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The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), a M, 38,000 transmembrane antigen also known as 17-1A or Ep-CAM, is commonly used for targeted immunotherapy of carcinomas because it is strongly expressed by most carcinomas. EGP-2 is, however, also expressed in most normal epithelia, To evaluate anti-EGP-2-directed treatment-associated effects on tumors and on EGP-2-positive normal tissue, we generated EGP-2-expressing transgenic mice. A 55-kb DNA fragment consisting of the 14-kb genomic coding sequence of the human EGP-2 gene with similar to 10-kb-upstream and similar to 31-kb-downstream sequences was isolated and used to direct EGP-2 expression in an epithelium-specific manner. In the EGP-2 transgenic mice, EGP-2 appeared to be specifically expressed in all of those epithelial tissues that also express EGP-2 in humans, whereas all of the other tissues were negative. The specific in vivo localization of the i.v. administered anti-EGP-2 monoclonal antibody MOC31 was studied in EGP-2-positive and -negative tumors induced s.c, in this EGP-2 transgenic mouse model. Immunohistochemical analysis showed specific localization of MOC31 in the EGP-2-positive tumors but not in the EGP-2-negative tumors. No anti-EGP-2 monoclonal antibody localization was observed in any of the EGP-2-positive normal mt,use tissues, which indicated a limited in vivo accessibility. In conclusion, an EGP-2 transgenic mouse model has been generated that expresses the EGP-2 antigen as in humans and, therefore, can serve as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities in both tumors and normal tissue.

The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (1) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (11) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients 2001 Wiley-Liss. Inc.

We investigated, in cervical cancer, the relation between telomerase activity, telomerase RNA (hTR) and mRNA of the catalytic subunit of telomerase, hTERT, with "classic" clinicopathological factors as well as survival. Frozen specimens were obtained from 107 consecutive patients with cervical cancer, treated with surgery or radiotherapy with or without chemotherapy. Telomerase activity was determined with fluorescence-based TRAP and hTR and hTERT with semi-quantitative RT-PCR, Eight normal cervical specimens served as controls, Analysis of prognostic factors and survival was limited to early-stage patients, treated primarily with radical hysterectomy. Telomerase activity was not detected in normal cervices and was present in 85 of 107(79%) cervical cancers (p

This study was performed to determine upregulation of the human telomerase RNA component (hTR) and mRNA of the catalytic subunit of telomerase (hTERT) in (pre)malignant cervical lesions, to analyze possible intralesional heterogeneity of hTR expression, and to relate hTR and hTERT mRNA levels to telomerase activity levels and human papillomavirus (HPV) typing. hTR expression was determined by in situ hybridization (ISH) on paraffin-embedded sections, obtained from patients with cervical intraepithelial neoplasia (CIN) I-III or cervical cancer and from normal controls. hTR and hTERT mRNA expression were determined by semiquantitative rt-PCR on frozen samples from the same lesions. Data on telomerase activity and HPV were obtained from a previous study. hTR expression as determined by ISH was observed in 0 of 8 normal cervices, 1 of 14 CIN I, 15 of 28 CIN II, 21 of 30 CIN III, and 16 of 18 cervical cancer specimens. In general, hybridization patterns for hTR expression were homogeneous throughout the lesion. Frequency of hTR expression was related to grade of CIN/cervical cancer (P

