Familial ovarian screening--effective or ineffective?
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Adult↗
Biomedical subjects
A N Rosenthal
Publications and source records attributed to A N Rosenthal.
Immunohistochemical analysis of p53 in vulval intraepithelial neoplasia and vulval squamous cell carcinoma.
Human papillomavirus (HPV) is thought to cause some vulval squamous cell carcinomas (VSCC) by degrading p53 product. Evidence on whether HPV-negative VSCC results from p53 mutation is conflicting. We performed immunohistochemistry for p53 product on 52 cases of lone vulval intraepithelial neoplasia (VIN), 21 cases of VIN with concurrent VSCC and 67 cases of VSCC. We had previously performed HPV detection and loss of heterozygosity (LOH) analyses on these samples. Abnormal p53 immunoreactivity (p53-positive) rates in HPV-positive VSCC and HPV-negative VSCC were 22% (12/54) and 31% (4/13), respectively (P<0.74). p53 immunoreactivity was associated with LOH at the p53 locus (P<0.004), but neither technique differentiated between HPV-positive and HPV-negative VSCC. p53 immunoreactivity was associated with overall LOH rates (p53-positive VSCC vs p53-negative VSCC mean fractional regional allelic loss 0.41 vs 0.24, respectively, P<0.027). LOH at 3p25 was more frequent in p53-positive VSCC cf p53-negative VSCC (70 vs 21%, respectively, P<0.007). There was a trend in p53 disruption associated with invasive disease; HPV-positive VSCC demonstrated more disruption than VIN associated with VSCC, which had more disruption than lone VIN III (22 vs 10 vs 0%, respectively, P<0.005). In all, three out of 73 cases of VIN were p53-positive. All three were associated with concurrent or previous VSCC. Meta-analysis of previous studies revealed significantly more p53 disruption in HPV-negative VSCC cf HPV-positive VSCC (58 vs 33%, respectively; P<0.0001). p53 immunoreactivity/mutation in VIN only appeared in association with VSCC. These data suggest that HPV-independent vulval carcinogenesis does not exclusively require disruption of p53, p53 disruption may work synergistically with LOH at specific loci and p53-positive VIN should be checked carefully for the presence of occult invasion.
Adult↗
High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC).
Vulval intraepithelial neoplasia (VIN) is thought to be the premalignant phase of human papillomavirus (HPV)-associated vulval squamous cell carcinoma (VSCC). Various molecular events have been suggested as markers for progression from VIN to VSCC, but loss of heterozygosity (LOH) in vulval neoplasia has rarely been studied in this context. We performed LOH analysis by polymerase chain reaction (PCR) amplification of polymorphic microsatellite markers at 6 chromosomal loci (17p13-p53, 9p21-p16, 3p25, 4q21, 5p14 and 11p15). The presence of HPV was assessed using consensus PCR primers and DNA sequencing. To examine any association between LOH and the presence of invasive disease, we analyzed 43 cases of lone VIN III, 42 cases of lone VSCC and 21 cases of VIN with concurrent VSCC. HPV DNA was detected in 95% of lone VIN III samples and 71% of lone VSCC samples. Fractional regional allelic loss (FRL) in VIN associated with VSCC was higher than in lone VIN (mean FRL 0.43 vs. 0.21, p < 0.005). LOH at 3p25 occurred significantly more frequently in HPV-negative VSCC than in HPV-positive VSCC (58% vs. 22%, p < 0.04). These data suggest that genetic instability in VIN, reflected by LOH, may increase the risk of invasion. In addition, molecular events differ in HPV-positive and -negative VSCC and 3p25 may be the site of a tumor suppressor gene involved in HPV-independent vulval carcinogenesis.
Carcinoma, Squamous Cell↗
The frequency of significant pathology in women attending a general gynaecological service for postcoital bleeding.
