Search

The article focuses on the threshold for radical hysterectomy in the treatment of low-risk cervical cancer, currently between stages T1a2 and T1b1, and the criteria proposed in the SHAPE trial by Plante et al. that advocate for a simpler hysterectomy approach for tumors up to 2 cm in size combined with limited stromal invasion.

The "intermediate-risk" (IR) group of early-stage cervical cancer patients is characterized by negative pelvic lymph nodes and a combination of tumor-related prognostic risk factors such as tumor size ≥2 cm, lymphovascular space invasion (LVSI), and deep stromal invasion. However, the role of adjuvant treatment in these patients remains controversial. We investigated whether adjuvant (chemo)radiation is associated with a survival benefit after radical surgery in patients with IR cervical cancer. We analyzed data from patients with IR cervical cancer (tumor size 2–4 cm plus LVSI OR tumor size >4 cm; N0; no parametrial invasion; clear surgical margins) who underwent primary curative-intent surgery between 2007 and 2016 and were retrospectively registered in the international multicenter Surveillance in Cervical CANcer (SCCAN) study. Of 692 analyzed patients, 274 (39.6%) received no adjuvant treatment (AT−) and 418 (60.4%) received radiotherapy or chemoradiotherapy (AT+). The 5-year disease-free survival (83.2% and 80.3%; P DFS = 0.365) and overall survival (88.7% and 89.0%; P OS = 0.281) were not significantly different between the AT− and AT+ groups, respectively. Adjuvant (chemo)radiotherapy was not associated with a survival benefit after adjusting for confounding factors by case-control propensity score matching or in subgroup analyses of patients with tumor size ≥4 cm and <4 cm. In univariable analysis, adjuvant (chemo)radiotherapy was not identified as a prognostic factor in any of the subgroups (full cohort: P DFS = 0.365; P OS = 0.282). Among patients with IR early-stage cervical cancer, radical surgery alone achieved equal disease-free and overall survival rates to those achieved by combining radical surgery with adjuvant (chemo)radiotherapy. • We investigated the survival benefit of adjuvant therapy (AT) after radical surgery in intermediate-risk (IR) cervical cancer. • Of 692 IR cervical cancer patients in the SCANN study, 60.4% received AT (AT+) and 39.6% did not (AT−). • 5-year DFS (83.2% vs. 80.3%) and OS (88.7% vs. 89.0%) rates were similar in the AT− and AT+ groups. • AT did not confer a significant survival benefit even after applying propensity score matching for confounding factors. [ABSTRACT FROM AUTHOR]

Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS. Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS. The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%–44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675–0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%. We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients. • The 5-year post-recurrence disease-specific survival (PR-DSS) rate was 39.1% in patients with early-stage cervical cancer. • The strongest factors for PR-DSS were primary tumour size and the presence of symptoms at diagnosis of recurrence. • The presence of symptoms at recurrence remained a significant prognostic factor after correction for lead-time bias. • PR-DSS was best in patients without LN involvement or LVSI suffering from solitary asymptomatic recurrence. [ABSTRACT FROM AUTHOR]

Current guidelines for surveillance strategy in cervical cancer are rigid, recommending the same strategy for all survivors. The aim of this study was to develop a robust model allowing for individualised surveillance based on a patient's risk profile. Data of 4343 early-stage patients with cervical cancer treated between 2007 and 2016 were obtained from the international SCCAN (Surveillance in Cervical Cancer) consortium. The Cox proportional hazards model predicting disease-free survival (DFS) was developed and internally validated. The risk score, derived from regression coefficients of the model, stratified the cohort into significantly distinctive risk groups. On its basis, the annual recurrence risk model (ARRM) was calculated. Five variables were included in the prognostic model: maximal pathologic tumour diameter; tumour histotype; grade; number of positive pelvic lymph nodes; and lymphovascular space invasion. Five risk groups significantly differing in prognosis were identified with a five-year DFS of 97.5%, 94.7%, 85.2% and 63.3% in increasing risk groups, whereas a two-year DFS in the highest risk group equalled 15.4%. Based on the ARRM, the annual recurrence risk in the lowest risk group was below 1% since the beginning of follow-up and declined below 1% at years three, four and >5 in the medium-risk groups. In the whole cohort, 26% of recurrences appeared at the first year of the follow-up, 48% by year two and 78% by year five. The ARRM represents a potent tool for tailoring the surveillance strategy in early-stage patients with cervical cancer based on the patient's risk status and respective annual recurrence risk. It can easily be used in routine clinical settings internationally. • The recurrence risk model in cervical cancer was composed of five prognostic factors. • The developed annual recurrence risk model (ARRM) stratifies the cohort into five significantly distinctive risk groups. • The ARRM represents a powerful tool for tailoring of appropriate surveillance strategy. • The ARRM can easily be used in routine clinical settings internationally. [ABSTRACT FROM AUTHOR]

