The present investigation evaluated the relationship between dysplasia of the uterine cervix and telomerase activity, expression of p53, MIB‐1 and PCNA. Telomerase activity was measured on cervical cytobrush material from 126 women suspected of having dysplasia and 61 controls using the telomeric repeat amplification protocol. Immunohistochemistry was used to detect the tumor suppressor protein p53 and cell proliferation, the latter by MIB‐1 and PCNA expression. Infection with human papillomavirus 16 was detected by PCR amplification and Southern blot hybridization of DNA extracted from the same brush material. Positive telomerase activity was found in 5 of 43 (11.6%) normal samples, 12 of 57 (21.1%) samples with inflammation or koilocytosis, 7 of 17 (41.2%) CIN 1 (cervical intraepithelial neoplasia, grade 1), 8 of 20 (40.0%) CIN 2, and 25 of 42 (59.5%) CIN 3/CIS. Telomerase activity was significantly related to the level of dysplasia (p<0.001) and proliferation measured by MIB‐1 (p=0.019), but not to the level of PCNA (p=0.445), HPV 16 status (p=0.098) or staining for p53 (p=0.271). Dysplasia was also related to PCNA, MIB1, p53, and presence of HPV 16. A sequential increase in the examined parameters, paralleling the progression of abnormality, was observed. PCNA and telomerase showed an increase in CIN 1, MIB‐1 and HPV16 in CIN 2, and finally p53 in CIN 3/CIS.

International Journal of Gynecology & ObstetricsVolume 70, Issue S1 p. A55-A55 Cesarean section 2 Telomerase and cervical neoplasia — a longitudinal study U.B. Knudsen, U.B. KnudsenSearch for more papers by this authorM. Herbslet, M. HerbsletSearch for more papers by this authorT. Oerntoft, T. OerntoftSearch for more papers by this authorP. Bichel, P. BichelSearch for more papers by this authorB. Norrild, B. NorrildSearch for more papers by this authorO. Mogensen, O. MogensenSearch for more papers by this author U.B. Knudsen, U.B. KnudsenSearch for more papers by this authorM. Herbslet, M. HerbsletSearch for more papers by this authorT. Oerntoft, T. OerntoftSearch for more papers by this authorP. Bichel, P. BichelSearch for more papers by this authorB. Norrild, B. NorrildSearch for more papers by this authorO. Mogensen, O. MogensenSearch for more papers by this author First published: 01 January 2017 https://doi.org/10.1016/S0020-7292(00)82643-0AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume70, IssueS12000Pages A55-A55 RelatedInformation

Purpose: To analyse the possible prognostic importance of a combination of serum CA 125 levels. tumor cell DNA distribution and histopathologic grade in patients with epithelial ovarian cancer.Method: The study included 41 patients with ovarian cancer stages II-IV. CA 125 was measured before the start of chemotherapy and after every course. The DNA distribution was analysed by flow cytometry in biopsy specimens from the primary tumour. The histopathologic grading was performed according to WHO criteria.Results: The CA 125 level was of major prognostic significance. All patients with an abnormal value (> 35 U/ml) after three courses died within 16 months. The DNA distribution did not add significant prognostic information, but the histopathologic grade was of significant prognostic importance as investigated by Cox analysis.Conclusion. CA 125 is an important prognostic marker in epithelial ovarian cancer. The value after three courses of chemotherapy is significant. The histopathologic grade adds further prognostic information.

We evaluated the following nine parameters with respect to their prognostic value in females with endometrial cancer: four stereologic parameters [mean nuclear volume (MNV), nuclear volume fraction, nuclear index and mitotic index], the immunohistochemical expression of cancer antigen (CA125) and the postsurgical stage (P-stage), the malignancy grade, the depth of myometrial tumor invasion and the age of the female. Tissue was obtained from 68 consecutive endometrial cancer patients with clinical FIGO stage I tumors who were registered in the Danish endometrial cancer study (DEMCA). The primary operation included total abdominal hysterectomy and bilateral salpingo-oophorectomy. All patients underwent radical operations. The tumors were classified postsurgically as P-stage I-III. All patients received the same postoperative radiation therapy. The surviving patients were observed for a median of 6.4 years (range 5.0-8.4 years). Cox regression analysis (automatic forward selection) showed the MNV to be the most significant prognostic parameter followed by the P-stage. Patients who had localized tumors or tumors with small nuclei had a better probability of surviving than did women with advanced tumors or tumors with large nuclei. No significant relationship between survival and the remaining seven parameters was demonstrated. This first investigation of the prognostic value of the MNV in females with endometrial cancer demonstrates that it may assist the distinction between those patients who can be cured by hysterectomy alone and those who need adjuvant therapy.

