HPV DNA in autopsy-derived material from multiple metastases of a cervical carcinoma.

Fresh tissue from primary tumor and a metastasis of a cervical carcinoma and 13 autopsy-derived tissue specimens of the same patient were analyzed for HPV DNA by Southern blot hybridization and PCR. Primary tumor and 7 of 10 histologically proven distant metastases contained HPV 16 DNA by Southern blot. PCR detected HPV 16 in all 10 metastases and in 2 of 3 additional tumor-free autopsy-derived tissues. The restriction pattern was identical in all HPV-positive lesions and only slight variations in copy number occurred. Two-dimensional gel electrophoresis showed the viral DNA fully integrated in the cellular genome without any difference between primary tumor and metastasis. The relevance of HPV also for the metastatic spread of the malignant disease is indicated by its conserved presence in multiple distant metastases of cervical carcinoma.

Human papillomavirus DNA in distant metastases of cervical cancer.

Eighteen distant metastases from cervical cancer to the extrapelvic abdomen, extraabdominal lymph nodes, vulva, suburethral region, skin, and breast in 17 patients were analyzed by Southern blot hybridization under nonstringent and stringent conditions for the prevalence of human papillomavirus (HPV) type 11, 16, 18, 31, 33, and 35 DNA. Fourteen metastases in thirteen patients were HPV-positive. Thirteen tumors contained HPV-16 and one HPV-related sequences with varying copy number. In 9 of 11 cases, where the corresponding primary tumor could be studied, HPV positivity and type were identical. Two HPV-negative primary lesions had HPV-positive metastases; in three cases differences in restriction pattern or copy number were revealed. The HPV status showed no clear association with age of the patient, latency period between primary tumor and metastasis, histological findings, therapy, and clinical course of the disease after metastasis. The rather conserved presence of HPV DNA in distant metastases of cervical carcinoma underlines the importance of these viruses also for the maintenance of the malignant state.

HPV 16 DNA in autopsy material of a metastatic cervical carcinoma.

Human papillomavirus (HPV) DNA has been regularly detected in primary cervical carcinomas and in some metastatic lesions. Using Southern blot hybridization on autopsy material we found HPV 16 DNA in a primary cervical carcinoma and in multiple metastases therefrom.

[Surgical therapy of progressive or recurrent malignant ovarian tumors]. / Operative Therapie progredienter oder rezidivierender maligner Ovarialtumoren.

Out of a total of 120 patients operated on for recurrent ovarian cancer, two at the very best, but possibly not even one, will have a definitive chance of cure. Despite the poor long-term prognosis, as well as the lengthy operation and postoperative treatment involved, it does not seem justified to withhold surgery for recurrent disease totally. In some cases, symptoms can be treated with surgery, such as tumour pain or an impending ileus. In other cases, patients live for 10 years and longer, after multiple operations for relapse, without suffering severe physical symptoms. These are mainly patients with circumscribed, solitary, and very slowly growing tumours, in which cases, it is possible to remove the tumour again and again by surgery. The most relevant prognostic factors include the size of the residual tumour left at the primary operation, the time between the primary operation and the recurrence of the tumour, the type of growth of the recurrent tumour, as well as the extent of the tumour size reduction achieved at the first recurrence operation.

[Cervical carcinoma recurrences and their treatment at the University of Freiburg's Women's Clinic from 1976 to 1985]. / Zervixkarzinomrezidive und ihre Behandlung an der Universitäts-Frauenklinik Freiburg in den Jahren 1976 bis 1985.

From 1976 to 1985 151 recurrent carcinomas of the uterine cervix were diagnosed and in 118 cases they have been treated at the Gynaecological Centre of the University of Freiburg. The recurrences were divided according to the localisation scheme of Munnell and Bonney. 55 patients (47%) received radiotherapy, 22 (19%) surgery, 12 (10%) combined therapy of surgery and radiotherapy and 13 women (11%) chemotherapy or hormone therapy. 16 patients (13%) received a different type of therapy. We found most of the recurrences three or four years after the primary therapy. There was no correlation between the point of time of diagnosis of the recurrences and the prognosis. The distribution of the histology was no parameter for the OAS. The operative procedure demonstrates better results than the radiotherapy at recurrences in the centre of the pelvis--but there is no significance. The radiotherapy achieves significant better results than the operative treatment when we have large recurrences in the whole pelvis. If there is an answer of the tumour to the therapy, the OAS gets better--in these cases we should use, in spite of the risk of more side effects, the whole therapeutic range.

In vitro responsiveness of ovarian epithelial carcinomas to endocrine therapy.