DCVAC/OvCa is an active cellular immunotherapy designed to stimulate an immune response against ovarian cancer. We explored the safety and efficacy of DCVAC/OvCa plus carboplatin and gemcitabine in platinum-sensitive ovarian cancer. In this open-label, parallel-group, phase 2 trial (ClinicalTrials.gov number NCT02107950), patients with platinum-sensitive ovarian cancer relapsing after first-line chemotherapy were randomized to DCVAC/OvCa and chemotherapy or chemotherapy alone. DCVAC/OvCa was administered every 3–6 weeks (10 doses). Endpoints included safety, progression-free survival (PFS; primary efficacy endpoint) and overall survival (OS; secondary efficacy endpoint). Between November 2013 and May 2015, 71 patients were randomized to chemotherapy in combination with DCVAC/OvCa or to chemotherapy alone. Treatment-emergent adverse events related to DCVAC/OvCa, leukapheresis and chemotherapy occurred in six (16.2%), two (5.4%), and 35 (94.6%) patients in the DCVAC/OvCa group. Chemotherapy-related events occurred in all patients in the chemotherapy group. Seven patients in the DCVAC/OvCa group were excluded from primary efficacy analyses due to failure to receive ≥1 dose of DCVAC/OvCa. PFS was not improved (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.42–1.28, P = 0.274, data maturity 78.1%). Median OS was significantly prolonged (by 13.4 months) in the DCVAC/OvCa group (HR 0.38, 95% CI 0.20–0.74, P = 0.003; data maturity 56.3%). A signal for enhanced surrogate antigen-specific T-cell activity was seen with DCVAC/OvCa. DCVAC/OvCa combined with chemotherapy had a favorable safety profile in patients with platinum-sensitive ovarian cancer. DCVAC/OvCa did not improve PFS, but the exploratory analyses revealed OS prolongation and enhanced surrogate antigen-specific T-cell activity. • Randomized trial of DCVAC/OvCa, dendritic cell-based immunotherapy in platinum-sensitive ovarian cancer. • The addition of DCVAC/OvCa to second-line chemotherapy had a favorable safety profile. • DCVAC/OvCa did not improve progression-free survival, but did prolong overall survival by 13.4 months. • DVCAC/OvCa plus chemotherapy enhanced surrogate T-cell activity. [ABSTRACT FROM AUTHOR]

Background: Models predicting recurrence risk (RR) of cervical cancer are used to tailor adjuvant treatment after radical surgery. The goal of our study was to compare available prognostic factors and to develop a prognostic model that would be easy to standardise and use in routine clinical practice.Methods: All consecutive patients with early-stage cervical cancer treated by primary surgery in a single referral centre (01/2007-12/2016) were eligible if assessed by standardised protocols for pre-operative imaging and pathology. Fifteen prognostic markers were evaluated in 379 patients, out of which 320 lymph node (LN)-negative.Results: The best predictive model for the whole cohort entailed a combination of tumour-free distance (TFD) ≤ 3.5 mm and LN positivity, which separated two subgroups with a substantially distinct RR 36% and 6.5%, respectively. In LN-negative patients, a combination of TFD ≤ 3.5 mm and adenosquamous tumour type separated a group of nine patients with RR 33% from the rest of the group with 6% RR.Conclusions: A newly identified prognostic marker, TFD, surpassed all traditional tumour-related markers in the RR assessment. Predictive models combining TFD, which can be easily accessed on pre-operative imaging, with LN status or tumour type can be used in daily practice and can help to identify patients with the highest RR. [ABSTRACT FROM AUTHOR]

SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. Trial registration: ClinicalTrials.gov (NCT02494063). We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases. • Bilateral sentinel lymph node (SLN) detection over 90% can be achieved in sites with previous experience with SLN biopsy. • Majority of SLN are located in the pelvis below the level of iliac vessel bifurcation. • Risk of isolated positive SLN cranial to iliac vessel bifurcation is very low (2%). • SLN frozen section detects about half of positive SLN if macrometastases and micrometastases are considered N1. [ABSTRACT FROM AUTHOR]

Context.-- Ultrastaging of sentinel lymph nodes (SLNs) is a crucial aspect in the approach to SLN processing. No consensual protocol for pathologic ultrastaging has been approved by international societies to date. Objective.-- To provide a review of the ultrastaging protocol and all its aspects related to the processing of SLNs in patients with cervical cancer. Data Sources.-- In total, 127 publications reporting data from 9085 cases were identified in the literature. In 24% of studies, the information about SLN processing is entirely missing. No ultrastaging protocol was used in 7% of publications. When described, the differences in all aspects of SLN processing among the studies and institutions are substantial. This includes grossing of the SLN, which is not completely sliced and processed in almost 20% of studies. The reported protocols varied in all aspects of SLN processing, including the thickness of slices (range, 1-5 mm), the number of levels (range, 0--cut out until no tissue left), distance between the levels (range, 40-1000 μm), and number of sections per level (range, 1-5). Conclusions.-- We found substantial differences in protocols used for SLN pathologic ultrastaging, which can impact sensitivity for detection of micrometastases and even small macrometastases. Since the involvement of pelvic lymph nodes is the most important negative prognostic factor, such profound discrepancies influence the referral of patients to adjuvant radiotherapy and could potentially cause treatment failure. It is urgent that international societies agree on a consensual protocol before SLN biopsy without pelvic lymphadenectomy is introduced into routine clinical practice. [ABSTRACT FROM AUTHOR]

