro and in vivo, suggesting that the SCCA2 promoter had a tumor-specific effect. These results suggest that transduction of SCCA2 promoter-controlled suicide genes by adenoviral vectors can confer transcriptionally targeted cytotoxicity in SCCA2-producing lung SCC cells, and represents a novel strategy for gene transfer specifically targeted to SCC in the lung.Cancer Gene Therapy advance online publication, 19 May 2006; doi:10.1038/sj.cgt.7700953.

Clin Cancer Res 2006 May 15; 12(10): 3078-84 (Read article online)

Dziadziuszko R, Witta SE, Cappuzzo F, Park S, Tanaka K, Danenberg PV, Barón AE, Crino L, Franklin WA, Bunn PA, Varella-Garcia M, Danenberg KD, Hirsch FR

PURPOSE: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non-small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression]. EXPERIMENTAL DESIGN: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens. RESULTS: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35). CONCLUSION: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.

Cancer Res 2006 May 15; 66(10): 5338-45 (Read article online)

Dohadwala M, Yang SC, Luo J, Sharma S, Batra RK, Huang M, Lin Y, Goodglick L, Krysan K, Fishbein MC, Hong L, Lai C, Cameron RB, Gemmill RM, Drabkin HA, Dubinett SM

Elevated tumor cyclooxygenase-2 (COX-2) expression is associated with tumor invasion, metastasis, and poor prognosis in non-small cell lung cancer (NSCLC). Here, we report that COX-2-dependent pathways contribute to the modulation of E-cadherin expression in NSCLC. First, whereas genetically modified COX-2-sense (COX-2-S) NSCLC cells expressed low E-cadherin and showed diminished capacity for cellular aggregation, genetic or pharmacologic inhibition of tumor COX-2 led to increased E-cadherin expression and resulted in augmented homotypic cellular aggregation among NSCLC cells in vitro. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human lung adenocarcinoma tissue sections. Second, treatment of NSCLC cells with exogenous prostaglandin E(2) (PGE(2)) significantly decreased the expression of E-cadherin, whereas treatment of COX-2-S cells with celecoxib (1 mumol/L) led to increased E-cadherin expression. Third, the transcriptional suppressors of E-cadherin, ZEB1 and Snail, were up-regulated in COX-2-S cells or PGE(2)-treated NSCLC cells but decreased in COX-2-antisense cells. PGE(2) exposure led to enhanced ZEB1 and Snail binding at the chromatin level as determined by chromatin immunoprecipitation assays. Small interfering RNA-mediated knockdown of ZEB1 or Snail interrupted the capacity of PGE(2) to down-regulate E-cadherin. Fourth, an inverse relationship between E-cadherin and ZEB1 and a direct relationship between COX-2 and ZEB1 were shown by immunohistochemical staining of human lung adenocarcinoma tissue sections. These findings indicate that PGE(2), in autocrine or paracrine fashion, modulates transcriptional repressors of E-cadherin and thereby regulates COX-2-dependent E-cadherin expression in NSCLC. Thus, blocking PGE(2) production or activity may contribute to both prevention and treatment of NSCLC. (Cancer Res 2006; 66(10): 5338-45).

Support Care Cancer 2006 May 18; (Read article online)

Hauser CA, Stockler MR, Tattersall MH

GOALS OF WORK: To review the literature and develop a conceptual framework about prognostic factors for people presenting to medical oncologists with recently diagnosed incurable cancer. MATERIALS AND METHODS: Medline was searched from January 2000 to October 2003 to identify articles testing associations between clinical or laboratory variables and survival time in adults with advanced solid tumours and median survival of 3 to 24 months. We recorded how frequently prognostic factors were significantly associated with survival in univariable and multivariable analyses. RESULTS: There were 53 studies included. The factors associated with survival were organised into four categories related to attributes of the host the tumour, the treatment and the interactions between host, tumour and treatment (symptoms, quality of life, performance status and laboratory tests). Co-morbidity was consistently associated with shorter survival. Age and gender were not consistently associated with survival duration, except in lung cancer where females survived longer. Tumour-related factors associated with shorter survival included primary tumour (lung), metastatic site (liver, brain and visceral) and disease extent. Symptoms associated with shorter survival included those of the anorexia-cachexia syndrome, dyspnoea, pain and impaired physical well being. Performance status was strongly associated with survival in most studies. Laboratory tests associated with shorter survival included anaemia, thrombocytopenia, hypoalbuminaemia and elevated serum levels of both alkaline phosphatase and lactate dehydrogenase. CONCLUSION: Prognostic factors in patients with advanced cancer can be conceptualised as attributes of the host, tumour, treatment and interactions between the three reflected in symptoms, quality of life performance status and laboratory tests.