OBJECTIVES: To document the frequency of pathology in women who complain of postcoital bleeding. To determine whether negative cervical cytology excludes serious pathology in women with postcoital bleeding. To determine whether postcoital bleeding increases the risk of serious pathology in women with an abnormal smear. DESIGN: A retrospective study. SETTING: A university teaching hospital. POPULATION: 314 women with postcoital bleeding seen in the gynaecology service from first January 1988 to 31 December 1994. METHODS: Women were identified from the computerised records of the colposcopy service and copies of correspondence, which was routinely retained on computer. The latter was searched for the text strings coital and intercourse. MAIN OUTCOME MEASURE: Histopathological diagnosis. RESULTS: Twelve women (4%) had invasive cancer: 10 were cervical or vaginal cancers and two endometrial cancers. Eight of the 10 cervical or vaginal cancers were clinically apparent. Four women of these 10 had had a normal smear before being referred for further investigation of postcoital bleeding. Two of these cancers were visible only with the aid of the colposcope. Thus, 0.6% of women attending a gynaecology service with postcoital bleeding, a normal looking cervix and a normal smear had invasive cancer of the cervix. Cervical intraepithelial neoplasia were found in 54 women (17.%) and 15 women (5%) had cervical polyps. Nineteen of the 63 women (30%) with significant pathology had a normal or inflammatory cervical smear. No explanation for the postcoital bleeding was found in 155 women (49 %). CONCLUSIONS: Although invasive cancer is rare in women with postcoital bleeding, it is much commoner than in the general population. It seems likely that cervical intraepithelial neoplasia is also associated with postcoital bleeding, perhaps because the fragile cervical epithelium becomes detached during intercourse. Postcoital bleeding should continue to be regarded as an indication of high risk for invasive cervical cancer and for cervical intraepithelial neoplasia. Prompt referral to a colposcopy clinic is indicated, but most women with postcoital bleeding will have no serious abnormality.
Adolescent↗
Fibroid embolisation: a technique not without significant complications.
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Age Factors↗
Evidence of infection with simian type D retrovirus in persons occupationally exposed to nonhuman primates.
Simian type D retrovirus (SRV) is enzootic in many populations of Asian monkeys of the genus Macaca and is associated with immunodeficiency diseases. However, the zoonotic potential of this agent has not been well defined. Screening for antibodies to SRV was performed as part of an ongoing study looking for evidence of infection with simian retroviruses among persons occupationally exposed to nonhuman primates (NHPs). Of 231 persons tested, 2 (0.9%) were found to be strongly seropositive, showing reactivity against multiple SRV antigens representing gag, pol, and env gene products by Western immunoblotting. Persistent long-standing seropositivity, as well as neutralizing antibody specific to SRV type 2, was documented in one individual (subject 1), while waning antibody with eventual seroreversion was observed in a second (subject 2). Repeated attempts to detect SRV by isolation in tissue culture and by using sensitive PCR assays for amplification of two SRV gene regions (gag and pol) were negative. Both individuals remain apparently healthy. We were also unable to transmit this seropositivity to an SRV-negative macaque by using inoculation of whole blood from subject 1. The results of this study provide evidence that occupational exposure to NHPs may increase the risk of infection with SRV and underscore the importance of both occupational safety practices and efforts to eliminate this virus from established macaque colonies.
Animals↗
Ascites and a raised serum Ca 125--confusing combination.
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Ascites↗
p53 codon 72 polymorphism in vulval cancer and vulval intraepithelial neoplasia.
p53 codon 72 polymorphism was analysed in UK women with human papillomavirus (HPV)-associated vulval intraepithelial neoplasia and vulval squamous cell carcinoma. Arginine homozygotes were significantly less common in either group compared with controls. We conclude that the arginine polymorphism may confer protection against the development of HPV-associated vulval neoplasia.
Adult↗
Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening.
OBJECTIVE: To assess the performance of ultrasonography in a multimodal ovarian cancer screening strategy. DESIGN: Prospective ovarian cancer screening trial between December 1986 and June 1993. SETTING: General practice, occupational health departments and an ovarian cancer screening clinic at a London teaching hospital. POPULATION: Postmenopausal women, > or = 45 years with a raised CA125. METHODS: Volunteers with a CA125 > or = 30 U/mL underwent a pelvic ultrasound. Scans were classified as normal, abnormal (ovarian volume > or = 8.8 mL) or equivocal (normal volume with abnormal morphology). Abnormal ovarian morphology was subclassified as simple cyst (single, thin walled cyst with no septa or papillary projections) or complex (all other abnormalities). Volunteers with abnormal scans were referred for a gynaecological opinion. Follow up was via the cancer registry and postal questionnaires. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive predictive value of different ultrasound criteria for detection of index cancer (e.g. primary invasive epithelial carcinoma of the ovary and fallopian tube). RESULTS: Seven hundred and forty-one women underwent 1,219 scans and 20 index cancers occurred during a median follow up of 6 x 8 years. The sensitivity for detection of ovarian cancer of different ultrasound criteria was 100% for abnormal morphology, 89 x 5% for abnormal volume and 84% for complex morphology. The highest specificity (97%) and positive predictive value (37 x 2%) was achieved using complex morphology. CONCLUSION: A variety of ultrasound criteria can achieve high sensitivity, specificity and positive predictive value for index cancers in postmenopausal women with an elevated CA125. Use of ovarian morphology to interpret ultrasound may increase sensitivity and use of complex ovarian morphology may increase the positive predictive value.
Aged↗
Screening for ovarian cancer: a pilot randomised controlled trial.
