Prognostic role of transcription factor ARID1A in patients with endometrial cancer of no specific molecular profile (NSMP) subtype.

OBJECTIVE: As more than 50% of newly diagnosed endometrial cancers remain classified as 'no specific molecular subtype' (NSMP) due to a lack of established biomarkers to further improve molecular subtyping, this study aims to evaluate the prognostic value of ARID1A in endometrial cancers of NSMP subtype. METHODS: Prospectively collected molecular profiling data of all consecutive patients with endometrial cancer who underwent primary surgery at our department between August 2017 and June 2022 and for whom both molecular profiling and clinical follow-up data were available were retrospectively evaluated. Tumor specimens were evaluated by combined mismatch repair protein immunohistochemistry and targeted next-generation hotspot sequencing. ARID1A mutational status, as defined by full-length gene sequencing, was matched with risk of recurrence, progression-free and disease-specific survival within the NSMP cohort. RESULTS: A total of 127 patients with endometrial cancer were included. Among 72 patients with tumors of NSMP subtype (56.7%), ARID1A mutations were identified in 24 cases (33.3%). ARID1A mutations were significantly associated with a higher risk of recurrence (37.5% vs 12.5%, OR 4.20, 95% CI 1.28 to 13.80, p=0.018) and impaired progression-free survival (HR 3.96, 95% CI 1.41 to 11.15, p=0.009), but not with disease-specific survival. The results for both risk of recurrence (OR 3.70, 95% CI 1.04 to 13.13, p=0.043) and progression-free survival (HR 3.19, 95% CI 1.10 to 9.25, p=0.033) were confirmed in multivariable analysis compared with advanced tumor stage International Federation of Gynecology and Obstetrics (2009) (FIGO ≥III) and impaired Eastern Clinical Oncology Group performance status (ECOG ≥1). CONCLUSION: ARID1A appears to identify patients with endometrial cancer of NSMP subtypes with a higher risk of recurrence and could be used as a future prognostic biomarker. After clinical validation, ARID1A assessment could help to further sub-classify selected endometrial cancers and improve personalized treatment strategies.

Biomarkers for checkpoint inhibitor therapy in mucinous epithelial ovarian cancer.

OBJECTIVE: The prognosis of patients with advanced stage mucinous epithelial ovarian cancer remains poor due to a modest response to platinum-based chemotherapy and the absence of therapeutic alternatives. As targeted approaches may help to overcome these limitations, the present study evaluates biomarkers indicative of potential immune-checkpoint inhibitor therapy response. METHODS: All patients who underwent primary cytoreductive surgery from January 2001 to December 2020 and for whom formalin-fixed paraffin-embedded tissue samples were available were included (n=35; 12 International Federation of Gynecology and Obstetrics (FIGO) stage ≥IIb). To define sub-groups potentially suitable for checkpoint inhibition, expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (CD3+, CD8+, CD20+, CD45+, CD68+, FoxP3+), and AT-rich interactive domain-containing protein 1A (ARID1A) immunostaining were evaluated in whole tissue sections and compared with clinicopathologic parameters and next-generation sequencing results, where available (n=11). Survival analyses were performed to assess whether identified sub-groups were associated with specific clinical outcomes. RESULTS: In total, 34.3% (n=12/35) of tumors were PD-L1 positive. PD-L1 expression was associated with infiltrative histotype (p=0.027) and correlated with higher CD8+ (r=0.577, p<0.001) and CD45+ (r=0.424, p=0.011), but reduced ARID1A expression (r=-4.39, p=0.008). CD8+ expression was associated with longer progression-free survival (hazard ratio (HR) 0.85 (95% CI 0.72 to 0.99), p=0.047) and disease-specific survival (HR 0.85 (95% CI 0.73 to 1.00), p=0.044) in the sub-group with FIGO stage ≥IIb. Three (8.6%) samples demonstrated high PD-L1 expression at a combined positive score of >10, which was associated with increased CD8+ expression (p=0.010) and loss of ARID1A expression (p=0.034). Next-generation sequencing, which was available for all samples with a combined positive score of >10, showed KRAS mutations, BRCA wild-type status, and mismatch repair proficiency in all cases, but did not reveal genetic alterations potentially associated with a pro-immunogenic tumor environment. CONCLUSIONS: A sub-group of mucinous ovarian cancers appear to demonstrate a pro-immunogenic tumor environment with high PD-L1 expression, decreased ARID1A expression, and characteristic tumor-infiltrating lymphocyte infiltration patterns. Further clinical validation of anti-PD-L1/PD-1 targeting in selected mucinous ovarian cancers appears promising.

Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial.

OBJECTIVE: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. METHODS: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. RESULTS: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. CONCLUSION: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

Impact of frailty on the management of patients with gynecological cancer aged 80 years and older.

PURPOSE: To assess the impact of frailty on compliance of standard therapy, complication, rate and survival in patients with gynecological malignancy aged 80 years and older. METHODS: In total, 83 women with gynecological malignancy (vulva, endometrial, ovarian or cervical cancer) who underwent primary treatment between 2007 and 2017 were retrospectively analyzed. Frailty index was calculated and its association with compliance of standard treatment, peri- and postoperative mortality and morbidity, and survival was evaluated. RESULTS: Frailty was observed in 24.1% of cases. Both frail and non-frail patients were able to receive standard therapy in most cases - 75.0% and 85.7%, respectively (p = 0.27). Frail patients did not show an increased postoperative complication rate. Frail patients had shorter 3 years overall survival rates (28%) when compared to non-frail patients (55%) (p = 0.02). In multivariable analysis high frailty index (Hazard Ratio [HR] 12.15 [1.39-106.05], p = 0.02) and advanced tumor stage (HR 1.33 [1.00-1.76], p = 0.05) were associated with poor overall survival, but not age, histologic grading, performance status, and compliance of standard therapy. CONCLUSION: Majority of patients was able to receive standard therapy, as suggested by the tumor board, irrespective of age and frailty. Nonetheless, frailty is a common finding in patients with gynecological malignancy aged 80 years and older. Frail patients show shorter progression-free, and overall survival within this cohort.

Molecular Guided Treatments in Gynecologic Oncology: Analysis of a Real-World Precision Cancer Medicine Platform.

INTRODUCTION: Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. PATIENTS AND METHODS: In this single-center, real-world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next-generation sequencing panel and immunohistochemistry (IHC). RESULTS: In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). CONCLUSION: Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. IMPLICATIONS FOR PRACTICE: Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy-refractory gynecologic malignancy to offer molecular-based treatment concepts.

Prognostic factors in patients with vulvar cancer: the VULCAN study.

OBJECTIVE: This study aimed to analyze the prognostic factors for overall and progression-free survival in patients with vulvar cancer. METHODS: This international, multicenter, retrospective study included 2453 patients diagnosed with vulvar cancer at 100 different institutions. Inclusion criteria were institutional review board approval from each collaborating center, pathologic diagnosis of invasive carcinoma of the vulva, and primary treatment performed at the participating center. Patients with intraepithelial neoplasia or primary treatment at non-participating centers were excluded. Global survival analysis and squamous cell histology subanalysis was performed. RESULTS: After excluding patients due to incomplete data entry, 1727 patients treated for vulvar cancer between January 2001 and December 2005 were registered for analysis (1535 squamous, 42 melanomas, 38 Paget's disease and 112 other histologic types). Melanomas had the worse prognosis (p=0.02). In squamous vulvar tumors, independent factors for increase in local recurrence of vulvar cancer were: no prior radiotherapy (p<0.001) or chemotherapy (p=0.006), and for distant recurrence were the number of positive inguinal nodes (p=0.025), and not having undergone lymphadenectomy (p=0.03) or radiotherapy (p<0.001), with a HR of 1.1 (95% CI 1.2 to 1.21), 2.9 (95% CI 1.4 to 6.1), and 3.1 (95% CI 1.7 to 5.7), respectively. Number of positive nodes (p=0.008), FIGO stage (p<0.001), adjuvant chemotherapy (p=0.001), tumor resection margins (p=0.045), and stromal invasion >5 mm (p=0.001) were correlated with poor overall survival, and large case volume (≥9 vs <9 cases per year) correlated with more favorable overall survival (p=0.05). CONCLUSIONS: Advanced patient age, number of positive inguinal lymph nodes, and lack of adjuvant treatment are significantly associated with a higher risk of relapse in patients with squamous cell vulvar cancer. Case volume per treating institution, FIGO stage, and stromal invasion appear to impact overall survival significantly. Future prospective trials are warranted to establish these prognostic factors for vulvar cancer.