J Clin Oncol 2006 May 20; 24(15): 2252-2260 (Read article online)

Erlichman C, Hidalgo M, Boni JP, Martins P, Quinn SE, Zacharchuk C, Amorusi P, Adjei AA, Rowinsky EK

PURPOSE The maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors. PATIENTS AND METHODS Planned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days 1 and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort. Results Thirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean +/- standard deviation terminal half-life was 21.7 +/- 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non-small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively. CONCLUSION The MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.

Cancer Res 2006 May 15; 66(10): 5409-18 (Read article online)

Imre G, Gekeler V, Leja A, Beckers T, Boehm M

Recently, the inhibition of histone deacetylase (HDAC) enzymes has attracted attention in the oncologic community as a new therapeutic opportunity for hematologic and solid tumors including non-small cell lung cancer (NSCLC). In hematologic malignancies, such as diffuse large B-cell lymphoma, the HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA), has recently entered phase II and III clinical trials. To further advance our understanding of their action on tumor cells, we investigated the possible effect of HDI treatment on the functionality of the nuclear factor-kappaB (NF-kappaB) pathway in NSCLC. We found that in the NSCLC cell lines, A549 and NCI-H460, the NF-kappaB pathway was strongly inducible, for example, by stimulation with tumor necrosis factor-alpha (TNF-alpha). Incubation of several NSCLC cell lines with HDIs resulted in greatly reduced gene expression of TNF-alpha receptor-1. HDI-treated A549 and NCI-H460 cells down-regulated TNF-alpha receptor-1 mRNA and protein levels as well as surface exposure, and consequently responded to TNF-alpha treatment with reduced IKK phosphorylation and activation, delayed IkappaB-alpha phosphorylation, and attenuated NF-kappaB nuclear translocation and DNA binding. Accordingly, stimulation of NF-kappaB target gene expression by TNF-alpha was strongly decreased. In addition, we observed that SAHA displayed antitumor efficacy in vivo against A549 xenografts grown on nude mice. HDIs, therefore, might beneficially contribute to tumor treatment, possibly by reducing the responsiveness of tumor cells to the TNF-alpha-mediated activation of the NF-kappaB pathway. These findings also hint at a possible use of HDIs in inflammatory diseases, which are associated with the overproduction of TNF-alpha, such as rheumatoid arthritis or Crohn's disease. (Cancer Res 2006; 66(10): 5409-18).

Biosci Rep 2006 May 19; (Read article online)

Damera G, Xia B, Ancha HR, Sachdev GP

Compromised epithelial cell integrity is a common feature associated with chronic lung inflammatory states such as asthma. While epithelial cell damage is largely due to sustained effects of inflammatory mediators localized to airways, the subsequent process of epithelial cell differentiation is attributed to members of the transmembrane receptor tyrosine kinase family called the ErbB's. MUC4, a large molecular weight membrane-bound glycoprotein, has recently been identified as a potential ligand for the ErbB-2 receptor. In this study, we investigated the possible role of interleukin-9 (IL-9), a Th2 cytokine, on MUC4 expression using a lung cancer cell line, NCI-H650. We determined that IL-9 up-regulates MUC4 expression in a time and concentration-dependent fashion. Nuclear run-on assays indicated transcriptional regulation of MUC4 while no post-transcriptional mRNA stabilization was observed by actinomycin D chase experiments. IL-9 also increased MUC4 glycoprotein expression as determined by Western blots using a monoclonal antibody specific for a non-tandem repeat region on ASGP-2 region of MUC4. Furthermore, a JAK3-selective inhibitor 4-(4'-hydroxyphenyl) amino-6, 7-dimethoxyquinazoline (WHI-P131), substantially reduced IL-9-induced MUC4 mRNA expression in a dose-dependent fashion. These results implicate a potential role for IL-9 upon MUC4 expression in human airway epithelial cells.

