Primary Non-small Cell Lung Carcinoma Research Articles

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Abstract A15: Establishment and characterization of a new patient-derived non-small cell lung cancer xenograft panel for pharmacological assessment.

Abstract Background: Development of targeted therapies in non-small cell lung carcinoma (NSCLC) is rapidly growing and offers promising treatment perspectives for cancer patients. However, the assessment of new therapeutic compounds requires preclinical models defined by precise tumor molecular features that could impact their antitumor efficacy. The aim of this study was then to develop and characterize a new reliable panel of human NSCLC xenografts. Material and methods: From 28 samples of NSCLC specimens obtained from patient's surgery and grafted into Swiss nude mice, 18 transplantable xenografts were established (64%). Molecular characterization included histological features, gene mutation status (EGFR, KRAS, and BRAF), and research of ALK translocation in both xenografts and their corresponding patient's tumors. For determination of the predictive value of the models, a standard pharmacological assessment was then performed in 6 adenocarcinoma (ADK) models using the EGFR inhibitor erlotinib (50 mg/kg/day, 5 days/week, 4 weeks, orally). Tumor Growth Inhibition (TGI) was calculated to measure the efficiency of erlotinib. Finally, to evaluate responses to erlotinib according to individual mouse variability, we decided to consider each mouse as one tumor-bearing entity. In all in vivo experiments, a relative tumor volume variation (RTVV) of each erlotinib-treated mouse was calculated from the following formula: Vt/Vc, where Vt is the volume of the treated mouse and Vc the median volume of the corresponding control group at a time corresponding to the end of treatment. An overall response rate (ORR) was then calculated for both EGFR-mutated and -non mutated tumors. Results: Among the 18 established models, we have diagnosed 9 ADK, 6 epidermoid carcinomas, and 3 undifferientiated large cell cancers, with a high degree of similarity with the originated patient's tumors in regard to histological characteristics (Morphology and IHC), and a complete concordance for gene mutation status. Among the 18 NSCLC xenografts, 3 were EGFR mutated (exon 18 G719A, exon 19 del18b, and exon 21 L858R) and 3 others were KRAS mutated (G12C). No BRAF mutation nor ALK translocation were found. Erlotinib induced a TGI of 30%, 62%, and 93% for the 3 EGFR-mutated xenografts, and 0% (preliminary result), 37%, and 52% (KRAS-mutated model) for the 3 wild type EGFR tumors. Moreover, the individual mouse ORR ORR ≥ 90% was 26% in the first group and 4% in the second one, respectively (p < 0,05). Conclusions: We have developed and characterized a new panel of primary human NSCLC xenografts that is highly representative of the heterogeneity of the disease and responses to the anti-EGFR targeted therapy, and provides precious tools to assess innovative therapeutic approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A15.

PARP inhibition induces BAX/BAK‐independent synthetic lethality of BRCA1‐deficient non‐small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases

Background:Anti-angiogenic therapy with bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) predominantly targets immature blood vessels. Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases. However, it is not known whether bevacizumab is effective against brain metastases or whether metastases are representative of their primary in terms of VEGF expression, hypoxia, proliferation and vascular phenotype. The aim of this study was to evaluate these factors in a series of matched primary NSCLCs and brain metastases.Methods and Results:Immunohistochemistry showed strong correlation of carbonic anhydrase 9 expression (a marker of hypoxia) in primary and secondary cancers (P=0.0002). However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers. The mean proportion of mature vessels was 63.2% higher in the brain metastases than the primary tumours (P=0.004). Moreover, the vascular pattern of the primary tumour was not representative of the metastasis.Conclusions:Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy. These findings may have implications for clinical trials and biomarker studies evaluating anti-angiogenic agents in brain metastases.

