Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

OBJECTIVE: To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. METHODS: This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. RESULTS: Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8-9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25(th) -75(th) centiles, 6.03-7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79-1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5-1.03%); and for Type II it was 0.34% (95% CI, 0.33-0.79%). In the subgroup (n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08-6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9-4.6%) and for Type II it was 1.3% (95% CI, 0.6-2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. CONCLUSION: Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening.

Absorption of carbon dioxide during laparoscopy in children measured using a novel mass spectrometric technique.

BACKGROUND: Carbon dioxide (CO(2)) is absorbed during pneumoperitoneum and may cause adverse haemodynamic effects. The aim of this study was to measure the elimination of exogenous CO(2) during laparoscopy in children. METHODS: Ten children [27.6 (56.5) months; mean (SD)] undergoing laparoscopic and nine [24.5 (17.3) months] undergoing open surgery were studied. Breath samples were collected at the line for end-tidal CO(2) and analysed for (13)CO(2)/(12)CO(2) ratio expressed as deltaPDB (difference from standard), by isotope-ratio mass spectrometry. The proportion of absorbed CO(2) was calculated comparing exhaled (13)CO(2)/(12)CO(2) before and during CO(2) pneumoperitoneum. RESULTS: (13)CO(2)/(12)CO(2) in medical CO(2) was -32.7 (2.1) deltaPDB. (13)CO(2)/(12)CO(2) in breath of patients undergoing open procedures was -24.3 (2.4) deltaPDB at the start of operation and did not change during the operation (P > 0.2). (13)CO(2)/(12)CO(2) in breath of patients undergoing laparoscopy was -21.5 (5.4) deltaPDB at the start of insufflation, and decreased during pneumoperitoneum by 2.5 (1.6) deltaPDB, indicating absorption of exogenous CO(2). The percentage of expired CO(2) absorbed rose to 15.5 (7.7)% after 30 min of pneumoperitoneum and decreased rapidly after desufflation. CONCLUSION: After 10 min of laparoscopy 10-20% of expired CO(2) derives from the exogenous CO(2). CO(2) absorption can be measured using a simple mass spectrometric technique.

Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women.

OBJECTIVE: To analyse the fertility rates, complications and recurrences in a group of women who have undergone radical vaginal trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. DESIGN: An observational series. SETTING: A Gynaecological Oncology Centre. POPULATION: One hundred and twenty-three consecutive women who underwent radical vaginal trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. METHODS: Data were collected prospectively. MAIN OUTCOME MEASURES Complications, recurrences, pregnancies and live births are presented as percentages of the total population. Fertility is presented as a 5-year cumulative rate, with women attempting to conceive as the denominator. RESULTS: A total of 123 women were followed up for an average of 45 months. Eleven (8.9%) had completion treatment (two radical hysterectomies and nine chemoradiotherapy) at the time of initial treatment. There were three recurrences (2.7%) among the women who did not have completion treatment and two (18.2%) in those who did. There were 6 perioperative and 26 postoperative complications. Sixty-three women attempted pregnancy. There were 55 pregnancies in 26 women and 28 live births in 19. Three women had continuing pregnancies. The 5-year cumulative pregnancy rate among women trying to conceive was 52.8%. All but two women were delivered by classical caesarean section and seven (25.0%) babies were born at 31+6 weeks or less. CONCLUSIONS: For selected women with early-stage cervical cancer, radical vaginal trachelectomy and pelvic lymphadenectomy are fertility-sparing options, with a low incidence of recurrence and acceptable cumulative conception rates. Complications are few, although there is a high premature labour and miscarriage rate among pregnant women.

Routine computerized tomography scanning, groin ultrasound with or without fine needle aspiration cytology in the surgical management of primary squamous cell carcinoma of the vulva.

