Dietary folate and related micronutrients, folate-metabolising genes, and ovarian cancer survival.

OBJECTIVE: Folate is essential for DNA synthesis and methylation and is implicated in tumour progression. Few studies have examined its role in ovarian cancer survival. Our objective was to determine relationships between intake of folate, related one-carbon nutrients, single nucleotide polymorphisms (SNPs) in folate-metabolising genes and survival following ovarian cancer diagnosis. METHODS: This analysis included 1270 women with invasive epithelial ovarian cancer diagnosed in 2002-2006. Pre-diagnostic and some post-diagnostic lifestyle, dietary, and sociodemographic information was collected via self-administered questionnaires. DNA samples were genotyped for SNPs in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) genes. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. RESULTS: Multivariate analyses did not identify associations between higher pre-diagnostic intake of folate, folic acid, vitamins B2, B6, and B12, methionine, betaine or choline and survival overall. In stratified analyses, higher folic acid and folate intake was associated with significantly worse survival among women with mucinous tumours (HRs per 100 µg 1.30 and 1.43, respectively) and smokers (HRs per 100 µg 1.23 and 1.16 respectively). There was also a suggestion that higher supplemental folic acid use post-diagnosis was associated with worse survival (HR per 100 µg 1.03, 95%CI 1.00-1.05). MTHFR SNP rs2066470 was significantly associated with survival (per allele HR 0.81, 95%CI 0.67-0.98). CONCLUSIONS: Our data provide little evidence that folate intake affects ovarian cancer survival. However, combined effects with smoking, and findings within the mucinous subtype and for post-diagnosis folic acid, warrant further investigation.

An overview of Clinical Quality Registries (CQRs) on gynecological oncology worldwide.

INTRODUCTION: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future. METHODS: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators. RESULTS: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals. CONCLUSION: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators.

Progestogen treatment options for early endometrial cancer.

OBJECTIVE: Premenopausal women with early endometrial cancer may wish to maintain their fertility, and for some patients non-surgical treatment options may be attractive. We have examined our own experience with such patients, as there are limited published data so far to support clear guidelines in this area. DESIGN: Retrospective analysis of a case series. SETTING: Case series from a specialist gynaecological oncology unit in a major tertiary referral hospital. SAMPLE: Sixteen patients receiving progestogen therapy for stage-1 endometrial cancer. METHODS: We reviewed our experience of all patients receiving progestogen therapy for stage-1 endometrial cancer, and we particularly examined their cancer-free outcome and fertility potential. MAIN OUTCOME MEASURES: Response to treatment, duration of response, and subsequent pregnancies. RESULTS: Of the 16 patients investigated, four received an oral progestogen, five received the levonorgestrel-releasing intrauterine system (Mirena), and seven received both forms of treatment. Ten patients (63%) responded to treatment, with a median time to response of 5.5 months. Six patients did not respond to treatment, but all were either early in treatment or opted for surgical management before the average time of response. No patient who responded had a later recurrence. The mean total follow-up time was 27 months (range 3-134 months), with no patient deaths. Three patients had successful pregnancies, with one patient having two children. CONCLUSIONS: This form of treatment appears to be a realistic treatment option in selected patients in the closely supervised environment of a specialist gynaecological oncology unit.

Prognostic factors for recurrence in patients with FIGO stage I and II, intermediate or high risk endometrial cancer.

BACKGROUND: The aim of this study was to determine predictors for loco-regional or distant recurrence of disease in a subgroup of intermediate or high risk stage I and II endometrial cancer. METHODS: A retrospective analysis of 295 patients with histopathological stage I and II, intermediate or high risk endometrial cancer is reported. The following factors were studied: stage, grade, age, histologic diagnosis, lymphadenectomy, lymphovascular space invasion, and adjuvant radiotherapy. The Log-Rank test was used for statistical analyses and the Kaplan-Meyer method was used for time-to-event analysis. Multivariate analysis was also performed. RESULTS: Thirty-four (11.5%) patients developed a recurrence; 20 (59%) developed loco-regional recurrence, and 14 (41%) developed distant recurrence. In 20 women (59%), recurrence appeared within 3 years of surgery, and the actuarial survival at 3 years after recurrence was 29%. Multivariate analysis showed that for recurrence, age >60 years was a significant unfavourable prognostic factor (p < 0.05). CONCLUSIONS: We found low rates of recurrence in patients with early stage intermediate or high risk endometrial cancer. Only age was identified as an independent significant predictor for recurrence.