Non–Small Cell Lung Carcinoma: Accuracy of PET/CT in Determining the Size of T1 and T2 Primary Tumors

The purpose of this study was to compare the measurements of primary T1 and T2 non-small cell lung carcinomas (NSCLCs) at PET/CT to determine which modality has the more accurate correlation with the histologic findings. A retrospective study was performed with the images of 59 patients who underwent surgical resection of T1 and T2 NSCLC and preoperative PET/CT. The maximum measurement of the primary lung tumor was recorded on the PET and unenhanced CT (soft-tissue and lung windows) scans in the largest plane and compared with the maximum dimensions of the histologic specimen. PET and CT measurements both had high concordance with the histologic measurements. CT soft-tissue window measurements had the highest concordance with histologic measurements, but PET had a smaller SD. The greatest linear correlation was between CT soft-tissue and CT lung window measurements, indicating they can be used interchangeably. Outliers were found in both the PET (four tumors) and the two CT (five tumors) groups owing to low (18)F-FDG uptake due to tumor type and surrounding consolidation, respectively. PET is better for delineating primary NSCLC if surrounding collapse or consolidation is present. Otherwise, CT with either soft-tissue or lung windows is accurate. Owing to low FDG accumulation, CT is more accurate for assessment of alveolar cell carcinoma.

Abstract 5130: Neuropilin-1 expression in breast, colorectal and lung cancer

Abstract Neuropilin-1 is a coreceptor for vascular endothelial growth factor, which is expressed by endothelial cells and tumor cells. Preclinical data suggest that targeting neuropilin-1 would directly inhibit tumor cell growth and invasion, in addition to suppressing angiogenesis with indirect suppression of tumor growth. A humanized monoclonal antibody to neuropilin-1 is currently being evaluated in a phase one clinical trial of patients with solid malignancies. The aim of this study was to characterize the in situ expression of neuropilin-1 in normal and neoplastic human tissues. A monoclonal antibody to human neuropilin-1 was generated and validated for immunohistochemistry by comparison with isotopic in situ hybridization data, use of formalin-fixed human embryonic kidney (HEK)-293 cell pellets transfected with neuropilin-1, western blotting and quantitative reverse transcriptase (RT)-PCR on microdissected pure cell populations. Neuropilin-1 expression was assessed in whole sections of 65 primary breast carcinomas, 95 primary colorectal adenocarcinomas and 80 primary non-small cell lung carcinomas. An additional 50 breast, colorectal and lung metastases were also evaluated. The neuropilin-1 monoclonal antibody showed appropriate reactivity by western blotting and in formalin-fixed cell pellet controls, with co-localization of protein (immunohistochemistry) and mRNA (in situ hybridization and laser-capture microdissection followed by quantitative RT-PCR). Immunoreactivity for neuropilin-1 was seen in endothelium from normal tissues adjacent cancer and 98 to 100% of primary and secondary carcinomas. Tumor cell expression of neuropilin-1 was also observed in 34% of primary non-small cell lung carcinomas and 6% of primary breast carcinomas, but no colorectal adenocarcinomas. This is the first comprehensive analysis of neuropilin-1 protein expression in neoplastic human tissue with validated reagents. The assay will inform the likely activity and toxicity of agents that target neuropilin-1 and warrants evaluation as a biomarker of anti-neuropilin-1 activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5130. doi:10.1158/1538-7445.AM2011-5130

An in vitro chemoresponse assay defines a subset of colorectal and lung carcinomas responsive to cetuximab

