Outcome analysis of 4 years' follow-up of patients referred for colposcopy with one smear showing mild dyskaryosis.

OBJECTIVE: To assess the 4-year outcome of patients after one smear showing mild dyskaryosis with respect to smear regression rate, prevalence of cervical intraepithelial neoplasia (CIN) and the effect of age. METHODS: Retrospective analysis of patients diagnosed with initial mildly dyskaryotic smear during the year 2000 with a follow-up period of 48 months. These women had not had any previous abnormal smears. SETTINGS: Cytopathology Department and Colposcopy Unit, King's College Hospital, London, UK. RESULTS: We identified 524 patients of whom 375 patients with complete follow-up data are included. The age range was 19-67 years with a median of 29 years. There were 207 patients aged 35 years or less (55%). At 6 months, 258 smears were performed and 47.8% of them were negative (95% CI: 41.6-54.0%). The total number of negative follow-up smears in the first year was 198 out of a total of 397 smears performed (50%). This proportion has significantly increased between 1 and 4 years' follow-up to 67.5% (RR: 1.24; 95% CI: 1.14-1.35). Over the 4-year period, 791 smears were performed and 477 were negative (60.3%; 95% CI: 56.9-63.7%). Of the 477 negative smears there were only 61 smears (12.8%; 95% CI: 10-16%), in 54 patients (14%; 95% CI: 11-18%) that reverted back to low-grade cytological abnormality. In only one case the repeat smear showed high-grade abnormality after initial negative follow-up; however, on biopsy, histology showed CIN I. Out of the 375 patients, 70 required treatment with excisional biopsy (19%; 95% CI: 15.0-22.9%). Histology confirmed high-grade CIN in only 41 cases giving a prevalence of 11% (95% CI: 8.1-14.5%). There were no cases of microinvasive or invasive cancer detected. Age (< or =35 years versus >35 years) did not significantly affect either cytological or histological outcome. CONCLUSION: Sixty per cent of follow-up smears after initial mild dyskaryosis subsequently became negative; of them 87.2% remained negative over the 4 year follow-up. Treatment was only required in 19% of patients, with 11% prevalence of high-grade CIN. Age did not affect the outcome. These results are reassuring and indicate that colposcopic referral may not be necessary after only one mildly dyskaryotic smear.

M2-PK as a novel marker in ovarian cancer. A prospective cohort study.

BACKGROUND: Pyruvate kinase isoenzyme M2-PK is instrumental to tumour metabolism and hence over-expressed in tumour cells leading to detectable plasma concentrations. OBJECTIVES: To assess the degree of association between M2-PK plasma concentrations and ovarian cancer and to determine the cut-off values for its sensitivity and specificity for differentiating between benign and malignant ovarian disease. SETTINGS: The Gynaecological Cancer Centre at both King's College and St. Thomas' Hospitals, London, UK. METHODS: Patients with suspected ovarian cancer referred to the above centre were recruited prospectively during the years 2004-2005. Blood samples were collected before surgery for plasma M2-PK assays. Results were assessed with respect to cancer diagnosis, patient and tumour characteristics. Statistical analysis including the receiver operator characteristic (ROC) curve was performed using Analyse-It and SPSS V 13. RESULTS: 100 patients with age range 14-88 years and a median of 57 years were recruited in the study. Of whom 52 were diagnosed with invasive ovarian cancer. Of these 35 (67%) were Stage III and above with two secondary tumours. M2-PK was not related to patient age (p = 0.43). There was a significant correlation between CA125 and M2-PK (p < 0.001). The mean M2-PK concentration in cancer patients was 52 U/ml versus 27 U/ml in patients with benign conditions (p < 0.001). At a cut-off value of 22 U/ml the sensitivity of M2-PK for detecting cancer was 70% with a specificity of 65%. CONCLUSION: M2-PK was significantly raised in ovarian cancer patients, however its role in clinical practice needs further evaluation.

Tumour M2-PK as a predictor of surgical outcome in ovarian cancer, a prospective cohort study.

