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Background: Cervical cancer is caused by specific types of the human papilloma virus (HPV), but not all infected women develop cancer. It has been hypothesized that hormonal contraceptives may potentiate the oncogenicity of HPV infection. Methods: In a case–control study of colored and black women in the Western Cape Province, South Africa, 524 incident cases of clinically evident invasive cervical cancer (stages lb–1V) were compared with 1541 controls, and with a subgroup of 254 HPV-positive controls. Findings: For injectable progestogen contraceptives (95% of which were depot medroxyprogesterone acetate) the overall relative risk, adjusted for confounding, was 1.0 (95% confidence interval 0.8–1.3); for combined estrogen/progestogen oral contraceptives the corresponding estimate was 0.8 (0.7–1.1). When the data were divided into categories of duration of use extending to ≥15 years, or according to age, ethnic group, or recency of use, there was no consistent evidence of an increased risk. The findings were unchanged when the cases were compared with the HPV-positive controls. Interpretation: The present findings suggest that neither injectable progestogen-only nor combined estrogen/progestogen oral contraceptives increase the risk of clinically evident invasive cancer of the cervix. [ABSTRACT FROM AUTHOR]

Human papillomavirus is the principal risk factor associated with cervical cancer, the most common malignancy among women in Colombia. We conducted a survey, aiming to report type specific prevalence and determinants of human papillomavirus infection in women with normal cytology. A total of 1859 women from Bogota, Colombia were interviewed and tested for human papillomavirus using a general primer GP5+/GP6+ mediated PCR-EIA. The overall HPV DNA prevalence was 14.8%; 9% of the women were infected by high risk types, 3.1% by low risk types, 2.3% by both high risk/low risk types and 0.4% by uncharacterized types (human papillomavirus X). Thirty-two different human papillomavirus types were detected, being human papillomavirus 16, 58, 56, 81(CP8304) and 18 the most common types. The human papillomavirus prevalence was 26.1% among women younger than 20 years, 2.3% in women aged 45-54 years, and 13.2% in women aged 55 years or more. For low risk types the highest peak of prevalence was observed in women aged 55 years or more. Compared to women aged 35-44 years, women aged less than 20 years had a 10-fold increased risk of having multiple infections. Besides age, there was a positive association between the risk of human papillomavirus infection and number of regular sexual partners and oral contraceptive use. In women aged below 25 years, high educational level and having had casual sexual partners predicted infection risk. In conclusion, there was a broad diversity of human papillomavirus infections with high risk types being the most common types detected. In this population multiplicity of sexual partners and, among young women, high educational level and casual sexual partners seem to determine risk. [ABSTRACT FROM AUTHOR]

In 1990, 215 patients with operable breast cancer were entered into a prospective study of the prognostic significance of five biochemical markers and 15 other factors (pathological/chronological/patient). After a median follow-up of 6.6 years, there were 77 recurrences and 77 deaths (59 breast cancer-related). By univariate analysis, patient outcome related significantly to 13 factors. By multivariate analysis, the most important of nine independent factors were: number of nodes involved, steroid receptors (for oestrogen or progestogen), age, clinical or pathological tumour size and grade. Receptors and grade exerted their influence only in the first 3 years. Progestogen receptors (immunohistochemical) and oestrogen receptors (biochemical) were of similar prognostic significance. The two receptors were correlated (r=+0.50, P=0.001) and displaced each other from the analytical model but some evidence for the additivity of their prognostic values was seen when their levels were discordant. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the loss of heterozygosity (LOH) of BRCA1 (17q21) and TP53 (17p13.1) in early-onset breast cancer patients; to correlate biopathological characteristics with molecular alterations; and to investigate the survival of LOH-related cancers.BRCA1 and TP53 LOH were evaluated in 78 early-onset breast cancers (≤40 years, Group 1) and 80 patients with age <55 years (Group 2). Cases were characterized for multiple biological markers (ER, PR, proliferation index (PI), NEU and p53). LOH was carried out on microdissected paraffin embedded tissues; microsatellites D17S855 (BRCA1) and D17S786 (TP53) were amplified by fluorescent PCR and analyzed by an automated DNA sequencer. Early-onset breast cancers showed a higher frequency of ductal histotype (89,7% vs. 56,3% p<0.001), node-positive (53,8% vs. 38,7%), larger size ( p=0.017), higher mitotic rate ( p=0.025), higher nuclear and final grade ( p=0.01 and p=0.001, respectively). D17S855 LOH was 32,8% in group 1 vs. 21% in group 2; D17S786 LOH was 50,7% vs. 31.3% ( p=0.03), respectively. BRCA1 LOH was correlated with higher PI ( p=0.032) and higher p53 expression ( p<0.001) in group 1 and with higher NEU expression ( p=0.028) in group 2. TP53 LOH was correlated with p53 overexpression ( p=0.03) in group 1. A worse clinical outcome in early-onset LOH related cancers emerged from follow-up data: TP53 and BRCA1 LOH were associated with a shorter relapse free interval (RFI) ( p=0.03) and a poorer overall survival (OS) ( p=0.04), respectively. This study underlines different biological profiles in the two age groups investigated, probably reflecting different mechanisms of carcinogenesis. In accordance with adverse histopathological features in early-onset patients, LOH-related cancers have an unfavorable prognosis. [ABSTRACT FROM AUTHOR]