We set out to study whether computerized tomography (CT) scanning of the vulva and the groin and groin ultrasound scanning (USS) alone or with fine needle aspiration cytology (FNAC) (USS/FNAC) influenced or could influence the surgical management of primary squamous cell carcinoma of the vulva (SCCaV). Forty-four patients underwent surgery for primary SCCaV following radiologic imaging by one or more modalities. Patient details included the clinical assessment of the carcinoma, radiologic findings, the operation performed, and whether the decision regarding the type and extent of surgery for the vulval carcinoma and, in particular, for the groin node dissection was or could be influenced by the radiologic findings. The age range was 38-87 years, with a median of 74 years. A total of 75 groin dissections were performed. Twenty-five of the 44 patients (56.8%) did not have groin node metastasis, 14 had unilateral metastasis (31.8%), and 5 (11.4%) had bilateral metastasis. All cases with histologically proven nodal status were analyzed to compare the preoperative imaging status with the histology. The calculated sensitivity, specificity, negative predictive value, and positive predictive value for CT were 58%, 75%, 75%, and 58%, for USS alone-87%, 69%, 94%, and 48%, and for USS-guided FNAC-80%, 100%, 93%, and 100%, respectively. There was no patient in whom surgical planning for the vulval carcinoma or the groin nodes was or could be altered by the CT findings. The data do not support the routine use of CT scanning in patients with primary SCCaV, either in assessment of the primary vulval carcinoma or in detecting groin nodal metastases. For the groin nodes, USS/FNAC is superior to CT in assessing disease status. In contrast to CT, USS/FNAC may have a useful clinical role in the management of the groin nodes in vulval carcinoma.

The pathology and management of endocervical glandular neoplasia.

The incidence of cervical glandular intraepithelial neoplasia and adenocarcinoma is rising, and our limited knowledge about these lesions presents the gynecologist with a management dilemma. Recently, pathologists have paid increasing attention to the diagnosis and pathogenesis of adenocarcinoma of the cervix. Although there is no uniformity in the management of these lesions, nonradical surgery appears to give satisfactory results especially in young women who want to preserve their fertility. This review focuses on the issues surrounding the histologic diagnosis of endocervical glandular abnormalities, including their classification, and discusses the management of cervical preinvasive glandular disease, including follow-up after treatment.

Placement of a Malecot catheter to enable embryo transfer after radical trachelectomy.

OBJECTIVE: To describe the use of a Malecot catheter as a stent after radical trachelectomy (RT). DESIGN: Case report. SETTING: Assisted conception unit at a teaching hospital in the United Kingdom. PATIENT(S): A 36-year-old woman undergoing IVF after her cervix had been excised for cervical carcinoma. Previous attempts at embryo transfer (ET) had been very traumatic and required a transmyometrial transfer on one occasion. INTERVENTION(S): A Malecot catheter was inserted into the uterine cavity after a dilatation procedure had been performed and removed before ovarian stimulation. MAIN OUTCOME MEASURE(S): Ease of ET. RESULT(S): The subsequent ET was much more straightforward. CONCLUSION(S): This technique can facilitate ET after RT if the passage is found to be stenosed.

A retrospective clinical audit of cervical smears reported as 'glandular neoplasia'.

The aims of this study were to review the diagnostic pathway of women with smears reported as 'glandular neoplasia' and to outline the management, colposcopy findings, treatment and final histological diagnosis in these women. The design was a retrospective review. A total of 114 women were identified over a 5-year period from the cytology database at the Royal Liverpool University Hospital Cytology Department, whose hospital case notes were available for review. Methods included a review of the case notes for the demographic details, indication for smear, colposcopic findings, investigation and/or treatment procedures, histology, final diagnosis and current disease status. Of 114 smears reported as 'glandular neoplasia', 67 were reported as consistent with cervical glandular intra-epithelial neoplasia (CGIN), six with endocervical adenocarcinoma, 36 with endometrial adenocarcinoma and five with other glandular neoplastic abnormalities. The average age was 46.5 years. 79 (69.3%) smears were routine call/recall and 36 (30.7%) women were symptomatic. The positive predictive value (PPV) for a significant histological abnormality in the CGIN smear group was 80.6% (23.9% invasive carcinomas, 43.3% CGIN and 13.4% CIN) and the PPV of an 'endometrial adenocarcinoma' smear was 86.1%. Smears indicating glandular neoplasia are associated with a high probability of clinically significant lesions, the PPV of a CGIN smear being over 80%. Immediate referral for colposcopy and assessment by an experienced colposcopist is recommended.

Perforation with the GyneFix intrauterine implant: is there a common factor?

This report describes an asymptomatic perforation with the GyneFix intrauterine contraceptive implant. A review of all other reports of this complication has been performed. Analysis of these reports suggests prolonged amenorrhoea secondary to continuous progestogen use as a possible common predisposing factor.

A randomised, prospective, phase III clinical trial of primary bleomycin, ifosfamide and cisplatin (BIP) chemotherapy followed by radiotherapy versus radiotherapy alone in inoperable cancer of the cervix.