BACKGROUND: Optimal cytoreduction is a major prognostic factor in ovarian cancer; several clinical, radiological and biochemical predictors have been studied. Tumour M2-PK (TU M2-PK) is over-expressed in tumour cells and can be detected in plasma samples but its role in ovarian cancer has not yet been evaluated. OBJECTIVES: To assess the potential clinical applications of TU M2-PK in ovarian cancer particularly in relation to surgical cytoreduction. SETTINGS: The Gynaecological Cancer Centre at both King's College and St Thomas' Hospitals; London; UK. METHODS: Patients with suspected ovarian cancer were recruited prospectively during the years 2004-2005. Blood samples were collected before surgery for plasma TU M2-PK assays. Data were analysed in relation to cancer diagnosis and outcome. Statistical analysis was performed using Analyse-It' and SPSS' V13. RESULTS: 100 patients were recruited; 52 diagnosed with invasive ovarian cancer, 13 with borderline tumours and 35 patients had benign conditions. The mean M2-PK concentration in cancer patients was 52 U/ml vs 31 U/ml in patients with borderline tumours and 22 U/ml in those with benign conditions (p < 0.001); it was significantly raised in association with late stage disease and higher grade (p < 0.05). Taking 35 U/ml as a reference point, TU M2-PK predicted sub-optimal cytoreduction in advanced stage disease with a sensitivity of 69%, specificity of 60% and overall efficacy of 61% (95% CI: 44-75%). CONCLUSION: TU M2-PK was significantly raised in ovarian cancer patients, particularly those with higher stage disease. The potential clinical application as a predictor of surgical outcome in ovarian cancer needs further evaluation.

Chronic pelvic pain: a rare complication following a large-loop excision of the transformation zone.

This is the unique report of a patient with deep-seated, left-sided pelvic pain following a large-loop excision of the transformation zone (LLETZ) for cervical intraepithelial neoplasia III. She transpired to have a definite diagnosis of pelvic varicosities which were only on the left side. Our surmise was that the varicosities had risen on the back of an arteriovenous malformation following her LLETZ performed by a colleague. The first attempted treatment was radiologic embolization. When this failed, she had a formal surgical procedure, and the left unilateral varicosities were ligated. Her pain ceased entirely thereafter, and she remained pain free at her 1-year review.

Prospective evaluation of three different models for the pre-operative diagnosis of ovarian cancer.

OBJECTIVE: To test the accuracy of the risk of malignancy index, the revised risk of malignancy index and Tailor's regression model to diagnose malignancy in women with known adnexal masses. DESIGN: Prospective collaborative study. SETTING: Gynaecology Assessment Unit, Department of Obstetrics and Gynaecology, King's College Hospital, London. SAMPLE: Sixty-one women with known adnexal masses were examined pre-operatively. Women were recruited from three South London hospitals. METHODS: The demographic, biochemical and sonographic data recorded for each patient included: age; menopausal status; CA125 levels; tumour volume; ultrasound characteristics; and Doppler blood flow analysis (peak and mean blood velocities, the pulsatility and resistance indices). The diagnosis of malignancy was made for each woman using all three models and the results compared with the final histopathological diagnosis. RESULTS: Thirty-eight women had benign tumours and 23 had ovarian cancer. Women with malignant tumours were significantly older than those with benign masses. There were also significant differences in CA125 levels, locularity, presence of papillary proliferations and ascites between the two groups. Tailor's regression model achieved a 43% sensitivity and 92% specificity in the diagnosis of malignancy. This compared with a 74% sensitivity and 92% specificity with the risk of malignancy model, and a 74% sensitivity and 89% specificity with the revised risk of malignancy model. CONCLUSION: When applied prospectively all three diagnostic models performed less accurately than originally reported, despite clinical signs of malignancy being present in many cases. It is likely that their accuracy would be even less in a population of women in whom there was a substantial clinical uncertainty. Intra-tumoral blood velocity and CA125 levels were the best individual parameters for discrimination between benign and malignant tumours.

A pilot study of the efficacy and tolerability of intralesional recombinant human beta-interferons in cervical intraepithelial neoplasia.