The value of pretreatment serum butyrylcholinesterase level as a novel prognostic biomarker in patients with cervical cancer treated with primary (chemo-)radiation therapy.

BACKGROUND: Deficiency in butyrylcholinesterase (BChE), a condition commonly noticed in liver damage, inflammation, and malnutrition, has previously been associated with impaired prognosis in different malignancies. The aim of the present study was to investigate the value of pretreatment serum BChE levels as a prognostic biomarker in patients with cervical cancer treated with primary (chemotherapy-[chemo-])radiation therapy. METHODS: We retrospectively evaluated data of a consecutive series of patients with cervical cancer treated with primary (chemo-)radiation therapy between 1998 and 2015. Pretreatment serum BChE levels were correlated with clinico-pathological parameters and response to treatment. Uni- and multivariate survival analyses were performed to assess the association between decreased serum BChE levels and progression-free (PFS), cancer-specific (CSS), and overall survival (OS). RESULTS: A total of 356 patients were eligible for inclusion into the present study. The median (IQR) pretreatment serum BChE level was 6180 (4990-7710) IU/l. Lower serum BChE levels were associated with lower BMI (p < 0.001), advanced tumor stage (p = 0.04), poor treatment response (p = 0.002), the occurrence of disease recurrence (p = 0.003), and the risk of death (p < 0.001). In uni- and multivariate analyses, low pretreatment serum BChE levels were independently associated with shorter PFS (HR 1.8 [1.2-2.6]; p = 0.002), CSS (HR 2.2 [1.4-3.5], p < 0.001), and OS (HR 2.0 [1.4-2.9]; p < 0.001). CONCLUSIONS: Low pretreatment serum BChE levels are associated with advanced tumor stage and poor response to treatment, and serve as an independent prognostic biomarker for shorter PFS, CSS, and OS in patients with cervical cancer treated with primary (chemo-)radiation therapy.

Lymph node ratio in inguinal lymphadenectomy for squamous cell vulvar cancer: Results from the AGO-CaRE-1 study.

OBJECTIVE: Lymph node ratio (LNR) can predict treatment outcome and prognosis in patients with solid tumors. Aim of the present analysis was to confirm the concept of using LNR for assessing outcome in patients with vulvar cancer after surgery with inguinal lymphadenectomy in a large multicenter project. METHODS: The AGO-CaRE-1 study multicenter database was used for analysis. LNR was defined as ratio of number of positive lymph nodes (LN) to the number of resected. Previously established LNR risk groups were used to stratify patients. LNR was investigated with respect to clinical parameters. Univariate and multivariable survival analyses were performed to assess the value of LNR in order to predict overall (OS) and progression-free (PFS) survival. RESULTS: In total, 1047 patients treated with surgery including inguinal lymph node resection for squamous cell carcinoma of the vulva were identified from the database. Of these, 370 (35.3%) were found to have positive inguinal LN. In total, 677 (64.7%) had a LNR of 0% (N0), 255 (24.4%) a LNR of >0% < 20%, and 115 (11%) a LNR of ≥20%. Patients with higher LNR were found to have larger tumor size (P < .001), advanced tumor stage (P < .001), high tumor grade (P < .001), and deep stromal invasion (P < .001), more frequently. Three-year PFS rates were 75.7%, 44.2%, and 23.1% and three-year OS rates were 89.7%, 65.4%, and 41.9%, in patients with LNRs 0%, >0% < 20%, and ≥20%, respectively (P < .001, P < .001). On multivariable analyses LNR (HR 7.75, 95%-CI 4.01-14.98, P < .001), FIGO stage (HR 1.41, 95%-CI 1.18-1.69, P < .001), and patient's performance status (HR 1.59, 95%-CI 1.39-1.82, P < .001), were associated with PFS. In addition, LNR (HR 12.74, 95%-CI 5.64-28.78, P < .001), and performance status (HR 1.72, 95%-CI 1.44-2.07, P < .001) were also the only two parameters independently associated with OS. LNR generally showed stronger correlation than number of affected LN when comparing the two different multivariable models. CONCLUSIONS: In women with vulvar cancer LNR appears to be a consistent, independent prognostic parameter for both PFS and OS and allows patient stratification into three distinct risk groups. In survival analyses, LNR outperformed nodal status and number of positive nodes.