Objectives. The goals of this study were to analyze preoperative serum levels of CA 125, carcinoembryonic antigen (CEA), and CA 19-9 in patients with borderline ovarian tumors and to investigate if routine assessment of these markers in follow-up may lead to earlier detection of recurrence. Methods. For patient identification a database was used, in which data from all patients treated for gynecologic malignancies in the Department of Gynecologic Oncology, University Hospital Groningen, The Netherlands, are compiled. Between 1982 and 1997, 44 patients with borderline ovarian tumors were identified. Clinical data and serum CA-125 and CEA levels were retrieved from the database. CA 19-9 levels were determined in retrospect in available stored preoperative (24 patients) and follow-up (43 patients) serum samples. Results. Preoperative CA 125 levels were elevated in 8 of 33 (24%), CEA levels in 3 of 32 (9%), and CA 19-9 levels in 11 of 24 (46%) cases. In patients with mucinous tumors preoperative CA 19-9 was more frequently elevated (8/14, 57%) than CA 125 (3/20, 15%) (P = 0.02) or CEA (2/18, 11%) (P = 0.02). Complete follow-up serum CA 125, CEA, and CA 19-9 levels were available for 43 of 44 patients. Median follow-up was 84 months (range, 22-204). During follow-up two patients (5%) had recurrent disease. In one patient CA 125 became elevated at the time of recurrence; in the other patient (in retrospect) the CA 19-9 level did not return to normal after surgery, but kept rising, preceding clinical symptoms of recurrence for 13 months. Conclusions. If one chooses to use serum markers in follow-up of mucinous borderline ovarian tumors CA 19-9 should be included. Measurement of serum tumor markers in the follow-up of patients with borderline ovarian tumors may lead to earlier detection of recurrence in only a very small proportion of patients, while the clinical value of earlier detection of recurrence remains to be established. (C) 2000 Academic Press.

Hereditary nonpolyposis colorectal cancer (HNPCC) (Amsterdam criteria) is often caused by mutations in mismatch repair (MMR) genes, and tumors of patients with HNPCC show microsatellite instability (MSI-high phenotype), Germline mutations of MMR genes have rarely been found in families that have HNPCC or suspected HNPCC and that do not show microsatellite instability (MSI-low phenotype). Therefore, an MSI-high phenotype is often used as an inclusion criterion for mutation testing of MMR genes. Correction of base-base mismatches is the major function of MSH6. Since mismatches present with an MSI-low phenotype, we assumed that the phenotype in patients with HNPCC-related tumors might be associated with MSH6 germline mutations. We divided 36 patients with suspected HNPCC into an MSI-low group (n = 18) and an MSI-high group (n = 18), on the basis of the results of MSI testing. Additionally, three unrelated patients from Amsterdam families with MSI-low tumors were investigated. All patients were screened for MSH2, MLH1, and MSH6 mutations. Four presumably causative MSH6 mutations were detected in the patients (22%) who had suspected HNPCC and MSI-low tumors. Furthermore, we detected one frameshift mutation in one of the three patients with HNPCC and MSI-low tumors. In the MSI-high group, one MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phenotype. These results suggest that MSHG may be involved in a substantial proportion of patients with HNPCC or suspected HNPCC and MSI-low tumors. Our data emphasize that an MSI-low phenotype cannot be considered an exclusion criterion for mutation testing of MMR genes in general.

The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGF beta resistance, we screened the 7 exons of the type II (T beta R-II) TGF beta receptor and the 9 exons of the type I (T beta R-I) TGF beta receptor genes for mutations in 16 paraffin-embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G-->T transversion in exon 3 of T beta R-II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor, In one tumor, a silent A-->C transversion mutation that may affect mRNA splicing was present in exon 6 of T beta R-I, In addition, 7 of 16 cases were heterozygous for a C-->A polymorphism in intron 7 of T beta R-I. Finally, we identified a 9 base pair in-frame germline deletion in exon I of T beta R-I resulting in loss of 3 of 9 sequential alanine residues at the hi-terminus in 6 of 16 cases. Analysis of specimens from case-control studies indicated that carriers of this del(GGC)(3) T beta R-I variant allele may be at a increased risk for the development of cervical carcinoma (p = 0.22), Furthermore, the response of cells expressing the variant receptor to TGF beta was diminished. Our results support the notion that diverse alterations in the TGF beta signaling pathway may play a role in the development of cervical cancer. (C) 1999 Wiley-Liss, Inc.

