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Kava

Lavage of the Cavum uteri and proximal fallopian tubes

Paul Speiser, Prof.,Dr.,MD

The ovarian surface, the Fallopian tubes, the uterine cavity and the peritoneal cavity all together form a communicating compartment. The physiologic function of the ciliated lining of the tubes is to transport the egg, after ovulation, into the uterine cavity. Thus, making it very likely that exfoliated cells from pathologic changes of the ovarian surface and Fallopian tube lining will be present in a lavage from the uterine cavity.

The proof of concept that malignant cells from the upper genital tract get transported even into the lower genital tract was recently published by Kind I. et al. Liquid-based cervical cytology allows not only cytological evaluation but also collection of DNA. A panel of genes that are commonly mutated in endometrial and ovarian cancers was assembled with new whole-exome sequencing data from 22 endometrial cancers and previously published data on other tumour types, including mutations in the TP53 gene. This panel was used to search for mutations in 24 endometrial and 22 ovarian cancers and identified mutations in all 46 samples. With a sensitive massively parallel sequencing method, it was possible to identify the same mutations in the DNA from liquid Pap smear specimens in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22).

In the current project the investigators will study the specificity and sensitivity of the lavage of uterine cavity and proximal tubes as a test to differentiate between malign and benign ovarian tumours. The investigators aim to detect cells from EOCs or genetic material from those cells in the lavage.

Epithelial ovarian cancer (EOC) is the leading cause of death among gynaecologic malignancies in western civilized countries, with an estimated prevalence in Europe and the US of 752,600 in 2007 and 59,828 deaths annually. Treatment and survival of the patients depend primarily on the stage of the disease. Of all EOC patients only 25% are diagnosed at an early stage while the tumour is confined to the pelvis. In these cases the five-year survival rate is 80% to 90% and the disease can often be cured by the combination of surgery and chemotherapy. Unfortunately, almost 75% of women affected have advanced stage disease with metastatic spread throughout the abdominal cavity or to retroperitoneal lymph nodes at the time of diagnosis; five-year survival rates drop to 10%-30% for advanced disease, despite maximum surgical effort and combination chemotherapy.

Currently, state of the art differential diagnosis between malignant and benign ovarian pathologies suspicious for EOC relies predominantly on transvaginal ultrasonography and serum cancer antigen (CA-125) measurements. The specificity of these diagnostic tools however is low, and both tests are not effective enough to reliably differentiate between benign and malignant conditions. Even in highly specialised units, of all patients receiving surgery for suspected ovarian cancer only about 20% will have a malignant disease. These findings underline the need for new diagnostic tests, able to better differentiate between benign and malignant ovarian changes. This would possibly spear many patients from unnecessary surgery completely and improve the triage of patients with malignant ovarian tumours to highly specialised gynaecologic oncology units.

A promising approach for improvement of differential diagnosis of suspicious ovarian changes has been established by Paul Speiser and Robert Zeillinger (Molecular Oncology Group, Department of General Gynaecology and Gynaecologic Oncology, Medical University of Vienna, Austria) (EK 1148/2011). This approach is called the ALPINE technique (Austrian Lavage Procedure for the Detection of tubal Intraepithelial Neoplasms) (manuscript under preparation). It includes a lavage of the uterine cavity and proximal fallopian tubes and subsequent analysis of this lavage fluid for the presence of pre-malignant and malignant cells.

For the proof of principle that tumour cells are shed from ovarian cancer and can be found in the lavages of the uterine cavity, uterine lavages were collected before a surgical intervention for suspected ovarian malignancy at the investigators' institution and at the Catholic University Leuven, Department of Obstetrics and Gynaecology. After malignancy was confirmed, genetic changes in the TP53 and KRAS gene were determined in tumour tissue. In a set of 9 epithelial ovarian cancer patients (EOC) and 1 ovarian metastases of a signet ring carcinoma, the presence of these genetic changes was examined in lavage samples, using digital droplet PCR (ddPCR). Ten genetic changes were identified in tumour tissue of these patients and 9/10 (90%) of these changes were detected in the corresponding lavage specimen too. Mutation rates were in the range between 0.01% and 39.65% in EOC patients. Furthermore, a filter approach, followed by p53 immunofluorescence staining was established, confirming the presence of tumour cells in the lavage sample of one additional patient.

In a next step, lavage samples of 22 ovarian carcinoma patients, and if applicable corresponding tumour tissue, were analysed through deep sequencing by the group of Bert Vogelstein (Johns Hopkins University, Baltimore, USA). The presence of genetic changes, indicative for ovarian cancer, could be confirmed in 16/22 (72.7%) lavage specimen. Of 18 patients, corresponding tumor tissues were available, showing the same mutation.