BACKGROUND: Phase II studies have shown primary (neo-adjuvant) chemotherapy with bleomycin, ifosfamide and cisplatin (BIP) is active against inoperable cervical cancer. We present here results of a randomised phase III multicentre trial comparing radical radiotherapy with neo-adjuvant BIP chemotherapy followed by radical radiotherapy in patients with inoperable cervical cancer, designed to discover whether this combination might improve survival. PATIENTS AND METHODS: Patients with inoperable cervical carcinoma were randomised to pelvic radiotherapy alone [RT] or two to three cycles of bleomycin 30 units/24-hour infusion, ifosfamide 5 g/m2/24 hours, and cisplatin 50 mg/m2) chemotherapy followed by pelvic radiotherapy (BIP + RT). Randomisation was stratified by stage and radiotherapy centre. RESULTS: One hundred seventy-two eligible women were randomised into this trial; eighty-six to RT and eighty-six to BIP + RT. A total of 190 cycles of chemotherapy were given. Median follow-up for the 47 patients still alive is 9 years with a minimum follow-up of 3 years. Complete or partial response occurred in 51 of 86 (59%) of those randomised to RT and 60 of 86 (69%) of those randomised to BIP + RT. The difference between response rates does not reach statistical significance (chi2 = 2.06, P = 0.15). Median survival is two years with an actuarial survival at five years of 32% (95% confidence interval (95% CI): 25%-39%). There is no significant difference between the treatment groups (chi2log-rank = 0.11, P = 0.74). CONCLUSIONS: This study does not show any survival benefit from the use of neo-adjuvant BIP chemotherapy in advanced cervical cancer.

Vulvar intraepithelial neoplasia: long term follow up of treated and untreated women.

OBJECTIVE: To investigate the long term outcome of patients with vulvar intraepithelial neoplasia. DESIGN: A retrospective study using information obtained from patient casenotes. SAMPLE: One hundred and thirty-three women with a primary diagnosis of vulvar intraepithelial neoplasia (VIN), identified during a 15-year period. RESULTS: The diagnosis of vulvar intraepithelial neoplasia increased throughout the study period. Human papilloma virus changes were noted in 104 patients (78%); these women were significantly younger than those without (P < or = 0.001). Nineteen (14%) were managed by observation or medical treatment and the remainder by surgical methods. Histological or symptomatic recurrence after surgical treatment occurred in 55 (48%). When disease recurred, it usually did so within four years of treatment. Recurrence was more common following laser vapourisation than after local excision (75% vs 40%; P < or = 0.01). Progression to invasive disease occurred in nine patients (7%), none of whom were in the group being observed. Four deaths occurred in this group, three from gynaecological malignancies of the lower genital tract. CONCLUSION: Patients with vulvar intraepithelial neoplasia require long term follow up, and the risk of invasion may be higher than previously thought. Surgical treatment when required should be by excisional rather than ablative methods in most instances. In selected cases it is also possible to safely manage patients by more conservative methods.

Vulvar intraepithelial neoplasia with superficially invasive carcinoma of the vulva.

OBJECTIVE: To investigate the long-term outcome of patients presenting with vulvar intraepithelial neoplasia (VIN) with superficially invasive carcinoma of the vulva (SICa). DESIGN: A retrospective study using information obtained from patient case notes. SAMPLE: Twenty-six women found at presentation to have VIN in association with superficially invasive carcinoma were identified during a 15-year period. RESULTS: Pruritus vulvae was the most frequent presenting symptom in 18 patients (69%). Sixteen women (61.5%) had multiple symptoms. Features noted at vulvar examination were variable and none were pathognomonic of either VIN or of superficial invasion. All patients had VIN 3 in association with a superficially invasive carcinoma. Histological changes associated with human papillomavirus were found in 19 (73%) women. Half had a co-existent or previous abnormality of the lower genital tract. Local excision was the most frequent initial treatment (n = 9 [35%]). Mean follow up time was 65 months (range 12-174). Disease persisted after primary treatment in five women (19%). Both histological recurrence (of either VIN or SICa) or symptomatic recurrence occurred in 10 patients (38%). All patients who experienced recurrence did so within 36 months of treatment. Overall, 12 patients (46%) relapsed (histological or symptomatic recurrence); the mean time was 18 months. Fourteen patients (54%) were managed satisfactorily by their initial treatment. One patient died of recurrent cervical cancer. Three progressed to frankly invasive disease: two (aged 31 and 39 years) with carcinoma of the vulva and one aged 34 years with carcinoma of the perianal margin. All are alive and well after treatment. One patient had recurrence of superficially invasive carcinoma treated by local excision with no further problems. No episode of metastasis via lymphatic or vascular channels has been seen. CONCLUSIONS: Patients with superficially invasive carcinoma of the vulva may be safely treated by local excisional methods without recourse to lymphadenectomy. Relapse after primary treatment is common, and there appears to be a significant risk of progression to frankly invasive carcinoma.

