BRCA1 gene mutations in sporadic ovarian carcinomas: detection by PCR and reverse allele-specific oligonucleotide hybridization.

BACKGROUND: Although germline mutations in BRCA1 play a central role in familial breast and ovarian cancers, to date, no somatic mutations in BRCA1 have been reported in sporadic breast cancer, and only five somatic mutations have been identified in the sporadic ovarian carcinomas. Because loss of heterozygosity appears frequently at the BRCA1 locus in nonfamilial breast and ovarian carcinomas, we searched for mutations in the BRCA1 gene in sporadic ovarian tumors. METHODS: We developed a detection system based on PCR and reverse allele-specific oligonucleotide hybridization on membrane strips for the simultaneous detection of 17 frequently occurring mutations in the BRCA1 gene. RESULTS: As little as 2% mutant DNA in a sample could be detected. Two of 122 DNA samples isolated from sporadic ovarian tumor biopsies contained the Cys61Gly mutation. Both mutations were germline mutations. One of these was an ovarian metastasis of a primary fallopian tube carcinoma. The tubal carcinoma was also confirmed to contain the Cys61Gly mutation. CONCLUSIONS: This is the first report that a germline BRCA1 mutation is associated with primary tubal carcinoma. The 17 specific mutations in the BRCA1 gene do not play a major role in the tumorigenesis and progression of sporadic ovarian cancer.

CD44v3 and v6 variant isoform expression correlates with poor prognosis in early-stage vulvar cancer.

Expression of alternatively spliced CD44 isoforms has been reported to correlate with poor prognosis in human squamous cell cancers, i.e. squamous cell cancer of the lung and cervix. The aim of this study was to evaluate whether CD44 isoform expression is a prognostic factor in early-stage squamous cell cancer of the vulva. Seventy cases of squamous cell carcinoma of the vulva International Federation of Gynaecology and Obstetrics (FIGO) stage I were examined immunohistochemically for expression of CD44 isoforms. We used four different variant exon sequence-specific murine monoclonal antibodies to epitopes encoded by exons v3, v5, v6 and v7-8 of human variant CD44. The correlation of CD44 expression with histological grade and disease-free and overall survival was investigated. CD44 isoforms CD44v3, CD44v5, CD44v6 and CD44v7-8 were detected in 28% (20/70), 47% (33/70), 33% (23/70) and 17% (12/70) of the tumour samples respectively. Patients suffering from tumours expressing CD44v6 had a poorer relapse-free (log-rank test, P = 0.02) and overall survival (log-rank test, P = 0.03). Likewise, patients suffering from tumours expressing CD44v3 had a poorer relapse-free (log-rank test, P = 0.04) and overall survival (log-rank test, P = 0.01). Expression of CD44v5 and CD44v7-8 did not compromise the patients' outcome. Histological grade did not correlate with CD44 isoform expression. Immunohistochemically detected expression of CD44 isoforms containing variant exon v6 or v3 is correlated with a poor relapse-free and overall survival in FIGO stage I vulvar cancer patients.

Primary malignant melanoma of the vagina: long-term remission following radiation therapy.

OBJECTIVE: To describe the characteristics and clinical course of patients with primary vaginal melanoma treated at three large Austrian institutions. METHODS: The medical records of 14 patients treated at the Departments of Obstetrics and Gynecology of the Universities of Graz and Vienna and the Salzburg Women's Hospital between 1982 and 1996 were reviewed. RESULTS: The median age at diagnosis was 73 years. Presenting symptoms included vaginal bleeding in all patients. Three of seven patients (43%) with tumors < or = 3 cm survived longer than 5 years compared to none of seven patients with a tumor size > 3 cm. Three of nine patients (33%) who received radiotherapy either in addition to surgical excision or as primary treatment, survived for 5 years. Other potential prognostic factors such as age, location, FIGO stage, depth of invasion, Chung level, histology, cell type, mitotic count, vessel involvement, ulceration, p53 accumulation, type of surgery, type of radiotherapy, or chemotherapy did not seem to correlate with the patients' outcome. The median overall survival was 10 months (range 1-153). The 5-year disease-free and overall survival rates were 14 and 21%, respectively. All three long-term survivors recurred locally. CONCLUSION: All three patients who had long-term survival had lesions < or = 3 cm and received either primary radiotherapy (n = 2) or adjuvant radiotherapy after complete excision of the primary lesion (n = 1). In view of the poor overall survival rates, regardless of treatment, radiotherapy may be a limited valuable alternative or adjunct to surgery in patients with primary malignant melanoma of the vagina < or = 3 cm in diameter.