Background. The increased risk of endometrial carcinoma following the use of tamoxifen has stimulated studies on endometrial diagnostic screening methods. In tamoxifen users the endometrial thickening observed with transvaginal ultrasonography (TVU) frequently cannot be confirmed by hysteroscopy or histology. Objective. The aim was to investigate the relationship between TW and hysteroscopic and histologic endometrial findings in postmenopausal patients using tamoxifen. Methods. Fifty-three asymptomatic postmenopausal tamoxifen-using breast cancer patients underwent a gynecological examination combined with TVU, Patients with an endometrial thickness of >5 mm were offered hysteroscopy and endometrial biopsy. Findings. Thirty-one patients (58%) had an endometrial thickness of >5 mm with enhanced, inhomogeneous echogenicity. Hysteroscopy was performed in 22 patients and 3 underwent hysterectomy. Seven of 22 patients had endometrial polyps, histologically characterized by cystically dilated glands lined with atrophic epithelium and periglandular stromal condensation. Histology of the three hysterectomy specimens showed a similar picture of atrophic luminal epithelium, covering dilated glands lined with atrophic epithelium and surrounded by dense stroma, which resembled the histology of the endometrial polyps. In all three specimens the histologically measured endometrial thickness corresponded with that on TW. Interpretation, Tamoxifen can induce specific endometrial changes consisting of cystically dilated glands with periglandular stromal condensation while the overlying epithelium remains atrophic. The changes occur either in the endometrium itself or as a protrusion of the endometrium, i.e., as endometrial polyps. These findings explain the discrepancy between ultrasound, hysteroscopy, and histology. Due to the high number of false-positive findings, TVU is not an effective screening instrument in these patients, (C) 1999 Academic Press.

Endometrial cancer occurs primarily in postmenopausal women older than 60 years of age. Especially in young patients with endometrial cancer, a positive family history with respect to cancer and/or development of synchronous or metachronous tumors can be indicative of hereditary factors. One generic disorder, playing an important role in the development of endometrial cancer in young women, is hereditary non-polyposis colorectal cancer (HNPCC). The mean age to develop endometrial cancer because of a mutation in one of thr HNPCC-genes is below 50 years. Mutation carriers have a life-rime risk of about 50% for endometrial cancer. Especially young patients with endometrial cancer should always be asked for the family history and after primary treatment the family history should regularly he updated during follow-up. (C) 1999 Elsevier Science Ireland Ltd, All rights reserved.

To study DNA topoisomerase II alpha (Topo-II alpha) and -beta expression and regulation in human ovarian cancer, 15 ovarian tumour samples were investigated. To compare different levels of expression, the samples were screened for topo II alpha and -beta mRNA with Northern blotting and a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay for Topo-II alpha mRNA. Additionally. protein levels were determined with Western blotting and topoisomerase II activity levels with the decatenation assay. The results obtained were compared with each other and with the tumour Volume index of the samples. In tumours with a tumour volume index greater than or equal to 50%, the mRNA levels (as determined by Northern blotting) and protein levels for each isozyme were in accordance. Additionally, correlations were found between Topo-II alpha RT-PCR data and Topo-II alpha Northern blot results, and between Topo-II alpha RT-PGR data and Topo-II alpha protein levels. interestingly, Topo-II beta protein levels correlated better with Topo-II activity than Topo-II alpha protein levels. In eight ovarian cystadenoma samples, no Topo-II alpha protein could be found. In only three out of eight of these cystadenomas, Topo-II beta protein could be detected. These findings suggest that Tapo-II alpha and Topo-II beta protein levels are upregulated in ovarian cancer and may indicate that Topo-II beta is an interesting target for chemotherapy in ovarian tumours.

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In the majority of patients with early stage squamous cell cancer (SCC) of the vulva, an inguinofemoral lymphadenectomy is performed (in retrospect) for diagnostic reasons: exclusion of inguinofemoral lymph node metastases. The morbidity of this procedure, however, is significant. The aim of the present study was to evaluate noninvasive detection of inguinofemoral lymph node metastases by positron emission tomography (PET) using L-[1-C-11]-tyrosine (TYR) as tracer. In patients with SCC of the vulva, scheduled for resection of the primary tumor and uni- or bilateral inguinofemoral lymphadenectomy, results of preoperative palpation of the groins and TYR-PET imaging were compared with histopathology. PET imaging was performed using two different methods. In a first group (n = 16), nonattenuation corrected 'whole body' scans were performed, and in a second group (n = 9), attenuation corrected static emission scans. Sensitivity, specificity, accuracy, and positive and negative predictive value for palpation were 62%, 89%, 82%, 67%, and 87% per groin. Sensitivity, specificity, accuracy, and positive and negative predictive value for TYR-PET were calculated for the two methodologies separately and overall. There were no significant differences. Overall values were 53%, 95%, 94%, 33%, and 98% per lymph node and 75%, 62%, 65%, 41% and 88% per groin. Detection of inguinofemoral lymph node metastases by TYR-PET is not superior to palpation. Neither palpation nor TYR-PET is able to adequately predict or exclude presence of inguinofemoral lymph node metastases in patients with SCC of the vulva.

