HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib.

HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population.

Recurrent multilocular mandibular giant cell granuloma in neurofibromatosis type 1: Evidence for second hit mutation of NF1 gene in the jaw lesion and treatment with curettage and bone substitute materials.

Giant cell granuloma (GCG) of the jaw is a rare, well-known feature of neurofibromatosis type 1 (NF1), an inborn multisystem disorder. Recently, the development of GCG in NF1 was attributed to second hit mutations in the NF1 gene. The treatment of GCG is pragmatic with a preference for local curettage of lytic osseous areas.

EGFRvIII does not affect radiosensitivity with or without gefitinib treatment in glioblastoma cells.

Background: Glioblastomas (GBM) are often characterized by an elevated expression of the epidermal growth factor receptor variant III (EGFRvIII). We used GBM cell lines with native EGFRvIII expression to determine whether this EGFR variant affects radiosensitivity with or without EGFR targeting.

Methods: Experiments were performed with GBM cell lines lacking (LN229, U87MG, U251, CAS-1) or endogenously expressing EGFRvIII (BS153, DKMG).

Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest.

Purpose: How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects.

Materials And Methods: We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs.

Frequency of TERT promoter mutations in primary tumors of the liver.

Transcriptional regulation of the TERT gene is a major cause of the cancer-specific increase in telomerase activity. Recently, frequent somatic mutations in the TERT promoter have been described in several tumor entities such as melanoma, glioblastoma, bladder cancer, and hepatocellular carcinoma. By generating a putative consensus binding site for ETS transcription factors within the TERT promoter, these mutations are predicted to increase promoter activity and TERT transcription.

Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation.

Background And Purpose: There is a great need to improve the outcome of locoregionally advanced squamous cell carcinomas of the head and neck (HNSCC). Standard treatment includes a combination of surgery, radio- and chemotherapy. The addition of molecular targeting agents to conventional treatment may improve outcomes.

Lymphatic invasion predicts survival in patients with early node-negative non-small cell lung cancer.

Objective: The aim of this study was to assess the influence of lymphatic and vascular invasion on overall survival in patients with surgically resected non-small cell lung cancer (NSCLC) without lymph node and distant metastases.

Methods: From January 1999 to December 2009, a total of 190 NSCLC patients with node-negative pT1-pT4 disease underwent radical resection with lymphadenectomy. Pathologic reports were reclassified to the TNM-7 version, and the influence of lymphatic and vascular invasion on overall survival was examined using Kaplan-Meier and adjusted Cox proportional hazards analyses.

HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity.

Background And Purpose: When treated by radiotherapy, patients with squamous cell carcinomas of the head and neck (HNSCC) positive for HPV and p16(INK4a) possess a clearly favorable prognosis as compared to those with HPV-negative HNSCC. The aim of this work was to study whether the better outcomes might be caused by an enhanced cellular radiosensitivity.

Materials And Methods: The radiation response of five HPV/p16(INK4a)-positive and five HPV-negative cell lines was characterized with regard to cellular radiosensitivity by colony formation assay.

Frequent intratumoral heterogeneity of EGFR gene copy gain in non-small cell lung cancer.

Next to EGFR mutation, EGFR gene copy number evaluated by fluorescence in situ hybridization (FISH) emerged as a potential predictive marker for sensitivity to EGFR tyrosine kinase inhibitors, although controversial data exist. As the diagnostic accuracy of predictive biomarkers can be substantially limited by regional differences within tumors, heterogeneity of EGFR gene copy gain in NSCLC was assessed in this study. For this purpose, a novel tissue microarray (TMA) based analysis platform was developed.

Intratumoral heterogeneity of KRAS mutation is rare in non-small-cell lung cancer.

Background: Several lines of evidence indicate that mutational activation of KRAS is an early event in the carcinogenesis of non-small cell lung cancer (NSCLC). Nonetheless, previous studies report high frequencies of divergent KRAS mutational status between primary NSCLC and corresponding metastases. This suggests heterogeneity of the primary tumor in respect to its KRAS status.

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung.

The HER2 protein, encoded by the ERBB2 gene, is a molecular target for the treatment of breast and gastric cancer by monoclonal antibodies or tyrosine kinase inhibitors. While intratumoral heterogeneity of ERBB2 amplification is rare in breast cancer it is reported to be frequent in bladder and colorectal cancer. To address the potential heterogeneity of the HER2 status in adenocarcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas of the lung, 590 tumors were analyzed for HER2 overexpression and ERBB2 amplification using FDA-approved reagents for immunohistochemistry and fluorescence in-situ hybridization (FISH).

Epidermal growth factor receptor (EGFR) in salivary gland carcinomas: potentials as therapeutic target.

Aims: Epidermal growth factor (EGFR) is involved in angiogenesis, cell differentiation, proliferation and progression of many cancers and is an important therapy target in lung and colorectal cancer. To determine the potential applicability of EGFR targeted therapies, EGFR status of over 800 salivary gland tumors of different entities were analyzed on DNA and protein level by FISH and IHC.

Materials And Methods: A tissue microarray was constructed from 721 carcinomas and 205 adenomas of the salivary gland.

Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer.

Women with triple-negative breast cancer (TNBC) do not benefit from endocrine therapy or trastuzumab. Chemotherapy is the only systemic therapy currently available. To reduce the elevated risk of disease progression in these patients, better treatment options are needed, which are less toxic and more targeted to this patient population.

Reliability of human epidermal growth factor receptor 2 immunohistochemistry in breast core needle biopsies.

Purpose: Core needle biopsies (CNBs) are widely used to determine human epidermal growth factor receptor 2 (HER2) status in breast cancer. Recent publications reported up to 20% false-positive results on CNBs if immunohistochemistry (IHC) is compared with fluorescent in situ hybridization (FISH). To clarify, if confirmation of IHC positivity by FISH is generally required, we analyzed the reliability of IHC positivity on CNBs versus surgical specimens in a multi-institutional study.

The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells.

The death-associated protein kinase 2 (DAPK2) belongs to a family of Ca(2+)/calmodulin-regulated serine/threonine kinases involved in apoptosis. During investigation of candidate genes operative in granulopoiesis, we identified DAPK2 as highly expressed. Subsequent investigations demonstrated particularly high DAPK2 expression in normal granulocytes compared with monocytes/macrophages and CD34(+) progenitor cells.

Gene expression profiling reveals consistent differences between clinical samples of human leukaemias and their model cell lines.

Microarray gene expression profiles of fresh clinical samples of chronic myeloid leukaemia in chronic phase, acute promyelocytic leukaemia and acute monocytic leukaemia were compared with profiles from cell lines representing the corresponding types of leukaemia (K562, NB4, HL60). In a hierarchical clustering analysis, all clinical samples clustered separately from the cell lines, regardless of leukaemic subtype. Gene ontology analysis showed that cell lines chiefly overexpressed genes related to macromolecular metabolism, whereas in clinical samples genes related to the immune response were abundantly expressed.

P73 status in B-cell chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukemia is a heterogenous disease with disturbed apoptosis in which the precise molecular defects leading to this pathogenesis are still unclear. The p73 gene (a p53 homologue) encodes 2 proteins with opposing functions. TAp73 induces cell cycle arrest and apoptosis, whilst the oncogenic deltaNp73 inhibits both TAp73 and p53 induced apoptosis.