As previously reported, ovarian epithelial carcinomas may respond to endocrine therapy. We examined the direct effect of progesterone, medroxyprogesteroneacetate, gestoneron, 17-beta-estradiol, tamoxifen, 4-OH-tamoxifen, or N-desmethyltamoxifen on the proliferative capacity of ovarian carcinoma cells by means of the colony assay described by Hamburger and Salmon. The growth rate of 25 tested tumors (ascitic fluid, primary tumor, metastases) was 68%. The plating efficiency was 0.078%. Beside the drug testing estrogen and progesterone receptor levels were determined. The inhibition of colony survival was slightest with 17-beta-estradiol, more pronounced with medroxyprogesteroneacetate, gestoneron, N-desmethyltamoxifen, and progesterone, and greatest with 4-OH-tamoxifen and tamoxifen. Significant and dose-dependent inhibition of greater than 70% was observed with tamoxifen and 4-OH-tamoxifen in 80% of the tested tumors. There was no significant correlation between the in vitro responsiveness and the level of hormonal act not only via an estrogen receptor but also via an antiestrogen-binding site.

[Control of the response of ovarian cancers to cytostatic therapy and the value of the second-look operation]. / Kontrolle des Ansprechens von Ovarialkarzinomen auf die zytostatische Therapie und Stellenwert der Second-look-Operation.

The importance of a second-look operation (SLO) in 121 patients with ovarian carcinoma stages III and IV from 1979 to 1983 is forthwith discussed. This operation was carried out in 58% of the patients. If no tumor was suspected after chemotherapy (n = 33), this only applied in 19 cases after a SLO. Of the patients in partial remission the preoperative diagnosis was correct in 14 of 21 cases and in no change 4 of 9 cases. Clinically the progress was always diagnosed reliably. Additional removal of residual tumors was successful in 7 of 49 cases (14%). This is only possible in small quantities of residual tumor. An improvement in the prognosis did not occur. Predictions on the right time to carry out a SLO and the purpose of a secondary tumor resection cannot be made.

[Surgical therapy of ovarian carcinoma]. / Operative Therapie des Ovarialkarzinoms.

Ovarian carcinomas tend towards swift intraabdominal spreading and to frequent retroperitoneal involvement of the pelvic and paraaortic lymph nodes. At first surgery about 80% of the ovarian carcinomas have already left the small pelvis and are diagnosed as FIGO-stage III or IV. The preoperative diagnostics should register as accurately as possible the intra- and extra-abdominal spreeding. The postoperative residual tumor is of great importance for the prognosis. The aim of the operation being the reduction of the postoperative residual tumor to a diameter of less than 1-2 cm. If this is not successful, a substantial improvement of the prognosis cannot be expected from the first surgery. Exact staging with careful documentation of the postoperative residual tumor forms the essential basis for an optimal cytostatic or radiation therapeutical follow-up treatment. The trend towards radical surgical procedure led in our cases, unexpectedly to no increase in postoperative complications. A more conservative surgical procedure with the aim of preserving fertility in younger women, who wish to have children, requires the secure evidence of stage Ia and proof of a tumor with a low malignancy grade, given by an experienced histologist. It may be possible that other guide-lines are required for some germ cell tumors.

[Steroid hormone receptors in ovarian carcinomas and their clinical significance]. / Steroidhormon-Rezeptoren beim Ovarialkarzinom und ihre klinische Bedeutung.

Concentrations of estrogen (ER) and progesterone receptors (PR) were determined in 197 malignant tumors of the ovary. The frequency of receptors was the same as in breast cancer (ER 64%, PR 49%). In non-epithelial ovarian carcinomas steroid receptors were found only in granulosa cell tumors. PR was found less often in metastases than in primary tumors and after chemotherapy. Premenopausal tumors were more often PR-positive than postmenopausal carcinomas (71% versus 52%). ER were always constant. PR-negative tumors seemed to respond better to chemotherapy than positive tumors. Patients with PR-negative ovarian carcinomas seem to have a better prognosis than patients with PR-positive cancer. The clinical stage or the histological grade of the tumors did not correlate to the receptor status.

[Experiences with Volm's short-term tumor test in the primary treatment of ovarian carcinoma]. / Erfahrungen mit dem Kurzzeit-Tumortest nach Volm bei der Primärtherapie des Ovarialkarzinoms.

It is possible to examine about 95% of tumors using the short-term tumor test from Volm et al. The test results are available within one day. In 89 cases of ovarian tumor stages III and IV, the clinical progress using different chemotherapies could be compared with the results of the uridine-adriamycin-test. In the uridine-adriamycin-test, 82% of the cases with sensitive tumors showed either a remission or at least no change. Resistant tumors were, however, in 56% of cases progressive. Whilst combination largely of proliferation-inhibiting cytostatic drugs such as CF- or CAP-therapy showed a good relationship between the behavior of the tumors in vitro and their response to the cytostatic therapy a similar relationship under CP-therapy with a high cisplatin dosage, could not yet be proved, although until now in only a small number of cases. In vitro sensitive ovarian carcinomas stage III with the histological grade II or III, have a better prognosis under chemotherapy than resistant carcinomas. The importance attached to the short-term tumor test from Volm in the cytostatic therapy of ovarian carcinomas, must be similarly assessed as that of steroid receptors to the endocrine therapy of breast cancer.