Background: Our aim was to determine the value of 99mTc-Sestamibi scanning as functional detection method of P-glycoprotein (Pgp) blockade by PSC 833 in solid tumour patients. Patients and methods: Day 1 and day 4 after 2,200 mg orally administered PSC 833 the tumour area was scanned after intravenous (iv) administration of 400 MBq Tc-99m-Sestamibi. In rumours with net Tc-99m-Sestamibi uptake and in the hepatic region K-efflux was determined. Whole blood was analyzed for Tc-99m-Sestamibi, and PSC 833 levels. Results: Fourteen patients were included. In the only Pgp-positive tumour with positive Tc-99m-Sestamibi scanning K-efflux of Tc-99m-Sestamibi decreased significantly after PSC 833 intake. A net inhibition of liver efflux of Sestamibi after PSC 833 intake was observed in all evaluable patients. PSC 833 blood levels were all above 2 mg/L during scanning; Tc-99m-Sestamibi blood levels post versus pre PSC 833 were unchanged Conclusions: PSC 833 induced modulation of K-efflux of Tc-99m-Sestamibi in a Pgp positive tumour and in all patients in the liver.

The non-steroidal anti-oestrogen tamoxifen has a number of gynaecological side-effects. Apart from an increased risk of endometrial carcinoma, recently ovarian cyst formation during tamoxifen has been observed. This induces the problem of whether or not intervention for these cysts is required. In a cross-sectional study of breast cancer patients receiving tamoxifen, patients only developed ovarian cysts if ovaries responded to tamoxifen, as shown by oestradiol production. Ovarian cysts were not likely to develop in women with amenorrhoea > 1 year or following high-dose chemotherapy. (C) 1998 Elsevier Science Ltd. All rights reserved.

Purpose: To evaluate the diagnostic value of semiquantitative telomerase activity assessment in cervical scrapings together with human papillomavirus (HPV) typing for detection of (pre)neoplastic cervical lesions and to compare telomerase activity in cervical scrapings and frozen specimens from the same patients. Patients and Methods: A cross-sectional study was performed in 161 patients referred for an abnormal cervical cytology report. In cervical scrapings, telomerase activity was determined by modified telomere repeat amplification protocol (TRAP) assay and HPV typing by polymerase chain reaction (PCR) with general and type-specific primers. Final diagnosis was made by pathologic examination of biopsy and/or loop excision specimens. Results: Telomerase activity was detectable in assessable scrapings fram one of nine (11%) patients without cervical intraepitheleal neoplasia (CIN), in three of 26 (12%)with CIN I, eight of 35 (22%) with CIN II, 18 of 62 (29%) with CIN III, and four of 13 (31%) with cancer. Sensitivity and negative predictive value of the TRAP assay for CIN II/III and cancer lesions were 25% and 28%, respectively, while specificity for no CIN or CIN I was 89%. In representative frozen sections, frequency of detectable telomerase activity was related to grade of CIN/cancer; none of 21 normal cervices, none of two CIN I, two of 12 (17%) CIN II, 10 of 31 (32%) CIN III, and 18 of 21 (86%) cervical cancer lesions were telomerase-positive (P Conclusion: telomerase activity is more frequent in higher grade CIN/cervical cancer lesions. Telomerase activity assessment in cervical scrapings has a low sensitivity for CIN II/III and/or cervical cancer and does not appear to be useful in primary screening for cervical cancer. However, increased telomerase activity in frozen CIN sections may be a possible marker of progressive disease. (C) 1998 by American Society of Clinical Oncology.