The link between human Papillomavirus (HPV) and cervical carcinomas has become increasingly convincing recently, and the detection of infection with certain HPV types may become an important element in screening for cervical pre-cancer. We applied the polymerase chain reaction (PCR) technique to detect and type HPV-DNA in biopsies from the uterine cervix with a histological diagnosis of CIN and condylomatosis. Forty-eight consecutive cervical biopsies were analysed for HPV-DNA by PCR, using two different sets of consensus-primers. Typing was performed with HPV type-specific primers. Histological reevaluation revealed that 42 biopsies (87%) had condylomatous features. HPV was demonstrated in 46/48 (95.8%). HPV type 6/11 was found in seven biopsies, while HPV 16 was present in 23 samples, including two cases of double-infection. HPV type 18 was not found at all, and in 19 cases the HPV type present could not be determined. Apparently, HPV-DNA was absent in two cases. The results indicate that HPV-DNA screening is a valuable supplement to histopathological screening for cervical neoplasia. The value of different primer pairs is discussed.

In Denmark PAP-smear screening is performed by the GPs. The objective of this study is to report the proportion af smears taken on clinical indication over an eight week period in the county of Aarhus, and to obtain a precise reason for making a PAP-smear on clinical indication. Some 27% of all smears taken were on clinical indication. Some 55% of these smears were due to a follow-up on previous PAP-smears, while tests due to subjective symptoms account for the major part of the remaining tests. Testing the target group outside the screening programme is discouraged, but some 43% of tests on indication are not due to follow-up of previous smears. Further studies of the consequences of such testing are recommended.

AIMS:To evaluate correlations among clinical, pathological, morphometric, stereological, and DNA flow cytometric variables and their prognostic value in advanced ovarian cancer.METHODS:Tissue was collected from 180 patients with advanced ovarian cancer. All 180 had undergone debulking surgery and were being treated with cisplatin. Long term follow up was available for all patients. The mitotic activity index (MAI), volume % of epithelium (VPE), mean nuclear area (MNA), standard deviation of the nuclear area (SDNA), estimates of volume weighted mean nuclear volume (nu v), and variables obtained from minimum spanning tree (MST) analysis were assessed in the least differentiated tumour section in each case. DNA flow cytometry was also performed.RESULTS:Quantitative pathological features differed significantly with respect to histological grade. The MAI, MNA, SDNA, and the number of points connected to three neighbours differed significantly among the different DNA ploidy groups. The VPE and number of points connected to two or three neighbours differed significantly between FIGO stages III and IV. Fifty two (29%) patients survived. FIGO stage, residual disease and SDNA had prognostic significance on both univariate and multivariate survival analysis. In patients with FIGO III stage disease and residual tumour nodes < or = 2 cm in diameter (67 patients, 29 (43%) survivors) a prognostic index was established based on SDNA and of the line length of the MST. The median survival time was not reached in a subgroup of patients with favourable prognosis (overall survival 57%). Median survival was 32 months for patients with an unfavourable index score (overall survival 28%).CONCLUSION:Morphometric variables have important additional value in predicting prognosis in patients with advanced ovarian cancer.

Previous studies have shown DNA cytometric, morphometric and stereologic features to be strong prognosticators in advanced ovarian cancer. However, in one Danish study a new stereologic parameter, the volume-weighted mean nuclear volume ( nuv), was not of prognostic significance. In that study, sampling was performed in the whole tumor section, contrary to that in other studies where measurements were performed in the worst differentiated area (the measurement area). The aim of the present investigation was, therefore, to confirm or reject the hypothesis that random estimates of nuclear {ovbar|nu}v over the whole tumor, rather than in the measurement area, are the cause for the lack of prognostic value in the Danish patients. Additionally, the mitotic activity index (MAI), volume percentage of epithelium (VPE), mean nuclear area (MNA) and standard deviation of the nuclear area (SDNA), which have proved to be of strong prognostic significance in advanced ovarian cancer, were assessed in the measurement area. The MAI, VPE, MNA, SDNA and nuclear {ovbar|nu}v were well reproducible, but prognostically not significant. This study thus excludes differences in microscopic sampling as an explanation for the contrasting findings in the Danish study and other ones. Possible remaining explanations are: (i) differences in sampling at the macroscopic level; (ii) fixation differences; (iii) patient selection bias; and (iv) geographic differences in the degree of malignancy of advanced ovarian cancer in Denmark and the Netherlands. As to the latter, in comparison with two Dutch studies the Danish ovarian cancers in this series had residual disease <2 cm (33% vs 50%) less often, were less often well differentiated (4% vs 19%), and less often had favorable morphometric characteristics (6% vs 15%). Further studies are required to analyze whether other Danish patient groups with advanced ovarian cancers differ from the Dutch.