Cervical cancer is increasingly diagnosed in women who have not yet completed their reproductive plans. For women with early-stage disease (FIGO stage IA1-IB1), fertility-sparing procedures, such as conization, trachelectomy or radical trachelectomy, represent the treatments of choice. However, women who undergo repeated conization or trachelectomy represent a challenge for obstetricians because they are at increased risk of infertility, mid-trimester miscarriage, preterm premature rupture of membranes and preterm delivery. So far, the evidence-based guidance on the management of these pregnancies is limited. This article reviews the literature discussing pregnancy management in women after fertility-sparing surgery for early cervical cancer. Although the evidence is limited, certain measures are desirable, including screening and treatment of asymptomatic bacteriuria, screening for cervical incompetence and progressive cervical shortening by transvaginal ultrasonography, and fetal fibronectin testing. Vaginal progesterone supplementation should be primary prevention for all women after trachelectomy. Women with a history of preterm delivery or late miscarriage may benefit from cervical cerclage. Elective delivery by cesarean section in the early-term period is desirable. [ABSTRACT FROM AUTHOR]

Background: A population-based cervical cancer screening programme is implemented in the Czech Republic. However, participation is insufficient among women over 50 years. This study aimed to estimate the potential improvement in participation through directly mailed HPV self-sampling kits (HPVssk) compared with standard invitation letters in women aged 50-65 non-participating in screening. Methods: The study recruited 1564 eligible women (no cervical cancer screening in the last 3 years or more, no previous treatment associated with cervical lesions or cervical cancer). Eight hundred women were mailed with an HPVssk (HPVssk group), and 764 women were sent a standard invitation letter (control group) inviting them to a routine screening (Pap test). The primary outcome was a comparison of the overall participation rate between study groups using a binominal regression model. Results: The participation rate in the HPVssk group was 13.4% [95% confidence interval (CI) 11.2-15.9%; 7.4% of women returned the HPVssk and 6.0% attended gynaecological examination] and 5.0% (95% CI 3.6-6.8%) in the control group. Using the binominal regression model, the difference between the groups was estimated as 7.6% (95% CI 5.0-10.2%; P<0.001). In the HPVssk group, 22% of women who returned HPVssk had a positive result and 70% of them underwent a follow-up examination. Conclusions: Compared with traditional invitation letters, the direct mailing of the HPVssk achieved a significantly higher participation rate, along with a notable HPV positivity rate among HPVssk responders. This approach offers a potentially viable method for engaging women who have not yet attended a cervical screening programme. [ABSTRACT FROM AUTHOR]

Gouveia R, Cibula D, Soukup V, Hanuš T. Melanoma of the female urethra. Melanoma of the urethra, or melanomas originating from the gynecological tract, are extremely rare and aggressive malignant tumors, with high metastatic potential and a poor prognosis, affecting almost exclusively elder female patients. The aim of this case report is to present the case of a patient with urethral and bladder melanoma metastasis from a previously treated primary melanoma of the vulva. Radical cystourethrectomy and Bricker-Nesbit ureteroileostomy and bilateral extended pelvic lymphadenectomy were performed. Histology report confirmed melanoma invading the urethra and bladder, all removed lymphatic nodes were negative. On the 6-month follow-up PET-CT there was no evidence of residual disease. We concluded that in the presence of such a suspicious urethral lesion, prompt diagnosis to differentiate from other benign lesions and early radical management with careful post-operative follow-up schedules should be the standard treatment. [ABSTRACT FROM AUTHOR]

Abstract Sentinel lymph node (SLN) biopsy has been increasingly used in the management of early-stages cervical cancer instead of systematic pelvic lymph node dissection (PLND). The aim of this article is to give a critical overview of key aspects related to this concept, such as a necessity for reliable detection of micrometastases (MIC) in SLN and the requirements for SLN pathologic ultrastaging, low accuracy of intraoperative detection of SLN involvement, and still a limited evidence of oncological safety of the replacement of PLND by SLN biopsy only in ≥IB1 tumours due to unknown risk of MIC in non-SLN pelvic lymph nodes in patients with negative SLN, and absence of any prospective evidence. Highlights • Detection of micrometastases increases sensitivity of SLN, so SLN ultrastaging should be performed if PLND is avoided. • Intraoperative SLN evaluation fails to detect 30–50% of metastases. • Micrometastases in SLN is associated with decreased survival equivalent to macrometastases. • The risk of micrometastases in pelvic LN in cases with negative SLN is not known. • There is no prospective evidence on safety of SLN only concept in cervical cancer. [ABSTRACT FROM AUTHOR]