In patients with early-stage squamous cell cancer of the vulva, inguinofemoral lymphadenectomy is performed primarily as a diagnostic procedure. The morbidity of this procedure, however, is not negligible. The aim of this study was to evaluate the feasibility of minimally invasive detection of the sentinel inguinofemoral lymph node (SILN) and to investigate whether the histopathology of the SILNs is representative of that of the other non-SILNs. Methods: Patients with early-stage squamous cell cancer of the vulva, planned for resection of the primary tumor and uni- or bilateral inguinofemoral lymphadenectomy, were eligible for the study. Technetium-99m-labeled nanocolloid was injected intradermally at four locations around the tumor the day before operation. Images were recorded immediately and after 2.5 hr using a gamma camera. SILN locations were marked on the overlying groin skin. The next day, during general anesthesia, blue patent dye was injected intradermally at the same locations around the tumor. During the operation SILNs were identified at the place indicated using a handheld gamma-detection probe. It was noted if SILNs were found by the probe, by blue dye or by both techniques. After resection of the SILNs, a standard inguinofemoral lymphadenectomy was performed. The results of histopathology of the SILNs were compared with those of the non-SILNs, Results: The procedure was well tolerated by 10 of 11 patients. One patient, initially agreeing to participate, refused the injection of tracer because of fear of pain. In all 10 patients, identification of the SILNs was successful. The mean time for identification was 11 min. Identification of SILNs was primarily performed using the hand probe in all patients, whereas in 10 of 18 removed SILNs afferent lymph channels were also blue stained (56%). In 8 patients, pathologic examination showed no metastatic disease in both SILNs and non-SILNs, whereas in 2 patients metastases in the SILNs (one and two metastatic lymph nodes, respectively), as well as in other non-SILNs, were found. Conclusion: This study shows that identification of SILNs in squamous cell cancer of the vulva is feasible with preoperatively administered Tc-99m-labeled nanocolloid, Intraoperatively administered blue dye was only useful for confirmation of identification with nanocolloid, To date, no false-negative SILNs have been found, but expansion of the study is necessary to determine the possible clinical application of this new diagnostic technique.

A review is given of the clinical use and interpretation of serum tumor marker levels during the treatment of patients with cancer of the uterine cervix, Pretreatment serum squamous cell carcinoma (SCC) antigen provides a new prognostic factor in early stage squamous cell carcinoma of the uterine cervix, Elevated serum values of SCC antigen at the time of diagnosis of stage IB and IIA cervical cancer indicate a 3 x increased risk of tumor recurrence, independent of tumor diameter, grade or the presence of lymph node metastases, High pretreatment SCC antigen levels could therefore be used to select 'high-risk' patients for adjuvant therapy. Measurement of the serum SCC antigen levels provides a means of monitoring the effect of therapy. During the postoperative follow-up of patients with localized cancer of the uterine cervix the measurement of SCC antigen can lead to the early detection of recurrent disease when curative therapy is still an option. The profile of serum SCC antigen parallels the response to radiotherapy and provides a way of evaluating the effectiveness of chemotherapy. Serial measurements after surgery and during radio- and chemotherapy demonstrate that SCC antigen is a more sensitive marker for recognizing tumor progression or recurrence than CYFRA-21.1, TPS or CEA, When following up patients with a pure adenocarcinoma of the cervix measurements of serum CA 125 and CEA are preferred over SCC antigen measurements.

Ovarian carcinoma is often associated with overexpression of cytokines that may exert autocrine and paracrine growth effects, as well as genetic alterations in (proto)oncogenes and tumour suppressor genes, such as p53. The p53 protein is not only involved in the regulation of cell cycle and apoptosis, it is also involved in the in vitro regulation of IL-6 gene expression. In this study, 30 tumours of patients with a primary diagnosis of human ovarian carcinoma were characterised for p53 expression with immunohistochemistry and analysed for the expression of M-CSF, IL-6, IL-1 beta, IL-11 and TNF-alpha with Northern blotting. Nuclear and cytoplasmic p53 staining was observed in 27% (8/30), cytoplasmic staining in 30% (9/30), and no p53 staining in 43% (13/30) of the tumours. In 70% (21/30) of the tumours, M-CSF mRNA was expressed, in 40% (12/30) TNF-alpha, and in 30% (9/30) IL-6. None of the tumours expressed IL-1 beta or IL-11. The expression of TNF-alpha occurred more frequently in M-CSF positive tumours compared to M-CSF negative tumours (52% (11/21) versus 11% (1/9), P