Two hundred-two patients with FIGO stages III and IV epithelial ovarian cancer were randomized to 6 or 12 cycles of cyclophosphamide, Adriamycin, and cisplatin (CAP). Patients in complete clinical response underwent a second-look laparotomy, 1 month after cessation of chemotherapy. Patients randomized to 6 cycles and found to be in partial remission at second-look were to receive a further 6 cycles of CAP. Rate of complete pathological response was 23% for 6 cycles of CAP and 25% for 12 cycles; the median survival was 23 months for 6 cycles and 27 months for 12 cycles, and 3-year survival was 29% for 6 cycles and 35% for 12 cycles. None of these differences were statistically significant. Fifty-four patients randomized to 6 cycles were found to be in partial surgical remission at second-look laparotomy, and 24 of these patients agreed to a further 6 cycles and a third-look laparotomy. Six of these 24 patients had a complete pathological response at third-look, improving the complete response rate to 28% in those originally randomized to 6 cycles. However, 3 of these patients all had macroscopic tumors removed at second-look, and two had microscopic disease at second-look. Among patients achieving complete response mean cumulative doses in the CAP 6 cycle group were approximately 50% of those in the CAP 12 cycle group. However, when all patients were considered, this difference was only approximately 15% owing the continuation of chemotherapy in the partial responders of the 6 cycle group and early stopping for chemotherapy in the CAP 12 cycle group due to toxicity or progression. Patients in complete pathological response also showed similar survivals for 6 and 12 cycles. In conclusion, the study did not show a correlation between mean cumulative doses and complete pathological response and survival.

A randomised controlled clinical trial of Ro 03-8799 (pimonidazole) was performed in advanced stage II and stage III squamous cell carcinoma of the uterine cervix. A total of 183 patients were contributed by 15 centres in Western Europe and coordinated by the Medical Research Council Trials Office in Cambridge. Analysis has shown poorer local tumour control with a hazard ratio (HR) of 2.1 [95% confidence interval (CI) 1.2 to 3.7] and survival with a HR of 1.6 (95% CI 1.0 to 2.5) in the group given the Ro 03-8799. These results were not materially affected after adjustment of stage or haemoglobin levels in stratified analysis or to inadequate radiotherapy being given to the sensitiser group. A true adverse effect caused by the drug is a possible cause and this might be related to a drug-induced impairment of blood supply to the tumour. When compared with results recorded previously for advanced cervical carcinoma treated by radiotherapy, it was apparent that the tumour control and survival in the sensitiser arm was similar, but the control arm showed results superior to those previously recorded. Whatever is the explanation it can certainly be concluded that the radiosensitising drug, pimonidazole, gave no benefit in the radiotherapy of advanced cervical cancer.

The present study comprises a retrospective investigation of 126 patients with stage IB squamous cell carcinoma of the cervix, and a similar prospective investigation of 53 patients with stage IB and 6 patients with stage IIA disease. Tumour biopsies from these patients were analysed by means of flow cytometry and a semiquantitative histological grading system. The study showed that a combination of a low tumour cell DNA index and a low score value of the grading system indicated a very low risk of regional lymph node metastases (0% lymph node metastases in patients with low scores vs. 24-46% metastases in patients with high scores, P < 0.001). In order to study the reproducibility of the histological grading 20 randomly selected cases were studied blindly by three of the participating pathologists and after discussion of the grading criteria. A kappa coefficient of 722 demonstrated a substantial agreement between the observers. These results suggest that by combining flow cytometry with semiquantitative histological grading, a subgroup of patients with early squamous cell cancer of the cervix uteri may be selected that could be sufficiently treated with simple hysterectomy instead of radical hysterectomy including lymphadenectomy, which, in many oncology centres, is the standard treatment of this patient category.

The prognostic value of the volume-weighted mean nuclear volume (MNV) was investigated retrospectively in 100 ovarian cancer patients with FIGO-stage IB-II (n = 51) and stage III-IV (n = 49) serous tumors. No association was demonstrated between the MNV and the survival or between the MNV and two of five additional parameters: age and amount of residual tumor. However, both in stage IB-II and stage III-IV carcinomas, the MNV increased significantly with increasing tumor grade and DNA-index. Furthermore, FIGO-stage IB-II patients had significantly smaller nuclei than patients with stage III-IV disease.