Dose intensification of epidoxorubicin and cyclophosphamide in metastatic breast cancer: a randomised study with two schedules of granulocyte-macrophage colony stimulating factor.

A randomised phase II/III study was conducted in patients with advanced breast cancer to determine the dose intensity achievable through an acceleration of administration of chemotherapy with epidoxorubicin and cyclophosphamide (EC) alone, as compared with the combination of this regimen with two different schedules of granulocyte-macrophage colony stimulating factor (GM-CSF). 73 patients received EC intravenous (i.v.) (epidoxorubicin 100 mg/m2, cyclophosphamide 600 mg/m2) on day 1 (group A), or the same chemotherapy plus sub-cutaneous (s.c.) GM-CSF (5 micrograms/kg/day) either from days 3 to 12 (group B) or from days -6 to -3 (group C). The primary objective of the study was the investigation of dose intensity delivered in the three treatment arms, whereas the secondary objective was response rate. A significant increase (P = 0.006) in dose intensity of 21% was observed for treatment group B, whereas the increase in dose intensity achieved in group C (7%) was not significant (P = 0.086). Response rates (complete response (CR) + partial response (PR)) of 56% were observed in group A, 65% in group B, and 57% in group C, respectively. This difference in response rates did not reach statistical significance (P = 0.271). We thus conclude that an acceleration of the EC regimen over the standard schedule could be accomplished with postchemotherapeutic GM-CSF support, leading to an increase in dose intensity, whereas pretherapeutic short-term GM-CSF administration did not reach this goal.

Does T1, N0-1 vulvar cancer treated by vulvectomy but not lymphadenectomy need inguinofemoral radiation?

PURPOSE: The objective of our study was to demonstrate differences in relapse rates, total survival times, and complication rates between inguinofemoral radiation and its absence in cases of invasive vulvar carcinoma without lymph node involvement (FIGO Stages T1, N0-1). METHODS AND MATERIALS: From 1974 to 1990, 135 patients with invasive vulvar carcinoma in Stage T1 without clinical evidence of inguinal lymph node involvement underwent simple vulvectomy performed by hot-knife resection without lymphadenectomy. Although 65 patients (Group 1) received postoperative inguinofemoral radiation therapy, 70 patients (Group 2) did not, and none received local vulva irradiation. RESULTS: The 5-year survival rates were 93.7% in Group 1 and 91.4% in Group 2 (p = NS). Although clitoris involvement was significantly more prevalent in the irradiation group (p = 0.04), inguinal relapse was found less frequently in Group 1 (4.6% or 3 out of 65 patients) than in group 2 (10% or 7 out of 70 patients) (p = 0.32). The complication rates were, 7.7% in Group 1 and 2.9% in Group 2, 2.7% for vaginal stenosis (two patients in each group), 1.5% for inguinal pain (one patient in Group 1), 1.5% for rectovaginal fistula (one patient in Group 1), 1.5% for vulvar infection (one patient in Group 1). CONCLUSION: No statistically significant differences in the relapse rates and survival times were found. Risk factors were equally distributed in both study groups except for clitoris involvement. The 5-year survival rates in both groups were similar to those reported in the literature for radical vulvectomy and inguinal lymph-node dissection (83-96%). Morbidity in our study was low. Although our data showed similar results in both groups, we are not recommending at this time to omit groin radiation in general, but it may be justified in low-risk cases.

Erythropoietin treatment under polychemotherapy in patients with gynecologic malignancies: a prospective, randomized, double-blind placebo-controlled multicenter study.