[Estrogen and progesterone receptors in malignant ovarian neoplasms]. / Ostrogen- und Progesteronrezeptoren in malignen ovarialtumoren.

Estrogen receptors (ER) and progesterone receptors (PR) were evaluated in 173 primary ovarian cancers and in 6 ovarian metastases. In epithelial ovarian carcinomas 63% had ER and 46% PR. Almost all granulosa cell tumours were receptor-positive, while sarcomas, dysgerminomas, and teratomas lacked ER and PR. Both receptors were found less often in tumours of the histological grade I than in those of grade II and III. During the development of metastases and during chemotherapy there was a loss of PR in 27% and 53% of the cases, respectively, while the amount of ER remained more or less constant. In addition to ovarian cancers ER and PR were present in carcinomas of the fallopian tube as well. ER-negative and especially PR-negative tumours seemed to respond better to chemotherapy than receptor-positive carcinomas. The possible significance of ER and PR with regard to the success of an endocrine treatment is discussed.

Chemotherapy for stage III-IV ovarian cancer: the CAP-regimen in previously untreated patients.

Twenty-nine patients with advanced previously untreated epithelial ovarian cancer (FIGO stage III + IV) received induction chemotherapy with CAP (cyclophosphamide 500 mg/m2, adriamycin 50 mg/m2 and cis-platinum 50 mg/m2). Of twenty patients whose post-surgical tumor size was greater than 2 cm, fifteen (75%) achieved objective response. The median duration of complete response is greater than 20 months and the median duration of partial response is greater than 11 months. Among the 75% responders (15 of 20) overall, eleven were determined by surgical evaluation and four by clinical evaluation. The response rate in the present study compares favorably with previously reported studies. Toxicity from the CAP regimen was frequent and often severe but no irreversible side effects or treatment related deaths were observed. It is concluded that the CAP regimen appears to be an effective drug combination against advanced ovarian cancer that may improve overall response and ultimate survival of previously untreated patients.

[Sarcomas of the uterus: morphological criteria and clinical course (author's transl)]. / Sarkome des Uterus: Morphologische Kriterien und klinischer Verlauf.

Sixty-nine cases of uterine sarcoma were reviewed histologically withhh respect to their grade of malignancy. Mitotic activity is the most important criterion of malignancy. A histological grading was performed on the basis of mitotic counts per high power field. Clinical follow-up showed that except for the local extension of the tumor, the prognosis of sarcomas depends greatly on mitotic activity. There is a good correlation in the lower stages I and II between number of mitoses and survival rate. The 5 year survival rate of patients with grades I or II is 77% compared to 41% for grades III and IV. Vascular invasion is not evident in distant metastases in our material. Adjuvant chemotherapy is recommended in clinical stages II-IV and in histological grades III and IV.

[Sarcomas of the female genitalia: therapy and prognosis (author's transl)]. / Sarkome des weiblichen genitale: therapie und prognose.

216 sarcomas of the female genitalia were treated at the University hospitals for women of Freiburg and Tübingen between the years 1957 to 1977. 76% originated from the uterine corpus; 28% (46/164) of the sarcomas of the corpus uteri were detected as incidental findings. The 5 year survival rates is 54% in stage I, 25% in stage II, and 40% in all stages (52/131). Postoperative irradiation of stage I cases of sarcomas of the corpus uteri diminished local recurrence but not metastases. Extirpation of the ovaries has no influence on local recurrence. Sarcomas of the vulva and cervix have a comparatively good prognosis, whereas the prognosis of the sarcoma of the ovary is very bad. The bad prognosis of sarcomas of the female genitalia points out the necessity of developing cooperative clinical trials on the effectiveness of adjuvant chemotherapy.

[Investigations about the incorporation of nucleotide precursors in single cell suspensions of ovarian- and cervix-carcinomas under the influence of cytostatic therapy (author's transl)]. / Untersuchungen über den Einbau von Nucleotidpräcursoren in Einzelzellsuspensionen von Ovarial- und Zervixkarzinomen unter dem Einfluss von Zytostatika.

The behaviour of 34 carcinomas of the cervix and 30 ovarian carcinomas under the influence of cytostatic agents was investigated in vitro by the method of Volm et al. The ovarian carcinomas showed a significantly higher incorporation rate of nucleotide precursors in the single cell suspensions. The incorporation rate in "chemosensitive" carcinomas was higher than in "chemoresistent" carcinomas independent of the type of the carcinomas. Carcinomas with a high decrease in incorporation rates of nucleotide precursors under the influence of cytostatic drugs were called chemosensitive. A cyclophosphamide-sensitivity in vitro was found in 9% of the carcinomas of the cervix and in 34% of the ovarian carcinomas. An adriamycin-sensitivity in vitro could be shown in 17% of the carcinomas of the cervix and in 46% of the ovarian carcinomas. These findings agree well with the experiences of cytostatic therapy of these carcinomas.