Low anterior resection syndrome (LARS) in patients with epithelial ovarian cancer after primary debulking surgery.

OBJECTIVE: To evaluate the prevalence of low anterior resection syndrome (LARS) in patients with debulking surgery for primary advanced epithelial ovarian cancer and to identify potential risk factors for development of LARS. METHODS: We reviewed data on 552 consecutive patients with primary epithelial ovarian cancer (EOC), who underwent upfront or interval cytoreductive surgery including low anterior resection at two different academic institutions (Kliniken-Essen-Mitte, Germany, and Medical University of Vienna, Austria). Intestinal dysfunction was assessed by the validated LARS-questionnaire via telephone call. We performed descriptive statistics and a binary logistic regression model to evaluate risk factors for LARS. RESULTS: In total, 341 patients were eligible and 206 (60.4%) were successfully contacted and provided complete information. Major LARS was observed in 78 (37.9%) patients, minor LARS in 44 (21.4%) patients, and no LARS in 84 (40.8%) patients. The prevalence rate of major LARS was not influenced by time interval between surgery and LARS assessment, type of cytoreductive surgery, and recurrent disease at the time of assessment. In multivariate analyses, number of anastomosis was independently associated with an increased risk for presence of major LARS (OR 3.76 [1.95-7.24]). In the present cohort, 25.2% patients had more than one bowel anastomosis. CONCLUSIONS: LARS in general and major LARS in particular seem to be a frequent long-term complication after debulking surgery including low anterior resection in primary advanced EOC patients. Particularly EOC patients with more than one bowel anastomosis during surgery seem to be at an increased risk for major LARS.

Pre-operative hypoalbuminemia is associated with complication rate and overall survival in patients with vulvar cancer undergoing surgery.

OBJECTIVE: Hypoalbuminemia, a known marker for malnutrition, has been associated with an increased risk for perioperative morbidity and poor prognosis in patients with solid tumors. The aim of this study was to investigate the prognostic and predictive value of pre-treatment serum albumin levels for survival and postoperative complications in patients with vulvar cancer undergoing surgery. METHODS: Within in this retrospective study, we assessed data of 103 consecutive patients with vulvar cancer undergoing primary surgery into this study. Pre-treatment serum albumin levels were correlated with clinico-pathological parameters and complications. We performed univariate log-rank test and multivariable Cox regression models to evaluate the association between pre-treatment serum albumin and survival. RESULTS: We found hypoalbuminemia (< 35 mg/dl) in 9 of 103 (8.7%) patients. No difference in tumor characteristics was observed between patients with hypoalbuminemia and normal serum albumin levels. Difference in postoperative complications (55.6% and 37.8% of patients with hypoalbuminemia and normal serum albumin levels, respectively) was not statistically significant (p = 0.345). Shorter overall survival (OS) was observed in patients with hypoalbuminemia (5-year OS rate 17.1%) when compared to patients with normal serum albumin levels (5-year OS rate 58.6%, p = 0.004). In multivariable analysis, age (p = 0.017), FIGO stage (p = 0.011) and serum albumin levels (p = 0.013) were independently associated with OS. CONCLUSION: Pre-treatment hypoalbuminemia is an independent prognostic biomarker for OS in patients with vulvar cancer. We did not find an association between pre-treatment hypoalbuminemia and a higher risk for postoperative complications.

