Gain of chromosome 3q is an early and consistent genetic aberration in carcinomas of the vulva.

The aim was to determine whether specific gains of chromosome 3q and laminin-5gamma2-chain expression can improve early detection of invasive capacity in precancerous and squamous cell carcinoma of the vulva (VSCC). Six VSCC and three precancerous lesions were studied. Multicolor fluorescence in situ hybridization (FISH) probe sets were applied to nuclei suspensions prepared from archival material using the Hedley method. The probe panel consists of the centromers of chromosome 7, chromosome 3, and the TERC gene residing on the long arm of chromosome 3. Laminin-5gamma2-chain immunohistochemical analysis was performed on corresponding specimens and was expressed only in the VSCC. The genome-specific FISH analysis revealed 3q amplification in 43% of the nuclei analyzed for the VSCC and 22% of the nuclei for the precancerous lesions. Low-level 3q amplifications were found in precancerous lesions with an average fold increase of 1.15 for 3q. The invasive lesions showed higher average fold increases for 3q, averaging 1.32. Laminin-5gamma2-chain protein was expressed only in VSCC, whereas 3q gains were observed both in precancerous lesions and in VSCC, indicating that gain of chromosome 3q is an early and consistent event during carcinogenesis of VSCC.

Laminin-5 gamma 2 chain as an invasivity marker for uni- and multifocal lesions in the lower anogenital tract.

During recent decades it has become apparent that there are two types of vulvar disease: the classic type found in elderly women with unicentric and unifocal lesions, and the type found in younger women, in which precancerous and invasive changes develop in the anogenital lower tract in a multicentric and multifocal fashion, often over a long period of observation. The laminin-5 gamma 2 chain is an extracellular protein that is a component of the basement membrane. Recently its expression has been recognized as a marker in cervical cancer that permits identification of invasive capacity. The aim of our study was to determine if laminin-5 gamma 2 chain antibody can act as a sensitivity marker of invasive capacity in precancerous and invasive carcinoma in women with uni- and multifocal changes in the anogenital tract. The result showed that all patients in the older group of women with invasive carcinoma of the vulva had moderate to high positive expression of the laminin-5 gamma 2 chain. In the group of younger patients with multifocal precancerous changes observed over long periods, most of the patients with vulva intraepithelial neoplasia (VIN) 3 showed laminin-5 gamma 2 chain positivity already in the precancerous changes, and all of them developed invasivity during the period of observation. Normal epithelium without atypia was mostly negative or of low immunoreactivity of laminin-5. In conclusion, positive laminin-5 gamma 2 chain expression seems to indicate the invasiveness potential of precancerous lesions and is also expressed in all investigated invasive carcinomas of the anogenital tract.

Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study.

The aim of this study was to investigate the tumour response rate and toxicity of a combination chemotherapy consisting of mitomycin-C and cisplatin in patients with disseminated squamous-cell carcinoma of the uterine cervix. Chemotherapy consisted of mitomycin, 6 mg/m(2) intravenously (i.v.), and cisplatin, 50 mg/m(2) given i.v., both administered on day 1 of each cycle. The regimen was repeated at 4-weekly intervals. Mitomycin-C/cisplatin were used to treat 33 evaluable patients aged 29-67 years (median: 50 years). All patients except 1 had previously been treated with either surgery, radiation or both. At the initiation of chemotherapy, 8 patients had loco-regional and disseminated disease and 25 women had only distant metastases. The overall response rate was 42% (95% confidence interval (CI): 26-61%). Five complete and nine partial responses were observed with a median duration of response of 7.9 months (95% CI: 3.7-23.5 months). 9 patients had stable disease and 10 developed progressive disease during mitomycin-C/cisplatin-treatment. World Health Organization (WHO) grade III/IV side-effects were documented in 15 women, of whom 10 had gastro-intestinal toxicity, 3 had haematological toxicity, 1 had alopecia and 1 developed an allergic reaction to cisplatin. There were neither drug-related deaths nor severe or irreversible renal or hepatic dysfunction or peripheral neuropathy. The median progression-free survival was 5.0 months (95% CI: 3.6-6.2 months) for all patients and 10.5 months (95% CI: 6.2-15.2 months) for the responders. The median overall survival was 11.2 months (95% CI: 6.5-18.4 months).The mitomycin-C/cisplatin combination showed antitumour activity in the treatment of advanced or recurrent squamous-cell carcinoma of the uterine cervix. The regimen was well tolerated and could be administered on an outpatient basis.

