Ovarian cancer prevention by opportunistic salpingectomy is a new de facto standard in Germany.

PURPOSE: The most prevalent and aggressive subtype of epithelial ovarian carcinoma (EOC), high-grade serous carcinoma (HGSC), originates in many cases from the fallopian tubes. Because of poor prognosis and lack of effective screening for early detection, opportunistic salpingectomy (OS) for prevention of EOC is being implemented into clinical routine in several countries worldwide. Taking the opportunity of a gynecological surgery in women at average cancer risk, extramural fallopian tubes are completely resected preserving the ovaries with their infundibulopelvic blood supply. Until recently, only 13 of the 130 national partner societies of the International Federation of Obstetrics and Gynecology (FIGO) have published a statement on OS. This study aimed to analyze the acceptance of OS in Germany. METHODS: (1) Survey of German gynecologists in 2015 and 2022 by the Department of Gynecology of the Jena University Hospital in co-operation with the Department of Gynecology at Charité-University Medicine Berlin with support of NOGGO e. V. and AGO e. V. (2) Salpingectomy numbers in Germany for years 2005-2020 as retrieved from the Federal Statistical Office of Germany (Destatis). RESULTS: (1) Survey: Number of participants was 203 in 2015 and 166 in 2022, respectively. Nearly all respondents (2015: 92%, 2022: 98%) have already performed bilateral salpingectomy without oophorectomy in combination with benign hysterectomy with the intention to reduce the risk for malignant (2015: 96%, 2022: 97%) and benign (2015: 47%, 2022: 38%) disorders. Compared to 2015 (56.6%), considerably more survey participants performed OS in > 50% or in all cases in 2022 (89.0%). Recommendation of OS for all women with completed family planning at benign pelvic surgery was approved by 68% in 2015 and 74% in 2022. (2) Case number analysis: In 2020, four times more cases of salpingectomy were reported by German public hospitals compared to 2005 (n = 50,398 vs. n = 12,286). Of all inpatient hysterectomies in German hospitals in 2020, 45% were combined with salpingectomy, and more than 65% in women at the age of 35 to 49 years. CONCLUSION: Mounting scientific plausibility regarding involvement of fallopian tubes in the pathogenesis of EOC led to change of clinical acceptance of OS in many countries including in Germany. Case number data and widespread expert judgment demonstrate that OS has become a routine procedure in Germany and a de facto standard for primary prevention of EOC.

The brave new world of endometrial cancer : Future implications for adjuvant treatment decisions.

PURPOSE: For many decades, endometrial cancer (EC) has been considered as a homogenous tumor entity with good prognosis. The currently valid risk stratification considers clinical and pathological factors. Treatment recommendations differ considerably from country to country. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) Research Network has shown that ECs should be reclassified into four novel molecular prognostic groups, with the potential of changing adjuvant management of EC patients: ultra-mutated, hyper-mutated, copy-number low, and copy-number high. Clinical examples are shown, and the available literature has been highlighted. The European Society of Gynaecological Oncology (ESGO) guideline for endometrial cancer takes the new classification system into consideration for adjuvant treatment decisions and will be published this year. RESULTS: In the near future, we expect new treatment recommendations that may differ considerably from the clinicopathologically driven recommendations on the basis of our deeper insight and better understanding of molecular markers in endometrial cancer. The PORTEC 4a study is the only recruiting study which randomizes patients to adjuvant or no adjuvant treatment on the basis of the aforementioned new classification system. CONCLUSION: The aim of the new classification is a more personalized adjuvant radio(chemo)therapy decision and better oncologic outcomes or avoidance of overtreatment.

Jump in the fire--heat shock proteins and their impact on ovarian cancer therapy.

Ovarian cancer (OC) is a major problem in gynecological oncology. Options for diagnosis and treatment of advanced stages and thus for patient prognosis have not been improved substantially over the past decades. Heat shock proteins (HSP) are characterized as stress-induced molecular chaperones performing cell survival factor functions. In cancer cells, various crucial and clinically important cell responses are vitally influenced and modulated by HSPs, e.g., cell growth and treatment resistance. Despite the limited knowledge on HSPs in OC progression, their roles as biomarkers, prognostic factors and their drug target properties appears promising for future clinical applications and therapeutic approaches.