Factors associated with post-relapse survival in patients with recurrent cervical cancer: the value of the inflammation-based Glasgow Prognostic Score.

PURPOSE: The aim of the present study was to assess the value of the Glasgow Prognostic Score (GPS) as a prognostic tool for predicting post-relapse survival (PRS) in patients with recurrent cervical cancer. METHODS: We retrospectively evaluated the data of 116 patients with recurrent cervical cancer in whom serologic biomarkers had been assessed at the time of relapse. The GPS was calculated as follows: patients with elevated serum C-reactive protein levels and hypoalbuminemia were allocated a score of 2, and those with 1 or no abnormal value were allocated a score of 1 and 0, respectively. To assess the association between factors including the GPS and PRS, we performed uni- and multivariate survival analyzes. RESULTS: After a median follow-up of 20.9 months from recurrence, a 5-year PRS rate of 25% (SE 4.7%) was observed. Only in 29.8% of the patients, recurrence was limited to the pelvis. In uni- and multivariate survival analyzes, the GPS [HR 1.6 (95% CI 0.9-2.4), p = 0.01], a history of radiation therapy as part of initial treatment [HR 2.7 (95% CI 1.1-6.9), p = 0.03], and the presence of peritoneal carcinomatosis or multiple sites of relapse [HR 4.2 (95% CI 1.9-9.3), p < 0.001] were associated with shorter PRS. The GPS correlated with higher squamous cell carcinoma antigen levels (p = 0.001), shorter median PRS (p = 0.009), and less intensive treatment for relapse (p = 0.02). CONCLUSIONS: A higher GPS at the time of relapse, a history of radiation therapy, and the presence of peritoneal carcinomatosis or multiple sites of relapse are independently associated with shorter PRS in patients with recurrent cervical cancer.

A collagen-fibrin patch for the prevention of symptomatic lymphoceles after pelvic lymphadenectomy in women with gynecologic malignancies: A randomized clinical trial.

OBJECTIVE: To evaluate the efficacy of a collagen-fibrin patch for the prevention of symptomatic lymphoceles after pelvic lymphadenectomy in women with gynecologic malignancies. METHODS: In a multicenter, randomized, clinical trial, 164 women with pelvic lymphadenectomy were allocated either to bilateral pelvic application of two collagen-fibrin patches or no intervention. Main outcome was efficacy, defined as reduction of symptomatic lymphocele rate diagnosed within four weeks after surgery. Secondary outcomes were asymptomatic lymphoceles and subsequent interventions. Sample size was based on the assumption that application of a collagen-fibrin patch reduces the prevalence of symptomatic lymphoceles by at least 66%. The study was single-blinded, i.e., patients and primary outcome assessors, but not surgeons, were blinded to the treatment allocation. RESULTS: A total of 75 women were randomized to the intervention and 89 to the control group. All women received the allocated intervention. In total, 42 (27.4%) lymphoceles and 8 (5.2%) symptomatic lymphoceles were observed. Symptomatic lymphoceles were observed in 5/68 (7.4%) women in the intervention group and 3/85 (3.5%) women in the control group (p = 0.47). Asymptomatic lymphoceles were observed in 16 (23.5%) women in the intervention group compared to 18 (21.2%) in the control group (p = 0.85). In a multivariate logistic regression model, no independent risk factor for the development of a symptomatic lymphocele was ascertained. DISCUSSION: Intraoperative application of collagen-fibrin patches to the pelvic side walls does not reduce the incidence of symptomatic lymphoceles in women with gynecologic malignancies undergoing pelvic lymphadenectomy.