Cetuximab is a chimeric monoclonal antibody for the epidermal growth factor receptor (EGFR) that may provide benefit to select cancer patients; however, identification of the characteristics of those patients who may benefit from its use is not complete. The ChemoFx® drug response marker (DRM) is an in vitro assay that can provide drug response data on tumor specimens before any patient treatment is initiated. We determined the feasibility of using the ChemoFx DRM to test tumor samples for sensitivity to cetuximab. We exposed four non-small cell lung carcinoma (NSCLC) cell lines (H358, H520, HCC827, and H1666) to cetuximab and determined their sensitivity using the ChemoFx DRM and, in parallel, EGFR status using immunocytochemistry, Western blotting, and In-Cell WesternTM analysis. We used the ChemoFx DRM to determine cetuximab sensitivity of primary NSCLC and colorectal tumor samples. The ChemoFx DRM distinguished between cetuximab-sensitive and -resistant cell lines. Cetuximab sensitivity was not dependent on EGFR mutational status; H358 cells were non-responsive to cetuximab yet contain wild-type EGFR, whereas H1666 cells were intermediately responsive to cetuximab and contain wild-type EGFR. HCC827 (EGFR-mutant) cells were intermediately responsive and, as expected, H520 cells (EGFR-null) were non-responsive to cetuximab. ChemoFx-determined cetuximab sensitivity of primary NSCLC and colorectal tumor samples was 9.0% and 7.5%, respectively. Use of the ChemoFx DRM is feasible for determining cetuximab sensitivity. The ChemoFx-determined cetuximab responses of primary NSCLC and colorectal tumor specimens were similar to published response rates of patients to treatment with cetuximab monotherapy.

Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

Purpose: The anaplastic lymphoma kinase (ALK) gene is a potential m olecular target in non-small cell lung carcinoma (NSCLC). The clinicopathologic implication of a change in the ALK gene copy number (GCN) is unclear. Materials and Methods: A total of 434 primary NSCLC samples were analyzed by fluorescence in situ hybridization (FISH) for ALK GCN. Results: Ninety-six cases (22.1%) showed ALK GCN gain with amplification in 16 (3.7%) cases. The cases with ALK GCN gain consisted of 47 adenocarcinomas (49.0%), 41 squamous cell carcinomas (42.7%), 5 adenosquamous carcinomas (5.2%) and 3 other NSCLCs (3.1%). ALK gene am plification was identified in 7 adenocarcinom as (43.7%) and 9 squamous cell carcinomas (56.3%). There was no significant difference between ALK GCN gain/amplificati on and histologic subtypes. Univariate survival analysis revealed that patients with ALK GCN gain/amplificati on showed shorter progression-free survival durations and decreased overall survival rates (p ＜0.001). However, multivariate analysis proved that ALK GCN gain/ampl ification is not an independent prognostic factor for progression-free survival or overall survival. Conclusion: ALK GCN gain is frequently identified in NSCLCs and the incidence is similar among histologic subtypes. Although ALK G CN gain/ampl ification is not an independent prognostic m arker, it is associated with tumor progression in NSCLC. (J Lung Cancer 2011;10(2):87 �� 93)

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear. mRNA expression levels of UHRF1, DNMT1, DNMT3A, DNMT3B, and E2F1 were evaluated in 105 primary nonsmall cell lung carcinomas by quantitative polymerase chain reaction. The methylation status of CDKN2A and RASSF1 promoters was examined by pyrosequencing. UHRF1 was knocked down by short hairpin RNA in A549 lung adenocarcinoma cells. All 4 genes were overexpressed in a coordinated manner in the lung tumor tissues, and their expression correlated with that of E2F1. Higher UHRF1 expression in tumor tissues correlated with the hypermethylation of CDKN2A (P = .005) and RASSF1 promoters (P = .034), and the relationship with a combined epigenotype was even stronger (P = 2.3 × 10(-4) ). When UHRF1 was knocked down in A549 lung adenocarcinoma cells, lower methylation levels of RASSF1, CYGB, and CDH13 promoters were observed. Also, UHRF1 knockdown clones demonstrated reduced proliferation and decreased cell migration properties. Our data demonstrate that UHRF1 is a key epigenetic switch, which controls cell cycle in nonsmall cell lung carcinoma through its ability to sustain the transcriptional silencing of tumor suppressor genes by maintaining their promoters in a hypermethylated status. Thus, UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification.