Eur Respir J 2006 May; 27(5): 1033-9 (Read article online)

Wewel AR, Crusius JA, Gatzemeier U, Heckmayr M, Becher G, Magnussen H, Jörres RA, Holz O

This study was designed to assess the effect of differential leukocyte depletion during chemotherapy by monitoring the levels of exhaled hydrogen peroxide H2O2 and nitric oxide (F(eNO)) present. In 39 patients with lung cancer (chronic obstructive pulmonary disorder up to stage II, median forced expiratory volume in one second 78% predicted), measurements were performed before a cycle of therapy (day 1), at least once during the cycle (day 8: n = 34; day 15: n = 19), and afterwards (days 21-29). There were significant changes in the level of H2O2, F(eNO) and peripheral blood cell differentials over the visits. The level of H2O2 was decreased only on day 15, with a median (difference between the upper and lower quartiles) fall of 31 (57)%, while F(eNO) was reduced only on day 8, by 22 (40)%. Neutrophil numbers were unchanged on day 8 and decreased by 59 (48)% on day 15, while monocyte numbers were decreased on day 8 by 87 (39)%. On days 21-29, values had returned to baseline. Taken together with previous findings, the parallel course of levels of exhaled hydrogen peroxide and neutrophil counts suggests that a major part of exhaled hydrogen peroxide is due to neutrophils via the conducting airways. In contrast, the production of exhaled nitric oxide seems to be primarily associated with monocytes.

Nucl Med Commun 2006 Jun; 27(6): 507-514 (Read article online)

Ferran N, Ricart Y, Lopez M, Martinez-Ballarin I, Roca M, Gámez C, Carrerea D, Guirao S, Leon AF, Martin-Comin J

AIM: To evaluate the diagnostic accuracy of 99m Tc-depreotide vs PET-18FDG scans in patients with suspicion of lung cancer MATERIAL AND METHODS: Prospective study in 29 patients (age: 38-80 years) diagnosed of inderteminate lung lesions. Diagnosis was established by histology based on samples of surgical resection, fine needle aspiration (FNA) or broncoalveolar lavage (BAL). Within a maximum of 10 days, without pre-established fixed order the following exams were performed: 1) Whole body and chest SPECT-CT with Tc-depreótide (DEP-SPECT) and 2) PET-CT study with F-FDG (PET-FDG). Every exam was evaluated by Nuclear Medicine especialist blinded to patient data. RESULT: Malignancy was confirmed in 20 patients. PET-FDG was positive in all cases. DEP-SPECT was positive in 17 and falselly negative in 3, one carcinoid tumor, one undifferentiated non-small cell adenocarcinoma, and a moderately differentiated adenocarcinoma. In the remaining 9 patients benignancy was confirmed; both studies were normal in 8 and falselly positive in one case of non-specific inflammatory lung process.In 9 out of the 20 cases with malignancy extrapulmonar uptake was seen, with a total number of 19 lesions. In two cases the extrapulmonar uptake were non ganglionar metastasis (bone and adrenal) and in 7 due to mediastinic ganglionar involvement. ROC analysis using peak SUV FDG (cut-off point of 3.5) uptake and target/background depreotide uptake (cut-off point of 1.3) provided, sensitivity and specificity values of 95% and 89% of 84% and 88% for PET and SPECT respectively. It does not exist statistically significant differences between both methods (Z-test SPSS).In summary, FDG-PET has a greater sensitivity and diagnostic accuracy for assessing malignancy of indeterminate lung lesions, and for detection of extrapulmonary involvement, DEP-SPECT represents a good diagnostic alternative for centers where PET is not available.

Int J Cancer 2006 May 17; (Read article online)

Parise RA, Egorin MJ, Kanterewicz B, Taimi M, Petkovich M, Lew AM, Chuang SS, Nichols M, El-Hefnawy T, Hershberger PA

1alpha,25-Dihydroxyvitamin D(3) (1,25D(3)) displays potent antiproliferative activity in a variety of tumor model systems and is currently under investigation in clinical trials in cancer. Studies were initiated to explore its potential in nonsmall cell lung cancer (NSCLC), as effective approaches to the treatment of that disease are needed. In evaluating factors that may affect activity in NSCLC, the authors found that CYP24 (25-hydroxyvitamin D(3)-24-hydroxylase), the enzyme that catabolizes 1,25D(3), is frequently expressed in NSCLC cell lines but not in the nontumorigenic bronchial epithelial cell line, Beas2B. CYP24 expression by RT-PCR was also detected in 10/18 primary lung tumors but in only 1/11 normal lung tissue specimens. Tumor-specific CYP24 upregulation was confirmed at the protein level via immunoblot analysis of patient-matched normal lung tissue and lung tumor extracts. Enzymatically active CYP24 is expected to desensitize NSCLC cells to 1,25D(3). The authors therefore implemented a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for 1,25D(3) and its CYP24-generated metabolites to determine whether NSCLC cells express active enzyme. Analysis of NSCLC cell cultures revealed time-dependent loss of 1,25D(3) coincident with the appearance of CYP24-generated metabolites. MK-24(S)-S(O)(NH)-Ph-1, a specific inhibitor of CYP24, slowed the loss of 1,25D(3) and increased 1,25D(3) half-life. Furthermore, combination of 1,25D(3) with MK-24(S)-S(O)(NH)-Ph-1 resulted in a significant decrease in the concentration of 1,25D(3) required to achieve maximum growth inhibition in NSCLC cells. These data suggest that increased CYP24 expression in lung tumors restricts 1,25D(3) activity and support the preclinical evaluation of CYP24 inhibitors for lung cancer treatment. (c) 2006 Wiley-Liss, Inc.