Predictive and Prognostic Implication of Bowel Resections During Primary Cytoreductive Surgery in Advanced Epithelial Ovarian Cancer.

OBJECTIVES: The aims of this study were to assess anastomotic leakage (AL) rate and risk factors for AL in patients with advanced epithelial ovarian cancer (EOC) undergoing cytoreductive surgery including bowel resections and to evaluate the prognostic implication of AL. METHODS: Data of 350 consecutive patients with International Federation of Gynecology and Obstetrics EOC stage IIB-IV who underwent cytoreductive surgery at the Department of General Gynecology and Gynecologic Oncology of the General Hospital of Vienna between 2003 and 2017 were collected. Within this cohort, 192 patients (54.9%) underwent at least 1 bowel resection and were further analyzed. Preoperative risk factors for AL were computed using logistic regression models. Prognostic factors for overall survival were evaluated by using log-rank tests and multivariable Cox regression model. RESULTS: Overall, the AL rate was 4.7% for patients with advanced EOC undergoing cytoreductive surgery with at least 1 bowel resection, including patients with multiple large bowel resections. The AL rate for patients with isolated rectosigmoid resection was 1.9%. In univariate analysis, the number of anastomoses per surgery (P = 0.04) was associated with the occurrence of AL. In multivariable analysis, rectosigmoid resection with additional large bowel resection was associated with a higher risk of AL compared with isolated rectosigmoid resection (P = 0.046; odds ratio, 7.23 [95% confidence interval, 1.04-50.39]). Anastomotic leakage was associated with decreased overall survival (P = 0.04) in univariate but not in multivariable survival analysis. CONCLUSIONS: Anastomotic leakage rate after rectosigmoid resection in advanced EOC is acceptably low and outweighs increased perioperative risks when performed in a high-volume institution. Nonetheless, the occurrence of AL is a severe adverse event, which even seems to negatively affect patients' overall prognosis. As no factor could be identified to clearly predict AL, extensive procedures comprising multiple bowel resections, should be avoided particularly when complete resection cannot be achieved.

Activity of Pembrolizumab in Recurrent Cervical Cancer: Case Series and Review of Published Data.

OBJECTIVES: Recent data support the use of pembrolizumab in cervical cancer. The aim of this study was to investigate pembrolizumab in heavily pretreated patients with recurrent cervical cancer. METHODS: Data from consecutive patients treated with pembrolizumab at a single academic institution were assessed. Programmed cell death ligand 1 (PD-L1) status and microsatellite instability were assessed from tumor samples. Irrespective of PD-L1 expression status, pembrolizumab was administered at fixed dose of 200 mg intravenously every 3 weeks. Treatment response was evaluated by computed tomography, using iRECIST (2017) criteria. Descriptive statistics were performed. Results from previous publications were summarized. RESULTS: In total, 11 heavily pretreated patients with recurrent cervical cancer received pembrolizumab. Of these, 2 (18%) patients showed partial response and 2 (18%) patients showed disease stabilization on computed tomography, resulting in a clinical benefit rate of 36%. These 4 patients are still on treatment and durable antitumor activity of up to 52 weeks was observed. Treatment was generally well tolerated with 1 patient showing dose-limiting toxicity. Median overall survival was 26 (3-53) weeks, and a 6-month overall survival rate of 65% was observed. Of the 5 patients with high PD-L1 expression, 3 showed response to treatment. CONCLUSIONS: Pembrolizumab shows promising activity in heavily pretreated patients with recurrent cervical cancer in a real-life clinical setting. Treatment was generally well tolerated, and adverse effects were manageable. Growing evidence supports the use of pembrolizumab in this group of patients.

Uterine and Tubal Lavage for Earlier Cancer Detection Using an Innovative Catheter: A Feasibility and Safety Study.

