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  • 1
    Online Resource
    Online Resource
    Differential canonical pathways derived from microarrays using RNA from paraffin-embedded non-small cell lung cancer tissue
    American Society of Clinical Oncology (ASCO) ; 2006
    In:  Journal of Clinical Oncology Vol. 24, No. 18_suppl ( 2006-06-20), p. 7226-7226
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 18_suppl ( 2006-06-20), p. 7226-7226
    Abstract: 7226 Background: Several molecular targets have been approved for use in patients with non-small cell lung cancer (NSCLC) and several hundred are in various phases of investigation. However, the efficacy of these targets range from 5–15% of the overall population of NSCLC patients. Therefore, the challenge remains to appropriately match the most active target with the individual patient. Our goal was to investigate a novel strategy for identifying active pathways from formalin-fixed, paraffin-embedded (FFPE) NSCLC samples. Methods: Ten 5 um sections of FFPE tumor were collected from 66 NSCLC patients consisting of equal numbers of long- (+5-year) and short-term ( 〈 2 year cancer death) survivors. Sixty samples were microdissected (6 samples contained no tumor tissue) and RNA was extracted using a proprietary procedure of Response Genetics, Inc. Amplification and labeling of RNA were done using the Affymetrix two cycle amplification kit. Resulting cRNA was hybridized to the U133 plus 2.0 GeneChip. A differentially expressed gene list between long and short survivors was determined. These data were also analyzed for differential canonical pathways using Ingenuity Pathway Analysis. Results: We identified the differential pathways indicated by the unique gene signatures between early stage patients surviving 〈 2 yrs and 〉 2 yrs for both adenocarcinomas and squamous cell carcinomas. Adenocarcinoma pathways that differed between short- and long-term survivors were: G2M DNA damage checkpoint, EGF, estrogen receptor, hypoxia, VEGF, PDGF, IL-6 JAK/Stat and neurotrophin/Trk signaling. In contrast, for squamous cell carcinomas the main differing pathways were: Wnt/b-catenin signaling and retinol metabolism. Conclusions: We have demonstrated the feasibility of generating differential canonical pathways from FFPE NSCLC specimens which may serve as a tool to guide selection of molecular targets for the individual patient. In addition, these pathways may be a rational method for selecting the correct subset of patients most likely to respond to agents being investigated in early phase clinical trials. These data require validation in a larger prospective study. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2006.24.18_suppl.7226
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2006
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    A lung cancer genomic risk prediction model derived from paraffin-embedded tissue
    American Society of Clinical Oncology (ASCO) ; 2006
    In:  Journal of Clinical Oncology Vol. 24, No. 18_suppl ( 2006-06-20), p. 10059-10059
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 18_suppl ( 2006-06-20), p. 10059-10059
    Abstract: 10059 Background: We previously developed a validated fresh tissue-based genomic risk model in patients with early stage non-small cell lung cancer (NSCLC) using the Affymetrix U133 plus 2.0 Genechip. Limitations of this fresh tissue-based model include the need for immediate processing and limited availability; however, formalin-fixed, paraffin-embedded (FFPE) tissue is readily available and archived on every patient resected in North America. We investigated the ability of gene expression profiles generated on DNA microarrays using RNA isolated from FFPE NSCLC specimens to distinguish short-term and long-term survivors. Methods: Five to ten 5 um sections of FFPE tumor were collected from 61 NSCLC patients consisting of equal numbers of long- (+5-year) and short-term ( 〈 2 year cancer death) survivors. Fifty-five samples were microdissected (6 samples contained no tumor tissue) and RNA was extracted using a proprietary procedure of Response Genetics, Inc. For this feasibility study, Actin 300 〈 30 cTs was chosen as a threshold for adequate RNA quantity for amplification to the GeneChip. Amplification and labeling of RNA were done using the Affymetrix two cycle amplification kit. The resulting cRNA was successfully hybridized to the U133 plus 2.0 GeneChip in 54/55 samples (98%). Data were analyzed using the SAM statistical software with Kaplan Meier survival analyses. Results: All analyses were performed using unsupervised hierarchical clustering and blinded duplicate samples had nearly identical gene expression profiles, indicating reproducibility. Adenocarcinoma segregated from squamous cell carcinoma with 98% accuracy (p=0.00004). A differentially expressed gene list between long and short survivors was determined. Distinct gene clusters were observed within each histological type segregating the tumors according to outcome. Kaplan Meier survival analysis stratifying on these clusters revealed significant differences in survival (cluster 1 and cluster 2 median survival 〉 75 mos. vs. 30 mos., respectively; p 〈 0.001). Conclusions: We have demonstrated the feasibility of creating a preliminary genomic risk prediction model using FFPE NSCLC tissue. Data will be presented on a larger training set (100+ patients) and a separate validation cohort of 100 patients. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2006.24.18_suppl.10059
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2006
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    Gene expression signatures for prognosis in NSCLC, coupled with signatures of oncogenic pathway deregulation, provide a novel approach for selection of molecular targets
    American Society of Clinical Oncology (ASCO) ; 2005
    In:  Journal of Clinical Oncology Vol. 23, No. 16_suppl ( 2005-06), p. 7020-7020
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 23, No. 16_suppl ( 2005-06), p. 7020-7020
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2005.23.16_suppl.7020
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2005
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications.