The aim of this trial was to study the value of adding post-operative radiotherapy to lumpectomy in a subgroup of breast cancer patients with favourable patient-, tumour-, and treatment-related prognostic features. 152 women aged over 40 with unifocal breast cancer seen in preoperative mammography were randomly assigned to lumpectomy alone (no-XRT group) or to lumpectomy followed by radiotherapy to the ipsilateral breast (50 Gy given within 5 weeks, XRT group). All cancers were required to be invasive node-negative, smaller than 2 cm in diameter and well or moderately differentiated, to contain no extensive intraductal component, to be progesterone receptor-positive, DNA diploid, have S-phase fraction ≤7 and be excised with at least 1 cm margin. During a mean follow-up time of 6.7 years, 13 (18.1%) cancers recurred locally in the no-XRT and 6 (7.5%) in the XRT group (P = 0.03). There was no difference between the groups in the ultimate breast preservation rate (95.0% vs. 94.4% in XRT and no-XRT, respectively,P = 0.88), distant metastasis-free survival (P = 0.36), or 5-year cancer-specific survival (97.1% in XRT and 98.6 in no-XRT). Radiation therapy given after lumpectomy reduces the frequency of ipsilateral breast recurrences even in women with small breast cancer with several favourable clinical and biological features. However, the breast preservation rate may not increase due to more frequent use of salvage mastectomies in patients treated with postoperative radiotherapy. [ABSTRACT FROM AUTHOR]

The transforming properties of fibroblast growth factor 3 (FGF-3) were investigated in MCF7 breast cancer cells and compared to those of FGF-4, a known oncogenic product. The short form of fgf-3 and the fgf-4 sequences were each introduced with retroviral vectors and the proteins were only detected in the cytoplasm of the infected cells, as expected. In vitro, cells producing FGF-3 (MCF7. fgf-3) and FGF-4 (MCF7. fgf-4) displayed an amount of estrogen receptors decreased to around 45% of the control value. However, MCF7. fgf-3 cell proliferation remained responsive to estradiol supply. The sensitivity of the MCF7. fgf-4 cells, if existant, was masked by the important mitogenic action exerted by FGF-4. In vivo, the MCF7. fgf-3 and MCF7. fgf-4 cells gave rise to tumors under conditions in which the control cells were not tumorigenic. Supplementing the mice with estrogen had the paradoxical effect of totally suppressing the start of the FGF-3 as well as the FGF-4 tumors. Tumorigenicity in the presence of matrigel was similar for MCF7. fgf-3 and control cells and was increased by estrogen supplementation. Once started, the MCF7. fgf-4 tumors grew with a characteristic high rate. Remarkably, FGF-4 but not FGF-3, stimulated the secretion of vascular endothelial growth factor (VEGF65) without altering the steady-state level of its mRNA, suggesting a possible regulation of VEGF synthesis at the translational level in MCF7 cells. The increased VEGF secretion is probably involved in the more aggressive phenotype of the MCF7. fgf-4 cells while a decreased dependence upon micro-environmental factors might be part of the increased tumorigenic potential of the MCF7. fgf-3 cells. [ABSTRACT FROM AUTHOR]