OBJECTIVES: Poor survival of high-grade serous pelvic cancer is caused by a lack of effective screening measures. The detection of exfoliated cells from high-grade serous pelvic cancer, or precursor lesions, is a promising concept for earlier diagnosis. However, collecting those cells in the most efficient way while fulfilling all requirements for a screening approach is a challenge. We introduce a new catheter for uterine and tubal lavage (UtL) and the clinical evaluation of its performance. METHODS/MATERIALS: In study I, the clinical feasibility of the UtL using the new catheter was examined in 93 patients admitted for gynecologic surgery under general anesthesia. In study II, the safety of the UtL procedure was assessed. The pain during and after the UtL performed under local anesthesia was rated on a visual analog scale by 22 healthy women. RESULTS: In study I, the UtL was carried out successfully in 92 (98.9%) of 93 cases by 16 different gynecologists. It was rated as easy to perform in 84.8% of patients but as rather difficult in cancer patients (odds ratio, 5.559; 95% confidence interval, 1.434-21.546; P = 0.007). For benign conditions, dilatation before UtL was associated with menopause status (odds ratio, 4.929; 95% confidence interval, 1.439-16.884; P = 0.016). In study II, the pain during UtL was rated with a median visual analog scale score of 1.6. During a period of 4 weeks after UtL, none of the participants had to use medication or developed symptoms requiring medical attention. The UtL took 6.5 minutes on average. The amount of extracted DNA was above the lower limit for a sensitive, deep-sequencing mutation analysis in all cases. CONCLUSIONS: Our studies demonstrate that the UtL, using the new catheter, is a safe, reliable, and well-tolerated procedure, which does not require elaborate training. Therefore, UtL fulfils all prerequisites to be used in a potential screening setting.

Influence of training level on cervical cone size and resection margin status at conization: a retrospective study.

OBJECTIVE: To explore whether a surgeon's training level influences the rate of incomplete resections or the amount of resected cervical tissue in women treated with large loop excision of the transformation zone (LLETZ). METHODS: The present study is a retrospective analysis of the data of women who had undergone LLETZ for cervical intraepithelial neoplasia (CIN) within the years 2004-2008 at the Medical University of Vienna. Women were grouped according to the level of training of the operating surgeon (i.e, resident or staff gynecologist) and univariate and multivariable analyses were performed to identify independent risk factors for excessive cone volume, depth and incomplete resection (i.e., positive resection margin). RESULTS: Data of 912 women were analysed. Residents had a significantly larger cone volume [median 2681 (interquartile range 1472-4109) mm3] than staff gynecologists [2094 (1309-3402) mm3] (p = 0.001) in univariate analysis. The depth of resection and the rate of incomplete resection were comparable between both groups. In a binary logistic multivariable analysis, the level of training as well as patient's age was significantly associated with a cone volume larger than 2500 mm3. CONCLUSION: Conization performed by residents as opposed to staff gynecologists does not compromise the procedure's effectiveness but may expose women to a potential additional risk for adverse obstetrical outcomes due to excessive resection of cervical tissue.

Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image-guided adaptive brachytherapy.

BACKGROUND AND PURPOSE: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients. MATERIALS AND METHODS: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV. RESULTS: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified. CONCLUSION: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting.

Prognostic value of lymph node ratio and number of positive inguinal nodes in patients with vulvar cancer.

