Uterine cervical carcinogenesis is probably dependent on cellular genetic damage in addition to the integration of high-risk HPV DNA in the epithelial cell genome. Gain of chromosome 3q24-29 is commonly observed in cervical neoplasia. The putative oncogene PIK3CA located in this region encodes a phosphatidylinositol 3-kinase (PI3K). In a process reversed by PTEN, PI3K generates inositol phospholipids that trigger AKT phosphorylation, which in turn effects tumor driving signals. We studied 46 specimens of formalin-fixed, paraffin-embedded cervical neoplastic tissue. The activation state of the PI3K-AKT pathway was assessed immunohistochemically using an antibody with specificity towards serine 473-phosphorylated AKT. AKT phosphorylation was found in 39 out of 46 examined specimens. To examine the possible molecular basis for this activation, we searched for PIK3CA amplification using quantitative real-time polymerase chain reaction. PIK3CA gene copy number was estimated to be 3 or more in 28 out of 40 successfully examined cases. Further, a PTEN mutation analysis of all 9 PTEN exons was carried out, but except for 1 metastasis with an exon 9 V369I heterozygosity, all cases showed normal PTEN sequence. Immunohistochemical staining for PTEN was strong in all lesions. In conclusion, an increased activation state of AKT kinase appears to be present in cervical carcinogenesis, and may be accounted for by PIK3CA amplification, whereas PTEN mutation seems to be of little importance. ' 2005 Wiley-Liss, Inc.Key words: cervical cancer; AKT; PIK3CA; PTEN; quantitative realtime PCR Cervical carcinoma is the second most common cancer in women world-wide. 1 High-risk human papillomavirus (HPV) DNA present in the neoplastic cells plays a causative role. 2 Integration of HPV DNA in the epithelial cell genome is accompanied by expression of the viral gene products E6 and E7 that abrogate the Rb and p53 tumor suppressor pathways, increase telomerase activity, and give rise to mitotic defects and numerical and structural chromosome instability. 3-5 Both E6 and E7 are required for the neoplastic process and they cooperate to immortalize human genital keratinocytes. 6 Even so, only a small proportion of highrisk HPV-positive lesions eventually progress to carcinoma, indicating that accumulation of additional genetic events in the host cell is needed for malignant conversion. 3,4 Cervical carcinomas show a recurrent pattern of cytogenetic instability where a gain of the long arm of chromosome 3 is commonly observed. [7][8][9][10][11] The same aberration has been demonstrated in HPV-transfected keratinocytes, pre-malignant cervical precursor lesions and cervical cancer cell lines. 7 , 8 , 12-14 By comparative genomic hybridization (CGH), the areas of gain have been refined to parts of chromosomal bands 3q24-29. 9-11 , 15 A possible oncogene in this region is PIK3CA at 3q26.3, encoding the p110a catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3K). 16 Upon activation by receptor tyrosine kinases, PI3K generates inosito...

Abstract. Tropé C, Kaern J, Hogberg T, Abeler V, Hagen B, Kristensen G, Onsrud M, Pettersen E, Rosenberg P, Sandvei R, Sundfor K, Vergote I. Randomized study on adjuvant chemotherapy in stage I high‐risk ovarian cancer with evaluation of DNA‐ploidy as prognostic instrument. Purpose. Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. Patients and Methods. Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n=81) or no adjuvant treatment (n=81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non‐clear cell carcinomas or clear cell carcinomas. Disease‐free (DFS) and disease‐specific (DSS) survival were end‐points. Results. Median follow‐up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated 5 year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% CI 0.52‐1.83) regarding DFS and 0.94 (95% CI 0.37‐2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log‐rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNA‐ploidy (p=0.003), extracapsular growth (p=0.005), tumor rupture (p=0.04), and WHO histologic grade (p=0.04) were significant independent prognostic factors for DFS with p<0.0001 for the model in the multivariate Cox Analysis. FIGO substage (p=0.01), DNA ploidy (p<0.05), and histologic grade (p=0.05) were prognostic for DSS with a p‐value for the model <0.0001. Conclusion. Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA‐ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

The rates of ectopic pregnancy increased in age groups older than 20 years during 1976-93, moderately in younger age groups, but considerably in older age groups, who also contributed with higher total rates of pregnancy. More older women, with presumably accumulated risk factors getting pregnant, thus explain part of the increased rates of this disease.