Beta-interferons possess anti-viral, cell proliferation inhibition and immunomodulatory characteristics which may be of use in the treatment of cervical intraepithelial neoplasia (CIN). Intralesional administration may avoid systemic side effects. Twenty-six women with cervical punch biopsy proven CIN I and II were treated by interferon injection into the cervical transformation zone according to three dosage regimens--6 million international units (IU) weekly for six weeks, 9 million IU weekly for six weeks and 12 million IU bi-weekly for three weeks. At the last treatment visit, cervical cytology and biopsy were taken to ensure no disease progression and large loop excision of the transformation zone (LLETZ) was carried out six months after treatment. Therapy was well-tolerated with 93% of the scheduled 156 treatments given. Side effects which caused cessation of treatment included severe myalgia, headaches and prolonged flu-like symptoms. The 2 patients who failed to attend for LLETZ at six months and another 2 patients who received fewer than five scheduled treatments were excluded from analysis. LLETZ histology was negative in 12 patients (54%), showed inflammatory changes or squamous metaplasia in 4 (18%), was unchanged in 4 patients and had progressed in 2 (10%). Whilst intralesional beta-interferon clearly has activity in CIN, the response rate is less than that seen for excisional or ablative procedures. Nevertheless, it may have a role in the management of CIN where, for medical reasons of patient preference, there is a desire to avoid surgical therapy.

Fallopian tube carcinoma--a review.

Although a common site of metastases, primary fallopian tube carcinoma comprises only 0.3% of all gynaecological malignancies. Presenting symptoms are variable and non-specific, with preoperative diagnosis rarely entertained. The FIGO system assigns nearly two-thirds of patients to stage I or II and is based on surgical staging criteria similar to those for ovarian cancer. Likewise, management is based on that for ovarian cancer-radical debulking followed by platinum-based combination chemotherapy. Five-year survival for patients with disease confined to the tube at diagnosis (stage I) is only about 60% and only 10% of patients with advanced disease will be cured.

Pelvic spleen masquerading as an ovarian neoplasm.

A case of a 53-year-old perimenopausal woman who presented with an 18-month history of irregular vaginal bleeding is reported. Vaginal ultrasonography revealed a 10 x 7 cm pelvic mass with an increased blood flow. Her serum CA125 was within the normal range. At laparotomy a normal spleen was found within the pelvic cavity.

Gonadotrophin-releasing hormone (GnRH) analogues in the treatment of mixed mullerian tumours of the uterus: two case reports and review.

Subjects/Discussion. Two cases of clinical and radiological response of recurrent mixed Mullerian tumours following treatment with either nasal (Buserilin) or intramuscular (Goserilin) GnRH analogues are reported and a short review of the evidence to support this treatment option presented.

Massive ascites due to abdominal pregnancy.

We describe a case of an abdominal pregnancy which presented in the first trimester with rapid accumulation of blood stained ascites. The ascites resolved completely following surgical removal of a gestational sac from the peritoneal cavity. The pathophysiology of ascites in this case may be similar to that in cases of ascites in other non-malignant gynaecological conditions.

The diagnostic value of endometrial thickness and volume measurements by three-dimensional ultrasound in patients with postmenopausal bleeding.

We compared endometrial thickness and volume in patients with postmenopausal bleeding, and examined the value of each parameter in differentiating between benign and malignant endometrial pathology. A total of 103 patients with a history of postmenopausal bleeding were recruited into the study. Patients who were taking hormone replacements therapy or other hormonal preparations with a known effect on the endometrium were excluded. Each patient underwent three-dimensional ultrasonography for the measurement of endometrial thickness and volume. In 97 cases both of these measurements were obtained and the results were compared to the histological diagnosis after endometrial biopsy or dilatation and curettage. Endometrial cancer was diagnosed in 11 patients. The mean endometrial thickness was 29.5 mm (SD 12.59) and the mean volume was 39.0 ml (SD 34.16). In the remaining 86 patients there were eight cases with endometrial hyperplasia and seven with endometrial polyps. The endometrial thickness and volume in patients with benign pathology was 15.64 mm (SD 5.26) and 5.47 ml (SD 6.32), respectively. In 71 patients with atrophic or normal endometrium the mean thickness and volume was 5.29 mm (SD 3.97) and 0.91 ml (SD 1.71), respectively. Receiver operating characteristic curves showed endometrial volume to be superior to endometrial thickness for the diagnosis of endometrial cancer. The optimal cut-off value of endometrial thickness for the diagnosis of cancer was 15 mm, with the test sensitivity of 83.3% and positive predictive value of 54.5%. With the cut-off level of 13 ml for endometrial volume measurement the sensitivity was 100% and the positive predictive value 91.7%. Both the thickness and volume were higher in patients with advanced and less differentiated cancers. The measurements of endometrial volume was superior to that of endometrial thickness as a diagnostic test for the detection of endometrial cancer in symptomatic postmenopausal women.