Abstract Objectives The role of adjuvant radiotherapy for lymph node-negative stage IB patients with tumor-related negative prognostic factors is not uniformly accepted. It is advocated based on the GOG 92 trial, which was initiated in 1989. The aim of the current study is to report the oncological outcome of "intermediate risk" patients treated by tailored surgery without adjuvant radiotherapy. Data from two institutions that refer these patients for adjuvant radiotherapy served as a control group. Methods Included were patients with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, who had negative pelvic lymph nodes but a combination of negative prognostic factors adopted from the GOG 92 trial. Data were obtained from prospectively collected databases of three institutions. Radical surgery was a single-treatment modality in one of them and in the remaining two institutes it was followed by adjuvant chemoradiation. Results In 127 patients who received only radical surgery, with a median follow-up of 6.1 years, the local recurrence rate was 1.6% (2 cases), and total recurrence was 6.3% (8 cases). Disease-specific survival at 5 years was 95.7% (91.9%; 99.4%) and 91% (83.7%; 98.3%) at 10 years. The only significant factor for disease-specific survival was tumor size ≥4 cm (P = 0.032). The recurrence rate, local control or overall survival did not differ from the control group. Adjuvant radiotherapy was not a significant prognostic factor within the whole cohort. Conclusions An excellent oncological outcome, especially local control, can be achieved by both radical surgery or combined treatment in stage IB lymph node-negative cervical cancer patients with negative prognostic factors. The substantially better outcome than in the GOG 92 trial can be attributed to more accurate pre-operative and pathological staging and an improvement in surgical techniques. Highlights • Intermediate risk patients with IB N0 cervical cancer have excellent oncological outcome after radical surgery only. • Recurrence rate in this group was 6% and local recurrence rate 2%, without adjuvant treatment. • No significant differences in oncological outcome were found between the groups with or without adjuvant radiotherapy. • Substantially better outcome was reported in our groups in comparison to the original GOG 92 trial. [ABSTRACT FROM AUTHOR]

In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives. These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined. [ABSTRACT FROM AUTHOR]

Background: HNF-1β is a commonly used marker in the differential diagnosis of clear cell carcinoma of the ovary and endometrium. Recent studies have found HNF-1β expression to a lesser extent in other ovarian and endometrial tumors including endometrioid, mucinous and, rarely, serous carcinoma. Regarding cervical carcinoma, HNF-1β expression has been mentioned exceptionally in mesonephric and some other types of adenocarcinoma. However, a systematic analysis of HNF-1β expression in cervical carcinomas has not been performed to date. Methods: We analyzed HNF-1β expression in 155 cervical carcinomas (including 56 adenocarcinomas, 85 squamous cell carcinomas and 14 undifferentiated carcinomas). Expression of HNF-1β was correlated with the expression of other markers including estrogen receptors, progesterone receptors, CEA, p63, p40, p16, and D2-40. Results: Adenocarcinomas showed expression of HNF-1β in 42/56 cases (75%), CEA in 48/56 cases (85.7%), p63 in 4/56 cases (7.2%), p40 in 2/56 cases (3.6%), estrogen receptors in 9/56 cases (16.1%), progesterone receptors in 5/56 cases (8.9%), p16 in 56/56 (100%) cases, and D2-40 in 0/56 cases (0%). Squamous cell carcinomas showed expression of HNF-1β in 2/85 cases (2.35%), CEA in 77/85 cases (90.6%), p63 and p40 in 85/85 cases (100%), estrogen receptors in 9/85 cases (10.6%), progesterone receptors in 1/85 cases (1.2%), p16 in 84/85 cases (98.8%), and D2-40 in 45/84 cases (53.6%). Undifferentiated carcinomas showed expression of HNF-1β in 2/14 cases (14.3%), CEA in 8/14 cases (57.1%), p16 in 14/14 cases (100%), hormone receptors in 0/13 cases (0%), p63 in 7/14 cases (50%), p40 in 5/14 cases (35.7%), and D2-40 in 1/14 cases (7.1%). Conclusions: In cervical carcinoma, expression of HNF-1β is mostly restricted to adenocarcinomas and can be used as an auxiliary adenocarcinoma marker in the differential diagnosis of poorly differentiated cervical carcinomas. HNF-1β as an adenocarcinoma marker and p63/p40 and D2-40 as a squamous cell carcinoma markers are highly specific with variable sensitivity. Optimal results can be achieved using these markers in a panel. [ABSTRACT FROM AUTHOR]