Electrocoagulation diathermy for cervical dysplasia and carcinoma in situ: a 15-year survey.

The present report assesses 15 years' experience with electrocoagulation diathermy in the treatment of cervical intraepithelial neoplasia (CIN). Selection is based on the ability to visualize the boundaries of the lesion colposcopically. Visualization, together with cytology and target biopsy, should exclude invasive carcinoma. Histologically confirmed CIN of varying severity (almost two thirds were CIN III) was treated by diathermy in 1864 patients. The size of the lesion varied, and at times the lesion extended into the endocervical canal. Cervical intraepithelial neoplasia was eradicated in 97.3% of patients by a single diathermy treatment. Ninety-three percent of all patients under the age of 30 with CIN were treated by this method. Progression to invasive carcinoma after diathermy has not been demonstrated. A single treatment with electrocoagulation diathermy has proved consistently to be the most effective superficial ablative method for primary eradication of CIN whether deep, extensive, or of major severity.

Low malignant potential tumors of the ovary: a study of 76 cases.

This study analyzes the clinical and pathological features of 76 patients who were diagnosed as having ovarian low malignant potential tumor over a 20-year period: 39 (51.3%) of the tumors were mucinous, 29 (38.2%) serous, three (3.9%) endometrioid, and five (6.6%) mixed. Patients with serous tumors were significantly younger (mean age 40 years) than those with mucinous tumors (mean age 50.5 years). Serous tumors were more frequently bilateral (48.3%) than mucinous tumors (12.8%). The extent of tumor (FIGO stage) at the primary laparotomy was related to the prognosis: the survival of 14 patients with stage III and six patients with stage II tumor was significantly inferior to that of the 56 patients with stage I tumors (P less than .01). Patients with stage III mucinous low malignant potential tumors and pseudomyxoma peritoneii fared badly. Four patients with stage II and 13 patients with stage III tumors had residual tumor after primary surgery. Five of these patients received no subsequent treatment of whom four are alive and well from 5.5 to 19 years after diagnosis. Three patients received pelvic radiotherapy. Eleven patients were treated with chemotherapy for residual or recurrent tumor but only one (9.1%) had an unequivocal response.

Functioning ovarian tumors in postmenopausal women.

Estrogen excretion was higher than normal (more than 9 microgram/24 hr) in 40 of 80 postmenopausal women with benign and malignant epithelial tumors of the ovary, including 8 metastatic tumors. High estrogen excretion was noted in 19 of 27 (70.4%) patients with mucinous tumors in only 1 of 25 (4%) patients with serous tumors (P less than .001). Endometrioid and metastatic tumors were also noted to be frequently associated with high estrogen excretion. In the high estrogen excretion group 27 of 37 (73%) patients showed stromal luteinization and/or condensation in the tumor, but in the normal estrogen excretion group these changes were seen in only 6 of 38 (15.8%) patients (P less than .001). A possible mechanism of stromal stimulation in these tumors is discussed. Although there was often evidence of estrogen activity in the endometrium and the tubal epithelium in the high estrogen excretion group, the correlation between these epithelia and estrogen excretion was imperfect. Postoperative estrogen excretion remained elevated in 3 of 16 patients, of whom 1 was obese and 2 had residual tumor. This study emphasizes the importance of identifying epithelial tumors of the ovary as functioning or endocrine tumors.

Micro-invasive squamous cell carcinoma of the cervix: a clinico-pathologic study of 200 cases with long-term follow-up.

The clinico-pathologic details of 200 patients with micro-invasive squamous-cell carcinoma of the cervix have been analyzed. All tumors invaded 5 mm or less below the basement membrane. One hundred and nine were categorized as FIGO stage 1a1 (early stromal invasion) and 91 as FIGO stage 1a2 (micro-carcinoma). The horizontal spread (length) of 12 micro-carcinomas exceeded 7 mm. Twenty-three had stromal invasion 3 mm or more, and 22 had capillary-like space involvement. Fifty-eight patients underwent pelvic lymphadenectomy in addition to hysterectomy and none had positive nodes. Univariate and multivariate analyses of possible prognostic factors including depth, horizontal spread, width, area, volume, grade, growth pattern, capillary-like space involvement, and stromal reaction failed to show any to be significantly associated with recurrence. The median duration of follow-up is now 8 years (0-22 years). Despite complete resection, seven (3.5%) patients developed recurrence of in situ or invasive carcinoma (three after early stromal invasion and four after micro-carcinoma), all of which were located at the vaginal vault. There were two deaths, one due to pulmonary squamous-cell carcinomatosis 21 years after early stromal invasion, the connection being tenuous, and the other due to local recurrence. There have been no recurrences to date in 23 patients treated by conization alone. The uniformly good prognosis of patients in this study is attributed to meticulous sampling of operative specimens resulting in accurate diagnosis and appropriate treatment, which may be conization alone provided the margins are free, there is no capillary-like space involvement, and the depth of penetration is less than 3 mm.