Use of transvaginal ultrasonography with color Doppler imaging to determine an appropriate treatment regimen for uterine fibroids with a GnRH agonist before surgery: a preliminary study.

The aim was to obtain data that could be used to determine the most appropriate treatment regimen for uterine fibroids with a gonadotropin releasing hormone analog (goserelin) before surgery. Fifteen premenopausal women (aged 27-53 years; mean 40 years) were referred from a gynecological outpatients' clinic. They all had uterine fibroids and were awaiting hysterectomy or myomectomy. All women were scheduled to receive an implant of goserelin (3.6 mg), undergo transvaginal ultrasonography and have a sample of peripheral blood taken at monthly intervals for 6 months. The main outcome measures were fibroid size and indices of blood flow (the pulsatility index and peak systolic velocity) in both uterine arteries and the principal artery supplying the largest fibroid. The concentrations of follicle stimulating hormone, estradiol, luteinizing hormone and progesterone were measured in peripheral plasma. Twelve women (80%) completed 2 months of treatment, but only three (20%) completed the study (due to side-effects of the drug). After 2 months of treatment, the plasma hormone levels were all in the low-normal range; the mean fibroid volume had decreased by 53% and the mean peak systolic blood velocity in the fibroid artery had decreased by 45%. Mean changes in all indices were < 10% over the next 4 months of treatment. Six women (40%) had fibroids with an initial volume of > 100 ml; these tumors showed the largest reduction in size. We conclude that women with a uterine fibroid of > 100 ml are the best candidates for treatment with goserelin (3.6 mg/month) before surgery. Two months' treatment effects a marked reduction in fibroid volume and blood flow and is associated with good compliance.

Surgery for gynecologic cancer.

Surgery is an integral part of staging procedures for ovarian, endometrial, and vulvar cancers, with a move toward surgicopathologic rather than clinical staging in cervical cancer. Morbidity can be reduced without compromising patient cure by individualizing surgery for patients with early vulvar cancer, and reproductive potential can be maintained in some women with early ovarian cancer. The place of prophylactic oophorectomy and primary and secondary surgery in ovarian cancer remain controversial and await prospective study. Recent developments in laparoscopic techniques have been applied to a number of problems in gynecologic cancer surgery, and the feasibility of laparoscopic lymphadenectomy and radical pelvic surgery has been demonstrated. Care must be taken, however, to ensure that the tenets of surgical oncology are not sacrificed in order to offer minimal-access surgery to women with gynecologic cancer.

Association of ovarian malignancy with expression of platelet-derived endothelial cell growth factor.

BACKGROUND: At the present time, the pathogenesis of ovarian cancer remains poorly understood, with invasive diagnosis and ineffective treatment for women with the disease. Despite scientific and medical advances in oncology, the overall 5-year survival rate of 30% for ovarian cancer patients has not changed in 20 years. An understanding of the angiogenic process as it occurs in ovarian cancer would not only increase our knowledge of the pathogenesis of this cancer but also might offer novel opportunities for therapeutic intervention. PURPOSE: Our aim was to study the expression of messenger RNA (mRNA) coding for four putative angiogenic factors in normal ovaries and benign and malignant ovarian tumors: platelet-derived endothelial cell growth factor (thymidine phosphorylase), vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta 1. METHODS: Four normal ovaries and 25 tumors (seven benign, one of borderline malignancy, and 17 malignant) were collected from 29 patients during elective oophorectomy. The site of sampling (areas of high-velocity blood flow) was directed by transvaginal color Doppler imaging performed within 24 hours of the surgery. Increased blood flow within the tissues was demonstrated by the presence of color (i.e., the velocity was > 7 cm/s) and, together with a pulsatile index of less than 1.0, constituted a positive scanning result. In scan-positive tissues, the area of maximum blood flow was chosen. In scan-negative tissues, a solid area was chosen in complex lesions, or the cyst wall was chosen in simple lesions. Ovarian RNA was subsequently extracted from areas of high-velocity flow (i.e., tissues with a positive scanning result) or from solid areas or septa in tissues with a negative scanning result. A ribonuclease protection assay was used to assess the expression of mRNA coding for the four angiogenic factors. RESULTS: Two normal ovaries (containing a corpus luteum) and one benign and 17 malignant tumors (plus the borderline) gave a positive scanning result. There was a significant difference between the expression of mRNA for platelet-derived endothelial cell growth factor between scan-positive and scan-negative tissues (P < .001) and between benign and malignant tumors (P < .001). CONCLUSIONS: Areas of high blood velocity in ovarian tumors are associated with increased expression of platelet-derived endothelial cell growth factor. IMPLICATIONS: Drugs that affect the angiogenic activity of platelet-derived endothelial cell growth factor offer a potential route for therapeutic intervention.

