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Pathology and genetics of tumours of the lung , pleura, thymus and heart

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

Causes and consequences of comorbidity: a review.

Bladder cancer: Epidemiology, staging and grading, and diagnosis

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. In this review, the association of HER-2/neu gene and protein abnormalities with prognosis and response to therapy with trastuzumab and to other therapies in breast cancer is presented. By considering a series of 80 published studies encompassing more than 25,000 patients, the relative advantages and disadvantages of Southern blotting, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is presented as well as its potential impact on responses to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review also evaluates the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.

The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy

https://iris.unito.it/bitstream/2318/36168/1/Pich_Ann_Oncol_2004.pdf

Prognostic relevance of cell proliferation in head and neck tumors

Prognostic relevance of AgNORs in tumor pathology.

PURPOSE: To investigate the prognostic value of biomarkers in male breast carcinoma (MBC). PATIENTS AND METHODS: Fifty patients (mean age, 62.2 years) with invasive ductal carcinoma were retrospectively studied. All patients received surgery; 35 had adjuvant postoperative therapy. The median follow-up was 59 months (range, 1 to 230 months). c-myc, c-erbB-2, p53, and bcl-2 proteins were immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using 9E11, CB11, DO7, and bcl-2 124 monoclonal antibodies (mAbs). Estrogen, progesterone, and androgen receptors were detected using specific mAbs. Cell proliferation was assessed by MIB-1 mAb. RESULTS: In univariate analysis, c-myc, c-erbB-2, and p53 protein overexpression was significantly correlated with prognosis. The median survival was 107 months for c-myc–negative and 52 months for c-myc–positive patients (P = .01), 96 months for c-erbB-2–negative and 39 months for c-erbB-2–positive patients (P = .02), and 100 months for p53-ne...

Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival.

Objective: Even though diagnostic oral exfoliative cytology is a useful, economical and practical tool in the diagnosis of oral dysplasia and carcinoma, it is not yet extensively used. The results of conventional exfoliative and liquid-based diagnostic cytology in oral potentially malignant lesions (PML) are herein reported and compared with the histological diagnosis.



Methods:  Either conventional (89) or liquid-based (384) exfoliative cytology was used for the diagnosis of oral dysplasia/carcinoma in 473 subjects and the results were compared with scalpel biopsy histology. Cells were collected using a Cytobrush device for conventional smears and with a dermatological curette for the liquid-based cytology. The ‘curette technique’ also allowed for the collection of ‘accidental’ tissue fragments, utilized as microbiopsies.



Results:  Histological diagnosis was squamous carcinoma in 96 of 473 cases, high-grade dysplasia (oral intraepithelial neoplasia two to three) in 24 and other lesions in 353 cases. The smears in the conventional cytology group were inadequate in 12.4%, with an 85.7% sensitivity and a 95.9% specificity. There were 8.8% of inadequate specimens in the liquid-based cytology group; sensitivity was 95.1% and specificity was 99.0%.



Conclusions:  Although conventional cytology is useful when diagnosing oral PML (better sensitivity and predictive positive value if compared with the cervical smear test with similar specificity) and can improve the accuracy of histological diagnosis, liquid-based cytology gives better results, as it not only enhances both sensitivity and specificity, but also provides material for further investigation (AgNORs, DNA, microbiopsies, etc.).

The impact of liquid-based oral cytology on the diagnosis of oral squamous dysplasia and carcinoma

Androgen receptor (AR) expression was retrospectively analysed in 47 primary male breast carcinomas (MBCs) using a monoclonal antibody on formalin-fixed, paraffin-embedded tissues. AR immunopositivity was detected in 16 out of 47 (34%) cases. No association was found with patient age, tumour stage, progesterone receptor (PGR) or p53 protein expression. Well-differentiated MBCs tended to be AR positive more often than poorly differentiated ones (P= 0.08). A negative association was found between ARs and cell proliferative activity: MIB-1 scores were higher (25.4%) in AR-negative than in AR-positive cases (21.11%; P= 0.04). A strong positive association (P= 0.0001) was found between ARs and oestrogen receptors (ERs). In univariate analysis, ARs (as well as ERs and PGRs) were not correlated with overall survival; tumour histological grade (P= 0.02), size (P= 0.01), p53 expression (P= 0.0008) and MIB-1 scores (P= 0.0003) had strong prognostic value. In multivariate survival analysis, only p53 expression (P= 0.002) and histological grade (P= 0.02) retained independent prognostic significance. In conclusion, the lack of association between AR and most clinicopathological features and survival, together with the absence of prognostic value for ER/PGR status, suggest that MBCs are biologically different from female breast carcinomas and make it questionable to use antihormonal therapy for patients with MBC. © 1999 Cancer Research Campaign

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Achille Pich

Papers

Prognostic relevance of cell proliferation in head and neck tumors

Prognostic relevance of AgNORs in tumor pathology.

Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival.

The impact of liquid-based oral cytology on the diagnosis of oral squamous dysplasia and carcinoma

Androgen receptor expression in male breast carcinoma: lack of clinicopathological association.