Management of vaginal intraepithelial neoplasia: A series of 132 cases with long-term follow-up.

A series of 132 cases of vaginal intraepithelial neoplasia (VAIN) is presented, including nine (6.8%) where early invasive carcinoma of the vagina was found in the course of initial management of the VAIN. The majority of patients (75%) had high-grade VAIN (two or three). Seventy-two (55%) had undergone a prior hysterectomy; 22 for preinvasive disease (CIN), 33 for invasive gynecological cancer, 13 for benign reasons, and in 4 the reason for the hysterectomy and/or the Pap smear history was not known. Twenty-one (16%) had received prior pelvic radiotherapy. VAIN was noted to involve either the vaginal vault (in the post-hysterectomy group) or the upper vagina (in the no hysterectomy group) in more than 80% cases. A variety of treatment modalities was used with varying degrees of success. For high-grade VAIN excisional treatments had an overall (first-line plus subsequent) cure rate of 69% (53/77). The state of the surgical margins did not correlate with the risk of residual disease. CO2 laser ablation was curative in 69% (18/26) of cases and was significantly better than electrocoagulation diathermy which was curative in only 25% (3/12) of cases (P = 0.013). Five-fluorouracil cream was curative in 46% (5/11) of cases, including four patients who had received prior radiotherapy. Radiotherapy was effective in eradicating VAIN in the two cases where it was used as the primary treatment modality. Progression of high-grade VAIN to invasive cancer occurred in eight (8%) cases; after no treatment in two cases, after treatment failure in five cases, and as a late recurrence in one case. For low-grade VAIN an observational approach after biopsy was initially adopted in eight patients and regression occurred in seven (88%) of these patients. Other miscellaneous treatments were also effective in low-grade VAIN. These data provide evidence that high-grade VAIN is a precursor to invasive cancer of the vagina and every attempt should be made to eradicate it. Based on our experience and a review of the literature we have proposed a plan for optimal management of this condition.

Early diagnosis of gynaecological malignancy.

This paper deals with diagnosis, detection and treatment of early female genital tract malignancy and its precursors. In general the precursors are eradicated easily and with preservation of childbearing function; the earlier stages of malignancy often can be treated with low morbidity and a high probability of cure.

Routine antenatal tests.

Numerous tests have been proposed in recent years to screen the antenatal population for various diseases which might contribute to perinatal and even maternal morbidity and mortality. Screening tests of any kind are currently the centre of controversy as measures are being strenuously taken to contain health costs. This paper critically examines twelve such screening tests.

Secondary postpartum haemorrhage.

The clinical features of 106 women who had a secondary postpartum haemorrhage were examined in detail; 39 were managed conservatively, 3 had a vaginal laceration resutured and 64 had a curettage. In 46 patients, material obtained by curettage was examined histologically. The clinical features associated with retained products of conception are defined and comparisons are made between conservative and surgical management of secondary postpartum haemorrhage.

The role of second-look laparotomy in the management of patients with ovarian carcinoma.

Second-look laparotomy has been performed on 76 patients with ovarian carcinoma each of whom was clinically free of tumour after completing a programme of postoperative chemotherapy (60 patients), pelvic radiotherapy followed by chemotherapy (14 patients) or observation (2 patients). The initial stage, bulk of residual tumour, completion of hysterectomy and bilateral salpingo-oophorectomy and an interval of 11 months or more between diagnosis and second-look surgery were all significantly (p less than .05) associated with negative findings. Recurrences occurred after a negative operation in 10 of 42 (23.8%) patients and were more frequent amongst patients with grade 3 tumours (p = .03). Macroscopic cancer was found in 23 (30.3%) patients and microscopic cancer in 11 (14.8%) patients. Survival was related to the surgical findings and to the amount of residual tumour at the conclusion of the second-look operation. Survival of patients with no macroscopic residue (those found to have microscopic tumour and those who had complete excision of macroscopic tumour) was significantly longer than that of patients with macroscopic residue (median survival 38.2 versus 19.0 months, p = .01). These results suggest that benefit from second-look laparotomy is confined to patients with microscopic or totally resectable tumour for whom second-line therapy may still be curative.

