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.

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.

Surgery for invasive gynecologic cancer in the elderly female population.

Radical, curative surgery may not be considered in elderly patients with gynecologic cancer, yet the morbidity for this population from radiotherapy and cytotoxics may be high. This study compared the feasibility and outcome of such surgery in 226 consecutive patients, 72 women over 70 years old and 154 younger patients, in our institution over a 26-month period. Older patients presented with more advanced-stage cancers and, as a group, had significantly poorer presurgical performance status and more intercurrent medical problems. Nevertheless, the planned radical surgical procedure could be carried out in 90% of elderly patients, with a postoperative mortality of 1.5%. Minor postoperative complication rates were similar for the two groups and, except for vulvectomy patients, the mean inpatient stay was the same for both groups. Chronological age alone is a poor determinant of surgical risk, and elderly patients withstand radical surgery almost as well as their younger counterparts.

Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced, unresected epithelial ovarian cancer.

Thirty-six patients with epithelial ovarian cancer, incompletely resected at primary laparotomy, were treated with one of two intensive cis-platinum-based combination chemotherapy regimens. The intention was to perform further surgical debulking (intervention debulking surgery) after three cycles in patients responding to treatment. Intervention debulking surgery was carried out in 28 of 36 patients (78%) at a median interval of 12.7 weeks from primary diagnosis. Omentectomy and total abdominal hysterectomy were the most commonly performed procedures at intervention debulking. As a result of such surgery, 16 of the 28 women (57%) were left with no macroscopic residual disease, five (18%) had less than 1 cm, four (14%) less than 2 cm residuum, and three (11%) remained with more extensive disease. Post-intervention debulking surgical complications were few, with a median postoperative hospital stay of 10 days and a median interval of 21 days from debulking surgery to resumption of chemotherapy. Neoadjuvant (cytoreductive) chemotherapy combined with early secondary surgical debulking is feasible, with little severe morbidity, and can leave a high proportion of patients free of macroscopic disease. The effect of such a program on patient survival is now being tested in a randomized study.

Survival after negative second-look laparotomy.

Complete pathological responses, as defined by multiple negative intraperitoneal biopsies at second-look laparotomy, were recorded in 22 of 120 patients with epithelial ovarian cancer. Patients had been previously treated with either high-dose single agent cisplatinum (19) or total abdominal and pelvic irradiation (3). Nine of 21 (43%) evaluable patients developed recurrent disease after 'negative' second-look laparotomy. The median time to relapse was 15 months (3-19) and the median survival after relapse, 4 months (1-6). One patient remains alive with evidence of disease.

Early second surgery in ovarian cancer--improving the potential for cure or another unnecessary operation?

The presence and amount of residual disease after primary surgery is a major adverse prognostic factor in epithelial ovarian cancer [EOC]. Rapid initial cytoreduction employing second surgery early in the primary chemotherapeutic management of patients with gross residual disease has been advocated as a means of improving outcome. To evaluate the prognostic value of such an approach we have reviewed the outcome of 24 patients with gross residual disease, who were debulked to less than 2 cm residuum at a second operation, performed after three cycles of cis-platinum-based chemotherapy (a median of 14 weeks from the initial laparotomy), and compared this with an historical series of 195 patients with residual disease (70 patients with less than 2 cm residuum) who received cis-platinum but no early secondary surgery. In the control series, stage and residual disease status were important prognostic factors. There was no significant difference in patient or disease characteristics between those patients in the early second surgery group and control patients with greater than 2 cm disease (n = 125). Initially the survival curve for the early second surgery group was similar to the less than 2 cm disease group, but at about 18 months, there was a rapid deterioration until the survival parallels that of the patients with bulky disease at presentation. Early secondary surgery did not significantly prolong survival in patients with greater than 2 cm of residual disease.

Survival following intestinal obstruction in ovarian cancer.