Background: The detection rate of small, often subclinical breast cancers is increasing in affluent societies. Concomitantly, the demand for more conservative surgical approaches is also increasing among the women affected. Predictors of the absence of nodal invasion would spare many patients with early breast cancer the risks, costs and side effects of lymphadenectomy, and thus treatment with curative intent would be applied using really minimal surgery. Patients and Methods: We reviewed the records of 135 patients with unifocal invasive breast cancers, 2 cm or less in diameter, operated upon at 'Fundación Tejerina-Centro de Patología de la Mama', Madrid, Spain, between January 1993 and December 1997. Full clinical and pathological data were available for all of them, together with estrogen and progesterone receptor determinations, which had been routinely performed in 134 and 133 cases, respectively. Additionally, Ki67, c-erb-B2, p53, nm23, HSP27, HSP60 and CD44std expression was studied on archival, paraffin-embedded tumor material from these same patients by means of immunohistochemistry. Results: In the univariate analysis, only histologic grade 3 (p < 0.001), Ki67 expression in more than 10% of tumor cells (p = 0.005) and CD44std negativity (p = 0.004) were significantly associated with axillary node involvement. In multivariate analysis, histologic grade 3 and CD44std negativity retained statistical significance, and thus emerged as independent predictors of nodal invasion. The combination of both, furthermore, identified a subgroup in which the axillary nodes were invariably affected. Conclusion: Some pathological and molecular features of small breast cancers were able to predict nodal metastasis significantly. However, none, either alone nor combined, was able to exclude axillary node invasion completely. Copyright © 1999 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Tissue from 20 surgically resected uteri was examined in order to test the hypothesis that the oestrogen receptor content of the myometrium may not be uniform throughout the uterus. All patients were premenopausal, had no history of any exogenous steroid hormone use and were in the proliferative phase of the menstrual cycle. Material was taken from the subserosal, midmyometrical and subendometrial regions of both the fundal and lower uterine segments. Care was taken to remove all endometrium. Suitable samples were analysed by radioimmunoassay (RIA) for oestrogen receptors. An adjacent block from each area was fixed in formalin and stained immunocytochemically for oestrogen receptors. The results of the RIA show a significantly higher receptor content in the subendometrial region than in either the midmyometrial or the subserosal region. No significant difference was demonstrated between the numbers of receptors in the fundus and in the lower uterine segments. The differences were also well demonstrated by immunocytochemistry, according to which 83% of all cells counted in the subendometrial region were positive, while only 61% of cells in the middle and 47% of those in the subserosal region were positive. [ABSTRACT FROM AUTHOR]

The association between epidermal growth factor receptor (EGFR) expression, clinicopathological variables, silver-stained nuclear organizer region (Ag-NOR) counts, and patient survival was determined in 93 patients with operable breast cancer. The EGFR expression was found to be significantly associated with the presence and number of axillary lymph node metastases ( P = 0.0429), but not with age, menopausal status, tumor size, histologic type or grade, or Ag-NOR counts. In a univariate analysis, a significant difference was also observed in the survival of patients stratified by tumor size ( P = 0.0091), histologic grade ( P = 0.0352), axillarly lymph node metastases ( P = 0.0001), and EGFR expression ( P = 0.0263). However, a multivariate analysis revealed that axillarly lymph node metastases was the only strong independent predictor ol'survival ( P < 0.0001). When axillary lymph node metastases were excluded from the Cox model, the EGFR expression tended to be an independent prognostic factor ( P = 0.0558). The results of this study thus indicate that the prognostic value of EGFR expression is limited because the EGFR expression is significantly associated with axillary lymph node metastases. [ABSTRACT FROM AUTHOR]

