Independent prognostic significance of cell cycle regulator proteins p16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group.

The purpose of the study is to test the hypothesis that expression of cell cycle regulatory proteins p16(INK4a) and pRb is significantly associated with prognosis in ovarian carcinomas. We performed immunohistochemical analysis of p16(INK4a) and pRb expression and correlated with survival in a series of 300 patients with FIGO stage IIb-IV ovarian carcinoma which were enrolled in a randomized prospective trial evaluating two different platinum and paxlitaxel chemotherapy combinations after radical surgery. p16(INK4a) negative tumours (17/300; 6%) had a significantly worse prognosis (univariate analysis, P<0.001; multivariate analysis: odds ratio 2.41, P=0.009). Among p16(INK4a)-positive tumours (283 out of 300; 94%), survival was better for patients with intermediate expression as compared to low or high expression levels (P=0.001). High expression levels of pRb were associated with an incremental deterioration of prognosis (univariate analysis, P=0.004; multivariate analysis: odds ratio 2.98, P=0.002). This observation held also true in the subgroup of optimally debulked patients (n=82), in whom the most important established prognostic factor, postoperative residual tumour cannot be applied. In conclusion p16(INK4a) and pRb are independent prognostic factors in advanced-stage ovarian carcinomas after radical surgery and postoperative chemotherapy. High pRb expression is a significant prognosticator in optimally debulked patients and may hold potential for subgroup stratification in postoperative treatment.

[Molecular pathogenesis of cervical cancer and its first steps]. / Molekulare Pathogenese des Zervixkarzinoms und seiner Vorstufen.

Specific types of the human papillomaviruses (high risk human papillomaviruses) play an essential role in the pathogenesis of cervical cancer. Although infections by these viruses are very common in the general population, only few result in clinically relevant lesions. Continuous and deregulated expression of two viral oncoproteins E6 and E7 in basal or parabasal cells are required to induce and maintain neoplastic growth. In the course of an acute HPV-infection these genes are exclusively expressed in cell cycle arrested, terminally differentiated cells in the intermediate or superficial layers of the epithelium. Accidental activation of these genes in proliferating cells in the basal or parabasal cell layers results in interference with the cell cycle regulation, disturbances of the mitotic spindle apparatus and centrosome functions. This results in numerical and structural chromosome aberrations, chromosomal instability, increasing aneuploidy and initiates cervical carcinogenesis. The deregulated expression of the viral oncogene E7 is indicated by strong over-expression of the cellular p16(INK4a) gene product. This finding may have significant influence on novel strategies in cervical cancer diagnosis and screening. This review summarizes the basic molecular mechanisms of how papillomaviruses contribute to cellular transformation and how this can influence future diagnostic applications.

Abdominal T-cell non-Hodgkin's lymphoma of the gamma/delta type in a patient with selective immunoglobulin A deficiency.

A 28-year-old man presented with selective immunoglobulin A deficiency and severe diarrhea responding to a gliadin-free diet. Biopsy samples of the small intestine showed dense T-cell infiltrations in the lamina propria and a slight increase of intraepithelial T-lymphocytes. No clonal rearrangement of the T-cell receptor c-beta chain genes was detectable by Southern blotting. Four years later, at the age of 32, the patient was hospitalized again with liver failure, abdominal lymphadenopathy, pancytopenia, and recurrent bacterial infections. Retrospective polymerase chain reaction analysis of formalin-fixed tissues of the intestinal biopsy samples obtained 4 years earlier showed monoclonal T-cell receptor gamma-chain gene rearrangement. Lymphoid cells of the peripheral blood showed an immunophenotype of CD3-positive gamma/delta T cells with a negativity for CD4 and CD8. A clonally rearranged T-cell receptor delta chain gene and a germline configuration of the c-beta chain genes was found by Southern blotting. Cytogenetics showed an abnormal karyotype with unbalanced translocations t(1;5) and t(9;13). The patient died of extensive lung infiltrations by gamma/delta T cells; autopsy showed a peripheral T-cell lymphoma of the gamma/delta type in the enlarged abdominal lymph nodes. This is the first report of an abdominal T-cell lymphoma of the gamma/delta type in a patient with selective immunoglobulin A deficiency.

Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma.

The origin of low-grade mucosa-associated lymphoid tissue (MALT)-type B-cell lymphoma is still unclear. Using a novel two-step procedure, we have sequenced the Ig VH genes expressed by cells from four patients with gastric low-grade MALT-type lymphoma. The nucleotide sequences of the complementarity determining region 3 (CDR3) of the genomic DNA were first amplified using consensus oligonucleotide primers, then sequenced. Based on the CDR3 sequence amplified from each MALT lymphoma, individual tumor-specific primers were synthesized and used directly in the polymerase chain reaction (PCR) to analyze the sequences of their Ig heavy-chain variable region. When compared with the germ-line sequence, many nucleotide substitutions, mainly in the CDRs, were found in the variable gene sequences of the four MALT lymphomas. The mutations showed a high replacement-to-silent ratio and were distributed in a way which suggested that the tumor cells had been positively selected through their antigen receptor. Our findings indicate that the MALT-type lymphoma B cells are hypermutated postgerminal center lymphocytes that have undergone antigen selection.