The prognostic significance of Bcl-2 and p53 expression in ovarian carcinoma.

Advanced ovarian cancer is characterized by poor prognosis and the development of resistance to chemotherapy. We have found that Bcl-2 and p53, two proteins implicated in the control of apoptosis, are differently expressed in the ovarian cell line A2780 and its cisplatin-resistant variant 2780CP, with the resistant line overexpressing both proteins. Transfection of the A2780 cells with a Bcl-2- or p53-expressing plasmid increases resistance to various drugs, including cisplatin, suggesting that Bcl-2 and p53 expression may influence the sensitivity of ovarian cancer cell lines to chemotherapy. Expression of these two proteins in vivo was determined by immunohistochemical staining of ovarian tumor biopsies from 70 patients. We found that Bcl-2 and p53 were expressed in 57 and 61% of specimens examined, respectively. Both p53 and Bcl-2 were found to be independent prognostic indicators of survival in ovarian cancer. Survival was poorer in patients with tumors expressing high levels of p53, whereas expression of Bcl-2 was associated with improved survival.

The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2.

Modulation of apoptosis may influence resistance to chemotherapy and therefore affect the outcome of cancer treatment. Ovarian cancer, one of the most fatal malignancies in women, is often associated with drug resistance but the cellular pathways contributing to this effect remain obscure. We have found that Bcl-2 and p53, two proteins implicated in the control of apoptosis, are frequently expressed in fresh biopsies of primary ovarian carcinoma. Examination of Bcl-2 and p53 protein levels in pairs of cis-platin sensitive and resistant ovarian cell lines demonstrated that the resistant variants over-express Bcl-2 and/or p53, apparently due to progressive expansion of Bcl-2 and/or p53 positive subpopulations during the in vitro development of resistance. Exogenous expression of Bcl-2 or a temperature sensitive mutant p53 (ts p53) in the ovarian cell line A2780 resulted in protection from drug-induced apoptosis and a delay in drug-mediated S-phase arrest. Interestingly, p53 accumulation in response to DNA damage induced by different agents was significantly delayed and reduced in the Bcl-2 transfectants compared to the control A2780 line, suggesting that Bcl-2 may act upstream of the p53 pathway. Similarly, the induction of Bax mRNA and protein was also found to be delayed in the presence of Bcl-2. Overall, our data provide further evidence for cross-talk between Bcl-2, p53 and Bax and suggest that these genes are important determinants of drug-induced apoptosis thereby modulating resistance to chemotherapy.

Characterization of a decapacitation factor associated with epididymal mouse spermatozoa.

Earlier studies demonstrated that epididymal mouse spermatozoa have a surface-associated factor which inhibits fertilizing ability in a reversible manner. The factor can be removed from uncapacitated spermatozoa by gentle centrifugation, resulting in immediately highly fertile gametes, and it can be added back to capacitated spermatozoa, resulting in poorly fertile cells in which the acrosome reaction has been blocked. Using such inhibition of in-vitro fertilizing ability as an assay, we have carried out experiments to characterize the factor. It appears to be an anionic polypeptide with Mr of approximately 40,000 (according to its behaviour on gel filtration). It is stable to heating at 100 degrees C for 15 min and is not destroyed by proteases at pH 8.0, yet inhibitory activity decreases during sperm incubation in capacitating conditions and is also destroyed in partially purified preparations by endogenous enzyme action during incubation at pH 5.0. Activity is not adsorbed to either concanavalin A-agarose or wheat-germ agglutinin-agarose, suggesting that terminal mannose and N-acetylglucosamine residues are not abundant. The factor causes rapid changes in the patterns of chlortetracycline fluorescence seen on sperm heads, a parameter used to assess the capacitated state. Removal of the factor from uncapacitated cells results in a shift to a predominance of capacitated patterns, while the addition of crude or partially purified factor to capacitated cells inhibits the acrosome reaction and causes a shift to the uncapacitated pattern in acrosome-intact spermatozoa. The factor therefore behaves as a decapacitation factor. However, it appears to differ from other characterized decapacitation factors in terms both of molecular size and of abundance of mannose and N-acetylglucosamine residues.