Nurs Res 2006 May/June; 55(3): 161-171 (Read article online)

Doorenbos A, Given B, Given C, Verbitsky N

BACKGROUND:: Individuals with cancer receiving chemotherapy suffer deterioration in physical functioning due to symptoms arising from the cancer disease process and its treatment. OBJECTIVES:: To determine if age, chronic health conditions (comorbidity), stage of cancer, depressive symptomatology, symptom limitations, sex, and site of cancer moderate the effects of cognitive behavioral intervention on physical function and to determine if symptom limitations mediate the effect of the intervention on physical functioning. METHODS:: Two hundred thirty-seven individuals with solid tumor cancer (118 experimental and 119 control group) participated in this 10-contact, 18-week randomized control trial. Cognitive behavioral theory guided the nurse-delivered problem-solving experimental intervention. The control group received conventional care. Interviews occurred at baseline and 10, 20, and 32 weeks. RESULTS:: Women with breast cancer had significantly better physical functioning than women with lung cancer. Chronic health conditions, symptom limitation, and depressive symptomatology at baseline were found to moderate the effect of intervention on physical function. Symptom limitation, however, was not found to mediate the effect of intervention on physical functioning. DISCUSSION:: The intervention was shown to affect physical function trajectories differently for individuals with different personal and health characteristics. Because poor physical functioning is strongly associated with mortality and poor quality of life, this information may be used by health professionals to target interventions to those who might be most responsive.

J Clin Pathol 2006 May 12; (Read article online)

Woenckhaus M, Bubendorf L, Dalquen P, Foerster J, Blaszyk H, Mirlacher M, Soler M, Dietmaier W, Sauter G, Hartmann A, Wild PJ

AIM: This study investigated whether nuclear and cytoplasmic Maspin expression is associated with distinct clinicopathologic parameters and TP53 expression in a representative series of primary non-small cell lung cancer (NSCLC). METHODS: Tissue microarrays (n = 487) were used to immunohistochemically analyze expression of Maspin and TP53. Cytoplasmic and nuclear expression of Maspin was scored based on the percentage of positive tumor cells. Univariate analysis of clinicopathologic variables potentially impacting tumor-specific survival was performed. RESULTS: Immunohistochemical Maspin expression (nuclear and cytoplasmic) was informative in 72.3% (352/487). Cytoplasmic and nuclear Maspin immunoreactivity in "d10% of tumor cells was detected in 37.8% (133/352) and 65.3% (230/352) of informative cases, respectively. Nuclear and cytoplasmic Maspin staining was observed more frequently in primary squamous cell carcinomas, compared to other lung cancer types. Only nuclear Maspin immunoreactivity was significantly associated with positive TP53 staining. Cytoplasmic or nuclear Maspin expression was not associated with tumor-specific survival. CONCLUSION: Maspin expression was found both in the nucleus and the cytoplasm of NSCLC, more frequently in squamous cell carcinomas. However, no association with tumor-specific survival could be demonstrated.

Treat Respir Med 2006; 5(3): 181-91 (Read article online)

Fanucchi M, Khuri FR

Paclitaxel and docetaxel, drugs that bind tightly to beta-tubulin and disrupt microtubule dynamics, are widely used in the treatment of non-small cell lung cancer (NSCLC), the most common cause of cancer death in men and women living in the US. These well tolerated drugs, alone or in combination with another cytotoxic agent, have been shown to increase the survival of patients with metastatic disease or malignant effusions. Both paclitaxel and docetaxel can be combined with concurrent chest irradiation for patients with locally advanced NSCLC. The combination of carboplatin and paclitaxel, when given postoperatively to patients with stage IB NSCLC, improved survival compared with surgery alone, with little toxicity. Taxane combinations are undergoing study as adjuvant therapy for patients with other stages of operable disease. Except for a recent trial with bevacizumab, efforts to improve the efficacy of taxane/platinum combinations in patients with advanced disease by adding a third 'targeted' drug have thus far been unsuccessful.