BACKGROUND: The value of screening for ovarian cancer is uncertain. We did a pilot randomised trial to assess multimodal screening with sequential CA 125 antigen and ultrasonography. METHODS: Postmenopausal women aged 45 years or older were randomised to a control group (n=10,977) or screened group (n=10,958). Women randomised to screening were offered three annual screens that involved measurement of serum CA 125, pelvic ultrasonography if CA 125 was 30 U/mL or more, and referral for gynaecological opinion if ovarian volume was 8.8 mL or more on ultrasonography. All women were followed up to see whether they developed invasive epithelial cancers of the ovary or fallopian tube (index cancers). FINDINGS: Of 468 women in the screened group with a raised CA 125, 29 were referred for a gynaecological opinion; screening detected an index cancer in six and 23 had false-positive screening results. The positive predictive value was 20.7%. During 7-year follow-up, ten further women with index cancers were identified in the screened group and 20 in the control group. Median survival of women with index cancers in the screened group was 72.9 months and in the control group was 41.8 months (p=0.0112). The number of deaths from an index cancer did not differ significantly between the control and screened groups (18 of 10,977 vs nine of 10,958, relative risk 2.0 [95% CI 0.78-5.13]). INTERPRETATION: These results show that a multimodal approach to ovarian cancer screening in a randomised trial is feasible and justify a larger randomised trial to see whether screening affects mortality.
CA-125 Antigen↗
Ultrasound assessment of ovarian cancer risk in postmenopausal women with CA125 elevation.
We have previously shown that, in asymptomatic post-menopausal women, serum CA125 elevation is associated with a 36-fold increase in risk of ovarian cancer. This study was undertaken to assess the value of pelvic ultrasound for further stratification of ovarian cancer risk. Of 22,000 post-menopausal women, aged > or = 45 participating in an Ovarian Cancer Screening Trial, 741 with a CA125 > or = 30 U ml(-1) underwent pelvic ultrasonography. Twenty index cancers (primary invasive epithelial carcinomas of the ovary and fallopian tube) were diagnosed amongst these 741 women during a median follow-up of 6.8 years. Ultrasound results separated the women with CA125 elevation into two groups. Those with normal ovarian morphology had a cumulative risk (CR) of index cancer of 0.15% (95% confidence interval (CI) 0.02-1.12) which is similar to that of the entire population of 22,000 women (0.22%, 95% CI 0.18-0.30). In contrast, women with abnormal ovarian morphology had a CR of 24% (15-37) and a significantly increased relative risk (RR) of 327 (156-683). Ultrasound can effectively separate post-menopausal women with raised CA125 levels into those with normal scan findings who are not at increased risk of index cancer and those with abnormal findings who are at substantially increased risk of index cancer.
CA-125 Antigen↗
p53 codon 72 polymorphism and risk of cervical cancer in UK.
BACKGROUND: A polymorphism at codon 72 of the human tumour-suppressor gene, p53, results in translation to either arginine or proline. A recent report suggested that the risk of human-papillomavirus-associated cervical cancer in white women is higher for those homozygous for the arginine allele than for those who are heterozygous. We examined a similar number of cervical cancers and a larger control group for their p53 codon 72 polymorphism status to see if we could confirm this result. METHODS: Three different groups of UK white women were studied: 96 who had volunteered to take part in a trial of ovarian-cancer screening; 150 attending for routine antenatal care in the Oxford region; and 50 women with cervical cancer. DNA from peripheral blood samples and from archival tissue samples was examined by PCR with allele-specific primers. FINDINGS: The proportions of individuals homozygous for the arginine allele, homozygous for the proline allele, and heterozygous for the two alleles were 59%, 4%, and 36% among women screened for ovarian cancer; 65%, 8%, and 27% among the antenatal-care group; and 54%, 6%, and 40% in women with cervical cancer. Chi2 analysis showed no significant differences in these proportions. INTERPRETATION: In the population studied, individuals homozygous for the arginine variant of codon 72 of the p53 gene were not at increased risk of cervical cancer.
Amino Acid Sequence↗
Screening for gynecologic cancers.
Although many advances in the management of gynecologic malignancy have been achieved over the last three decades, the prognosis for advanced stage disease remains disappointing. Screening to detect pre-invasive or early stage disease can significantly reduce mortality. Encouraging results outlined in this article demonstrate the potential benefits of both novel screening technologies and refinements to established programs. Methods under investigation include serum and molecular markers, and automated Pap test slide-reading systems. In addition, much work is now directed toward cost-benefit analysis and the psychological impact of screening.
BRCA1 Protein↗
Is there an incremental rise in the risk of obstetric intervention with increasing maternal age?