D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group Study.

Between March and September 1988, 74 patients with progressive ovarian cancer after prior platinum-based therapy were treated with the luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin (Decapeptyl degrees). Treatment consisted of i.m. injection of 3.75 mg of microencapsulated Triptorelin on days 1, 8 and 28 followed by 4-weekly injections until tumor progression. No objective responses were observed. Eleven out of 68 evaluable patients (16%) had stable disease. The median progression-free survival was 5 months in patients with disease stabilization and 2 months for all evaluable patients. The median survival for patients with disease stabilization was 17 months, whereas for all patients it was 4 months. The treatment was well tolerated; the only reported adverse events were incidental hot flushes. This study showed that the LHRH agonist Triptorelin has only modest efficacy in patients pretreated with platinum-containing chemotherapy.

Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma.

BACKGROUND: Previous studies on prognostic factors in stage I invasive epithelial ovarian carcinoma have been too small for robust conclusions to be reached. We undertook a retrospective study in a large international database to identify the most important prognostic variables. METHODS: 1545 patients with invasive epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] stage I) were included. The records of these patients were examined and data extracted for univariate and multivariate analysis of disease-free survival in relation to various clinical and pathological variables. FINDINGS: The multivariate analyses identified degree of differentiation as the most powerful prognostic indicator of disease-free survival (moderately vs well differentiated hazard ratio 3.13 [95% CI 1.68-5.85], poorly vs well differentiated 8.89 [4.96-15.9]), followed by rupture before surgery (2.65 [1.53-4.56]), rupture during surgery (1.64 [1.07-2.51]), FIGO 1973 stage Ib vs Ia 1.70 [1.01-2.85]) and age (per year 1.02 [1.00-1.03]). When the effects of these factors were accounted for, none of the following were of prognostic value: histological type, dense adhesions, extracapsular growth, ascites, FIGO stage 1988, and size of tumour. INTERPRETATION: Degree of differentiation, the most powerful prognostic indicator in stage I ovarian cancer, should be used in decisions on therapy in clinical practice and in the FIGO classification of stage I ovarian cancer. Rupture should be avoided during primary surgery of malignant ovarian tumours confined to the ovaries.

Long-term follow-up of the Stockholm screening study on ovarian cancer.

OBJECTIVES: Seventy percent of ovarian cancer is diagnosed at advanced stages. Having a method for early diagnosis is a very attractive concept. Several attempts have been made, using monoclonal antibody-based immunoassays, ultrasound, or combinations of both, to identify methods that might prove to be sufficiently sensitive and specific as a screening test. Despite promising results, a mortality study of a large population has yet to be completed due in part to the high cost involved. METHODS: One of the first studies aimed at devising a screening strategy for ovarian cancer used the CA 125 immunoassay followed by ultrasound. The study was performed in Stockholm from 1986 through 1988. Ten years now having passed, an analysis has been performed to further evaluate the results of that study. RESULTS: Screening led to the diagnosis of ovarian cancer in six patients, five of whom have since died of the disease. By searching the Cancer Registry, we were able to identify 20 ovarian cancer patients who developed the disease after the screening period. Of these, 12 died of the disease, 2 are alive with disease, and 6 have no evidence of disease following treatment. The median survival for patients diagnosed by screening was 100 months. Median survival for ovarian cancer patients identified subsequent to screening was 20 months. Although there was no difference in survival between these two groups, median survival was better for women diagnosed by screening (borderline significance, P = 0.059). CONCLUSION: These results indicate that a study of a large number of women with a sufficiently long observation time will be required to establish whether or not screening can reduce ovarian cancer mortality. Such a study may also provide insight into the natural history of ovarian cancer.

