Lyon L. Gleich

Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression

We have previously reported that loss of p53 tumor suppressor protein results in centrosome hyperamplification, which leads to aberrant mitosis and chromosome instability. Since p53 is either deleted or mutated in human cancers at a high frequency, we investigated whether human cancers showed centrosome hyperamplification. Screening of advanced stage breast ductal carcinomas and squamous cell carcinomas of the head and neck (SCCHN) revealed that centrosome hyperamplification is frequent in both tumor types. Moreover, through the analyses of p53 in SCCHN samples by direct sequencing and by loss-of-heterozygosity test, we found that p53 mutations correlated with occurrence of centrosome hyperamplification. However, in some cases, we observed centrosome hyperamplification in tumors that retained wild-type p53. These tumors contained high levels of Mdm2. Since Mdm2 can inactivate p53 through physical association, we investigated whether Mdm2 overexpression induced centrosome hyperamplification. We found that Mdm2 overexpression, like loss of p53, induced centrosome hyperamplification and chromosome instability in cultured cells.

Esthesioneuroblastoma and Sinonasal Undifferentiated Carcinoma: Impact of Histological Grading and Clinical Staging on Survival and Prognosis

Objectives Hyams proposed a histological grading system for esthesioneuroblastoma in which grade I tumors have an excellent prognosis and grade IV tumors are uniformly fatal. The Hyams grading system predated advanced craniofacial techniques, extensive use of immunohistochemistry, and the recognition of sinonasal undifferentiated carcinoma (SNUC) as a distinct entity. Therefore we aimed to determine whether Hyams classification is useful in predicting outcome for esthesioneuroblastoma and SNUC.

Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma : A clinical-pathologic correlation

Tumor angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis in breast and other cancers. Studies in head and neck cancer have suggested a similar correlation, but results have been inconclusive. This study was performed to determine the correlation between angiogenesis and oral tumor behavior.

Tumor angiogenesis in T1 oral cavity squamous cell carcinoma: Role in predicting tumor aggressiveness

Angiogenesis is necessary for tumor growth and metastasis. In breast and other cancers angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis. Some studies of head and neck cancer have shown a similar correlation, although results are inconclusive. This study was performed to determine whether tumor angiogenesis can be used as a prognostic indicator for early oral cancers.

A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma.

The anti‐cancer gene, E1A, can be complexed to a lipid carrier, DC‐Cholesterol:DOPE, to form tgDCC‐E1A, which can be injected directly into tumors.

Molecular genetics of head and neck cancer.

BACKGROUNDnHead and neck cancers have multiple genetic abnormalities that influence tumor behavior and may be useful in developing new treatments.nnnMETHODSnGenetic alterations implicated in head and neck cancer oncogenesis and behavior are reviewed, and molecular techniques for detection and treatment are evaluated.nnnRESULTSnThe large number of genetic changes present in head and neck cancer cells precludes meaningful use of simple molecular tests and treatments. Detection of abnormalities in multiple genes provides better prognostic information than the detection and assessment of single mutations. Screening tests that rely on amplification of genetic material present in bodily fluids are hindered by the genomic complexity of head and neck cancer. Introduction of genetic material into head and neck cancer cells for gene therapy has shown some efficacy.nnnCONCLUSIONSnHead and neck cancers comprise a complex genetic disease. Although much has been learned about the molecular genetics of head and neck cancers, continued study of multiple genes is critical for further progress. Gene therapy, although promising, must also overcome this complexity.

Gene Therapy for Head and Neck Cancer

Objectives/Hypothesis New treatment methods are needed for head and neck cancer to improve survival without increasing morbidity. Gene therapy is a potential method of improving patient outcome. Progress in gene therapy for cancer is reviewed with emphasis on the limitations of vector technology and treatment strategies. Given the current technological vector limitations in transmitting the therapeutic genes, treatments that require the fewest number of cells to be altered by the new gene are optimal. Therefore an immune‐based gene therapy strategy was selected in which the tumors were transfected with the gene for an alloantigen, human leukocyte antigen (HLA)–B7, a class I major histocompatibility complex (MHC). This would restore an antigen presentation mechanism in the tumor to induce an antitumor response. This gene therapy strategy was tested in patients with advanced, unresectable head and neck cancer.

Survival, Function, and Quality of Life After Total Glossectomy†

Advanced tongue cancer is associated with poor survival despite aggressive therapy. In an attempt at cure, many patients undergo total glossectomy, which significantly affects function and quality of life (QOL). This study was designed to determine the survival rate and QOL of patients who had undergone total glossectomy. A total of 54 patients underwent total glossectomy, with or without total laryngectomy, for advanced tongue cancer from 1970 to 1996. Patient outcomes were assessed for the following: 1. disease‐free survival, 2. function, utilizing the Performance Status Scale (PSS), and 3. QOL, using two general cancer questionnaires (FACT‐G and EORTC QLQ‐C30) and a series of questions specific for head and neck cancer patients. Corrected actuarial survival was 51% and 41% at 3 and 5 years, respectively. Functional assessment using the PSS demonstrated significant deficits in speech and deglutition. QOL questionnaires revealed problems with eating, speaking, socializing, and shoulder function. However, the over‐all responses demonstrated that these patients have adjusted to their deficits and have a good QOL. It was concluded that total glossectomy, with or without total laryngectomy, can result in meaningful survival and an adequate QOL can be achieved in selected patients.

Centrosome Hyperamplification in Head and Neck Squamous Cell Carcinoma: A Potential Phenotypic Marker of Tumor Aggressiveness†

Objectives/Hypothesis There is currently no single histological or genotypic marker that reliably predicts the biological behavior of head and neck squamous cell carcinoma (HNSCC). While multiple genetic mutations have been investigated, no single genotypic alteration has consistently correlated with tumor aggressiveness. Phenotypic markers may prove more predictive, because they can represent many different genetic alterations. We investigated the frequency of centrosome hyperamplification in HNSCC and examined its usefulness as a marker for tumor recurrence.

Prognostic Indicators for Squamous Cell Carcinoma of the Oral Cavity: A Clinicopathologic Correlation†

Fifty‐three patients with T1 squamous cell cancer of the floor of mouth and ventral surface of the tongue with a known clinical outcome were retrospectively analyzed and arbitrarily divided into “aggressive” and “nonaggressive” groups based on their clinical behavior. Various host and tumor factors were then evaluated in an attempt to determine whether the tumor behavior could have been predicted. The paraffin‐embedded tumor specimens were evaluated for tumor differentiation, tumor thickness and tumor invasion, microvessel density, and p53 expression. In addition, a composite morphologic grading score was obtained by combining cell differentiation, nuclear polymorphism, mitosis activity, depth of infiltration, type of infiltration, and lymphatic infiltration. No single technique appeared capable of identifying “aggressive” behavior, although possibly an evaluation of composite factors might show promise in the future.