Statement by the Kommission Ovar of the AGO: The New FIGO and WHO Classifications of Ovarian, Fallopian Tube and Primary Peritoneal Cancer.

More than 25 years after the last revision, in 2012 the FIGO Oncology Committee began revising the FIGO classification for staging ovarian, Fallopian tube and primary peritoneal cancers. The new classification has become effective with its publication at the beginning of 2014. Following recent findings on the pathogenesis of ovarian, Fallopian tube and primary peritoneal cancer and reflecting standard clinical practice, the three entities have now been classified uniformly. The histological subtype is included (high-grade serous - HGSC; low-grade serous - LGSC; mucinous - MC; clear cell - CCC; endometrioid - EC). Stages III and IV have been fundamentally changed: stage IIIA now refers to a localized tumor limited to the pelvis with (only) retroperitoneal lymph node metastasis (formerly classified as IIIC). Stage IV has been divided into IVA and IVB, with IVA defined as malignant pleural effusion and IVB as parenchymatous or extra-abdominal metastasis including inguinal and mediastinal lymph node metastasis as well as umbilical metastasis. A new WHO classification was published almost concurrently. The classification of serous tumors addresses the issue of the tubal carcinogenesis of serous ovarian cancer, even if no tubal precursor lesions are found for up to 30 % of serous high-grade cancers. The number of subgroups was reduced and subgroups now include only high-grade serous, low-grade serous, mucinous, seromucinous, endometrioid, clear cell and Brenner tumors. The category "transitional cell carcinomas" has been dropped and the classification "seromucinous tumors" has been newly added. More attention has been focused on the role of borderline tumors as a stage in the progression from benign to invasive lesions.

Polymorphism of the IL-8 gene and the risk of ovarian cancer.

Ovarian cancer still represents a challenge in gynecological oncology. Most patients are diagnosed in an advanced tumor stage. No specific screening or prevention strategies for ovarian cancer exist as of yet. Interleukin 8 (IL-8) is a pro-inflammatory chemokine known for its angiogenetic activity, and is supposedly responsible for tumor-associated angiogenesis in several malignant tumors. The aim of the study was to investigate the susceptibility of patients with an IL-8 gene polymorphism to developing ovarian cancer. Four single nucleotide polymorphisms (SNPs) (IL-8 -251, IL-8 +781, IL-8 +1633 and IL-8 +2767) of the IL-8 gene were screened, using the PCR method in 268 patients with ovarian cancer and 426 healthy women as a control group. Significant associations were noted in patients with the IL-8 +781 (T/T) genotype (p=0.0048) with increased frequencies of ovarian cancer, while women with the IL-8 +781 (C/C) allele suffer from ovarian cancer significantly less frequently (p=0.0003). Furthermore, the IL-8 +2767 (T/T) genotype is also associated with a higher risk of ovarian cancer (p=0.0177). Our results indicate, for the first time, that IL-8 polymorphism is associated with ovarian cancer.

Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology).

PURPOSE: The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC. METHODS: Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint. RESULTS: Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %. CONCLUSIONS: Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

Implementation of the quality management system improves postoperative pain treatment: a prospective pre-/post-interventional questionnaire study.