Background: HNF-1β is a commonly used marker in the differential diagnosis of clear cell carcinoma of the ovary and endometrium. Recent studies have found HNF-1β expression to a lesser extent in other ovarian and endometrial tumors including endometrioid, mucinous and, rarely, serous carcinoma. Regarding cervical carcinoma, HNF-1β expression has been mentioned exceptionally in mesonephric and some other types of adenocarcinoma. However, a systematic analysis of HNF-1β expression in cervical carcinomas has not been performed to date. Methods: We analyzed HNF-1β expression in 155 cervical carcinomas (including 56 adenocarcinomas, 85 squamous cell carcinomas and 14 undifferentiated carcinomas). Expression of HNF-1β was correlated with the expression of other markers including estrogen receptors, progesterone receptors, CEA, p63, p40, p16, and D2-40. Results: Adenocarcinomas showed expression of HNF-1β in 42/56 cases (75%), CEA in 48/56 cases (85.7%), p63 in 4/56 cases (7.2%), p40 in 2/56 cases (3.6%), estrogen receptors in 9/56 cases (16.1%), progesterone receptors in 5/56 cases (8.9%), p16 in 56/56 (100%) cases, and D2-40 in 0/56 cases (0%). Squamous cell carcinomas showed expression of HNF-1β in 2/85 cases (2.35%), CEA in 77/85 cases (90.6%), p63 and p40 in 85/85 cases (100%), estrogen receptors in 9/85 cases (10.6%), progesterone receptors in 1/85 cases (1.2%), p16 in 84/85 cases (98.8%), and D2-40 in 45/84 cases (53.6%). Undifferentiated carcinomas showed expression of HNF-1β in 2/14 cases (14.3%), CEA in 8/14 cases (57.1%), p16 in 14/14 cases (100%), hormone receptors in 0/13 cases (0%), p63 in 7/14 cases (50%), p40 in 5/14 cases (35.7%), and D2-40 in 1/14 cases (7.1%). Conclusions: In cervical carcinoma, expression of HNF-1β is mostly restricted to adenocarcinomas and can be used as an auxiliary adenocarcinoma marker in the differential diagnosis of poorly differentiated cervical carcinomas. HNF-1β as an adenocarcinoma marker and p63/p40 and D2-40 as a squamous cell carcinoma markers are highly specific with variable sensitivity. Optimal results can be achieved using these markers in a panel. [ABSTRACT FROM AUTHOR]

Summary Background The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. Methods In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m 2 , administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m 2 on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov , number NCT01081951 , and has been completed. Findings Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12·2 months [95% CI 9·7–15·0]) than in the chemotherapy alone group (median 9·6 months [95% CI 9·1–9·7) (HR 0·51 [95% CI 0·34–0·77]; p=0·0012), especially in patients with BRCA mutations (HR 0·21 [0·08–0·55]; p=0·0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) [ABSTRACT FROM AUTHOR]

Simple Summary: Maximal-effort debulking surgery is the recommended approach for advanced-stage ovarian cancer. The role of imaging is to provide a preoperative systematic and structured report of tumour dissemination with special emphasis on key sites that preclude optimal resectability in ovarian cancer surgery. Imaging methods cannot reliably detect small volume carcinomatosis but yield high diagnostic performance for detecting bulky disease at critical sites for cytoreduction and can thus be reliably used to avoid unnecessary explorations. Although diagnostic laparoscopy may directly visualize intraperitoneal involvement, it has inherent limitations when investigating tumours behind the gastrosplenic ligament, in the lesser sac, mesenteric root or when exploring the retroperitoneum. The major benefit of laparoscopy appears as an ultimate triage step in situations where the imaging diagnosis is uncertain regarding resectability and the presence of diffuse small-volume carcinomatosis. Maximal-effort upfront or interval debulking surgery is the recommended approach for advanced-stage ovarian cancer. The role of diagnostic imaging is to provide a systematic and structured report on tumour dissemination with emphasis on key sites for resectability. Imaging methods, such as pelvic and abdominal ultrasound, contrast-enhanced computed tomography, whole-body diffusion-weighted magnetic resonance imaging and positron emission tomography, yield high diagnostic performance for diagnosing bulky disease, but they are less accurate for depicting small-volume carcinomatosis, which may lead to unnecessary explorative laparotomies. Diagnostic laparoscopy, on the other hand, may directly visualize intraperitoneal involvement but has limitations in detecting tumours beyond the gastrosplenic ligament, in the lesser sac, mesenteric root or in the retroperitoneum. Laparoscopy has its place in combination with imaging in cases where ima-ging results regarding resectability are unclear. Different imaging models predicting tumour resectability have been developed as an adjunctional objective tool. Incorporating results from tumour quantitative analyses (e.g., radiomics), preoperative biopsies and biomarkers into predictive models may allow for more precise selection of patients eligible for extensive surgery. This review will discuss the ability of imaging and laparoscopy to predict non-resectable disease in patients with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate the sensitivity of sentinel node (SN) ultrastaging and to define parameters that may reduce the overall false-negative rate in women with early-stage cervical cancer. Methods: We analyzed data from a large retrospective multicenter cohort group with FIGO stages IA–IIB cervical cancer in whom at least one SN was identified and systematic pelvic lymphadenectomy was uniformly performed. All who were SN negative by initial evaluation were subjected to ultrastaging. Results: In all, 645 patients were evaluable. SN were detected bilaterally in 72% of cases and unilaterally in 28%. Patients with optimal bilateral SN detection were significantly more likely to have any metastasis detected (33.3% vs. 19.2%; P <0.001) as well as micrometastasis detected in their SN (39.6% vs. 11.4%). SN ultrastaging resulted in a low overall false-negative rate of 2.8% (whole group) and an even lower false-negative rate of 1.3% for patients with optimal bilateral mapping. Patients with false-negative SN after ultrastaging had a higher prevalence of LVSI and more frequent unilateral SN detection. Sensitivity of SN ultrastaging was 91% (95% CI: 86%–95%) for the whole group and 97% (95% CI: 91%–99%) in the subgroup with bilateral SN detection. Conclusion: These data confirm previous observations that optimal bilateral SN detection substantially decreases the false negative rate of SN ultrastaging and increases detection of micrometastasis. In patients with bilateral SN detection, the sensitivity of SN ultrastaging is not reduced in more advanced stages of the disease. SN mapping and ultrastaging should become standard practice in the surgical management of early-stage cervical cancer. [Copyright &y& Elsevier]

