Role of fertility-sparing surgery and further prognostic factors in borderline tumors of the ovary.

OBJECTIVE: Borderline tumors of the ovary are a rare group of ovarian neoplasms with distinctive histological features. Considering their favorable prognosis and occurrence at a younger age, fertility-sparing surgery may be considered. Several risk factors have been identified as contributing to a higher recurrence rate, while the impact of pathohistological features varies in the literature. This study aimed to analyze risk factors for recurrence in patients with borderline tumors of the ovary. METHODS: Analysis included patients treated with first diagnosis of a borderline tumor at our center between January 1997 and December 2022 to analyze disease-free survival and to identify the role of fertility-sparing surgery, defined as preservation of at least one ovary, pathohistological features, and other prognostic factors for relapse. All stages classified according to the International Federation of Gynecology and Obstetrics (FIGO) were included. RESULTS: Among 507 patients, 26 patients (5.2%) had a recurrence, with 21 (4.1%) showing borderline histology and 5 (1%) with invasive relapses. Recurrence rate was higher following fertility-sparing surgery (p<0.0001). Median follow-up period was 49.2 (range 42.0-57.6) months. Among 153 patients (30.2%) who had fertility-sparing surgery, 21 (13.7%) experienced a recurrence (including one invasive relapse). Fertility-sparing surgery (HR 20; 95% CI 6.9 to 60; p<0.001), FIGO stage I with bilateral presence of tumor (HR 6.4; 95% CI 1.3 to 31; p=0.020), FIGO stage II (HR 15; 95% CI 3.4 to 68; p<0.001), FIGO stages III-IV (HR 38; 95% CI 10 to 140; p<0.001) in comparison with FIGO stage I with unilateral tumor, microinvasion (HR 8.6; 95% CI 2.7 to 28; p<0.001), and micropapillary growth patterns (HR 4.4; 95% CI 1.8 to 10; p=0.001) were identified as independent risk factors for recurrence in multivariate analysis. None of these factors were associated with an increased risk of disease-related death. CONCLUSIONS: Our study showed that although a fertility-preserving approach is associated with increased recurrence rates of a borderline tumor, it does not affect overall survival and can therefore be regarded as oncologically safe for patients desiring to preserve fertility. Additionally, presence of micropapillary patterns and microinvasion were identified as prognostic risk factors.

Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer.

The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8-97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable.

Cell-free tumor DNA, CA125 and HE4 for the objective assessment of tumor burden in patients with advanced high-grade serous ovarian cancer.

BACKGROUND: The present prospective study aimed at determining the impact of cell-free tumor DNA (ct-DNA), CA125 and HE4 from blood and ascites for quantification of tumor burden in patients with advanced high-grade serous epithelial ovarian cancer (EOC). METHODS: Genomic DNA was extracted from tumor FFPE and ct-DNA from plasma before surgery and on subsequent post-surgical days. Extracted DNA was subjected to hybrid-capture based next generation sequencing. Blood and ascites were sampled before surgery and on subsequent post-surgical days. 20 patients (10 undergoing complete resection (TR0), 10 undergoing incomplete resection (TR>0)) were included. RESULTS: The minor allele frequency (MAF) of TP53 mutations in ct-DNA of all patients with TR0 decreased significantly, compared to only one patient with TR>0. It was not possible to distinguish between patients with TR0 and patients with TR>0, using CA125 and HE4 from blood and ascites. CONCLUSIONS: Based upon the present findings, ct-DNA assessment in patients with high-grade serous EOC might help to better determine disease burden compared to standard tumor markers. Further studies should prospectively evaluate whether this enhancement of accuracy can help to optimize management of patients with EOC.

Clinical outcome in patients with primary epithelial ovarian cancer and germline BRCA1/2-mutation - real life data.