In order to examine the influence of erythropoietin (rHuEPO) on serum hemoglobin levels, transfusion requirements, and quality of life in patients with gynecologic malignancies under polychemotherapy and chronic tumor anemia (hemoglobin <11 g/dl), we performed a prospective, randomized, double-blinded placebo-controlled clinical trial. Between October 1992 and October 1993, 35 patients from 5 gynecologic departments were entered into this trial. Inclusion criteria were hemoglobin level <11 g/dl, ferritin level >29 ng/ml, stool negative for occult blood, and life expectancy for more than 3 months. Patients received either 150 U/kg body wt rHuEPO (Erypo by Cilag-Janssen) sc three times a week for 12 weeks (n = 23) or a placebo (n = 12). If the hemoglobin levels of the 4th, 8th, or 12th week were >2 g/dl above the baseline value and/or >12 g/dl, the patient was classified as a responder. Patients who required blood transfusions (hemoglobin <8 g/dl, erythrocytes <3 x 10(6)/ml, or clinical symptoms of anemia) were classified as nonresponders. A nonvalidated quality of life questionnaire was completed by the patient at the beginning of the treatment and then every fourth week before receiving chemotherapy. In the rHuEPO group 56.6% of the patients responded to the treatment (chi2 = 10.79, P = 0.001) and only 5 patients (21.7%) required blood transfusions, whereas 8 of 12 patients in the placebo group (66.6%) had to be transfused (chi2 = 6.81, P = 0.009). Quality of life did not differ significantly between the rHuEPO group and the placebo group of patients. Within the rHuEPO group those patients that responded showed a significant increase in physical activity after response in comparison to the preresponsive phase (P = 0.02, paired t test). We therefore concluded that rHuEPO significantly increases serum hemoglobin levels and decreases transfusions requirements while maintaining quality of life in patients with gynecological malignancies who are undergoing polychemotherapy.

[Survival prognosis in ovarian carcinoma Figo stages III and IV: 1980-1985 versus 1986-1993. A comparison of 2 treatment periods]. / Uberlebensprognose bei Ovarialkarzinomen in den Figo-Stadien III und IV: 1980-1985 versus 1986-1993. Ein Vergleich zweier Behandlungsperioden.

We examined the survival prognosis of 638 patients who had ovarian carcinoma Figo stages III and IV. We considered two separate time periods, 1980-1985 versus 1986-1993, including the size of the postoperative residual tumor, polychemotherapy with and without platinum, histological grading 1 versus 2 and 3, Figo stage III versus IV, and ascites present versus no ascites. Since 1986, 96% of the patients received platinum-containing polychemotherapy at a dosage of > or = 75 mg/m2, whereas between 1980 and 1985, only 76% of these patients received platinum-containing polychemotherapy at a dosage of 50 mg/m2, and 24% of the patients received polychemotherapy without platinum. The size of residual tumor masses and also the time period of treatment had an independent influence on survival prognosis. Patients treated from 1980 to 1985 had a relative risk to die which was 1.44 times higher than for the patients who were studied from 1986 to 1993.

Influence of delayed diagnosis on established prognostic factors in endometrial cancer.

To evaluate the influence of delayed diagnosis on prognostic factors in endometrial cancer, we conducted a retrospective chart analysis based on the data of 116 postmenopausal patients with FIGO stage I-IV endometrial carcinoma. The interval from the first episode of post-menopausal vaginal bleeding to definitive, histological diagnosis (bleeding interval) was compared with tumor stage and various histomorphologic features in endometrial cancer. The mean bleeding interval was 12.7 +/- 17.8 weeks in 74 patients with FIGO stage IA, IB endometrial carcinoma and 35.2 +/- 69.3 weeks in 42 patients with stage IC-IV disease (t-test, p: 0.011). FIGO stage IA, IB disease was diagnosed in 23/26 (88%) patients with a bleeding interval <4 weeks, and in 22/34 (64%) and 29/56 (51%) patients with bleeding intervals of 4-8 weeks and >8 weeks, respectively (Chi-square 10.358, p=0.006). The correlation with histologic grade, lymph-node status, vessel invasion and histologic subtypes did not reach statistical significance. Our data confirm the clinical impression that postmenopausal vaginal bleeding is an early symptom in patients with endometrial cancer, and that advanced disease in the majority of cases might come from delayed diagnosis in women with poor compliance.