Grading of malignancy in squamous cell carcinomas of the uterine cervix is based on qualitative, morphologic examination and suffers from poor reproducibility. Using modern stereology, unbiased estimates of the three-dimensional, volume-weighted mean nuclear volume (nuclear v(v)BAR), were obtained in pretreatment biopsies from 51 patients treated for cervical cancer in clinical Stages I through III (mean age of 56 years, follow-up period > 5 years). In addition, conventional, two-dimensional morphometric estimates of nuclear and mitotic features were obtained. DNA indices (DI) were estimated by flow cytometry. Finally, the semiquantitative malignancy grade score value (MGS) was determined according to previously published methods. Estimates of nuclear v(v)BAR were on average increased in euploid lesions (2P = 0.01), but the overall relationship between nuclear v(v)BAR and DI was poor. Different clinical stages of disease did not differ with regard to nuclear v(v)BAR (2P = 0.99) and DI (2P = 0.56). No relationship was disclosed between MGS and nuclear v(v)BAR (2P = 0.85). Single-factor analysis showed prognostic impact of clinical stage of disease (2P = 0.0001) and DI (2P = 0.04), whereas estimates of nuclear v(v)BAR were only of marginal prognostic significance (2P = 0.07). However, Cox multivariate regression analysis showed independent prognostic value of patient age and nuclear v(v)BAR along with clinical stage and DI. All other investigated variables were rejected from the model. A prognostic index with highly distinguishing capacity between prognostically poor and favorable cases was constructed (2P = 1.9 x 10(-7)). It is concluded that realistic estimates of nuclear volume are independent of nuclear DNA conent and are of prognostic value for objective malignancy grading in patients with squamous cell carcinoma of the uterine cervix.

The study comprises 66 patients with stage Ill and IV serous ovarian carcinomaWhile the percentage of CA-125 positive cells and the staining intensity showed no correlation to patient survival, the pattern of CA-125 distribution, membranous versus cytoplasmic, was significantly correlated to survival. In accordance with other observations on switching of the antigen reaction f rom membrane to cytoplasm with increasing grade of atypia or malignancy, patients with membrane positive CA-125 tumors had a significantly better prognosis than did patients with CA-125 in the cytoplasm.Furthermore, there was excellent agreement between, on the one hand, the binding pattern of CA-125 and, on the other, the ploidy of the tumor cells and the HGI histopathologic grading index, both previously shown to be of prognostic significance.

The current status of cervical cancer treatment in Denmark is discussed. Diagnostic aspects and problems of classification are presented briefly supplemented with a comment on new prognostic parameters based on a semiquantitative score system and flow cytometry. Surgery is the treatment of election for the early stages whereas radiotherapy is the treatment of choice in advanced stages. Chemotherapy should only be employed in the framework of clinical trials. It is concluded that centralised treatment should be maintained.

Flow cytometric analysis of single cell DNA content was performed in 99 malignant ovarian tumors FIGO stages III and IV. The tumors were divided into two groups with DNA index ⩽ 1.5 and > 1.5, respectively. The tumor DNA index correlated with histopathological differentiation, frequency of complete pathological remission, and prognosis.

A semiquantitative histopathologic grading system was used in combination with flow cytometric measurements of tumor cell DNA content to predict the risk of lymph node metastases in early cervical cancer. A retrospective study of 126 stage IB patients showed that a group with no risk of lymph node involvement could be identified by the use of both the histopathologic score and the DNA index. The results were confirmed in a prospective investigation of 59 new patients. Simple hysterectomy may be advised in low-risk patients.

The ploidy level was measured in tumour specimens from 64 patients with advanced epithelial ovarian cancer (FIGO stages III and IV) by flow cytometric analysis. The same tumours were histopathologically graded based on a score system considering eight histopathological parameters. The results showed that both the histopathological grading index (HGI) and the DNA index were important to the frequency of complete pathological remission as assessed by second look operation. A combination of the two parameters allowed a division of the patients into three groups with different frequencies of complete pathological remission and survival. It is concluded that flow cytometric analysis and extended histopathological grading may be important adjuncts in the evaluation of malignant epithelial ovarian tumours.

It is generally believed that the degree of differentiation or tumor grade is of prognostic value in human ovarian carcinoma, but the methods of evaluation are subject to considerable variation. The present work investigates the prognostic value of a new Histologic Grading Index (HGI), containing most of the known systems and taking into account both the usual histologic and cytologic features (tumor structure, nuclear polymorphism, nucleolar features, nuclear-cytoplasmic ratio, frequency of mitosis) and the probably more independent parameters (mode of invasion, capsular penetration, and vascular invasion). This study shows that the index correlates significantly with both presence of tumor at second-look operations and survival.

Flow-cytometric DNA analysis and extended histopathologic grading were performed in specimens from 126 patients with squamous cell carcinoma of the uterine cervix stage Ib. Archival material was used for the measurements and the ploidy level was analysed according to the method described by Hedley with some modifications. The histopathologic grading was based on eight well-defined parameters all scored 1-3. The results showed that the ploidy level held significant prognostic information about the 10 year survival according to a division of DNA indices above and below 1.5. Further prognostic information appeared from a combination of DNA index and histopathologic score value. The combination held its prognostic importance in subgroups of patients with different tumour sizes. It is concluded that flow-cytometric analysis and histopathologic grading can identify subsets of patients who need more aggressive treatment.