BACKGROUND: We evaluated the clinical impact of germline (g)BRCA1/2-mutation on initial disease presentation, surgical implications, surgical morbidity and survival in patients with advanced epithelial ovarian cancer (EOC) undergoing debulking surgery (DS). METHODS: Data of all consecutive EOC patients with stage III/IV, high-grade serous disease and known gBRCA1/2 status (gBRCA; non-gBRCA), who underwent DS at our department between 01/2011 and 06/2019 were analyzed. Associations between gBRCA-status and severe postoperative complications and survival were analyzed. RESULTS: gBRCA-status was determined in 50.1% (612/1221) of all patients. gBRCA was present in 21.9% (134/612). Significant differences were observed in terms of median age (p = 0.001) and histology (high-grade serous histology gBRCA: 98.5%, non-gBRCA 76.2%; p < 0.001). gBRCA-status had no impact on intraoperative disease presentation, surgical complexity or complete resection rate (gBRCA: 74.4%, non-gBRCA: 69.0%; p = 0.274). gBRCA-status was not predictive for severe postoperative complication (gBRCA: 12.0%, non-gBRCA: 19.1%; p = 0.082). Median PFS and OS was 31/22 and 71/53 months in patients with/without gBRCA-mutation, respectively. gBRCA was a significant prognostic factor for PFS (HR 0.57 p < 0.001) and for OS (HR 0.64, p = 0.048) after adjusting for established prognostic factors. CONCLUSIONS: gBRCA-status had no impact on initial disease presentation, surgical results or postoperative complications. gBRCA patients have a significantly longer PFS but the impact on the long term prognosis is unclear. Complete resection remains the most important prognostic factor in patients with EOC independent of gBRCA-status.

Modern day screening for Lynch syndrome in endometrial cancer: the KEM experience.

PURPOSE: Current guidelines for Lynch syndrome detection in endometrial cancer (EC) patients rely either on risk evaluation, based on personal/family history, or detection of mismatch repair (MMR) deficiency on tumor tissue. We present a combined screening algorithm for Lynch syndrome. METHODS: In this study, 213 consecutive patients treated for EC at Kliniken Essen-Mitte between 2014 and 2018 were included. Personal/family history was evaluated by the Amsterdam II, revised Bethesda/German-DKG criteria and prediction model PREMM5. MMR testing was performed by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) based microsatellite analysis on tumor tissue. MLH1 promoter methylation analysis was performed in case of MLH1 loss or microsatellite instability. RESULTS: Based on personal/family history 2/213 (Amsterdam II), 31/213 (revised Bethesda/German-DKG) and 149/213 (PREMM5) patients were identified as at risk for Lynch syndrome. MMR analysis was performed by IHC in 51.2%, by PCR in 32.4%, and in 16.4% of patients both methods were used. MMR deficiency was detected in 20.6% (44/213). Methylation analysis was performed in 27 patients of whom, 22 (81.4%) showed MLH1 promoter hypermethylation. Only 9% of MMR deficient patients were identified as at risk for Lynch syndrome by the revised Bethesda/German-DKG criteria. A pathogenic germline mutation was discovered in 3 out of 20 patients that underwent genetic testing. None of these patients were younger than 50 years or had a family history of Lynch syndrome-associated malignancies. CONCLUSION: General MMR assessment is a feasible strategy to improve the detection of Lynch Syndrome in patients with EC.

Response evaluation after neoadjuvant therapy: evaluation of chemotherapy response score and serological and/or radiological assessment of response in ovarian cancer patients.

PURPOSE: The chemotherapy response score (CRS) is a histopathological tool to evaluate response to neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (OC). We critically evaluated the clinical value of CRS and compared its predictive power to standard serological (CA125) and radiological response. METHODS: A retrospective analysis of 277 OC patients, who received primary chemotherapy, was performed. CRS, serological, and radiological findings were correlated with progression-free (PFS) and overall survival (OS). RESULTS: CRS could be determined in 172 of 277 patients (62.1%). In patients with CRS3, a longer median PFS and OS was observed compared with CRS1/2 patients (31.2 vs. 18.9, P < 0.001; 55.0 vs. 36.1 months, P = 0.050). CA125 and radiological response evaluation were also predictive for PFS and OS. Patients with serological and radiological complete response showed longer PFS (23.0 vs. 14.4, P = 0.011; 21.4 vs. 9.6 months, P < 0.001) and OS (49.5 vs. 29.0, P = 0.003; 45.0 vs. 12.9 months, P < 0.001). Patients with pathological complete response (pCR) had the best median PFS (52.8 months), even compared with non-pCR CRS3 (27.8 months). In the total study cohort, serological, and radiological complete response was better at predicting PFS (hazard ratio 2.23 and 2.77). CONCLUSION: In this study, evaluation of response to chemotherapy by CRS was not superior to conventional methods (CA125 or radiology). Independent of the evaluation method, response to NACT was predictive of PFS and OS. We observed no added value for CRS as a prognostic marker. The clinical relevance of CRS should be discussed, as no therapeutic consequences result from CRS evaluation.

Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer-Impact for Diagnosis and Treatment Monitoring.

BACKGROUND: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment. METHODS: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set. RESULTS: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively. CONCLUSION: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

Dataset on patients with Recurrent Borderline Ovarian Tumors and Table with Review of Literature on Fertility and Oncologic Outcomes of patients with Borderline Ovarian Tumors.

The data presented here is related to the research article entitled "FERTILITY-SPARING SURGERY AND REPRODUCTIVE-OUTCOMES IN PATIENTS WITH BORDERLINE OVARIAN TUMORS" by Plett et al. in Journal of Gynecologic Oncology [1] and is analysed and discussed in detail. 18 Patients with Recurrent Borderline Ovarian Tumors (BOT) were identified and listed in Table 1. All patients underwent treatment for primary BOT either per radical surgery (RS) or fertility sparing surgery (FSS) by the same team in Horst Schmidt Klinik (HSK) in Wiesbaden and the Department of Gynecology and Gynecologic Oncology at Kliniken Essen-Mitte between January 2000 and December 2018 and were followed up closely. Details on patients` and surgical characteristics are given as well as management of character of recurrent disease. In Table 2 important publications from the last 20 years are listed in order to visualize better the oncologic outcomes (invasive and non-invasive relapses) and calculated risks of recurrence with the purpose to understand better the important findings of the related article cited above.

Fertility-sparing surgery and reproductive-outcomes in patients with borderline ovarian tumors.

BACKGROUND: Borderline ovarian tumors (BOT) are considered a biological category with increased epithelial proliferation and cellular atypia in the absence of invasive growth. Since BOT occur often in young patients fertility sparing surgery (FSS) is an important issue. With this study we aimed to evaluate risk factors for relapses and fertility of patients after FSS. METHODS: Patients diagnosed with BOT and treated between 2000 and 2018 were included. External pathological review was done in all patients. FSS was performed after individual discussion and a complete surgical staging according to FIGO, without lymphadenectomy and with a waiver for preservation of uterus and one ovary. RESULTS: Among 352 Patients 80.2% had FIGO I and 63.9% had a serous BOT. Eighteen patients (5.1%) relapsed and 4 cases of malignant transformation were reported (1.1%). One patient of the latter died, all others have no evidence of disease. The overall recurrence-rate was 1.1% in FIGO-Stage I and 25.5% in FIGO III-IV (HR = 27; 95%-CI 7.7-95; p ≤.001). 95 patients underwent FSS. Thirteen (13.7%) of these patients relapsed, all as BOT. In multivariate analysis FIGO stages II-IV (HR = 27; 95%-CI: 8.1-102; p ≤.001) and FSS (HR = 12; 95%-CI: 2.9-47; p = .001) remained significant risk factors for recurrent disease. Pregnancy rate among forty-one patients attempting to conceive was 82.9%. 29 patients experienced at least one life-birth, in total 38 life-births were reported. CONCLUSION: FSS in stage I is a safe procedure and life-birth-rates after FSS are high. More advanced FIGO stages have to be discussed individually and relapse rates have to be weighed against FSS. A central review of pathology, as we performed routinely, is mandatory and may have contributed to our low rate of invasive relapses.

Sentinel lymph node mapping with fluorescent and radioactive tracers in vulvar cancer patients.