Background: The aim was to evaluate changes of bone mineral density (BMD) and markers of bone turnover in healthy adolescents, and in adolescent users of combined oral contraceptives (COCs) with different ethinylestradiol (EE) contents. Methods: Inthis prospective crossover study,56healthy females (15-19.5 years)with desire touse hormonal contraception were randomized to COC with either 30 or 15 mg of EE in crossover design of 9-month intervention each in reverse order. Nonusers of the same age (nZ28) served as controls. BMD at lumbar spine (LS), total femur, femoral neck, distal radius, and total body, and serummarkers (N-propeptide of type I procollagen, and type I collagen C-telopeptide) were measured at baseline and after 9 and 18 months. Results: In COC nonusers, BMD significantly increased at LS and radius, whilemarkers decreased. In COC users, BMD did not increase, with the exception of LS BMD in the 30 mg COC group (P!0.05). In the crossover design, a difference between the low- and very low-dose COC users was found in LS BMD changes (P!0.05),where increase in BMD was more impaired in the 15 mg COC users. The skeletal effects of COC remained significant after adjustments for age and smoking status. Markers declined faster in COC users during the first period, while they remained stable or even increased during the second 9 months. Conclusion: Physiological acquisition of LS BMD during adolescent age may be prevented by use of COC, especially those containing very low dose of EE. [ABSTRACT FROM AUTHOR]

A recently published meta-analysis of 21 studies confirmed a protective effect of tubal ligation on the risk of invasive ovarian cancer. This protective measure has received little attention, particularly due to the elusive underlying mechanism. In this commentary we discuss available data concerning the contribution of different potential mechanisms by which tubal ligation might prevent ovarian cancer. Included were studies published in English, identified through a literature search using PubMed and EMBASE. Four main mechanisms are discussed: (a) a screening effect, (b) alteration of ovarian function, (c) a mechanical barrier against ascending carcinogenic agents and (d) prevention of endometrial and proximal Fallopian tube cell ascent. There are arguments supporting the major role of a mechanical barrier to the ascent of endometrial cells into the peritoneal cavity for decreasing risk of ovarian cancer after tubal ligation. Prevention of retrograde transport of carcinogenic substances from the vagina may be an additional mechanism. [ABSTRACT FROM AUTHOR]

Objectives To assess current and past contraceptive usage, awareness of and satisfaction with available methods, and sexual and reproductive behaviour of women in 14 European countries (Spain, Italy, UK, France, Germany, Sweden, Denmark, Norway, the Czech Republic, Austria, Estonia, Latvia, Lithuania, and the Russian Federation). Methods A random sample of women aged 15–49 years underwent web-based or computer-aided face-to-face interviews in June 2006. All data were weighted to correct for differences between the samples surveyed in each country relative to their general population, and further weighted relative to the size of the overall female population across the participating countries. Results A total of 11,490 women participated in the study. The mean age at first sexual intercourse ranged between 16.5 and 18.5 years. The use of contraception at first intercourse varied significantly across Europe – the rates were the highest in Germany (76%) and France (72%), and the lowest in Russia, the Czech Republic and the Baltic States (29–40%). There was considerable heterogeneity in the general pattern of current contraceptive usage between countries. Oral contraceptives were the most popular current method of contraception, with usage rates highest in France (49%) and the Czech Republic (44%) and lowest in Russia, the Baltic States and Spain (15–18%). The current absence of contraception was fairly consistent across countries, ranging from 21–30%. However, Russia (57%) and the Baltic States (50%) had the highest proportion of women using either no contraception or ‘other methods’ (mostly methods considered unreliable). Conclusions Oral contraceptives remain a popular method of contraception in Europe; however, great differences exist in contraception acceptance and in the rates of use of the various methods. A sizeable proportion of women do not currently use contraception or use contraceptive methods considered to be unreliable. [ABSTRACT FROM AUTHOR]