BACKGROUND: An organizational approach is proposed as an immediate solution for improving postoperative pain (POP) management. The aim was to evaluate the clinical effectiveness of a quality management system (QMS), based on procedure-specific, multimodal analgesic protocols, modified to meet the individual patients' requirements. METHODS: Patients from the orthopaedic, gynaecological, visceral, and trauma surgery departments of the university hospital were involved in two prospective surveys. Survey 1 was performed at baseline and survey 2 was performed after the implementation of QMS within an interval of 1 year. The patients were asked to report pain intensity on the visual rating scale, incidence of analgesia-related side-effects, and incidence of pain interference with the items of life quality and their satisfaction with the treatment of POP. RESULTS: Patients from Survey 2 (n=251) reported 25-30% less pain than those from Survey 1 (n=269) (P<0.0001). Nausea was reported by 40% of the patients from Survey 1 vs 17% from Survey 2, vomiting by 25 vs 11% and fatigue by 76% in Survey 1 vs 30% in Survey 2 (P<0.0001). Life quality and patients' satisfaction improved in Survey 2 vs Survey 1 (P<0.001). CONCLUSIONS: The implementation of QMS allowed the reduction in POP intensity with a simultaneous decrease in analgesia-related side-effects. This has led to an increased quality of life and patient satisfaction.

Statement by the Kommission OVAR of the AGO Study Group on the Use of HIPEC (Hyperthermic Intraperitoneal Chemotherapy) to Treat Primary and Recurrent Ovarian Cancer.

HIPEC is offered to patients with ovarian, fallopian tube or primary peritoneal cancer at some hospitals. Altogether, there is still no evidence that HIPEC leads to an improvement of prognosis in any gynecologic tumor, neither in primary therapy nor in treatment of relapse. The available data indicate an increased complication rate which might negatively impact the benefit-risk balance of this procedure. In addition, standard treatment with proven efficacy might be withheld due to application of unproven methods. The use of HIPEC outside of well designed, prospective and controlled clinical trials is therefore disregarded.

Decreased IL-1 RA concentration in ascites is associated with a significant improvement in overall survival in ovarian cancer.

BACKGROUND: Cytokines play a major role in promoting the growth and metastatic spread of cancer cells. Interleukin-1 alpha and beta (IL-1) and IL-1 RA are known to be critically involved in carcinogenesis and in various solid tumors. There are limited data on expression of IL-1 alpha, beta and RA in serum and ascites in patients with advanced ovarian cancer. Objectives of this study were to investigate the level of IL-1 alpha, IL-1 beta and IL-1 RA in serum and ascites from patients with ovarian cancer and their impact on the prognosis. METHODS: Fifty-three women with ovarian cancer (OC) (33 patients with primary OC and 20 with relapsed OC) and 50 women with benign gynaecological diseases as a control group (CG) were enrolled onto this prospective study. IL-1 alpha, beta and RA levels were analyzed in serum and ascites by ELISA technique. RESULTS: The median age was 55 years (range 19-80) in the ovarian cancer group and 40 years (range 15-89) in the controls. The distribution of histological type of ovarian cancer was as follows: serous-papillary 43 (81.1%), 4 (7.5%) mucinous, 3 (5.7%) endometroid and 3 (5.7%) clear cell carcinoma. The concentrations of IL-1 beta and RA in ascites or peritoneal fluid were significantly increased in patients with OC in comparison to the CG, for both cytokines (p<0.0001); also the concentration of IL-1 RA in serum was increased in OC (p=0.003) vs. CG. An increased level of IL-1 beta in ascites correlated significantly with a poorer histopathological grading (p=0.038). IL-1 RA concentration in ascites was correlated with advanced FIGO stage (p=0.049) and the IL-1 RA serum level with ascites volume (< or =500 ml vs. >500 ml) (p=0.046). Patients with IL-1 RA level in ascites lower than the cut off value of 695.6 pg/ml showed a significant better progression-free median survival (24.6 vs. 12.8 months, p=0.008) and postoperative median overall survival (34.6 vs. 17 months, p=0.01) in comparison to patients with an IL-1 RA level in ascites higher than the cut off level. Additionally, a higher expression of IL-1 beta in serum (p=0.004) and ascites (p=0.05) reduced significantly the progression-free survival. In the multivariate analysis, expression of IL-1 RA in ascites was an independent prognostic factor for good progression-free and postoperative overall survival (HR, 0.39 95% CI, 0.18-0.83, p=0.01, HR, 0.36 95% CI, 0.16-0.8, p=0.01). CONCLUSIONS: IL-1 RA levels in ascites lower than the cut off value of 695.6 pg/ml are associated with a significant improvement in postoperative and progression-free survival. IL-1 RA shows a prognostic relevance in ovarian cancer.

