Tissue microarray analysis of EGFR and erbB2 copy number changes in ovarian tumors

The objective of this study was to assess the implication of copy number changes of epidermal growth factor receptor (EGFR) and erbB2 genes in the etiology and progression of ovarian tumors. In our study, we used the highly reliable method of fluorescent in situ hybridization, applied on tissue microarray, containing 1006 ovarian tumors from different malignancy, histologic type and grade, and tumor stage, in order to analyze the correlations between gene copy number changes and tumor phenotype. We established copy number changes of erbB2 in 15.30% of malignant ovarian tumors-8.16% amplifications and 7.14% gains. The frequency of EGFR copy number changes was 10.67%-3.65% amplifications and 7.02% gains. EGFR gains occurred with approximately the same frequency in malignant (7.02%), low malignant potential (8.33%), and benign (7.19%) ovarian tumors. ErbB2 amplification was associated with clear cell type of ovarian cancer (P < 0.04). No amplification of EGFR and erbB2 genes was established in tumors with low malignant potency and in benign tumors. Regarding cancer phenotype, there was no statistically significant association between erbB2 copy number changes and histologic grade as well as tumor stage of ovarian cancer. EGFR gains are early events in ovarian tumorigenesis. Our results showed similar frequencies of EGFR gains in different grade tumors, while EGFR amplification increased from grades 1 to 2 to 3.     

Symptomatic osteoradionecrosis of pelvic bones in patients with gynecological malignancies—result of a long-term follow-up

The aim of this study was to assess the incidence and risk factors of pelvic fractures as a result of radiation therapy in women with gynecological cancer. We retrospectively reviewed 3530 female patients treated at our institute between 1980 and 1998 with megavoltage radiation with or without brachytherapy for cancer in the pelvic area. Eligible were patients with vulvar, vaginal, cervical, endometrial, and fallopian tube cancer. Median follow-up was 88 months (range 0-240). Emphasis was put on treatment-related and patient-related risk factors. Of the eligible 3155 patients, 15 developed symptomatic bone fracture caused by osteoradionecrosis, which makes an overall incidence of 0.44% The diagnosis was based on anamnesis, clinical course, and X-ray or computed tomography images. Median time of onset was 44 months (range 6-197). All patients had pain as the first symptom. The only independent predictive factor for developing osteoradionecrosis seemed to be preexistent osteoporosis. Other risk factors that are related to osteoporosis include higher age, postmenopausal status, or steroid treatment. We did not find any significant treatment-related predictive factor for pelvic osteoradionecrosis. Patients with osteoporosis are probably at the highest risk for developing osteoradionecrotic fractures after pelvic radiotherapy. More studies are needed to find out other endogenous predictive factors.     

X chromosomal and autosomal loss of heterozygosity and microsatellite instability in human cervical carcinoma

The study analyzes tumor material and normal tissue from 27 patients with pure squamous cell carcinoma of the uterine cervix for loss of heterozygosity (LOH) and microsatellite instability (MSI) on 14 autosomal and 11 X chromosomal loci. Overall, 4-40% of the informative cases showed LOH at autosomal regions with the highest frequency at 3p (21-40%) and a marked frequency at 2q35-q37.1 (12.5%) and 17p13.3 (10%), representing regions with putative tumor suppressor gene (TSG) function. The frequency of X chromosomal LOH ranged from 4% to 20%, with a maximum at Xq28 (20%) and Xq11.2-q12 (17%), again indicating alterations in TSG. A 12% LOH was seen at Xq21.33-q22.3, a region encoding a protein with a regulatory function in the cell cycle via cyclin-dependent kinases. MSI was detected in autosomal regions in up to 7% in regions linked to the X chromosome in up to 11%, probably indicating alterations of mismatch repair mechanisms. Our results and those obtained from the literature suggest that autosomal LOH and MSI in carcinomas of the cervix uteri are predominantly found at regions with putative TSG function. Beside TSG alterations, X chromosomal LOH is probably more strongly connected to disturbances in cell cycle regulation.     

Matrix metalloproteinases-2 and -9 in cervical cancer: different roles in tumor progression

The incidence of uterine cervical cancer has increased slightly in Western countries, with an increase in relatively young women. Overexpression of matrix metalloproteinases (MMPs)-2 and -9 has turned out as a prognostic factor in many cancers. We compared the expression of the proteins MMP-2 and MMP-9 in cervical primary tumors with clinical outcome and risk factors of cervical cancer. One hundred sixty-one patients with cervical cancer treated in Ume? University Hospital or Sahlgrenska University Hospital, Sweden, between 1991 and 1995 were included in the study. Paraffin-embedded tissue samples obtained prior to treatment were examined immunohistochemically by specific antibodies for MMP-2 and MMP-9. Forty-two percent of the tumors were intensively positive for MMP-2 and 31% for MMP-9. Nineteen percent of the samples were intensively positive for both proteinases and 47% negative or weak for both. Overexpression of MMP-2 seemed to predict unfavorable survival under Kaplan-Meier analysis and in the multivariate analysis. Early sexual activity and low parity seemed to correlate to overexpression of MMP-2. MMP-9 was not associated with survival or sexual behavior. Intensive MMP-9 was noted in grade 1 tumors. We conclude that MMP-2 and MMP-9 have different roles in uterine cervical cancer. MMP-2 could be associated with aggressive behavior, but MMP-9 expression diminishes in high-grade tumors.     

Statistical analysis of pathologic risk factors for intramyometrial lymphvascular space involvement in myoinvasive endometrial carcinoma

In a retrospective study using univariate analysis, we identified tumor type (nonendometrioid vs endometrioid), depth of myoinvasion (MI), mode of MI (infiltrative vs cohesive), and direct anatomic invasion of the cervical wall from the isthmus as significant positive risk factors for intramyometrial lymphvascular space involvement (LVSI). On multivariate analysis, tumor grade, depth of MI, and mode of MI retained their significance. We created a grid for the relative risks of LVSI with respect to these variables individually or in combination. We suggest that our indirect estimate of the risk of LVSI can help in assessing prognosis and determining the need for adjuvant therapy whenever LVSI is important in clinical decision making, but its pathologic diagnosis is uncertain.     

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing

The main objectives of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are to harmonise breakpoints for antimicrobial agents in Europe, and to act as the breakpoint committee for the European Medicines Agency (EMEA) during the registration of new antimicrobial agents. Detailed EUCAST procedures for harmonising and setting breakpoints for antimicrobial agents are available on the EUCAST website. Beginning with the current issue, a series of EUCAST Technical Notes will be published in CMI, based on the rationale documents produced by EUCAST for each of the antimicrobial agents studied, with the aim of highlighting important background information underlying decisions on breakpoints made by EUCAST.