To investigate the clinical significance of the enhanced sensitivity of antibody detection by radio immunoprecipitation assays (RIPA), using in vitro translated HPV-16 E6 and E7 proteins, over synthetic-peptide enzyme-linked immunosorbent assay (ELISA), RIPA for HPV-16 E6 and E7 were performed. The results obtained with E6 and E7 RTPA were related to clinico-pathological data from cervical carcinoma patients positive for HPV type 16 DNA in their primary tumour. The data obtained with E6 and E7 RIPA were then compared to the results obtained using the E7/6-35 synthetic-peptide ELISA. The prevalence of antibodies to E6, E7, E6 and/or E7 and E6 and E7, as determined by RIPA, was significantly higher in cervical cancer patients than in both controls and cervical intraepithelial neoplasia patients. Odds ratios, calculated for cervical carcinoma patients versus controls, ranged from 7.4 to 15.4. Antibodies to E6 and/or E7 were largely restricted to patients with HPV DNA in their primary tumour. Analysis of the relation between prevalence of antibodies to E6 and E7 and clinico-pathological parameters was limited to 85 patients positive for HPV-16 The strongest relation with clinico-pathological data, such as lesion size, lymph node involvement, and prognosis, was found for E7 synthetic-peptide ELISA, whereas E6 and E7 RIPA did hot reach significance. The significance of these findings is discussed.

The level of risk for carcinoma in the uterine cervix depends on the type of human papillomavirus (HPV) present. We examined whether the HPV type influences the proliferation rate and occurrence of mitotic figures with lagging chromosomes in the precursor of cervical carcinoma. The study group comprised 180 women who were referred because of cytologic changes indicating dysplasia and who were subsequently diagnosed with cervical intraepithelial neoplasia grade III. The HPV-16-associated lesions showed a significantly higher number of mitoses per 1,000 nuclei than the lesions without HPV (p

Background: The feasibility of concurrent chemotherapy and radiotherapy for advanced primary carcinoma of the cervix was evaluated and the results were compared to historical controls. Patients and methods: In a single institution study, patients (n = 74) with primary cervical carcinoma received 3 cycles carboplatin/5-fluorouracil concurrent with radiotherapy, followed by salvage hysterectomy (group I). Treatment results were compared with those of a historical control group (n = 39) (group II), treated similarly but without chemotherapy. Results: In group I median follow-up is 28 months (12-68+) and in group II 23 months (14-90+ months). The 5-year overall survival, progression-free survival and local recurrence free survival for group I and II are, respectively, 69% versus 38% (P

The aim of this paper was to provide epidemiological evidence to support the notion that cervical intraepithelial neoplasia (GIN) without human papillomavirus (HPV) is a true entity. If a diagnosis of HPV-negative cervical neoplasia is erroneous, one would not expect there to be any differences in risk factors between HPV-positive and HPV-negative patients. Patients at a gynaecological outpatient clinic of a university hospital [a total of 265 consecutive women with dyskaryotic cervical smears who were subsequently diagnosed with CIN I (n=37), CIN II (n=43) or CIN III (n=180)] completed a structured questionnaire regarding smoking habits and sexual history. Analysis of an endocervical swab for Chlamydia trachomatis, analysis of a cervical scrape for HPV, and morphological examination of cervical biopsy specimens were also performed. HPV was found in 205 (77.4%) out of the 265 women. Univariate analysis showed that current age (P= 0.02), current smoking behaviour (P=0.002) and the number of sexual partners (P=0.02) were significantly associated with the presence of HPV. Age at first sexual intercourse, a past history of venereal disease or genital warts, and current infection with Chlamydia trachomatis were not associated with the presence of HPV. Using multivariate logistic regression analysis, the number of sexual partners and current smoking behaviour showed an independent significant association with HPV. HPV-negative and HPV-positive CIN patients differ with respect to the risk factors for HPV. These findings suggest that HPV-negative CIN is a separate true entity.