Nitric oxide synthase activity in human gynecological cancer.

Nitric oxide is generated by the NO synthases, a family of isoenzymes expressed in a wide range of mammalian cells. In the vascular and nervous systems distinct isoforms generate NO to act as a signal transduction mechanism. The isoform induced by cytokines, on the other hand, provides a sustained release of NO which mediates some cytotoxic and cytostatic effects of the immune system. Solid tumors are a heterogeneous population of cell types, including tumor, vascular, and infiltrating immune cells. Studies in vitro show that NO synthase can be present in many of these cells. However, its presence in situ in solid human tumors has not been reported. In this study, we have investigated NO synthase activity and its cellular localization in malignant and nonmalignant human gynecological tissue. Nitric oxide synthase activity was observed in malignant tissue, was highest (> or = 250 pmol/min/g tissue) in poorly differentiated tumors, and was below detectable levels in normal gynecological tissue. Furthermore, investigations with a polyclonal NO synthase antibody revealed immunoreactivity only in malignant tissue. This was associated with NO synthase activity and localized to tumor cells. Thus NO synthase is present in human gynecological tumors, and its presence seems to correlate inversely with the differentiation of the tumor.

Intervention debulking surgery in advanced epithelial ovarian cancer.

OBJECTIVE: To study whether intervention debulking surgery improves survival in patients with advanced ovarian cancer who have bulky (> 2 cm) residual disease after primary surgery. DESIGN: A prospective multicentre randomised study. SETTING: Hospitals in the West Midlands. SUBJECTS: Ovarian cancer patients with bulky residual disease after primary surgery who are considered well enough to receive cis-platinum based chemotherapy and further surgery. METHODS: Eligible patients were randomised to receive combination chemotherapy alone or combined with intervention debulking surgery. MAIN OUTCOME MEASURE: Survival was assessed using product limit method and log-rank test. RESULTS: Seventy-nine patients were entered into the study. Thirty-seven patients were randomised to intervention debulking surgery, 25 (67%) of whom underwent intervention debulking surgery, which was performed a median of 13 weeks after primary surgery. The median survival for the intervention debulking surgery group was 15 months (95% CI 10-20 mo) and that of those randomised to chemotherapy alone, which was 12 months (95% CI 8-16 mo), were not significantly different (hazard ratio = 0.71; 95% CI 0.44-1.13). CONCLUSION: Intervention debulking surgery may not improve survival in patients with advanced ovarian cancer.

Use of intracavity saline instillation and transvaginal ultrasonography to detect tamoxifen-associated endometrial polyps.

There is sometimes a discrepancy between the apparent thickness of postmenopausal endometria, as determined by transvaginal ultrasonography, and the examination of endometrial biopsies. We describe a case which showed that tamoxifen (20 mg/day over 12 months) decreased impedance to blood flow in the uterine arteries and increased the apparent thickness of the endometrium. Conversely, the analysis of biopsies suggested the presence of an atrophic endometrium. The introduction of sterile saline into the uterine cavity during a repeat ultrasound scan revealed the presence of a large, free-floating endometrial polyp, which was subsequently difficult to see by hysteroscopy.

The West Midlands epithelial ovarian cancer adjuvant therapy trial.

In a multicentre prospective randomized controlled trial, single agent cisplatinum was compared with whole abdomino-pelvic moving strip radiotherapy in the management of Stage IC-III epithelial ovarian cancer patients who had no macroscopic residual disease after primary surgery. Over a 6-year period 40 eligible patients were recruited, 15 of whom had Stage III disease. The overall 5-year survival was 60% with no significant survival difference between the treatment groups. Acute toxicity was common in both arms and six (11%) patients experienced significant long term disability.