OBJECTIVE: To estimate the prognostic significance of lymph node ratio and number of positive nodes in vulvar cancer patients. METHODS: This international multicenter retrospective study included patients diagnosed with vulvar cancer treated with inguinal lymphadenectomy. Lymph node ratio (LNR) is the ratio of the number of positive lymph nodes (LN) to the number of removed LN. Patients were stratified into risk groups according to LNR. LNR was correlated with clinical-pathological parameters. Survival analyses were performed. RESULTS: This analysis included 745 patients. In total, 292 (39.2%) patients had positive inguinal LN. The mean (SD) number of resected and positive LN was 14.1 (7.6) and 3.0 (2.9), respectively. High LNR was associated with larger tumor size and higher tumor grade. Patients with LNRs 0% (N0), >0<20%, and >20% had 5-year overall survival (OS) rates of 90.9%, 70.7%, and 61.8%, respectively (P<0.001). LNR was associated with both local and distant recurrence-free survival (P<0.001). Patients with 0, 1, 2, 3 or >3 positive lymph nodes had 5-year OS rates of 90.9%, 70.8%, 67.8%, 70.8% and 63.4% respectively (P<0.001). In multivariate analysis, LNR (P=0.01) and FIGO stage (P<0.001), were associated with OS, whereas the number of positive nodes (P=0.8), age (P=0.2), and tumor grade (P=0.7), were not. In high-risk patients, adjuvant radiotherapy was associated with improved survival. CONCLUSIONS: LNR provides useful prognostic information in vulvar cancer patients with inguinal LN resection in vulvar cancer. LNR allows for more accurate prognostic stratification of patients than number of positive nodes. LNR seems useful to select appropriate candidates for adjuvant radiation.

Preoperative C-reactive protein serum levels as a predictive diagnostic marker in patients with adnexal masses.

OBJECTIVE: To evaluate C-reactive protein (CRP) serum levels as a preoperative predictive marker for ovarian cancer in patients with adnexal masses. METHODS: CRP serum levels of 1843 adnexal masses and subsequent surgery were investigated (patients with benign ovarian tumors: n=1423; borderline tumor of the ovary [BTO]: n=83; EOC: n=337). Test characteristics and predictive values of CRP serum levels were investigated by univariate analysis and multivariate binary logistic regression models. RESULTS: Median (interquartile range) serum CRP levels in patients with benign ovarian tumors, BTO, and EOC were 0.4 (0.1-0.6)mg/dL, 0.5 (0.2-0.9)mg/dL, and 1.6 (0.5-5.4)mg/dL, respectively (p<0.001). Sensitivity and specificity of the combination of CRP and CA-125 was 80.1% and 90.8%, negative predictive value (NPV) and positive predictive value (PPV) was 92.2% and 76.9%, respectively. In univariate and multivariate analysis, CRP serum levels were independently associated with presence of BTO and EOC (HR 6.7 [5.2-8.5], p<0.001 and HR 2.2 [1.4-3.3], p<0.001). The combination of CRP and CA-125 serum levels resulted in a number needed to treat of 2.11 to detect one case of EOC or BTO. CONCLUSION: CRP serum levels independently predicted the presence of BTO and EOC in patients with suspicious adnexal masses. CRP serum levels seem to be of additional value to CA-125 in the preoperative differential diagnosis of adnexal masses and might be particularly in combination with CA-125 clinically useful.

The impact of type and number of bowel resections on anastomotic leakage risk in advanced ovarian cancer surgery.

OBJECTIVE: To identify risk factors for anastomotic leakage (AL) in patients undergoing primary advanced ovarian cancer surgery and to evaluate the prognostic implication of AL on overall survival in these patients. METHODS: We analyzed our institutional database for primary EOC and included all consecutive patients treated by debulking surgery including any type of full circumferential bowel resection beyond appendectomy between 1999 and 2015. We performed logistic regression models to identify risk factors for AL and log-rank tests and Cox proportional hazards models to evaluate the association between AL and survival. RESULTS: AL occurred in 36/800 (4.5%; 95% confidence interval [3%-6%]) of all patients with advanced ovarian cancer and 36/518 (6.9% [5%-9%]) patients undergoing bowel resection during debulking surgery. One hundred fifty-six (30.1%) patients had multiple bowel resections. In these patients, AL rate per patient was only slightly higher (9.0% [5%-13%]) than in patients with rectosigmoid resection only (6.9% [4%-10%]), despite the higher number of anastomosis. No independent predictive factors for AL were identified. AL was independently associated with shortened overall survival (HR 1.9 [1.2-3.4], p=0.01). CONCLUSION: In the present study, no predictive pre- and/or intraoperative risk factors for AL were identified. AL rate was mainly influenced by rectosigmoid resection and only marginally increased by additional bowel resections.