Online tumor conference in the clinical management of gynecological cancer: experience from a pilot study in Germany.

The concept of the online tumor conference was established in 2004 as a pilot project. We developed specific web-based software to organize and conduct online tumor board meetings of gynecologists, surgeons, radiologists, oncologists, and pathologists from different hospitals and gynecological practitioners, discussing individual patient's cases, defining therapy options, and exchanging clinical experience. Following a didactic approach, patient data are presented to the participants, with a special focus toward patient's preference and late toxicity from prior therapy. Then different national (eg, Arbeitsgemeinschaft Gynaekologische Onkologie, Deutsche Gesellschag fur Gynaekologic und Geburtshilfe) and international guidelines (eg, American Society of Clinical Oncology, National Cancer Institute), current study results based on literature review and open clinical trials are discussed. An individual diagnosis and therapy recommendation for each patient is reached by consensus. All protocols, guidelines, and publication data are upgraded and dispersed via Internet for all participants. In the period from December 2004 to August 2006, 39 tumor board conferences were performed with a total of 667 participants. One hundred forty-four patients' cases were presented, and 121 peer-reviewed second-opinions were sought. In an anonymous survey, 84% of the participants reported to be satisfied with the information content and 72% with the technical support. Overall 98% of the individual therapy recommendations were accepted and implemented. The tumor board conference presents an optimal possibility for extensive scientific discussions and exchange (92%) and improves advanced educational training (81%). In conclusion, the online tumor conference is feasible and represents a time-saving possibility for gynecological oncologist to receive a treatment recommendation based on the best available clinical and scientific evidence.

Role of the progesterone receptor for paclitaxel resistance in primary breast cancer.

Paclitaxel plays an important role in the treatment of primary breast cancer. However, a substantial proportion of patients treated with paclitaxel does not appear to derive any benefit from this therapy. We performed a prospective study using tumour cells isolated from 50 primary breast carcinomas. Sensitivity of primary tumour cells to paclitaxel was determined in a clinically relevant range of concentrations (0.85-27.2 microg ml(-1) paclitaxel) using an ATP assay. Chemosensitivity data were used to study a possible association with immunohistochemically determined oestrogen and progesterone receptor (ER and PR) status, as well as histopathological parameters. Progesterone receptor (PR) mRNA expression was also determined by quantitative RT-PCR. We observed a clear association of the PR status with chemosensitivity to paclitaxel. Higher levels of immunohistochemically detected PR expression correlated with decreased chemosensitivity (P=0.008). Similarly, high levels of PR mRNA expression were associated with decreased paclitaxel chemosensitivity (P=0.007). Cells from carcinomas with T-stages 3 and 4 were less sensitive compared to stages 1 and 2 (P=0.013). Multiple regression analysis identified PR receptor status and T-stage as independent predictors of paclitaxel chemosensitivity, whereas the ER, N-stage, grading and age were not influential. In conclusion, in vitro sensitivity to paclitaxel was higher for PR-negative compared with PR-positive breast carcinoma cells. Thus, PR status should be considered as a possible factor of influence when designing new trials and chemotherapy protocols.

An estrogen receptor alpha-dependent regulation of estrogen receptor-related receptor alpha in the proliferation of endometrial carcinoma cells.