The expression of platelet derived growth factors (PDGF), the PDGF-Receptor (R) (α and Β types), epidermal growth factor (EGF)-Receptor (R) and sex hormone (oestrogen and progesterone) receptors was studied in 22 meningiomas. All tumours were PDGF-R Β type positive and 21 (95%) were PDGF positive. Only 2 (9%) were PDGF-R α type positive, 13 (59%) were EGF-R positive. The expression of these proteins was not related to the histological type or the malignancy of the meningiomas although the expression of PDGF and PDGF-R Β tended to be stronger in malignant meningiomas. Oestrogen and progesterone receptor protein were examined in 19 patients (10 females and 9 males). None of the meningioma cells revealed oestrogen receptor protein while 17 (89%) of the 19 meningiomas were positive for progestrone receptor protein. The expression of progesterone receptor was not related to histological type or malignancy. Our studies suggest that the autocrine system, through PDGF and PDGF-R type Β, may play an important role in the tumourigenicity of meningiomas. EGF-R was present in almost half and progesterone receptor in most of the meningiomas. There was no correlation between the expression of either PDGF, PDGF-R or EGF-R and the expression of progesterone receptor protein. [ABSTRACT FROM AUTHOR]

Progesterone (PR) and oestrogen (ER) receptors were examined in meningiomas from 36 patients, using immunocytochemistry. The present experiments were performed to evaluate: (a) the presence and intracellular localization of these receptors, (b) whether PR immunostaining can be correlated (or not) with proliferation potential, as evaluated by histopathological features or the clinical evolution of this neuropathological tumour. Twenty six tumours (72%) tested were positive for PR but none for ER. The presence of PR immunostaining was more frequently observed in females (79% versus 58% in males) and premenopausal status (84% versus 3/5 in postmenopausal). Correlations of PR immunostaining with the histologic type showed 89% of meningothelial, 4/6 cases of transitional, 1/3 case of fibroblastic and 1/4 cases of anaplastic meningiomas to be immunostained for PR. Staining was confined to tumours arachnoidal cells. A heterogeneous distribution was observed in most PR-positive meningiomas. The preferential immunostaining in meningothelial histological types correlates with the presence of PR in normal arachnoidal cells. The proliferating potential of these meningiomas was evaluated by the immunostaining of an antigen only present in proliferating cells (Ki antigen). There was no significant correlation between PR status and the Ki labelling rate, or rapid clinical evolution. These data were compared with those previously reported. They confirm that the cellular biosynthesis of PR in meningiomas is not oestrogen regulated as it is in other sex steroid tissues, such as the breast and the endometrium. [ABSTRACT FROM AUTHOR]

Cytogenetic studies of normal and tumor cells in a patient with gonadal dysgenesis and bilateral gonadoblastoma were performed. The karyotype was 46,XY in peripheral blood lymphocytes and skin fibroblasts. The conserved region of the SRY gene was detected by polymerase chain reaction amplification. Sequencing of this region did not reveal any alterations. A 46,XY chromosome constitution was observed in the right gonadoblastoma, but a partial deletion of chromosome 13 was present in the left tumor. This deletion included band 13q14, where the retinoblastoma gene is mapped. The study of the polymorphism of the variable number of tandem repeats region in intron 17 of the RB1 locus disclosed loss of heterozygosity in both the left tumor, which showed the deletion of chromosome 13, and in the right tumor, where no chromosome alterations of chromosome 13 were detected. In situ hybridization covering 130 kb of RB1 showed that a partial deletion of one of the RB1 alleles had occurred in the right tumor. Since the deletions affected different alleles in each tumor, independent events must have been involved in the development of the tumors. These findings point toward a significant role of RB1 in the development of gonadoblastoma. [ABSTRACT FROM AUTHOR]

A 3-kb DNA fragment, inserted in Bluescribe vector, was used to localize the desmin gene by in situ hybridization on human metaphase chromosomes. The probe was labelled by Bio-11-dUTP and detected by immunofluorescence. Subsequent R-banding indicated that the desmin gene is located in band 2q35. [ABSTRACT FROM AUTHOR]