Global DNA hypomethylation-induced ΔNp73 transcriptional activation in non-small cell lung cancer

p73 possesses an extrinsic P1 promoter and an intrinsic P2 promoter controlling the expression of the pro-apoptotic TAp73 isoforms and the anti-apoptotic ΔNp73 isoforms respectively. In this study, we investigated the DNA methylation status of both promoters as a means of epigenetic transcriptional control of their corresponding isoforms in 102 primary non-small cell lung carcinomas (NSCLCs). We demonstrated that while P1 hypermethylation-associated reduction of TAp73 mRNA levels is relatively infrequent, the P2 hypomethylation-associated over-expression of ΔNp73 mRNA is a frequent event, particularly among squamous cell carcinomas. P2 hypomethylation strongly correlated with LINE-1 element hypomethylation, indicating that ΔNp73 over-expression may be a passive consequence of global DNA hypomethylation.

Cavitating Lymph Node Metastasis Demonstrated by Endobronchial Ultrasound

Cavitation of primary non-small cell lung carcinoma (NSCLC) occurs in a small number of patients. We report a case of cavitation of lymph node metastases in NSCLC. CT chest showed central low attenuation of the subcarinal lymph node, suggestive of necrosis, and endobronchial ultrasound (EBUS) imaging demonstrated two cystic spaces within the lymph node. Transbronchial needle aspiration of the cystic space confirmed the presence of metastatic NSCLC. Cystic necrosis was only demonstrable by EBUS. The incidence of such findings is unknown, however with the increasing use of EBUS for evaluation of the mediastinum such images may be more commonly encountered in the future.

Comparison of the dysadherin and E-cadherin expression in primary lung cancer and metastatic sites.

Dysadherin, a cancer associated cell membrane glycoprotein, has been reported to downregulate E-cadherin. Aberrant expression of E-cadherin has been associated with the development of metastases in patients with cancer. Even though the expression of dysadherin and E-cadherin has been studied in primary non-small cell lung carcinoma, little is known about its expression at the distant metastases sites. We investigate by immunohistochemistry the relationship between E-cadherin and dysadherin in 111 cases of primary lung carcinomas (53 squamous cell carcinomas, 21 adenocarcinomas, 13 large cell carcinomas, and 24 small cell carcinomas), and their distant metastases. The intensity, the expression pattern and the percentage of neoplastic cell staining were recorded and the results were correlated with clinicopathological findings of the subjects. Dysadherin immunostain was expressed in 61 (54.95%) of the cases, and increased dysadherin expression was significantly correlated with tumour size (p=0.003), distant metastases (p=0.0034), and metastasis size (p=0.0008). Reduced E-cadherin expression was noted in 46 (41.45%) of the cases, and was correlated with high-grade tumour (p=0.02), infiltrative growth pattern (p=0.042), and advanced stage (p=0.032). Although the correlation between the expression of dysadherin and E-cadherin was not significant, a group of patients showed reduced E-cadherin expression with dysadherin overexpression. In lung carcinomas dysadherin expression seems to reflect tumour aggressiveness and may be considered a positive marker of poor prognosis when considered alone or/and in combination with down-regulation of E-cadherin.

The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis

The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family and have been implicated in tumorigenesis. One isoform in particular, JNK2α, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes and to increase tumor formation in mice. As JNK is frequently activated in non-small cell lung carcinoma (NSCLC), we investigated the role of the JNK2α isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered that 60% of the tested primary NSCLC tumors had three-fold higher JNK2 protein and two- to three-fold higher JNK2α mRNA expression than normal lung control tissue. To determine the importance of JNK2α in NSCLC progression, we reduced JNK2α expression in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2α had decreased cellular growth and anchorage-independent growth, and the tumors were four-fold smaller in mass. To elucidate the mechanism by which JNK2α induces NSCLC growth, we analyzed the JNK substrate, signal transducer and activator of transcription 3 (STAT3). Our data demonstrates for the first time that JNK2α can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue, thereby regulating the expression of oncogenic genes, such as c-Myc. Furthermore, reintroduction of JNK2α2 or STAT3 restored the tumorigenicity of the NSCLC cells, demonstrating that JNK2α is important for NSCLC progression. Our studies reveal a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2α.