Preclinical cancer of the cervix: diagnostic pitfalls.

This paper outlines the pitfalls encountered in the diagnosis of 127 preclinical cancers of the cervix. Each patient had cervical cytology, colposcopy, and histology performed within the same institution. Early stromal invasion was diagnosed in 55 patients and occult invasion was diagnosed in 72 patients. For preclinical cancers as a group, the possibility of invasive carcinoma was predicted cytologically in 36% and suspected colposcopically in 41%. However, in over 85% of patients the abnormal transformation zone (TZ) extended into or was totally confined within the endocervical canal and could not be adequately evaluated with the colposcope. A feature of this study was the high incidence of incomplete excision of abnormal tissue by cone biopsy and a high incidence of residual disease at hysterectomy. Cone biopsy was necessary to accurately assess the maximum depth and extent of invasion prior to definitive therapy whenever invasion was suspected colposcopically or on target biopsy. In 10 of 16 such patients, the cone biopsy demonstrated occult invasion. Colposcopy and directed target biopsy alone was adequate for the diagnosis of frank invasive cancer in 22 of the 72 patients in the occult invasion group, enabling definitive therapy to be undertaken without further delay.

The benefits and risks of amniocentesis for the assessment of fetal lung maturity.

Amniocentesis for estimation of the lecithin: sphingomyelin (L/S) ratio was performed on 483 patients on 552 occasions. The introduction of this test has been associated with a highly significant (p less than 0-001) decrease of 59 per cent in the incidence of respiratory distress syndrome. The finding of a low L/S ratio (less than 2-0) enabled delivery to be deferred until lung maturity had been reached in 43 (10-3 per cent) of the 419 patients who had successful amniocentesis. Fetal death occurred after amniocentesis in two patients (0-41 per cent). One fetus died after haemorrhage occurred behind an anterior placenta and the other died of exsanguination. Failed amniocentesis occurred in 64 patients (13-2 per cent), and was more common when the placenta was anterior or was not located before the procedure and when fetal growth was retarded. Fetal distress in labour occurred more commonly after failed amniocentesis. Spontaneous labour followed amniocentesis in 47 patients (9-7 per cent) and was significantly more prone to occur after 38 weeks gestation. Rhesus isoimmunization did not occur in any of the rhesus-negative patients who delivered rhesus-positive babies and who were screened six or more months after amniocentesis, although anti-D immunoglobulin was not given routinely after amniocentesis. Suggestions are made as to how the success rate of this valuable procedure can be improved and how some of the serious fetal and maternal sequelae can be avoided.

Observations on the surface area of the abnormal transformation zone associated with intraepithelial and early invasive squamous cell lesions of the cervix.

The apparent area of the abnormal transformation zone (TZ) of the cervix was measured in a total of 104 patients by a simple method with the use of the 1 and 5 mm. diameter circle in the center of the field of the Leisegang colposcope and the field of the colposcope itself. The visible area (mean +/- S.E.M.) of the abnormal TZ for five patients with microinvasive or occult carcinoma of the cervix (180.8 mm.2 +/- 62.2) was significantly larger (p less than 0.01) than that of 64 patients with major intraepithelial lesions (62.5 sq. mm.2 +/- 7.3) and 35 patients with minor intraepithelial lesions (45.8 sq. mm.2 +/- 11.7). The visible area of the abnormal TZ measured over 40 mm.2 in each of the five patients with invasive lesions but in only 42 of 99 (42%) patients with intraepithelial lesions. The TZ extended into the endocervical canal and could not be fully visualized in four (80%) of the patients with invasive lesions, 24 (38%) of patients with major intraepithelial lesions, and 11 (31%) of patients with minor intraepithelial lesions. The implications of these findings are discussed.

Some observations on the value of endocervical curettage performed as an integral part of colposcopic examination of patients with abnormal cervical cytology.