A retrospective study of 67 human breast carcinomas of various types and grades was conducted using the avidin-biotin-peroxidase complex (ABC) to localize casein, lactalbumin, and GCDFP 70 on paraffin sections. Estrogen and progesteron receptors also were evaluated. This study demonstrated the following: (1) Casein positive cells were present in all cases with a variable distribution and degree of staining, whereas lactalbumin and GCDFP 70 were seen in only 40 and 43% of the cases, respectively. (2) No significant relationship was observed between casein, lactalbumin, GCDFP 70 and the histologic types of tumors or the extent of stromal elastosis, with the exception GCDFP 70, which was observed more often in well-differentiated ductal carcinomas. (3) No significance was established in the relationship between antigens and steroid receptor content, with the exception of casein; strong casein immunostaining was significantly related to high progestin receptor levels. (4) Lactalbumin and GCDFP 70 were significantly associated with each other, but independently so of the histologic grades and types, the extent of stromal clastosis, and the steroid receptor content of the tumor cells. [ABSTRACT FROM AUTHOR]

Preclinical as well as clinical studies with fibroblast interferon (IFN) are still lagging behind on those with leukocyte interferon. Its side-effects seem to be less pronounced than those of human IFN-α, yet it may be slightly pyrogenic after intravenous injection. Pyrogenicity of current impure preparations might for the larger part be due to impurities. Higher doses of HuIFN-β than of HuIFN-α are required to obtain measurable blood titers by intramuscular injections. Since there is concern about this being due to destruction of the interferon before it has reached its target organ(s), most current clinical studies use either local (e.g. intratumoral) treatment or intravenous infusions. A study of topical treatment for acute rhinovirus infection has indicated that there is very little if any chance for fibroblast interferon to be a clinically useful substance to prevent or cure common cold. In herpetic dendritic keratitis eye drops of fibroblast interferon may be useful as such or in combination with debridement. Topical treatment of warts (multiple intralesional injections) has been shown to yield a high success rate, especially in the case of verrucae vulgares, but less so in the case of verrucae planae juveniles. Studies on condyloma accuminatum are not so far advanced as to permit a documented conclusion. Topical (intralesional) treatment of neoplastic diseases has been investigated, especially in Japan, to demonstrate that fibroblast interferon does have an antineoplastic effect in vivo. While there seems to be little doubt that local delivery does indeed cause tumor nodules to regress, the question is whether this procedure can offer a true clinical benefit to the patient. Systemic (intravenous) administration for chronic hepatitis B has been investigated further: given alone or in combination with adenine-arabinoside, fibroblast interferon seems to be able to reduce the level of viral activity. Whether this will lead to a generally accepted treatment of chronic active hepatitis is difficult to say at this moment. In treating herpes zoster in cancer patients, results have been obtained which are comparable to those found for leukocyte interferon. The practical significance of this finding must be seen in the perspective of recent developments in the chemotherapy of herpes zoster. In breast cancer patients given intramuscular injections, metastases in the skin, but not in other organs, showed alterations suggestive of an effect on tumor progression. Yet there was no true clinical benefit for the patient. In other tumors, e.g. head and neck epithelioma, no effect was seen. Intravenous infusions have met with some success in nasopharyngeal carcinoma: temporary stabilization or regression occurred, but no definitive cures were noted. A large neuroblastoma trial yielded negative results. Disappointing results were also obtained in non-Hodgkin's lymphoma. In initial studies on myeloma and brain tumors 'response rates' of 25% were recorded; the significance of this in terms of clinical benefit to the patient is not clear yet. [ABSTRACT FROM AUTHOR]

The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT–PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no significant difference was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identified a single base substitution in each of the three cases: two tranversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type profile. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney. [ABSTRACT FROM AUTHOR]

Specific chromosomal aberrations might indicate the position of genes responsible for a particular disease. Neuroblastoma is characterized by frequent deletions and/or rearrangements of the subtelomeric 1p region which, accordingly, is believed to host one or more oncosuppressor gene(s) directly or indirectly involved in the development of this and other tumors. Identification of these genes could be facilitated if cell lines with well characterized interstitial deletions or reciprocal translocations could be available for application of ’positional cloning‘ strategies.In the present report we present additional and novel molecular data on three well established neuroblastoma cell lines (NLF, NMB and NGP). In one of these we have identified two sites that might be good candidates for hosting oncosuppressor genes; one of these is flanked by the D1S47 and ENO1 loci while the other is distal to the A12M2 locus. [ABSTRACT FROM AUTHOR]