Prognostic significance of cell cycle proteins and genomic instability in borderline, early and advanced stage ovarian carcinomas.

Disturbed cell cycle-regulating checkpoints and impairment of genomic stability are key events during the genesis and progression of malignant tumors. We analyzed 80 epithelial ovarian tumors of benign (n = 10) and borderline type (n = 18) in addition to carcinomas of early (n = 26) and advanced (n = 26) stages for the expression of Ki67, cyclin A and cyclin E, p21WAF-1, p27KIP-1 and p53 and correlated the results with the clinical course. Genomic instability was assessed by DNA ploidy measurements and, in 35 cases, by comparative genomic hybridization. Overexpression of cyclin A and cyclin E was observed in the majority of invasive carcinomas, only rarely in borderline tumors and in none of the benign tumors. Similarly, high expression of p53 together with undetectable p21 or loss of chromosome arm 17p were frequent events only in adenocarcinomas. Both borderline tumors and adenocarcinomas revealed a high number of chromosomal gains and losses. However, regional chromosomal amplifications were found to occur 13 times more frequently in the adenocarcinomas than in the borderline tumors. The expression pattern of low p27 together with high Ki67 was found to be an independent predictor of poor outcome in invasive carcinomas. The results provide a link between disturbed cell cycle regulatory proteins, chromosomal aberrations and survival in ovarian carcinomas.

Is there place for radiotherapy in the treatment of advanced ovarian cancer?

BACKGROUND AND PURPOSE: Irradiation of advanced ovarian cancer has been performed during the years 1976-1984 with six-field technique. Results of this treatment in a long follow-up have never before been evaluated. MATERIAL AND METHODS: Seventy-five patients with stage IIb-IV of invasive ovarian cancer have been treated with a combination of surgery, radiotherapy and chemotherapy. The results of the treatment were compared with 98 patients treated during the year 1991-1992 with surgery and chemotherapy only. RESULTS: After controlling for the differences in background factors between the groups considered, there was still a significantly better survival rate for the patients treated with radiotherapy. CONCLUSION: The results suggest that the role of radiotherapy in advanced ovarian cancer should be investigated in a prospective randomized trial.

Analysis of postoperative vaginal vault radiotherapy of stage I endometrial cancer with different radionuclides.

A total of 213 patients in stage I grade 1 endometrial cancer were treated postoperatively with either radium or caesium vaginal applicators. The rate of complication and the incidence of second malignancies were studied in both groups. The frequency of grades 2 and 3 vaginal complications was higher among patients treated with caesium applicators but not statistically significant. The observed number of second malignancies was significantly higher than expected in the radium-treated group, in which the observed number of second malignancies with distant location was also significantly higher than expected, which could not be found in the caesium group.

Age is not a limiting factor for radical radiotherapy in pelvic malignancies.