Lung Cancer 2006 May 11; (Read article online)

Jones JM, McGonigle NC, McAnespie M, Cran GW, Graham AN

OBJECTIVES: There is an association between coagulation and lung cancer. Therefore, pre-operative plasma fibrinogen and serum C-reactive protein (CRP) concentration were assessed to determine their association with tumour characteristics and to ascertain any role in patient selection for curative resection. METHODS: These parameters were compared with tumour size, pTNM stage, and possibility of complete resection in 93 patients with non-small cell lung cancer who underwent surgical resection. RESULTS: Plasma fibrinogen concentration (r(s)=0.34, P=0.001) and serum CRP concentration ((r(s)=0.34, P=0.001) were positively correlated with maximum pathological tumour size. A higher plasma fibrinogen concentration was associated with squamous cell carcinoma versus adenocarcinoma (4.5+/-0.13g/L versus 3.6+/-0.28g/L; P=0.008), with a trend towards a similar association for CRP (P=0.06). Pathological T stage was also associated with mean plasma fibrinogen and serum CRP concentration (P=0.01 and 0.04, respectively), but pN stage was not associated with either parameter. Incomplete resection occurred in 23% of patients with plasma fibrinogen>5g/L or serum CRP>40mg/L (versus only 8% when fibrinogen

Hum Mol Genet 2006 May 12; (Read article online)

Xinarianos G, McRonald FE, Risk JM, Bowers NL, Nikolaidis G, Field JK, Liloglou T

Lung cancer demonstrates the highest mortality in the UK. Previous studies have implicated allelic loss at chromosome 17q in the development of non-small cell lung carcinoma (NSCLC), and a number of known and putative tumour-suppressor genes reside within this region. One candidate tumour-suppressor gene is cytoglobin (CYGB), which is contained entirely within the 42.5kb Tylosis with Oesophageal Cancer (TOC) minimal region. CYGB abnormalities have only been demonstrated in sporadic head & neck cancers. In this study, we investigated the expression, promoter methylation and allelic imbalance status of this gene in 52 paired (normal / tumour) surgically excised lung tissue samples from patients with NSCLC. CYGB expression in tumour tissue was significantly reduced compared to corresponding adjacent normal in 54% of the examined cases (paired T-test, p < 0.001). The CYGB promoter was shown by pyrosequencing to be significantly hypermethylated (2-fold increase of methylation index in tumours) in 25/52 (48%) tumour compared to normal samples. The methylation index (MtI) of the CYGB promoter was associated with CYGB mRNA expression (linear regression analysis, p = 0.009) suggesting a primary role for the epigenetic events in CYGB silencing. In addition frequent LOH was detected at the locus 17q25 in 32/48 (67%) tumours examined. It is of note that the loss of expression intensified when both LOH and hypermethylation coincided in samples (Mann-Whitney, p = 0.049).The above findings provide the first evidence to suggest the implication of CYGB in the pathogenesis of NSCLCs.

BMC Public Health 2006 May 12; 6(1): 130 (Read article online)

Costanza MC, Salamun J, Lopez AD, Morabia A

ABSTRACT: BACKGROUND: Describe the recent evolution of cigarette smoking habits by gender in Geneva, where incidence rates of lung cancer have been declining in men but increasing in women. METHODS: Continuous cross-sectional surveillance of the general adult (35-74 yrs) population of Geneva, Switzerland for 11 years (1993-2003) using a locally-validated smoking questionnaire, yielding a representative random sample of 12,271 individuals (6,164 men, 6,107 women). RESULTS: In both genders, prevalence of current cigarette smoking was stable over the 11-year period, at about one third of men and one quarter of women, even though smoking began at an earlier age in more recent years. Older men were more likely to be former smokers than older women. Younger men but not women tended to quit smoking at an earlier age. CONCLUSIONS: This continuous (1993-2003) risk factor surveillance system, unique in Europe, shows stable prevalence of smoking in both genders. However, sharp contrasts in age-specific prevalence of never and former smoking and of ages at smoking initiation indicate that smoking continues a long-term decline in men but has still not reached its peak in women.