The purpose of this study was to analyze (1) the prognostic factors for survival of T1 and T2 carcinoma patients and (2) the impact of the initial groin node status for the time to recurrence and site of recurrence. We performed a follow-up study on 190 women with a T1 or T2 squamous cell carcinoma of the vulva. Data were obtained on age and general medical condition, the clinical and histological characteristics of the primary tumor and the inguinofemoral lymph nodes, treatment, recurrences, and survival. The standard treatment was radical vulvectomy with bilateral inguinofemoral lymphadenectomy supplemented with postoperative radiotherapy to the primary site, groin, and pelvic side walls if groin metastases were present. Compared to patients without lymph node metastases in the groin, the relative risk of dying within a given time period was estimated to be 2.47 (limits of the 95% confidence interval: 1.24, 4.93) and 9.69 (3.90, 24.03) for patients with unilateral and bilateral node metastases, respectively. The number of metastatic lymph nodes or their intra- or extranodal growth was not associated with survival. The relative risk of dying within a given time period was 2.71 (1.36, 5.40) for patients with a T2 tumor compared to those with a T1 tumor and 2.37 (1.31, 4.31) for patients with vasoinvasive growth compared to those without capillary-lymphatic tumor infiltration. Tumor thickness, differentiation grade, and multifocal growth did not determine survival. In the multivariate Cox regression analysis, the presence of inguinofemoral lymph node metastases proved to be the most important prognostic factor for patients' survival. Of the 119 patients who underwent lymphadenectomy but in whom no groin node metastases were found, 6 (5%) patients manifested an early recurrence (i.e., residual cancer or a recurrence within 2 years after the diagnosis). In contrast, of the 51 patients with histologically documented groin node metastases, 15 (29.4%) manifested an early recurrence and these recurrences appeared equally distributed over the primary site and other sites. Only 1 of the 51 women with documented inguinofemoral lymph node metastases presented with the first manifestation of recurrent cancer in the groin. Groin node metastases did not increase the risk for late recurrences. The presence of inguinofemoral lymph node metastases (none/unilateral/bilateral) is the most important predictor of failure to survive. Groin node metastases are associated with early recurrences which seldomly manifest primarily in the groin if it is hospital policy to supplement the surgical excision with adjunctive radiotherapy. (C) 1995 Academic Press, Inc.

We surveyed cervical intraepithelial neoplasia (CIN) to quantify the proliferation rate and the presence of normal and atypical mitotic figures. In the cervical tissue specimens of 127 women with CIN, the area with the highest cell proliferation was identified and, at that site, the proliferation rate was assessed by calculating the mitotic index (MI), Lesions with an MI

Background and Objectives: It has been suggested that bacterial vaginosis may play a role in the etiology of cervical neoplasia. The authors analyzed the prevalence, risk factors, and impact on histologic changes of bacterial vaginosis in women with cytological abnormalities of the uterine cervix. Methods: Two-hundred-eighty women with dyskaryotic smears were surveyed. Using a questionnaire, data were obtained on smoking habits and sexual history. Bacterial vaginosis was the diagnosis if the vaginal discharge produced a fishy odor upon alkalinization and if due cells were seen in the wet smear. Cervical scrapes were analyzed for the presence of human papillomavirus DNA, and cervical tissue specimens were analyzed for the presence and severity of (intraepithelial) neoplasia acid the proliferation rate (mitotic index) of the lesion. Chlamydia trachomatis was identified by culture of an endocervical swab. Results: Bacterial vaginosis was found in 56 (20%) out of the 280 women. The presence of bacterial vaginosis was significantly associated with the number of cigarettes smoked per day, age at first sexual intercourse, the lifetime number of sexual partners, and current Chlamydia trachomatis infection. The number of cigarettes currently smoked per day and the lifetime number of sexual partners were independent significant risk factors for the presence of bacterial vaginosis. There was no relation between the presence of bacterial vaginosis and the human papillomavirus infection. Bacterial vaginosis did not influence the severity of the (intraepithelial) neoplasia or the mitotic index. Conclusion: In women with dyskaryotic cervical smears, the prevalence of bacterial vaginosis did not seem to be increased, and bacterial vaginosis did not influence the histologic changes. Therefore, bacterial vaginosis is unlikely to be important in the etiology of cervical neoplasia, despite the similarity between its epidemiologic features and those of cervical human papa lomavirus infection and cervical neoplasia.