A total of 259 patients underwent endocervical curettage as an integral part of colposcopic examination of patients with abnormal cervical cytology. The transformation zone was entirely visualized in 140 patients (54.1 per cent), and, in 8.6 per cent of this group, the endocervical curettings were abnormal. On no occasion did the endocervical curettage harbor the worst lesion when compared to the histology of the ectocervical biopsy, cone biopsy, and hysterectomy specimens. In 117 patients (45.2 per cent), the transformation zone could not be visualized in its entirety, and in 57.3 per cent the endocervical curettings were abnormal. In one patient of this group invasive carcinoma was present in the endocervical curettage, and in another patient invasive carcinoma was present in both the ectocervical biopsy and the endocervical curettage. Thus, when the entire transformation zone is not visualized in its entirety or at all, endocervical curettage appears to be of value since a frank invasive carcinoma may be diagnosed and a cone biopsy avoided.

The natural history of human papillomavirus (HPV) atypia of the cervix.

This study examines the natural history of human papilloma virus (HPV) atypia of the cervix in 259 untreated patients who were followed for 3 to 74 months (median 18 months). Progression to cervical intraepithelial neoplasia (CIN) occurred in 41 patients (15.8%)--all but 3 progressions occurred within the first 24 months of follow-up. In no patient did invasive cancer develop during this study. Persistence occurred in 39.4% and regression in 44.8% patients. An increasing number of regressions were noted with the passage of time. Progression to histologically confirmed CIN which occurred in 23 of 46 (50%) patients in whom both the cytological and colposcopic assessment at the first visit suggested CIN did so significantly more frequently than when either the cytology or colposcopy alone suggested CIN (11 progressions in 83 patients--13.3%, p less than .00001) or when neither cytology nor colposcopy suggested CIN (7 progressions in 119 patients--5.9%, p less than .000001). We recommend that patients with both cytological and colposcopic features suggestive of CIN should be treated even though HPV atypia only is reported on biopsy. Those who are not treated should be followed closely until regression occurs and consideration should be given to treating those patients in whom the abnormality persists longer than 2 years.

CA125 serum levels and secondary laparotomy in epithelial ovarian tumours.

CA125 serum levels were assayed prior to 57 secondary laparotomies for ovarian epithelial tumours. Tumour was present in all 16 patients with an elevated level greater than 35 U/ml but the absence of tumour was incorrectly predicted in 15 of the 33 (45.5%) patients with CA125 levels less than 35 U/ml. For these patients the CA125 level was elevated in 14 of 20 (70%) with tumour greater than 1.5 cm, 1 of 7 (14.3%) with macroscopic tumour less than or equal to 1.5 cm and 1 of 4 (25%) with microscopic tumour. Tumour was resectable to less than or equal to 0.5 cm in 7 of 12 (58.3%) patients with CA125 less than 35 U/ml, 2 of 4 (50%) with CA125 in the range 35-100 U/ml and only 1 of 11 (9.1%) with CA125 greater than 100 U/ml (p less than .05). The CA125 level was elevated in 1 of 13 (7.7%) patients with less than 15 cm3 of tumour compared with 16 of 18 (88.9%) patients with 15 cm3 of tumour or more (p less than .0001). The correlation between the CA125 serum level and the tumour volume was almost statistically significant (r = +0.31, p = .053). The level of CA125 was normal in all 8 patients with mucinous tumours--4 of whom were found to have tumour at secondary surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of the amniotic fluid lecithin/sphingomyelin (L/S) ratio, creatinine concentration and nile blue sulphate tests, individually and in combination, in the assessment of fetal lung maturity.

The lecithin-sphingomyelin (LS) ratio is a good, but not absolute, test of fetal lung maturity. A total of 373 infants was delivered within 72 hours of amniotic fluid collection for assessment of the L/S ratio. Five of 43 infants (11-6 per cent) with an L/S ratio of 2-2 or less developed the respiratory distress syndrome (RDS), whereas only one of 320 infants (0-31 per cent) with a higher L/S ratio developed RDS. The risk of RDS could be further defined by using the creatinine concentration (critical value 19 mg/1) and the Nile blue sulphate test (critical value 4 per cent) in combination with the L/S ratio. All three tests were performed in 320 pregnancies and in each instance delivery took place within 72 hours. When all three test results were low, 3 of 5 infants (60 per cent) developed RDS, whereas when all three results were high, none of 175 infants developed RDS. When one or two results were low, 2 of 140 infants (1-4 per cent) developed RDS.