-CA-125 antigen as a prognostic factor for survival in patients with epithelial ovarian carcinoma of FIGO stage I--preliminary results-. / CA 125 als Prognosefaktor für das Uberleben bei Patientinnen mit epithelialen Ovarialkarzinomen des FIGO-Stadium I--preliminäre Ergebnisse.

The tumour marker CA 125 has proved useful in monitoring the course of disease and in indicating responsiveness to therapy in patients suffering from epithelial ovarian cancer. Due to its poor sensitivity, however, attempts to improve early detection by screening with this tumour marker have been unsuccessful to date. This study was performed to evaluate whether there was a relation between pre-operative CA 125 levels and the survival of patients with epithelial ovarian cancer FIGO stage I. If such a relation exists, CA 125 may be an effective variable in singling out those subsets of patients with stage I disease for whom adjuvant chemotherapy would bring an additional therapeutic benefit. Our results suggest CA 125 may be a significant prognostic factor. With a 5-year survival of 43%, marker-positive ovarian cancer carries a poor prognosis. Since the question as the whether follow-up treatment is required in this early, potentially curable stage of disease, is contingent upon numerous factors and since an individualised therapeutic regimen may lead to increased survival rates, the prognostic influence of CA 125 and its relationship to other prognostic factors should be evaluated by multivariate analysis.

[After-care and palliative therapeutic measures in ovarian carcinoma]. / Nachsorge und palliative Therapiemassnahmen beim Ovarialkarzinom.

In the palliative treatment of incurable cancer cytotoxic chemotherapy is frequently used. While prolongation of life may be a desired aim of treatment, this is only rarely achieved. Most studies concentrate on the assessment of tumor size as a index of response, but of more importance is the evaluation of symptom relief and the effects of treatment on quality of life. There is an urgent need of guidelines for palliative treatments and care, which are based on appropriate end points for assessing benefit to patients.

[The prognostic effect of scintigraphy-guided lymphadenectomy in therapy of stage Ib cervix carcinoma]. / Uber den prognostischen Einfluss der Szintigraphie-geleiteten Lymphadenektomie in der Therapie des Zervixkarzinoms im Stadium Ib.

In a retrospective study the survival rates of 161 patients with stage Ib cervical cancer after radical operation (Latzko, Wertheim-Meigs) including complete or incomplete pelvine lymphadenectomy were compared. To increase radicality of lymphadenectomy, preoperative targeting of pelvic lymph nodes was done in all the patients using 99mTc-Sb2S3 radiocolloid. Intraoperatively, a gamma-camera being integral part of an operating table allowed delineation and scintigraphy-guided resection of pelvic lymph nodes. Dependent on the evidence of remaining pelvine foci of radioactivity at the end of the operation, lymphadenectomy was assessed as complete or incomplete. Mean observation time of completely lymphadenectomised patients (n = 117,72.67%) were 80 months (5-169 months) and 42 months (1-149 months) of the incompletely lymphadenectomised patients (n = 44,27.33%). In 28 (23.93%) completely lymphadenectomised patients against only 5 (11.36%) patients with incomplete lymphadenectomy, lymph node metastases were proved histologically. Five year-survival rate of completely lymphadenectomised patients was 85.47% and 88.64% of incompletely lymphadenectomised patients (not significant, Mantel-Test). Also, selective comparison of lymph node-positive patients did not suggest a divergent trend indicated by 13 (46.43%) deaths of completely and 3 (60.0%) deaths of the incompletely lymphadenectomised patients after an observation of five years. The technique of scintigraphy-guided pelvic lymphadenectomy using 99mTc-Sb2S3 radiocolloid cannot be expected to improve prognosis of patients with cervical cancer stage Ib.

Prognostic impact of DNA content and AUER classification in primary fallopian tube carcinoma.