Estrogen receptor-related receptor alpha (ERRalpha) was reported to compete with estrogen receptor alpha (ERalpha) in a constitutive manner as an orphan nuclear closely related to (ERalpha). To discuss the role of ERRalpha in the endometrial carcinoma cells, this study was performed. ER-responsive endometrial carcinoma cells Ishikawa and ER-nonresponse HEC-1A cells were treated with different concentration of 17beta-E2 or E2 plus ICI 182780. Semiquantitative reverse transcription-polymerase chain reaction and western blot were performed to analysis the expression of human estrogen receptor-related receptor alpha (hERRalpha). Plasmid PLXSN-hERRalpha was constructed and transfected into cells. Selected in the medium containing high-dose G418, the Ishikawa and HEC-1A cells with stable overexpression of hERRalpha were constructed and renamed as Ishikawa/hERRalpha and HEC-1A/hERRalpha, respectively. To discuss the effect of overexpression of hERRalpha in the cell biological behavior (3-[4,5-dimethylth-lazol-2yl]-2,5-diphenyltetrazolium bromid) (MTT) cell assay was performed. Estrogen downregulates ERRalpha expression in ER-positive Ishikawa cells, while upregulates the expression of ERRalpha in ER-negative HEC-1A cells. In Ishikawa cells, the downregulation of 17beta-E2 in ERRalpha expression cells could be blocked by ICI 182780. A decreasing expression of hERalpha was observed in the ER-responsive cells with overexpression of ERRalpha (Ishikawa/hERRalpha). Overexpression of hERRalpha inhibits the cell proliferation in the ERalpha-responsive Ishikawa cells and stimulated the cell proliferation in the ERalpha-nonresponsive HEC-1A cells. Function of hERRalpha depends on the expression and function of hERalpha. ER-mediated signaling might be the important factor resulting in the hormone-dependent endometrial carcinoma, whereas ERRalpha-mediated pathway might act as the vital role in hormone-independent endometrial carcinoma.

Overexpression of the plasminogen activator inhibitor type-1 in epithelial ovarian cancer.

BACKGROUND: The plasminogen activator-plasmin cascade plays a central role in the progression of solid tumors. The type-1 plasminogen activator inhibitor (PAI-1) is the major physiological regulator of plasminogen activation. PAI-1 is suggested to play a crucial role in tumor cell invasion and metastasis of various solid tumors. The aim of this study was to analyze the clinical and prognostic roles of PAI-1 in epithelial ovarian cancer (OC). MATERIALS AND METHODS: Expression analysis was conducted by immunohistochemistry and ELISA. Tissue sections of paraffin-embedded tumor specimens and fresh-frozen tumor samples from patients with benign and malignant ovarian tumors (OT), who had undergone surgical intervention in the Department of Gynaecology and Obstetrics, Charité, Germany, from 02/01 to 06/02, were used. Correlation analysis with conventional clinical factors, univariate and multivariate analyses were performed using SPSS (SPSS Inc., V.11.0). RESULTS: Sixty-five patients (31 primary OC, 20 recurrent OC, 4 low-malignant potential OT, 6 benign OT, 4 normal ovary) were allocated to this trial. The median age was 57 years (range, 34-86) and the median follow-up was 20 months (range, 0-64). The distributions of (FIGO) tumor stage of all primary OC were: I = 16.1%, II = 3.2%, III = 45.2% and IV = 35.5%. PAI-1 was significantly overexpressed in the tumor epithelium of OC in comparison to the ovarian epithelium of benign OT and normal ovary (p < 0.001). The median PAI-1 level was 1.92-fold higher in malignant OT than in benign OT. Statistical analyses showed no significant correlation between the expression of PAI-1 and clinical parameters. The expression of PAI-1 and the PAI-1 level, according to 3 different cut-off values, showed no prognostic impact in univariate analysis. In multivariate analysis, only tumor stage (FIGO) (p = 0.003) and residual tumor (p = 0.009) remained independent prognostic factors for post-operative survival. CONCLUSION: PAI-1 is significantly overexpressed in OC.

[Role of PAI-1 in gynaecological malignancies]. / Funktion und klinische Bedeutung des Plasminogen-Aktivator-Inhibitors PAI-1 bei gynäkologischen Malignomen. Eine Ubersicht.

The plasminogen activator-plasmin cascade plays a central role in tumor cell invasion and metastasis of solid tumors. The type-1 plasminogen activator inhibitor (PAI-1) is the major physiologic regulator of the plasminogen activation. The PAI-1 is suggested to play a crucial role in tumor cell invasion and metastasis of different solid tumors. The aim of this article is to give an overview of the function, clinical and prognostic role of PAI-1 in gynaecological malignancies.