PURPOSE: Application of radioactive tracers for sentinel lymph node biopsy (SLNB) in vulvar cancer has been established, however, the use of radioisotopes is expensive and requires complex logistics. This exploratory study evaluated the feasibility of near-infrared fluorescence-based SLNB in comparison to the gold standard using radioactive guidance. METHODS: At Evangelische Kliniken Essen-Mitte (Essen, Germany) between 02/2015 and 04/2019, 33 patients with squamous cell vulvar cancer and unifocal tumors (32 midline, 1 lateral) smaller than 4 cm underwent SLNB as part of their routine primary surgical therapy. Radiolabeled nanocolloid technetium 99 (99mTc) was injected preoperatively and indocyanine green (ICG) intraoperatively. Demographic and clinical data were retrieved from patients' records, and descriptive statistics were applied. The detection rate of the ICG fluorescence technique was compared with the standard radioactive approach. RESULTS: In patients with midline tumors, bilateral SLNB was attempted. SLNB was feasible in 61/64 (95.3%) groins with 99mTc and in 56/64 (87.5%) with ICG. In total, 125 SLNs were excised; all SLNs were radioactive and 117 (93.6%) also fluorescent. In 8 patients with BMI > 30 kg/m2, SLNB was successful in 14/15 groins (93.3%) with 99mTc and 13/15 groins (86.7%) with ICG. Upon final histology, infiltrated nodes were present in 9/64 (14.1%) groins and 10/125 SLNs; one positive SLN was not detected with ICG. CONCLUSIONS: SLNB using ICG is a promising technique, however, the detection rate obtained was slightly lower than with 99mTc. The detection rate increased over time indicating that experience and training may play an important role besides further methodological refinements.

Pattern and impact of metastatic cardiophrenic lymph nodes in advanced epithelial ovarian cancer.

BACKGROUND: Cardiophrenic lymph nodes (CPLN) define FIGO stage IVB disease. We evaluate the pattern of CPLN metastases, their prognostic impact and the potential role of CPLN resection in patients with epithelial ovarian cancer (EOC). METHODS: Analysis of 595 consecutive patients with EOC treated in the period 01/2011-05/2016. CT scans were re-reviewed by two radiologists. Positive CPLN were defined as ≥5 mm in the short-axis diameter. The role of CPLN resection was evaluated in a case-control matched-pair analysis. RESULTS: Of 595 patients 458 had FIGO stage IIIB-IV disease. We excluded patients undergoing interval surgery (n = 54), without debulking surgery (n = 32) and without sufficient pre-operative imaging (n = 22), resulting in a study cohort of 350 patients. Of these, 133 (37.9%) had negative CPLN and 217 (62.0%) had radiologically positive CPLN. In patients with postoperative residual tumor, enlarged CPLN had no impact on survival. In patients with complete resection (n = 223), 98 (44.0%) had negative CPLN and a 5-year OS of 69% and a 5-year PFS of 41%; in contrast, in the 125 patients (56.0%) with positive CPLN, 5-year OS was 30% and 5-year PFS was 13%. In 52 patients we resected CPLN. The matched-pair case-control analysis did not demonstrate any significant impact on survival of CPLN resection. CONCLUSION: CPLN metastases are associated with impaired PFS and OS in patients with macroscopically completely resected tumor. Intraabdominal residual tumor has a greater prognostic impact than positive CPLN. The impact of the resection of CPLN remains unclear.

Skeletal Muscle Attenuation (Sarcopenia) Predicts Reduced Overall Survival in Patients with Advanced Epithelial Ovarian Cancer Undergoing Primary Debulking Surgery.

BACKGROUND: Sarcopenia was reported as a prognostic factor in cancer patients. Using computed tomography (CT), we analyzed the impact of sarcopenia on overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). METHODS: Preoperative CT scans of consecutive EOC patients (n = 323) were retrospectively assessed for skeletal muscle index (SMI) and muscle attenuation (MA; Hounsfield units [HU]). The optimal cut-off point for MA (32 HU) was calculated using the Martingale residuals method, and previously reported cut-offs for SMI were used. Logistic regression was used to determine univariate and multivariate factors associated with OS. RESULTS: Sarcopenia defined as SMI < 38.5, < 39, and 41 cm2/m2 was detected in 29.4, 33.7, and 47.1% of patients, respectively; however, none of these SMI cut-off levels were associated with OS. MA < 32 HU was present in 21.1% (68/323) of the total cohort. Significant differences between patients with MA < 32 and ≥ 32 HU were detected for median age (67 vs. 57 years), Eastern Cooperative Oncology Group (ECOG) > 0 (13.2 vs. 3.1%), comorbidity (age-adjusted Charlson Comorbidity Index [ACCI] ≥ 4; 36.8 vs. 13.3%), median body mass index (BMI; 27 vs. 24 kg/m2), International Federation of Gynecology and Obstetrics (FIGO) stage, histology (high-grade serous 95.6 vs. 84.7%), and complete resection (38.2 vs. 68.2%). MA < 32 HU remained a significant prognostic factor for OS in multivariate Cox regression analysis (hazard ratio 1.79, p = 0.003). Median OS in patients with MA < 32 HU versus MA ≥ 32 HU was 28 versus 56 months (p < 0.001). Furthermore, MA < 32 HU was significantly associated with OS in the prognostically poor population of patients with residual tumor (p = 0.015). CONCLUSIONS: Low MA was significantly associated with poor survival, especially in patients with residual tumor after PDS. MA assessment could be used for risk stratification after PDS.