BACKGROUND AND PURPOSE: Pelvic radiotherapy (RT) toxicity in the elderly is poorly documented. We developed a study aiming to evaluate whether or not a limit of age could be identified beyond which toxicities in patients receiving pelvic RT were more frequent or more severe. MATERIAL AND METHODS: 1619 patients with pelvic cancers enrolled in nine EORTC trials, RT arms, were retrospectively studied. Patients were split into six age ranges from 50 years to 70 years and over. Survivals and late toxicity occurrence were calculated with the Kaplan-Meier method and comparison between age groups with the logrank test. A trend test was done to examine if chronological age had an impact on acute toxicity occurrence. RESULTS: Survival was comparable in each age group for prostate (P = 0.18), uterus (0.41), anal canal cancer (P = 0.6) and slightly better for the younger group of rectum cancer (P = 0.04). A total of 1722 acute and 514 late grade > or = 1 were recorded. Acute nausea/ vomiting, skin complications and performance status deterioration were significantly more frequent in younger patients. There was no trend toward more aged patients to experience diarrhea (P = 0.149) and after adjustment on RT dose, acute urinary complications were observed equally in each age range (P = 0.32). Eighty percent of patients were free of late complication at 5 years in each age range (P = 0.79). For the grade > 2 late side-effects, a plateau was observed after 1 year at near 9% without any difference (P = 0.06) nor trend (P = 0.13) between age-groups. CONCLUSION: Age per se is not a limiting factor for radical radiotherapy in pelvic malignancies.

Pitfalls of endoscopic carpal tunnel release.

The article details various pitfalls of endoscopic carpal tunnel release. Highlighted are the two-portal Chow technique and the single-portal Agee technique.

Biological malignancy grading in early-stage ovarian carcinoma.

The usefulness of adjuvant therapy in early ovarian cancer is a matter of controversy and there is a need for predictive methods to distinguish between low and high risk patients. Specimens from 95 early-stage ovarian cancer patients have been analysed for conventional clinical variables as well as for the biological markers--DNA content, MIB-1, p53, WAF-1--and correlated to survival. Prognostic significance achieved in univariate analysis could be improved by using a score based on several biological markers. Using a score based on DNA content, MIB-1, p53 and WAF-1, a significant predictor could be achieved with the aim of determining the postsurgical therapy. By using this tool, it is hoped that adjuvant therapy can be avoided for one-third of the patients with early-stage ovarian cancer.

Cervical cancer (cervix uteri).

This synthesis of the literature on radiotherapy for cervical cancer (cervix uteri) is based on 59 scientific articles, including 8 randomized studies, 1 prospective study, and 36 retrospective studies. These studies involve 34,024 patients. Due to favorable anatomy and exceptionally good radiation tolerance of nearby pelvic organs, particularly the uterus, radiotherapy has become the dominant treatment method for cervical cancer. Surgery alone is used at the earliest stages where small tumor volumes are involved. Further pathological findings, where cancer is more extensive than expected preoperatively, or when lymph node metastases are discovered, motivate postoperative radiotherapy even at early stages. There is general agreement that advanced cervical cancer should be treated by radiotherapy alone. Clinical trials are under way that combine radiotherapy and chemotherapy, and even surgery. Two different methods of intracavitary brachytherapy are currently in use, low-dose rate therapy and high-dose rate therapy. High-dose rate therapy appears to be economically more favorable. The possibility of higher risks for later complications associated with high-dose rate therapy has not been fully studied.

Ovarian cancer.

This synthesis of the literature on radiotherapy for cancer originating in the ovaries is based on 74 scientific articles, including 12 randomized studies, 18 prospective studies, and 36 retrospective studies. These studies involve 6,140 patients. Treatment for patients at early stages of ovarian cancer (stages I and II) is surgery. The value of adjuvant treatment, ie, chemotherapy or radiotherapy, is not demonstrated. Tumor volume is decisive to the success of radiotherapy. Microscopic or small macroscopic cancer residuals, remaining after surgery, may respond to radiotherapy, thereby promoting survival. The importance of radiotherapy for advanced ovarian cancer is controversial, and studies frequently show contradictory results. Two studies have shown the favorable role played by radiotherapy in consolidation treatment of patients if they become cancer-free at advanced stages. The role of radiotherapy in treating larger volumes of residual cancer has not been demonstrated, except for strictly palliative treatment.

Uterine cancer (corpus uteri).