Objectives: To assess current and past contraceptive usage, awareness of and satisfaction with available methods, and sexual and reproductive behaviour of women in 14 European countries (Spain, Italy, UK, France, Germany, Sweden, Denmark, Norway, the Czech Republic, Austria, Estonia, Latvia, Lithuania, and the Russian Federation).Methods: A random sample of women aged 15-49 years underwent web-based or computer-aided face-to-face interviews in June 2006. All data were weighted to correct for differences between the samples surveyed in each country relative to their general population, and further weighted relative to the size of the overall female population across the participating countries.Results: A total of 11,490 women participated in the study. The mean age at first sexual intercourse ranged between 16.5 and 18.5 years. The use of contraception at first intercourse varied significantly across Europe - the rates were the highest in Germany (76%) and France (72%), and the lowest in Russia, the Czech Republic and the Baltic States (29-40%). There was considerable heterogeneity in the general pattern of current contraceptive usage between countries. Oral contraceptives were the most popular current method of contraception, with usage rates highest in France (49%) and the Czech Republic (44%) and lowest in Russia, the Baltic States and Spain (15-18%). The current absence of contraception was fairly consistent across countries, ranging from 21-30%. However, Russia (57%) and the Baltic States (50%) had the highest proportion of women using either no contraception or 'other methods' (mostly methods considered unreliable).Conclusions: Oral contraceptives remain a popular method of contraception in Europe; however, great differences exist in contraception acceptance and in the rates of use of the various methods. A sizeable proportion of women do not currently use contraception or use contraceptive methods considered to be unreliable. [ABSTRACT FROM AUTHOR]

Objective. The clinical symptoms of nonclassic adrenal hyperplasia (NCAH) are identical with polycystic ovary syndrome (PCOS). The aim of our study was to determine the prevalence of nonclassic adrenal hyperplasia (21-hydroxylase-deficiency) in hyperandrogenic women, its biochemical, endocrine and clinical characteristics and to compare them with parameters of patients with ovarian hyperandrogenism. Methods. Since 1999, 298 patients with elevation of at least one androgen and manifestation of one of the clinical androgenic symptoms (oligo/amenorrhea, hirsutism or acne) have been identified in our database. A diagnosis of NCAH was considered when the basal or stimulated 17-hydroxyprogesterone was elevated. Results. Only eight patients were identified as having 21- hydroxylase deficient NCAH in the whole group of 298 hyperandrogenic women. Hirsutism and acne were found only in three, two patients, five of them had oligo/amenorrhea. Seven patients had both elevated basal and stimulated 17-hydroxyprogesterone, while in one case only elevation of stimulated level was found. All of the NCAH patients had elevated concentrations of testosterone, six DHEA, lower SHBG was found in four patients. Surprisingly, none of the NCAH patients had increased DHEAS. Conclusion. In our study, the prevalence of NCAH in hyperandrogenic women was 2.68%. Their leading symptom was oligomenorrhea, skin androgenic disorders were a minor clinical problem. None of the NCAH patients had an elevated DHEAS, the androgen dominantly produced by the adrenal glands. [ABSTRACT FROM AUTHOR]

Abstract: This study addresses the question of whether changes in the biosynthesis and metabolism of neuroactive pregnanolone isomers (PIs) might participate in the timing of parturition in humans. The time profiles of unconjugated allopregnanolone (3α-hydroxy-5α-pregnan-20-one, P3α5α), pregnanolone (3α-hydroxy-5β-pregnan-20-one, P3α5β), isopregnanolone (3β-hydroxy-5α-pregnan-20-one, P3β5α) and epipregnanolone (3β-hydroxy-5β-pregnan-20-one, P3β5β), pregnenolone, their polar conjugates, progesterone, 5α-dihydroprogesterone (P5α), and 5β-dihydroprogesterone (P5β) were monitored in the plasma of 30 healthy women during the third trimester of pregnancy, at 1-week intervals from the 30th week of gestation using GC–MS. Changes in the steroid levels were evaluated by two-way ANOVA with gestational age and subject as independent factors. The mean concentrations of free PIs ranged from 2 to 50nmol/L, while the mean levels of their polar conjugates were 40–100× higher. The ratio of 5α-PIs to progesterone significantly but inconspicuously culminated in the 35th week. The decelerating biosynthesis of free 5β-PIs from the 31st week and their escalating sulfation was found from the 30th week. The changes were particularly evident in the second most abundant PI pregnanolone that may, like the allopregnanolone, sustain the pregnancy via attenuation of hypothalamic GABAA-receptors and prevent uterine contractility via binding to nuclear pregnane X receptor. [Copyright &y& Elsevier]