A retrospective survey of 38 ovarian cancer patients who developed radiologically confirmed intestinal obstruction was performed. Twenty-six patients underwent surgery. In the surgical treatment group, obstruction was not due to recurrent disease in six cases. The median survival for the group as a whole was 56 days. Patients in the operative group survived significantly longer than those in the non-operative group. There was an operative mortality of 15% and major postoperative morbidity was seen in 42%. Neither the site of the obstruction nor the type of operation influenced survival. No postoperative chemotherapy responses were seen in previously treated patients.

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.

Prospective comparative cytologic study of direct peritoneal smears and lavage fluids in patients with epithelial ovarian cancer and benign gynecologic disease.

Direct peritoneal samples obtained by scraping or brushing (with a Cytobrush) were compared to peritoneal lavages (washings) for the cytologic evaluation of patients with gynecologic disease. The direct samples were obtained during laparotomy or laparoscopy, following saline lavage if that was performed, and were immediately smeared on glass slides and fixed in 95% alcohol. Only 9 of the direct peritoneal samples taken from 64 patients with benign gynecologic disease were unsatisfactory for cytologic interpretation while 19 of the 33 lavage specimens simultaneously collected from these patients were considered unsuitable for analysis (P less than .001). Two direct smears from cases with benign histology were reported as suspicious. Nineteen patients with epithelial ovarian cancer also had cytologic specimens collected by direct sampling and by washing. The direct smears were positive for malignancy in 12 cases, suspicious in 4 cases and negative in 3 cases while the lavage samples were positive in 9 cases, suspicious in 4 cases, negative in 4 cases and unsatisfactory in 2 cases. These results indicate that direct peritoneal sampling is a simple and reliable alternative to peritoneal lavage and produces a significantly lower incidence of unsatisfactory specimens.

Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears.

OBJECTIVE: To determine the efficacy and morbidity of fine loop diathermy excision of the cervical transformation zone as applied to the management of outpatients with abnormal cervical smears. DESIGN: Prospective programme trial with six month follow up. SETTING: Two hospital based colposcopy clinics. PATIENTS: 616 Patients aged 16-60 with abnormal cervical smears. INTERVENTIONS: After colposcopic and cytological assessment excision of the cervical transformation zone by fine loop diathermy under local anaesthesia in the outpatient department. MAIN OUTCOME MEASURES: Time to complete the treatment, immediate morbidity in terms of discomfort and bleeding, and cytological and colposcopic findings at six months. RESULTS: Treatment was completed in a mean of 3.47 minutes (SD 1.99). Immediate morbidity was minimal, and histological specimens were adequate in over 90% of cases. Almost two thirds of patients were treated at their first visit to the clinic. 58 Patients (9.4%) failed to attend for follow up at six months and one had had a hysterectomy. Of the 557 patients who attended for colposcopic and cytological follow up at six months, 506 (91%) were normal cytologically and 19 (3.4%) had histologically confirmed persistence of cervical intraepithelial neoplasia. The overall confirmed failure rate of the technique was 4.4%. CONCLUSION: Loop diathermy excision is an effective treatment with low morbidity and is an appropriate modality for patients with abnormal cervical smears.

Patient consent for gynaecological examination.

Pelvic examination of women patients under general anaesthesia has long been practised by gynaecologists in order to teach clinical findings to medical students. Although this practice may spare patients discomfort and embarrassment, a recent survey has shown that it should not be carried out without patient consent. Consent, however, is rarely withheld.

Problems of peritoneal access in intraperitoneal treatment and monitoring of ovarian cancer.

A total of 154 peritoneal lavages was attempted through either a permanent (17) or a temporary percutaneous cannula (137) in 59 ovarian cancer patients undergoing intraperitoneal treatment or monitoring. Seven of the eight permanent catheters were removed because of complications; intraperitoneal adhesions were a major problem in this group. Overall, 137 temporary catheters were inserted (14G Venflon i.v. cannula in 119, Verres needle in 15, and a Trocath peritoneal dialysis catheter in 3 instances) but it was not possible to perform a peritoneal lavage in 42 (30%). Access to the peritoneal cavity was unsatisfactory on 29 (34%) occasions when a Venflon cannula was used, either because there was inadequate flow of lavage fluid into the peritoneal cavity or this was limited by pain. Perforation of the bowel occurred in 12 (9%) cases but there was no significant morbidity. Problems with achieving reliable peritoneal access using either permanent or temporary catheters may limit the potential advantages of the intraperitoneal route for treatment and monitoring.