Quantitative and qualitative aspects of topoisomerase (Topo) I and II were studied in 17 malignant ovarian tumors [eight untreated and nine after platinum/cyclophosphamide (Pt/Cy) chemotherapy]. Median Topo II catalytic activity was lower (P

Background: DNA topoisomerase II enzymes are key targets for the group of anti-tumour agents known as topoisomerase inhibitors. In general, cell lines which express high levels of topoisomerase II are sensitive to the cytotoxic effects of the topoisomerase poisons. The levels of topoisomerase II expression in tumour biopsies may therefore predict response to treatment with enzyme inhibitors. In the current study we have analysed ovarian tumours for expression of topoisomerase II alpha and genetic change at the topoisomerase II alpha locus on chromosome 17. Materials and methods: We have used methodology which allows the sequential extraction of protein and genomic DNA from the same biopsy sample to study the topoisomerase II alpha locus and the expression in ovarian cancer. Topoisomerase II alpha expression was quantified by Western blot analysis in 54 tumours. Results: Topoisomerase II alpha expression was detected in 65% of ovarian tumours with a 16 fold range in level. In adenocarcinomas, the topoisomerase II alpha gene can become amplified due to its proximity to ERBB2 on chromosome 17q. Of 86 ovarian tumours studied only 1 had amplification of ERBB2 and none had amplification of topoisomerase II alpha a sequences. Conclusions: Topoisomerase II alpha expression was detected in ovarian carcinomas by Western blot analysis. A sixteen-fold range in expression was detected with significantly higher levels of topoisomerase II alpha expression in advanced stage IV and grade III tumours. Molecular analysis of the topoisomerase II alpha locus failed to reveal any gross genetic alterations which could account for the variation in levels of expression.

Between 1982 and 1992, 32 patients with squamous cell vaginal cancer were treated. Fourteen patients had stage I, 11 stage II, two stage III and five stage IV disease. The mean age of stage I and II patients was 64, of stage III and IV patients 73. Six patients were pessary-bearing, two had a total procidentia, eight had been treated for cervical intraepithelial neoplasia (CIN), one for cervical cancer and one for vulvar cancer 5-21 years before diagnosis. One patient had had external irradiation for endometrial cancer 15 years before. Nine patients had no follow-up examinations after treatment for CIN, for vulvar cancer or after insertion of a pessary. In 14 patients doctors' or patients' delays were considerable. Most patients presented with vaginal discharge or bleeding, and urinary symptoms. Various treatment modalities were used. The selected patients who could be treated by surgery did best. Only patients with a stage I tumor or a stage II tumor with a diameter of at most 30 mm survived. Tumor stage and tumor diameter were the important prognostic factors. No patient died of disease after 33 months. Failure in obtaining local control was the usual cause of death. Recommendations for prevention or early diagnosis are formulated.

Within the group of primary cutaneous T-cell lymphomas (CTCLs), mycosis fungoides (MF), Sezary's syndrome (SS), and CD30-positive lymphomas have been delineated as clinicopathological entities. Primary CTCLs that do not belong to one of these entities represent a heterogeneous and ill-defined group of neoplasms. This paper describes the clinical and histological features of 35 of such cases. The object of this study was to define prognostic parameters for this group of primary CTCLs. Using a slightly modified version of the updated Kiel classification, a subdivision was made into CTCL, pleomorphic, small cell type (n=3); pleomorphic, medium-sized cell type (n=6); pleomorphic, large cell type (n=18); and immunoblastic lymphomas (n=8). Altogether, these lymphomas had a poor prognosis with estimated 2- and 4-year survival rates of 53 and 22 per cent, respectively. Patients with pleomorphic, small and medium-sized cell lymphomas (n=9) proved to have a significantly better survival that those with pleomorphic, large cell lymphomas (P=0.032) and immunoblastic lymphomas (P=0.008). Primary cutaneous immunoblastic lymphomas had the worst prognosis with an estimated 2-year survival rate of 14 per cent. Other parameters including age (P=0.345), sex (P=0.662), extent of skin lesions at presentation (P=0.0854), and mode of initial treatment (P=0.609) had no significant effect on the survival time. The results of this study suggest that primary CTCLs other than classical MF, SS, and CD30-positive lymphomas have a poor prognosis in most cases, and that the current classification may be a useful means of predicting the clinical behaviour in these lymphomas.