These results are proof that ovarian cancer cells are shed into the fallopian tubes and uterine cavity, and can be collected through our ALPINE technique. The fact that ovarian cancer cells were detected with high sensitivity in the lavage of the uterine cavity and proximal tubes shows that this approach has a great potential in differential diagnosis of ovarian masses.

Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma - Study of Sensitivity and Specificity

In the current project the investigators will study the specificity and sensitivity of the lavage of uterine cavity and proximal tubes as a test to differentiate between malign and benign ovarian tumours. The investigators aim to detect cells from EOCs by somatic mutation analysis of the genetic material from those cells in the lavage.

To detect cells from EOCs, analysis of lavage fluid will be carried out applying the sensitive massively parallel sequencing method published by Kinde et al. Mutations in the following genes will be analysed: AKT1, APC, ARID1A, BRAF, CTNNB1, CSMD3, CDKN2A, EGFR, FBXW7, FAT3, FGFR2, KRAS, MLL2, NRAS, PTEN, PIK3CA, PIK3R1, PPP2R1A, PIK3R, RNF43, and TP53.

Medical University of Vienna

Prof. Dr.

Precancerous Conditions

* Lavage of the Cavum uteri and proximal fallopian tubes
* Liquid-PAP (Papanicolaou) smear

Liquid-PAP smear

Paul Speiser, Univ.Prof.Dr.

Epithelial Ovarian cancer (EOC) is the leading cause of death among gynaecologic malignancies in western civilized countries, with an estimated prevalence in Europe and the US of 752,600 in 2007 and 59,828 deaths annually.

State-of-the-art diagnostic tests for EOC include transvaginal ultrasonography and serum cancer antigen (CA-125) measurements; the specificity of these diagnostic tools however is low, and both tests are not effective enough at detecting EOC early enough to improve clinical outcomes. Definitive diagnosis of EOC still relies on histological or cytological confirmation. These findings underline the importance for an effective test for early detection of EOC.

In the current project we will obtain a lavage of the uterine cavity. It will be investigated whether cells from EOCs or genetic material from those cells can be detected in the lavage fluid.

Aim of this study:

There is a clear clinical need for a diagnosis test to detect EOC at an earlier stage.

Epithelial Ovarian cancer is the leading cause of death among gynaecologic malignancies in western civilized countries, with an estimated prevalence in Europe and the US of 752,600 in 2007 and 59,828 deaths annually. Treatment and survival of the patients depend primarily on the stage of the disease. Of all EOC patients only 25% are diagnosed at an early stage while the tumour is confined to the pelvis. In these cases the five-year survival rate is 80% to 90% and the disease can often be cured by the combination of surgery and chemotherapy. Unfortunately, almost 75% of women affected have advanced stage disease with metastatic spread throughout the abdominal cavity or to retroperitoneal lymph nodes at the time of diagnosis; five-year survival rates drop to 10%-30% for advanced disease, despite maximum surgical effort and combination chemotherapy.

State-of-the-art diagnostic tests for EOC include transvaginal ultrasonography and serum cancer antigen (CA-125) measurements; the specificity of these diagnostic tools however is low, and both tests are not effective enough at detecting EOC early enough to improve clinical outcomes. Definitive diagnosis of EOC still relies on histological or cytological confirmation. These findings underline the importance for an effective test for early detection of EOC.

In the current project we will obtain a lavage of the uterine cavity. It will be investigated whether cells from EOCs or genetic material from those cells can be detected in the lavage fluid.

Aim of this study:

There is a clear clinical need for a diagnosis test to detect EOC at an earlier stage.

Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes.

Pilot Study of the Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes - LUDOC Study

If the adnexal tumor removed turns out to be an EOC, mutation analysis will be carried out applying the sensitive massively parallel sequencing method published by Kinde et al. Mutations in the following genes will be analysed: AKT1, APC, ARID1A, BRAF, CTNNB1, CSMD3, CDKN2A, EGFR, FBXW7, FAT3, FGFR2, KRAS, MLL2, NRAS, PTEN, PIK3CA, PIK3R1, PPP2R1A, PIK3R, RNF43, and TP53.

Obtaining material from the uterine cervix by applying a liquid-based Pap smear technique to directly compare the two sampling techniques - Lavage and liquid-based Pap.

Univ.Prof.MD.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma - Study of Sensitivity and Specificity	NCT02518256	Ovarian Epithel...	Lavage of the C...	18 Years - 85 Years	Medical University of Vienna
Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes.	NCT02062697	Ovarian Epithel...	Lavage of the C... Liquid-PAP smea...	18 Years - 80 Years	Medical University of Vienna
Lavage of the Uterine Cavity for the Diagnosis of Ovarian and Tubal Carcinoma and Their Premalignant Changes.	NCT02062697	Ovarian Epithel...	Lavage of the C... Liquid-PAP smea...	18 Years - 80 Years	Medical University of Vienna

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