[Conventional and experimental prognostic factors in ovarian cancer]. / Etablierte und experimentelle Prognosefaktoren des Ovarialkarzinoms.

Epithelial ovarian cancer is the leading cause of death from gynaecologic malignancies in western countries. In the clinical day treatment decision of the physician (e. g. surgery, chemotherapy) based on individual prognostic factors of the patient with ovarian cancer. The tumor stage at time of diagnosis and the postoperative residual tumor mass are prognostic factors and are unequivocally related to overall survival. Other prognostic factors are identified mostly in small series and are discussed in the literature controversially. This article discussing the value of conventional prognostic factors, as stage, postoperative tumor mass, age, lymph node status, ascites) and newer molecular biological factors, as Her-2-status, PAI-1, MMP, VEGF and CD24.

["IMO"--intraoperative mapping of ovarian cancer]. / "IMO"--Intraoperatives Mapping des Ovarialkarzinoms.

INTRODUCTION: The majority of patients diagnosed with ovarian cancer are in an advanced stage of the disease at the time of first diagnosis. The standard clinical staging (FIGO) occurs intraoperatively. The FIGO classification hides ambiguities and is useful as a means of orientation. However, an exact assessment of stage at first diagnosis, can form the basis for the evaluation of diagnostic and prognostic factors and furthermore has influence on adjuvant treatment. METHOD: We developed a systematic surgical and histopathological tumor documentation instrument, further we investigated its clinical and scientific application. RESULTS: Between September 2000 and July 2002, 128 patients with primary and recurrent ovarian cancer were operated and prospectively documented. The median age of the patients at the time of first diagnosis was 55 years. The majority of patients diagnosed with primary ovarian cancer had a diffuse tumor spread pattern (localised: 18 [32 %]; central: 14 [25 %]; diffuse: 24 [43 %]). In patients diagnosed with recurrent ovarian cancer the three defined tumor spread patterns showed a comparable distribution (localised 19 [28 %]; central: 19 [28 % ]; diffused: 29 [43 %]). While in most of the patients with primary ovarian cancer the highest tumor mass was concentrated in the lower abdomen/ pelvis, in comparison, in patients with recurrent ovarian cancer it was located mostly in the upper abdomen ("change of level", p=0,027). CONCLUSIONS: The IMO (Interoperative Mapping of Ovarian Cancer) represents a new instrument for a detailed and objective documentation of surgical and pathological results of patients with ovarian cancer and helps provide a more precise staging. Potentially this prospective documentation support the development of SOP's (Standard Operating Procedures) and could be an efficacious instrument of quality management.

Interleukin-1 receptor antagonist gene polymorphism is associated with increased risk of epithelial ovarian cancer.

BACKGROUND: Different studies indicate that immunological components play a key role in the development of cancer. Interleukin-1 (IL-1) is known to be critically involved in ovarian carcinogenesis and in other solid tumors. Therefore, we investigated the possible influence of the polymorphism of the IL-1 receptor antagonist (IL-1 RA) genes on the development of ovarian cancer. PATIENTS AND METHODS: In a prospective study we analyzed the polymorphism of the IL-1 RA gene in 108 women with ovarian cancer compared with 112 patients with benign gynecological diseases. Genomic DNA fragments were amplified by PCR. RESULTS: The distribution of genotype frequencies was significantly different between the study and control group with respect to allele 1/2 heterozygotes (32.4% versus 15.2%; P = 0.004). Patients who were heterozygous at allele 2 for IL-1 RA (IL-RA 1/2) had a significantly higher risk of ovarian cancer with a calculated odds ratio of 2.7 (95% confidence interval 1.4-5.2). There were no differences between IL-1 RA 1/2 polymorphism and all other alleles in tumor stage (International Federation of Gynecology and Obstetrics), histological type, grading, postoperative tumor volume, volume of ascites, recurrence status or age. CONCLUSIONS: The allele 2 polymorphism of the IL-1 RA gene seems to play a role in the occurrence of ovarian cancer and should be investigated for screening and risk evaluation.