Stage- and Histologic Subtype-Dependent Frequency of Lymph Node Metastases in Patients with Epithelial Ovarian Cancer Undergoing Systematic Pelvic and Paraaortic Lymphadenectomy.

PURPOSE: Tumor stage and distinct histological subtypes in epithelial ovarian cancer (EOC) show different prognostic outcome. The aim of this study is to evaluate whether the frequency of lymph node (LN) metastases in patients with different tumor stages and histological subtypes undergoing systematic pelvic and paraaortic lymphadenectomy is coincidentally divergent. METHODS: Patients with EOC treated with upfront staging or debulking surgery between January 2000 and December 2016 were included. Systematic lymphadenectomy was performed in all consecutive patients with optimal debulking and without medical contraindications. RESULTS: Seven hundred sixty-two patients including 27.2% with early-stage EOC were included. The median number of removed LNs was 69, and metastases to LNs were found in 54.7%. No LN metastases were found in patients with low-grade endometrioid carcinoma, independently of tumor stage. LN metastases in early-stage low-grade serous (N = 5), mucinous (N = 31), and clear cell (N = 28) EOC were found in one (20%), zero, and one (3.6%) patient, respectively. LN metastases were detected in more than 10% of patients with all other histological subtypes. On multivariate analyses, overall survival was significantly impaired in patients with LN metastases, as compared with patients without LN metastases (p = 0.001). CONCLUSIONS: The risk of LN metastases in patients with EOC is dependent on stage and histological subtype. Patients with incidental finding of early mucinous or low-grade endometrioid EOC are at very low risk of retroperitoneal lymph node metastases. Reoperation for lymph node staging only should be discussed individually with caution.

Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer.

BACKGROUND: We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center. PATIENTS AND METHODS: Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB-IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0-1), intermediate (2-3), and high (≥4), and postoperative surgical complications were graded according to the Clavien-Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS. RESULTS: Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3-5; odds ratio 3.27, 95% confidence interval 1.97-5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection. CONCLUSION: The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.

BACKGROUND: Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). METHODS: Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. RESULTS: Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. CONCLUSION: Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic and intrinsic pathways of apoptosis in RCCs. In this context, ARC cooperates with anti-apoptotic Bcl-2 family members to exert its strong anti-apoptotic effects and is therefore an important factor not only in the therapeutic resistance but also in future therapy strategies (i.e., Bcl-2 inhibitors) in RCC. In sum, targeting of ARC may enhance the therapeutic response in combination therapy protocols.

Serous Tubal Intraepithelial Carcinoma Associated With Extraovarian Metastases.

OBJECTIVE: The evolving knowledge of ovarian carcinogenesis sets the stage for our understanding of high-grade serous pelvic carcinoma (HGSC). Findings in prophylactic surgery introduced serous tubal intraepithelial carcinoma (STIC) as potential precursor of HGSC. The present study explores whether STIC instead should already be considered as an early stage of HGSC with a need for comprehensive staging and therapy. PATIENTS AND METHODS: We identified all consecutive patients with HGSC who received first-line therapy in our referral center for gynecologic oncology from January 2011 to April 2016. All chemo-naive patients with upfront debulking surgery in whom an association of STIC and tumor lesions could be analyzed were included. Patients with previous removal of the adnexa or overgrown of the fallopian tube by the tumor were excluded. Pathological workup of the fallopian tubes according to the SEE-FIM protocol was conducted. RESULTS: We analyzed a series of 231 consecutive patients with HGSC of whom 121 (52.4%) had ovarian cancer, 74 (32.0%) had cancer of the fallopian tubes and 36 patients (15.6%) had primary peritoneal cancer. Serous tubal intraepithelial carcinoma could be identified in 158 (68.4%) of 231 patients; of 22 patients, 28.1% is ovarian cancer, 30.8% cancer of the fallopian tubes, and 9.5% peritoneal cancer. Four patients without any further intra-abdominal disease were identified of whom 2 patients had stage FIGO IA and 2 patients had lymph node metastases only. CONCLUSIONS: Our data suggest that STIC should be regarded as a malignant lesion with metastatic potential. Therefore, we recommend a comprehensive surgical staging including lymphadenectomy.