OBJECTIVE: To determine whether increasing maternal age increases the risk of operative delivery and to investigate whether such a trend is due to fetal or maternal factors. DESIGN ANALYSIS: of prospectively collected data on a maternity unit database. SETTING: A postgraduate teaching hospital. POPULATION: 6410 nulliparous women with singleton cephalic pregnancies delivering at term (3742 weeks of gestation) between 1 January 92 and 31 December 95. MAIN OUTCOME MEASURES: Mode of delivery, rates of prelabour caesarean section, induction of labour and epidural usage. RESULTS: There was a positive, highly significant association between increasing maternal age and obstetric intervention. Prelabour (P < 0.001) and emergency (P < 0.001) caesarean section, instrumental vaginal delivery (spontaneous labour P < 0001; induced labour P = 0.001), induction of labour (P < 0.001) and epidural usage in spontaneous labour (P = 0.005) all increased with increasing age. In the second stage of labour fetal distress and failure to advance, requiring instrumental delivery, were both more likely with increasing maternal age (in both P < 0.001). Epidural usage in induced labour and the incidence of small for gestational age newborns did not increase with increasing maternal age (P = 0.68 and P = 0.50, respectively). CONCLUSIONS: This study demonstrates that increasing maternal age is associated with an incremental increase in obstetric intervention. Previous studies have demonstrated a significant effect in women older than 35 years of age, but these data show changes on a continuum from teenage years. This finding may reflect a progressive, age-related deterioration in myometrial function.
Adolescent↗
Screening for ovarian cancer.
Ovarian cancer is predominantly a disease of postmenopausal women which presents at a late stage and has an overall 5-year survival of less than 30%. If detected at stage I, survival is dramatically increased and this would suggest that screening for ovarian cancer may reduce mortality. However, the inaccessibility of the ovaries and the absence of a confirmed premalignant condition make screening for preclinical disease difficult. Recent advances in tumour marker interpretation and ultrasound technology have now allowed screening for ovarian cancer to become a real possibility. CA 125 is the most widely used tumour marker for ovarian cancer and it has been shown to be elevated several years before clinical presentation. A new approach to the interpretation of sequential CA 125 results, which uses a mathematical algorithm to determine an individual's risk of cancer, has improved the sensitivity of CA 125 in screening asymptomatic postmenopausal women. Screening using transvaginal ultrasound, Doppler and morphological indices gives encouraging results but, used alone, it currently lacks the specificity required of a screening test for the general population. Multimodal screening using tumour markers and ultrasound in combination gives high sensitivity and specificity and is also the most cost-effective potential screening strategy. The sensitivity and specificity of these techniques are sufficient to warrant large-scale clinical trials of ovarian cancer screening. Three such trials are currently underway and, in due course, will establish whether any screening strategy will ultimately reduce mortality from ovarian cancer.
Aged↗
Screening for simian type-D retrovirus infection in macaques, using nested polymerase chain reaction.
A nested polymerase chain reaction (PCR) assay was developed to detect proviral DNA in peripheral blood mononuclear cells (PBMC) of macaques infected with simian type-D retrovirus (SRV/D). Primers were designed to amplify gag gene sequences of SRV/D serotype 1, 2, and 3 viral genomes and were used in a single assay for simultaneous detection of infection with SRV/D-1, SRV/D-2, or SRV/D-3. Results of plasmid dilution studies indicate sensitivity of nested PCR in the range of 1 to 10 genomic copies. The PBMC samples from 395 macaques of unknown SRV/D status, obtained from several primate facilities, were tested in parallel by Western blot (immunoblot) analysis, virus isolation, and nested PCR. Infection was detected in 60 (15.2%) animals by nested PCR, in 40 (10.1%) animals by virus isolation, and in 28 (7.1%) animals by immunoblot. All 40 culture-positive samples were positive by nested PCR. In addition, 11 of 23 immunoblot-positive/virus isolation-negative samples, 2 of 20 immunoblot-indeterminate/virus isolation-negative samples, and 7 of 312 immunoblot-negative/virus isolation-negative samples were identified as positive by nested PCR. Nested PCR is a sensitive and specific assay for simultaneous screening for infection with serotypes 1, 2, and 3 of simian type D retrovirus, and is a powerful tool for rapid screening and surveillance in macaque colonies.
Animals↗
A study of pressure distributions measured during balanced and unbalanced sitting.
An instrument that measures pressures distribution during normal and unbalanced sitting was developed and tested. Analysis of the distribution of pressure during sitting in fifteen normal patients showed that approximately 18 per cent of the body weight is distributed over each ischial tuberosity; 21 per cent, over each thigh; and 5 per cent, over the sacrum. Three patients who had problems with sitting balance showed foci of unequal pressure which are at risk for decubitus ulceration.
Adolescent↗