Expression of capacitation-dependent changes in chlortetracycline fluorescence patterns in mouse spermatozoa requires a suitable glycolysable substrate.

Chlortetracycline (CTC) fluorescence patterns were assessed in epididymal mouse sperm suspensions capacitated in exogenous substrate-containing and substrate-free media. A capacitation-dependent transition from a majority of acrosome-intact cells expressing the uncapacitated F pattern of fluorescence to a majority with the capacitated acrosome-intact B and acrosome-reacted AR patterns was confirmed for suspensions incubated a total of 120 min in the presence of a glycolysable substrate, glucose. In contrast, assessment of spermatozoa incubated for 120 min in substrate-free medium revealed a majority of cells with the uncapacitated F pattern, despite an earlier demonstration that such cells are essentially capacitated: upon the introduction of glucose, suspensions are immediately highly fertile. When a suitable glycolysable substrate, either glucose or mannose but not fructose, was added to such suspensions, the distribution of CTC patterns changed within 10 min to a majority of B and AR patterns. Furthermore, the degree of change from uncapacitated to capacitated patterns was substrate concentration-dependent. In contrast, the introduction of the non-metabolizable substrates 2-deoxyglucose and 3-0-methylglucose and the oxidizable substrates sodium pyruvate and sodium lactate caused no change in the patterns from those seen in substrate-free medium. The in-vitro fertilizing ability of sperm suspensions to which increasing amounts of glucose or mannose were added, after initial substrate-free preincubation, directly paralleled the changes in CTC patterns and was as rapid as for suspensions incubated continuously in either hexose. We therefore conclude that the alteration in position of surface components to which CTC binds is not only capacitation-dependent, but also energy-dependent. In the absence of an appropriate exogenous glycolysable substrate, the final transition cannot occur, even though the cells are essentially capacitated.

The influence of diltiazem and nifedipine on the haemodynamic and tubular responses of the rat kidney to renal nerve stimulation.

An investigation was undertaken in the pentobarbitone anaesthetized rat to determine the influence of calcium entry blockade on the haemodynamic and tubular responses of the kidney to renal sympathetic nerve stimulation. Electrical activation of the nerves, at rates causing a 12% reduction in renal blood flow, did not change glomerular filtration rate but significantly reduced urine flow (32%) and absolute (34%) and fractional sodium excretion (33%). Intravenous administration of diltiazem (10 and 20 micrograms/kg/min) and nifedipine (1.0 and 2.0 micrograms/kg/min) caused significant reductions of systemic blood pressure. Stimulation of the renal nerves, to reduce renal blood flow between 15% and 18% in the presence of both low and high doses of diltiazem, caused significant falls in glomerular filtration rate of 9% and 23%, respectively. During the low dose of nifedipine glomerular filtration rate did not change but in animals receiving the higher dose it fell by 17%. The magnitude of the neurally induced changes in urine flow, absolute and fractional sodium excretions were not different at either dose level of diltiazem or nifedipine from that observed in the absence of drugs. Stimulation of the renal nerves at low rates, which did not change renal blood flow, had no effect on glomerular filtration rate but significantly reduced urine flow (38%) and absolute (39%) and fractional sodium excretion (35%). At these low rates of nerve stimulation glomerular filtration rate remained unchanged during the infusion of either dose level of diltiazem. However, during administration of both the low and high doses of nifedipine there were significant reductions of glomerular filtration rate of 20% and 17%, respectively. The magnitude of the neurally induced changes in urine flow, absolute and fractional sodium excretions in the presence of both low and high doses of diltiazem and nifedipine were the same as those observed in the absence of drugs. The results of this study provide no evidence to indicate that the nerve mediated increases in tubular sodium reabsorption, a response involving alpha-adrenoreceptors, is dependent on the movement of calcium into the epithelial cells. The data did not indicate that blockade of calcium entry into cells impaired the ability of the kidney to regulate glomerular filtration rate which appeared to be due to a lack of renal efferent arteriolar vasoconstriction.