DNA ploidy has been studied in 61 primary fallopian tube carcinomas using image-cytometry. The investigation also included survival analysis, and ploidy classification according to AUER was performed in order to evaluate its prognostic impact for fallopian tube carcinoma. A high number of aneuploid cases were observed (79% aneuploid vs. 21% euploid tumors). The high incidence of aneuploid tumors was consistently observed among all FIGO-stages as well as all groups of histologic grading. There was no correlation between ploidy and FIGO-stage or histologic grading. Patients with euploid DNA content showed a median survival of 34 months compared to 24 months for aneuploid cases (log-rank, P = 0.83). No correlation between the AUER classification and FIGO-stage or histologic grading could be observed. Tumors with an AUER type I and II (75th quantile 41 months) showed a better outcome than tumors with AUER III and IV (75th quantile 19 months). Although these results did not reach statistical significance (P = 0.07), a trend could be observed. Therefore AUER classification may be useful as an objective prognostic parameter. The high incidence of aneuploid tumors could be an expression of the high biologic aggressiveness of primary fallopian tube cancer which has been repeatedly mentioned in the past.

-Inguinal irradiation versus no lymph node therapy in small vulvar carcinoma with clinically negative lymph nodes (T1, NO-1)-. / Inguinalbestrahlung versus keine Lymphknotentherapie beim kleinen Vulvakarzinom mit klinisch negativen Lymphknoten (T1, NO-1).

OBJECTIVE: The objective of this retrospective study was to determine if groin radiation was superior to no therapy in patients with small vulvar cancer with not palpable or not suspicious inguinal lymph nodes (T1, N0-N1). METHODS: From 1974 to 1990, 135 patients with invasive T1, NO-1 vulvar cancer underwent radical vulvectomy with hot knife, groin nodes were left in situ. In 65 patients vulvectomy was followed by inguinofemoral irradiation: 70 patients had none. There were more cases with clitoris carcinoma (p < 0.04) in the group with groin irradiation but no other significant difference in prognostic factors was found. RESULTS: The actuarial 5-year survival was 93.7% with groin irradiation versus 92.4% without lymph node therapy. Inguinal relapses occurred in only 4.6% of cases with groin irradiation versus 10% without lymph node treatment (n.s.). CONCLUSIONS: Radiation therapy to the groin seems to reduce groin relapses in early vulvar cancer.

Lymphogenous metastasis in the primary carcinoma of the fallopian tube.

The bad prognosis of primary Fallopian tube carcinoma (FTC) is mostly ascribed to early lymphogenous metastasis. Yet, there is a lack of information on the tumor size at which lymph node metastasis must be expected to occur. Our study was therefore designed to correlate the anatomopathologic substratum and the histologic results with the lymph node status. Data were obtained from 21 women who received primary surgery, during which additional total pelvic and para-aortic lymphadenectomy was performed as well. The "surgical" staging was compared to the final clinical staging after histologic inspection of the lymph nodes according to the FIGO classification. Lymph node metastases never occurred as long as the tumor was confined to the tube (stage I). Lymphogenous dissemination set in only after further, local expansion of the tumor, involving the ovaries, the peritoneum, or the uterus (surgical stage II); 3 of the 7 patients of surgical stage II had to be reclassified to stage III because of manifest lymph node metastases. After the onset of intra-abdominal or general metastasis (stage IV), lymph node metastases occurred significantly more often (P = 0.048). Due to the specific lymphatic drainage, lymphogenous metastasis must be expected to spread as far as to the para-aortic region even in the early stages. Highly differentiated tumors (G I) do not disseminate into the lymphatic system, not even in advanced stages, whereas anaplastic tumors (G II and III) metastasize relatively early. As soon as metastasis has occurred, prognosis of life diminishes markedly, but not significantly (49 versus 24 months, P = 0.19). Correct FTC-staging is obtained only on the basis of pelvic and para-aortic lymphadenectomy.

DNA ploidy in primary fallopian-tube carcinoma using image cytometry.