Predictors of postoperative survival in patients with locally advanced non-small cell lung carcinoma

A surgical resection for locally advanced non-small cell lung carcinoma (NSCLC) remains controversial. This study analyzed the clinicopathological profile and surgical outcome of patients with locally advanced NSCLC to identify the predictors of survival. This study retrospectively analyzed clinical data from 86 patients with pathological T3 or T4 primary NSCLC treated at Chiba University Hospital, and evaluated prognostic factors. Sixty-eight of 86 cases were treated with a complete resection, and 18 were evaluated as an incomplete resection. The 5-year overall survival rate of all cases was 45.7%. Univariate analyses of survival were performed to determine the predictors of overall survival in patients with pathological T3 or T4 NSCLC. Age of 70 years or more, tumor length more than 5 cm, lymph node metastases, incomplete resection, and histology of non-adenocarcinoma were significantly associated with an unfavorable prognosis. Multivariate analyses revealed that older age, incomplete resection, and lymph node metastases were independent predictors of shorter survival. A complete resection for selected cases is acceptable in the management of T3 or T4 NSCLC.

Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies

Biological therapies, such as monoclonal antibodies (mAbs) that target tumor-associated antigens have been considered an effective therapeutic approach in oncology. In considering Notch-1 receptor as a potential target, we performed immunohistochemistry on tissue microarrays to determine 1) whether the receptor is overexpressed in tumor cells as compared to their corresponding normal tissues and 2) the clinical significance of its expression levels in human breast, colorectal, lung and prostate cancers. We found that the expression of Notch-1 protein was overexpressed in primary colorectal adenocarcinoma and nonsmall cell lung carcinoma (NSCLC), but not in primary ductal breast carcinoma or prostate adenocarcinoma. Further analysis revealed that higher levels of Notch-1 protein expression were significantly associated with poorer differentiation of breast and prostate tumors. Strikingly, for NSCLC, the expression levels of Notch-1 protein were found to be inversely correlated with tumor differentiation and progression. For colorectal tumors, however, no correlation of Notch-1 protein expression was found with any tumor clinicopathological parameters, in spite of its overexpression in tumor cells. Our data demonstrated the complexity of Notch-1 protein expression in human solid tumors and further supported the notion that the roles of Notch-1 expression in tumorigenesis are highly context-dependent. The findings could provide the basis for development of distinct therapeutic strategies of Notch-1 mAbs for its applications in the treatment of suitable types of human cancers.

Suppression of hydroxyurea-induced centrosome amplification by NORE1A and down-regulation of NORE1A mRNA expression in non-small cell lung carcinoma

The candidate tumor suppressor NORE1A is a nucleocytoplasmic shuttling protein, and although a fraction of the NORE1A in cells is localized to their centrosomes, the role of centrosomal NORE1A has not been elucidated. In this study we investigated the role of NORE1A in the numerical integrity of centrosomes and chromosome stability in lung cancer cells. Exposure of p53-deficient H1299 lung cancer cell line to hydroxyurea (HU) resulted in abnormal centrosome amplification (to 3 or more centrosomes per cell) as determined by immunofluorescence analysis with anti-γ-tubulin antibody, and forced expression of wild-type NORE1A partially suppressed the centrosome amplification. The nuclear export signal (NES) mutant (L377A/L384A) of NORE1A did not localize to centrosomes and did not suppress the centrosome amplification induced by HU. Fluorescence in situ hybridization analyses with probes specific for chromosomes 2 and 16 showed that wild-type NORE1A, but not NES-mutant NORE1A, suppressed chromosome instability in HU-exposed H1299 cells that was likely to have resulted from centrosome amplification. We next examined the status of NORE1A mRNA expression in non-small cell lung carcinoma (NSCLC) and detected down-regulation of NORE1A mRNA expression in 25 (49%) of 51 primary NSCLCs by quantitative real-time-polymerase chain reaction analysis. These results suggest that NORE1A has activity that suppresses the centrosome amplification induced by HU and that NORE1A mRNA down-regulation is one of the common gene abnormalities in NSCLCs, both of which imply a key preventive role of NORE1A against the carcinogenesis of NSCLC.