This synthesis of the literature on radiotherapy for cancer originating in the endometrium of the uterus (corpus uteri) is based on 55 scientific articles, including 2 randomized studies, 1 prospective study, and 48 retrospective studies. These studies involve 13597 patients. Endometrial cancer is a radiosensitive cancer. Research findings compiled for the period 1948 to 1954 showed that 69% of the patients could be cured by radiotherapy alone. During the 1970s it was shown that combined radiotherapy and surgery yielded better results. There is agreement that patients at stage I should receive primary surgery. According to the literature, there is controversy about whether patients with poorly differentiated tumors should be given preoperative radiotherapy. Radiotherapy alone can be used successfully in patients who are inoperable because of age, general condition, or advanced spread of cancer. Vaginal postoperative radiotherapy is used in most patients and reduces the percentage of patients who develop vaginal metastases from 7%-20% to less than 1%. Patients with good prognostic factors have such a low risk for metastasis that withholding radiotherapy may be considered in this group. Postoperative external radiotherapy improves survival in patients with unfavorable prognostic factors, such as deep myometrium invasion or signs of node metastasis. Radiotherapy is delivered, in principle, to all patients with poorly differentiated disease. It can be expected that most cases of endometrial cancer will continue to be referred for some form of radiotherapy.

Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers.

Stored samples from women in the Stockholm screening study were reassayed for CA125II (Centocor, Malvern, PA) and OVX1. The postmenopausal women older than age 50 without ovarian cancer were randomly split into a training set to develop a screening test based on longitudinal marker levels and a second set to validate the test. The CA125II data from each woman is summarized by the slope and intercept from a linear regression of log(CA125II) on time since first sample. The slope versus the intercept for the training set and the ovarian cancer cases formed a bivariate scatter plot. A curve was drawn on the scatter plot that separated most of the women with ovarian cancer from all other women; it delineated a screening test. The specificity of this test was examined on the validation set with a specificity of 99.8%. Bayes' theorem was used to calculate the risk of ovarian cancer (ROC) based on the intercept, slope, and assay variability. It is important to account for assay variability because it can produce large slopes over short periods of time. The maximum risk, which identified 83% (5 of 6) of the ovarian cancers detected within a year of last assay, was applied as a test to the training set and confirmed a high specificity of 99.7%. With this specificity and sensitivity, the ROC algorithm using the CA125II assay has an estimated positive predictive value of 16%, substantially greater than the positive predictive value based on a single assay. Further study is planned to confirm the sensitivity of this approach.

Different types of rupture of the tumor capsule and the impact on survival in early ovarian carcinoma.

The significance of tumor spill in the early stages of ovarian carcinoma has been the subject of controversy. Since rupture of the capsule of the tumor may occur in several different ways, we analyzed all cases of early ovarian cancer treated at Radiumhemmet, Stockholm, Sweden, during the period 1974-1986, in which possible spill of tumor cells was catalogued in different groups. In 247 out of 394 patients (62%) the risk of spill had to be considered. There was no difference in survival between patients whose tumors had intact capsules and patients in whom rupture occurred during surgery-78% and 85%, respectively. On the other hand, a significant difference in survival was found between patients in whom rupture occurred before surgery and those with intraoperative rupture-59% and 85%, respectively. The conclusion can be drawn that manipulation during surgery which results in puncture or rupture does not have a negative influence on the outcome for the patients.

Paget's disease of the vulva: the Radiumhemmet series 1975-1990.

Twenty-eight patients with a diagnosis of 'extramammary Paget's disease of the vulva' were referred to the Radiumhemmet, Karolinska Sjukhuset, Stockholm, during the period 1975-1990. A clinical and histopathologic retrospective review was undertaken. Six patients had associated malignancies (21.4%). The disease was considered primary invasive in three cases, whereas three patients later developed an invasive cancer. Surgery-local resection, hemivulvectomy or vulvectomy-was performed in 24 cases. Twelve patients, in which surgery was supposed to be radical with respect to free margins, had a significantly longer recurrence-free survival than 12 patients in which the surgical margins were dubious.