    American Society of Clinical Oncology (ASCO) ; 1998
    In:  Journal of Clinical Oncology Vol. 16, No. 7 ( 1998-07), p. 2468-2477
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 16, No. 7 ( 1998-07), p. 2468-2477
    Abstract: To retrospectively construct a comprehensive multivariate model of cancer recurrence and to design a molecular pathologic substaging system in stage I non-small-cell lung cancer (NSCLC). METHODS All patients with stage I NSCLC resected at Brigham and Women's Hospital (Boston, MA) between 1984 and 1992 with adequate clinical follow-up were studied. The importance of three demographic characteristics, surgical extent, 11 pathologic features, and seven molecular factors on cancer-free survival was examined. RESULTS Two hundred forty-four patients were studied, with 25 noncancer deaths and 80 patients with recurrent disease. Significant univariate predictors (P 〈 .05) of cancer recurrence were age older than 60 years, male sex, wedge resection, World Health Organization (WHO) adenocarcinoma subtype solid tumor with mucin, lymphatic invasion, and p53 expression. Multivariate analysis identified nine independent predictors of recurrence: solid tumor with mucin, a wedge resection, tumor diameter of 4 cm or greater, lymphatic invasion, age older than 60 years, male sex, p53 expression, K-ras codon 12 mutation, and absence of H-ras p21 expression. Multivariate cancer-free survival (CFS) analysis in the 180 patients who underwent lobectomy or pneumonectomy led to the elimination of sex and age, which left six independent factors. CONCLUSION Lobectomy or pneumonectomy should be performed in stage I NSCLC. Using the six independent factors for recurrent disease, we propose a pathologic molecular substaging system. Patients with two factors or less are graded Ia, with a 5-year CFS rate of 87%; those with three factors are graded Ib, with a 5-year CFS rate of 58%; and those with four factors or more are graded Ic, with a 5-year CFS rate of 21%.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.1998.16.7.2468
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 1998
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Molecular signature of esophageal adenocarcinoma derived from microarray analysis of paraffin-embedded specimens predicts systemic recurrence following resection
    American Society of Clinical Oncology (ASCO) ; 2007
    In:  Journal of Clinical Oncology Vol. 25, No. 18_suppl ( 2007-06-20), p. 4563-4563
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 25, No. 18_suppl ( 2007-06-20), p. 4563-4563
    Abstract: 4563 Introduction: Surveillance endoscopy in patients with Barrett’s esophagus has resulted in the diagnosis of an increasing number of early-stage adenocarcinomas. Surgical resection alone is curative in the majority of these patients, yet some will succumb to systemic disease. We hypothesize that among patients with early esophageal adenocarcinoma, there are distinct molecular signatures of tumors that are associated with systemic recurrence and those that are cured with resection alone. Methods: From a total of 36 patients with early-stage adenocarcinoma (T1–3, less than or equal to 4 involved nodes), 20 who were alive and without recurrence at a median follow-up of 61 months after resection alone were compared by microarray analysis with similar stage tumors from 16 patients that developed systemic disease and died at a median of 13 months after esophagectomy. Following microdissection of paraffin-embedded specimens, RNA was isolated, amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Results: A T-test with unequal variance assumption identified 328 differentially expressed probe sets (false discovery rate 〈 0.05; p67 mos. vs. 13 mos., respectively; p 〈 0.001). Significant canonical pathway deregulation between long and short survivors included GABA receptor, PDGF, PPAR, IL-6 signaling, oxidative phosphorylation and the pentose phosphate pathway. Conclusion: The molecular signature of early-stage esophageal adenocarcinomas may be able to distinguish patients at increased risk for the development of systemic disease and thereby guide use of adjuvant therapy and the intensity of follow-up. Confirmation of these findings in additional patients should prompt a prospective clinical trial. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2007.25.18_suppl.4563
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2007
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    Molecular and pathologic markers in stage I non-small-cell carcinoma of the lung.