Impact of Abdominal Wall Metastases on Prognosis in Epithelial Ovarian Cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) patients with the presence of abdominal wall metastasis (AWM) are categorized as stage International Federation of Gynecology and Obstetrics (FIGO) IVB, irrespective of other biologic factors or preceding invasive intervention before final surgery. We evaluated the impact of AWM on patients' overall survival (OS). PATIENTS AND METHODS: In this exploratory study, 634 consecutive patients with advanced EOC treated in our center from 2000 to 2014 were included. Patients were categorized into FIGO IIIC (n = 308), FIGO IVB AWM only (n = 86), and FIGO IV others (metastases other than AWM, n = 240). Clinicopathological parameters and survival data were extracted from our prospectively maintained tumor registry. Survival analyses were calculated using Kaplan-Meier method and Cox regression models. RESULTS: In 75 (87.2%) of 86 cases, AWM was seen after a preceding intervention, and only in 12.7%, the deposits were spontaneously established. The median OS in patients with stage FIGO IIIC, FIGO IVB AWM only, and FIGO IV others was 37, 58, and 25 months (P < 0.001), respectively. Patients with FIGO IVB AWM only had a significantly better OS than patients with FIGO IV others (P < 0.001). The numeric longer OS of patients with FIGO IVB AWM only compared with patients with FIGO IIIC was not statistically significant (P = 0.151). In multivariate analysis considering all confounding factors including residual disease, OS of patients with FIGO IIIC did not differ from patients with FIGO AWM only (hazard ratio, 0.84; 95% confidence interval, 0.56-12.26; P = 0.398). CONCLUSIONS: Most AWM are acquired after preceding intervention (puncture or laparoscopy). Prognosis of patients with AWM as the only site of distant metastasis is superior compared with other stage FIGO IV patients. Therefore, up-staging of patients only because of AWM to FIGO IVB may be questioned. A revision/clarification of the FIGO classification system should be considered to avoid unnecessary stigmatization of patients and to classify these patients more appropriately according to prognosis.

Prognostic Impact of Port-Site Metastasis After Diagnostic Laparoscopy for Epithelial Ovarian Cancer.

BACKGROUND: This study was designed to evaluate the prevalence, morbidity, and prognostic impact of port-site metastasis (PSM) in patients with epithelial ovarian cancer (EOC) undergoing laparoscopy before subsequent primary debulking surgery (PDS). METHODS: All consecutive patients treated between 2000 and 2014, who had a laparoscopy followed by PDS, were extracted from our prospectively maintained database. All patients with histological examination of port-sites were included in this unicentric exploratory analysis. RESULTS: A total of 250 (25.5 %) of 982 patients with EOC underwent laparoscopy before PDS. Port-site resection was performed in those 214 (85.6 %) patients in whom a complete or almost complete resection with residuals ≤1 cm was achieved. Median interval between laparoscopy and PDS was 25 days. PSM was detected in 100 of 214 patients (46.7 %). Risk factors for PSM were higher tumor stage (odds ratio [OR] 13.5, 95 % confidence interval [CI] 2.9-62.0, p = 0.04), positive lymph node status (OR 3.0, 95 % CI 1.3-6.7, p = 0.009), and ascites >500 mL (OR 3.9, 95 % CI 1.5-10.0, p = 0.005). Wound healing disorders and postoperative morbidity were significantly higher in patients with PSM (Clavien-Dindo Classification grade 3-5: 41.0 vs. 14.9 %, p < 0.001). However, multivariate Cox-regression models did not identify PSM as independent prognostic factor. CONCLUSIONS: The prevalence of PSM after laparoscopy in EOC patients is considerably high. PSM had no impact on survival; however, PSM were associated with more postoperative complications and a higher surgical treatment burden. This should be balanced with the expected benefit when laparoscopy is considered for the management of EOC.

The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?

OBJECTIVE: The revised 2014 FIGO staging system for epithelial ovarian cancer (EOC) included many changes of the previous system, particularly dividing FIGO stage IV in two subgroups. We evaluated if classifying patients with EOC in FIGO stage IVA and IVB has any prognostic implication.