Determination of DNA ploidy in 61 samples of primary Fallopian-tube carcinoma (FTC) by use of image cytometry is presented. Of these samples, 48 showed an aneuploid DNA content. Patients with euploid DNA content showed a median survival time of 33.8 months compared to 24.5 months for aneuploid cases. A high incidence of aneuploid tumors was consistently observed among all FIGO stages and in all groups of histologic grading. However, no correlation between ploidy and FIGO stage or histologic grading could be demonstrated. This observation could be regarded as a marker for the high aggressiveness of FTC which has been repeatedly described in the past.

[Conisation in stage Ia cervix cancer]. / Die Konisation beim Zervixkarzinom im Stadium Ia.

Between 1975 and 1988, a total of 78 patients suffering from cervical cancer stage Ia were treated by conisation based on a positive smear. According to FIGO, these 78 patients consisted of 53 (67.9%) stage Ia1 and 25 (32.1%) stage Ia2 cases. Complete removal of the tumour by conisation was achieved in 51 patients. In 23 cases (29.5%) the margin of resection was reached by a carcinoma in situ, in 4 cases (5.1%) invasive carcinoma was found. Conisation was not followed by further surgery in 10/51 patients with complete tumour removal. One patient (1/23) with incomplete removal underwent surgery elsewhere. In the other 67/78 patients following hysterectomy, the pathologist diagnosed three cases of cervical cancer, 11 cases of carcinoma in situ and 53 cases (67.9%) without pathological findings. Carcinoma in situ after hysterectomy was found in only 2 cases (4.9%) with primarily free resection margins of the conus. Among the 27 patients with carcinoma in situ or invasive carcinoma reaching the conus margin, 9 cases of carcinoma in situ and 3 invasive carcinomas were diagnosed histologically after hysterectomy and one patient underwent surgery elsewhere. In this study, the value of conisation as single therapy of cervical cancer stage Ia1 and stage Ia2 with good prognosis (depth of infiltration of < 3 mm and no invasion of blood vessels) is discussed and the importance of thorough and exact histological examination is emphasised.

Prognostic factors in primary fallopian tube carcinoma. Austrian Cooperative Study Group for Fallopian Tube Carcinoma.

A retrospective nationwide evaluation of primary fallopian tube carcinomas for a period of 10 years (1980-1990) was performed to evaluate the prognostic impact of various factors. Sixty-six cases were investigated for the prognostic influence of estrogen (ER) and progesterone (PgR) status, mitotic activity, degree of nuclear anaplasia, and inflammatory reaction. ER and PgR receptors were detected by immunohistochemistry from paraffin sections. Forty-two percent were PgR-positive and 26% were ER-positive. However, no correlation of steroid receptors with survival could be found. Ninety-two percent of all tumors showed a moderate and high degree of nuclear anaplasia and only 8% showed a low degree of nuclear anaplasia. Thirty-four (52%) samples from all patients revealed low mitotic activity compared to 32 (48%) with an intermediate and high mitotic rate. Twenty-four (37%) tissue samples showed a positive inflammatory reaction which correlated with a significantly better outcome compared with tumors without this feature. This finding was also confirmed in multivariate analysis as an independent prognostic factor.

A comparative analysis of management and prognosis in stage I and II fallopian tube carcinoma and epithelial ovarian cancer.

Staging and surgical as well as post-operative treatment of primary Fallopian tube carcinoma (FTC) followed the lines established for primary ovarian cancer (OC). In a nationwide retrospective analysis we were able to find a distinct difference between these two tumours. A total of 262 patients, 68 with FTC and 194 with OC, in stage I and II were included into this study. A univariate as well as a multivariate analysis for survival was performed, including factors such as age, histological type, grading and surgical and adjuvant treatment. A significantly poorer outcome (P = 0.0002) for FTC patients with a 5-year survival of 50.8% compared with 77.5% for OC patients was observed. This finding was persistent and independent of any investigated factor, in univariate as well as multivariate analyses. Therefore, we feel that a more aggressive therapeutic approach to the treatment of FTC even in early stages can be recommended. On the other hand, the retrospective character of our study has to be taken into account.