Short-duration (three cycles) cisplatin combination chemotherapy with alkylating agent consolidation in advanced epithelial ovarian cancer.

Forty-eight patients with advanced epithelial ovarian cancer were treated with a two-part cytotoxic regimen consisting of three cycles of cisplatin-based induction therapy followed by five cycles of escalating doses of cyclophosphamide, all given at 3-weekly intervals. The total cisplatin dose was 225 mg/m2. Seventeen patients with optimal primary surgery received chemotherapy only, while 17 of the 31 patients with suboptimal primary surgery underwent optimal interval cytoreductive surgery at the end of induction (cisplatin) therapy. Median survival for all patients was 15.4 months. Median survival was 15 months for patients with optimal primary surgery and 22 months for patients who had optimal secondary cytoreduction. Only 10 patients suffered WHO grade 3 or greater toxicity during therapy. This study suggests that the total dose of cisplatin can be reduced for patients with advanced ovarian carcinoma, resulting in reduced overall toxicity, without compromising response or response duration. A randomized trial to test this concept is now underway.

Predicting response to chemotherapy for patients with epithelial ovarian cancer using urinary polyamine excretion patterns.

Urinary polyamine (UPA) excretion patterns were measured in 39 patients with clinically evaluable epithelial ovarian cancer immediately before they were treated with a cycle of chemotherapy and 24-48 h after chemotherapy to ascertain if changes in UPA excretion patterns correlated with eventual response to treatment. Almost all of the 19 patients who responded to chemotherapy had a rise in the excretion of all UPA fractions after treatment while most patients with chemoresistant cancer showed only an increase in the excretion of the putrescine and spermine fractions. However, a two-fold increase in excretion of the spermidine fractions occurred exclusively in patients who would eventually respond to chemotherapy. This phenomenon was not seen in patients with chemoresistant cancer. If, 48 h after chemotherapy, a patient with epithelial ovarian cancer does not show at least a doubling of the urinary levels of spermidine, acetylspermidine or total polyamine excretion that chemotherapy should be stopped since it is unlikely to be effective.

Speed of response to platinum-based chemotherapy: implications for the management of epithelial ovarian cancer.

Seventy-nine patients with evaluable epithelial ovarian cancer following primary laparotomy and treated with one of three primary cis-platinum-containing regimens were studied to determine the rate at which clinical cytoreduction occurred and whether a rapid response to treatment was of prognostic significance by improving progression free interval (PFI) or survival. A rapid response to treatment improved PFI in patients treated with single agent cis-platinum (P = 0.04) and increased survival in patients treated with a sequential cis-platinum based combination regimen (P = 0.03). The rate of cytoreduction was not a significant variable, however, in a multiple regression analysis of prognostic factors. Over 75% of all clinical responses, regardless of the regimen, had begun by the completion of the third course of chemotherapy. We conclude that response to active chemotherapy is a rapid phenomenon in ovarian cancer and this has important implications in both the decision to change drug therapy and the timing of further surgical effort.

Poor maternal weight gain between 28 and 32 weeks gestation may predict small-for-gestational-age infants.

In a retrospective analysis of 158 women considered to have had normal, low-risk pregnancies, 30 gave birth to infants with a birthweight less than the 10th centile for gestation. These 30 women had a significantly poorer mean increase in weight (0.99 kg) between 28 and 32 weeks gestation than the other 128 women (1.95 kg) who gave birth to infants with birthweights above the 10th centile for gestation. There was no statistically significant difference in booking weight, overall weight gain or other variables associated with low birthweight between the two groups of women which suggests that poor maternal weight gain specifically between 28 and 32 weeks gestation may predict small-for-gestational-age infants.

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.