Abstract 310: The role of c-Jun N-terminal kinase 2alpha in non-small cell lung carcinoma tumorigenesis

Abstract c-Jun N-terminal kinases (JNKs) are members of the mitogen activated protein kinase (MAPK) family and have been implicated in tumorigenesis. One isoform in particular, JNK2alpha, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes, and to increase tumor formation in mice. It was reported that there is frequent activation of JNK in non-small cell lung carcinoma (NSCLC). In this study, we investigated the role of the JNK2alpha isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered 70% of the tested primary NSCLC tumors had 2 to 3-fold higher JNK2alpha protein and mRNA expression compared to normal lung tissue indicating a possible role of JNK2alpha in NSCLC tumorigenesis. To determine the importance of JNK2alpha in NSCLC progression, we reduced JNK2α in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2alpha had decreased cellular growth and anchorage-independent growth, and the tumors were 4-fold smaller in mass. To elucidate the mechanism by which JNK2alpha induces NSCLC growth, we analyzed the JNK substrate, STAT3. Our data show that JNK2alpha can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue of STAT3 thereby regulating expression of oncogenic genes, such as c-Myc protein. Our studies revealed a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2alpha. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 310.

Lobectomy of Second Primary Cancer in Survivor of Small Cell Lung Cancer With Brain Metastasis

Resection of a second primary nonsmall cell lung carcinoma in a long-term survivor of small cell lung carcinoma with brain metastasis is reported. The patient had squamous cell carcinoma as the second primary tumor and underwent lobectomy with node dissection. He was alive 79 months after the initial diagnosis of the small cell carcinoma, 64 months after the diagnosis of the brain metastasis, and 21 months after the curative pulmonary resection for his second primary carcinoma.

Abstract No. 78: Computed Tomography Guided Radiofrequency Ablation in the Management of Inoperable Primary Non-Small Cell Lung Carcinoma - Its Effect on Quality of Life and Survival

To evaluate the effect of computed tomography (CT) guided radiofrequency (RF) ablation on quality of life (QoL) and survival in patients with inoperable primary NSCLC. In addition, the association between the level of symptom relief and objective tumor response was investigated.

Somatic Alterations of the Serine/Threonine Kinase LKB1 Gene in Squamous Cell (SCC) and Large Cell (LCC) Lung Carcinoma

Somatic LKB1 serine/threonine kinase alterations are rare in sporadic cancers, with the exception lung adenocarcinoma, but no mutations in squamous cell or large cell primary carcinoma were discovered. We screened the LKB1 gene in 129 primary nonsmall cell lung carcinomas, adjacent healthy lung tissue, and control blood samples. Forty-five percent of nonsmall cell lung tumors harbored either intron or exon alterations. We identified R86G, F354L, Y272Y and three polymorphisms: 290+36G/T, 386+156G/T, and 862+145C/T (novel). R86G (novel) and F354L mutations were found in six squamous cell carcinomas and three large cell cancer carcinomas, but not in the adjacent healthy tissue or controls samples. The F354L mutation was found in advanced squamous cell carcinomas with elevated COX-2 expression, rare P53, and no K-RAS mutation. Results indicate that the LKB1 gene is changed in a certain proportion of nonsmall cell lung tumors, predominately in advanced squamous lung carcinoma. Inactivation of the gene takes place via the C-terminal domain and could be related to mechanisms influencing tumor initiation, differentiation, and metastasis.