    American Society of Clinical Oncology (ASCO) ; 1995
    In:  Journal of Clinical Oncology Vol. 13, No. 5 ( 1995-05), p. 1265-1279
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 13, No. 5 ( 1995-05), p. 1265-1279
    Abstract: Although standard treatment of stage I non-small-cell lung cancer (NSCLC) consists of surgical resection alone, approximately 50% of clinical stage I and 30% to 40% of pathologic stage I patients have disease recurrence and die following curative resection. A large number of traditional pathologic and newer molecular markers have been identified, which appear to have important prognostic significance in this population. This review attempts to summarize these data comprehensively. METHODS Criteria for study selection were English-language reports, identified using Medline and Cancerline, through the fall of 1994. Abstracts from the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLG) were also reviewed. RESULTS Molecular markers are classified as molecular genetic markers, differentiation markers, proliferation markers, and markers of metastatic propensity. A number of these markers have been reported to be highly predictive of outcome in stage I NSCLC, and several reports conclude that a specific biomarker may be, aside from clinical stage, the most powerful determinant of prognosis in NSCLC. However, little has been done to clarify the relationships between these newer biologic markers, classic clinicopathologic variables, and clinical outcome. CONCLUSION At present, a firm conclusion regarding which biomarkers are most important in predicting outcome is not possible, and a model that reliably integrates all independent prognostic variables cannot be developed. A prospective trial is mandatory to address this issue, and a study design is suggested that would facilitate the development of a prognostic index, while simultaneously asking a therapeutic question. The development of a prognostic index would facilitate future trials in which only high-risk stage I patients could be targeted for investigation of postresection adjuvant treatment strategies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.1995.13.5.1265
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 1995
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  • 7
    Online Resource
    Online Resource
    Stage I NSCLC: elucidating the prognostic factors
    BMJ ; 2009
    In:  Thorax Vol. 64, No. 3 ( 2009-03-01), p. 185-186
    Details
    In: Thorax, BMJ, Vol. 64, No. 3 ( 2009-03-01), p. 185-186
    Type of Medium: Online Resource
    ISSN: 0040-6376
    URL: Article
    DOI: 10.1136/thx.2008.105965
    Language: English
    Publisher: BMJ
    Publication Date: 2009
    detail.hit.zdb_id: 1481491-2
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  • 8
    Online Resource
    Online Resource
    A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC)
    American Society of Clinical Oncology (ASCO) ; 2006
    In:  Journal of Clinical Oncology Vol. 24, No. 18_suppl ( 2006-06-20), p. 7026-7026
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 18_suppl ( 2006-06-20), p. 7026-7026
    Abstract: 7026 Background. Although stage-specific classification identifies appropriate populations for adjuvant chemotherapy, this is likely an imprecise predictor for the individual patient with early stage NSCLC. Methods. Using previously-described methodologies that employ DNA microarray data, multiple gene expression profiles (‘metagenes’) that predict risk of recurrence in patients with stage I disease were identified. This analysis used an initial ‘test’ cohort of patients with NSCLC (n = 89) that represented an equal mix of squamous cell and adenocarcinoma. Also, each histologic subset had equal number of patients who survived more than 5 years and those who died within 2.5 years of initial diagnosis. The performance of the metagene-based model generated on the training cohort was then evaluated in independent ‘validation’ sets, including two multi-center cooperative group studies (ACOSOG Z0030 and CALGB 9761). Importantly, the CALGB validation was performed in a blinded fashion. Results. Classification tree analyses that sample multiple gene expression profiles were used to develop a model of recurrence, termed the Lung Metagene Model, that accurately assesses prognosis (risk of recurrence and survival), performing significantly (p 〈 0.001, odds ratio: 16.1, multivariate analysis) better than pathologic stage, T-size, nodal status, age, gender, histologic subtype and smoking history. The accuracy of prognosis using the Lung Metagene Model exceeded 90% (leave-one-out cross validation) in the initial training set (n = 89), 72% in the ACOSOG (n = 25), and 81% in the CALGB (n = 84) datasets. The prognostic accuracy was consistent across histologic subtypes and stages of NSCLC. Importantly, this provides an opportunity to re-classify stage IA patients to identify a subset of ‘high risk’ patients that may benefit from adjuvant chemotherapy. Further, stage IB and II patients identified as ‘low risk’ for recurrence, and who present co-morbidities, could potentially be candidates for observation, and those patients predicted to be at ‘high risk’ may benefit from novel therapeutic trials. Conclusions. The Lung Metagene Model provides a mechanism to refine the estimation of an individual patient’s risk for disease recurrence and thus guide the use of adjuvant chemotherapy in NSCLC. No significant financial relationships to disclose.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2006.24.18_suppl.7026
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2006
    detail.hit.zdb_id: 2005181-5
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  • 9
    Online Resource
    Online Resource
    Local/regional recurrence following surgery for early-stage lung cancer: A 10-year experience with 975 patients
    American Society of Clinical Oncology (ASCO) ; 2008
    In:  Journal of Clinical Oncology Vol. 26, No. 15_suppl ( 2008-05-20), p. 7542-7542
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 26, No. 15_suppl ( 2008-05-20), p. 7542-7542
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2008.26.15_suppl.7542
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2008
    detail.hit.zdb_id: 2005181-5
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  • 10
    Online Resource
    Online Resource
    Prospective phase II trial of pre-resection thoracoscopic (VATS) restaging following neoadjuvant therapy for IIIA(N2) non-small cell lung cancer (NSCLC): Results of CALGB 39803
    American Society of Clinical Oncology (ASCO) ; 2005
    In:  Journal of Clinical Oncology Vol. 23, No. 16_suppl ( 2005-06), p. 7065-7065
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 23, No. 16_suppl ( 2005-06), p. 7065-7065
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2005.23.16_suppl.7065
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2005
    detail.hit.zdb_id: 2005181-5
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