Simple Summary: Lower-limb lymphedema (LLL) is a well-recognized adverse outcome of the surgical management of cervical cancer. Recently, sentinel lymph node (SLN) biopsy has emerged as an alternative procedure to systematic pelvic lymphadenectomy (PLND) aiming to decrease the risk of complications, especially LLL development. Our study represents the first prospective analysis of LLL incidence in cervical cancer patients after a uterine procedure with SLN biopsy, without systematic PLND. In an international multicenter trial SENTIX, the group of 150 patients was prospectively evaluated using both objective and subjective LLL assessments in 6 months intervals for 2 years. Contrary to the expectations, our results showed that SLN biopsy does not eliminate the risk of LLL development which occurred in a mild or moderate stage in about 26% of patients with a median interval to the onset of 9 months. Background: To prospectively assess LLL incidence among cervical cancer patients treated by uterine surgery complemented by SLN biopsy, without PLND. Methods: A prospective study in 150 patients with stage IA1–IB2 cervical cancer treated by uterine surgery with bilateral SLN biopsy. Objective LLL assessments, based on limb volume increase (LVI) between pre- and postoperative measurements, and subjective patient-perceived swelling were conducted in six-month periods over 24-months post-surgery. Results: The cumulative incidence of LLL at 24 months was 17.3% for mild LLL (LVI 10–19%), 9.2% for moderate LLL (LVI 20–39%), while only one patient (0.7%) developed severe LLL (LVI > 40%). The median interval to LLL onset was nine months. Transient edema resolving without intervention within six months was reported in an additional 22% of patients. Subjective LLL was reported by 10.7% of patients, though only a weak and partial correlation between subjective-report and objective-LVI was found. No risk factor directly related to LLL development was identified. Conclusions: The replacement of standard PLND by bilateral SLN biopsy in the surgical treatment of cervical cancer does not eliminate the risk of mild to moderate LLL, which develops irrespective of the number of SLN removed. [ABSTRACT FROM AUTHOR]

Simple Summary: Constant technological development of modern imaging has led to substantial improvement in management and decision-making in the diagnostic and prognostic process of many different neoplasms. This also applies to cervical cancer. The main evidence, providing the base of recently updated ESGO-ESTRO-ESP recommendations (2023) on the management and treatment of cervical cancer, has been evaluated and reviewed in this paper. Ultrasound has been suggested as a valid alternative to MRI in primary diagnostic workup of cervical cancer if performed by an expert sonographer. Additionally, CT or PET/CT exhibits a substantial role in assessing the extrapelvic spread of the disease in locally advanced cases or when suspicious lymph nodes are detected. The purpose of this article is to provide a comprehensive review of the role of different imaging techniques in staging settings, displaying a focused interest in the use of ultrasound. Following the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) joint guidelines (2018) for the management of patients with cervical cancer, treatment decisions should be guided by modern imaging techniques. After five years (2023), an update of the ESGO-ESTRO-ESP recommendations was performed, further confirming this statement. Transvaginal/transrectal ultrasound (TRS/TVS) or pelvic magnetic resonance (MRI) enables tumor delineation and precise assessment of its local extent, including the evaluation of the depth of infiltration in the bladder- or rectal wall. Additionally, both techniques have very high specificity to confirm the presence of metastatic pelvic lymph nodes but fail to exclude them due to insufficient sensitivity to detect small-volume metastases, as in any other currently available imaging modality. In early-stage disease (T1a to T2a1, except T1b3) with negative lymph nodes on TVS/TRS or MRI, surgicopathological staging should be performed. In all other situations, contrast-enhanced computed tomography (CECT) or 18F-fluorodeoxyglucose positron emission tomography combined with CT (PET-CT) is recommended to assess extrapelvic spread. This paper aims to review the evidence supporting the implementation of diagnostic imaging with a focus on ultrasound at primary diagnostic workup of cervical cancer. [ABSTRACT FROM AUTHOR]

In this study, we conducted a comparative analysis of demographic, histopathological, and sonographic characteristics between pre- and postmenopausal women diagnosed with endometrial cancer, while also examining sonographic and anthropometric features in 'low' and 'intermediate/high-risk' cases, stratified by menopausal status. Our analysis, based on data from the International Endometrial Tumor Analysis (IETA) 4 cohort comprising 1538 women (161 premenopausal, 1377 postmenopausal) with biopsy-confirmed endometrial cancer, revealed that premenopausal women, compared to their postmenopausal counterparts, exhibited lower parity (median 1, IQR 0–2 vs. 1, IQR 1–2, p = 0.001), a higher family history of colon cancer (16% vs. 7%, p = 0.001), and smaller waist circumferences (median 92 cm, IQR 82–108 cm vs. 98 cm, IQR 87–112 cm, p = 0.002). Premenopausal women more often had a regular endometrial–myometrial border (39% vs. 23%, p < 0.001), a visible endometrial midline (23% vs. 11%, p < 0.001), and undefined tumor (73% vs. 84%, p = 0.001). Notably, despite experiencing a longer duration of abnormal uterine bleeding (median 5 months, IQR 3–12 vs. 3 months, 2–6, p < 0.001), premenopausal women more often had 'low' risk disease (78% vs. 46%, p < 0.001). Among sonographic and anthropometric features, only an irregular endometrial–myometrial border was associated with 'intermediate/high' risk in premenopausal women. Conversely, in postmenopausal women, multiple features correlated with 'intermediate/high' risk disease. Our findings emphasize the importance of considering menopausal status when evaluating sonographic features in women with endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Little is known about factors contributing to early post-operative morbidity and mortality in low and middle income countries with a paucity of data limiting global efforts to improve gynaecological cancer care. In this multicentre, international prospective cohort study of women undergoing gynaecological oncology surgery, we show that low and middle versus high income countries were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Gynaecological malignancies affect women in low and middle income countries (LMICs) at disproportionately higher rates compared with high income countries (HICs) with little known about variations in access, quality, and outcomes in global cancer care. Our study aims to evaluate international variation in post-operative morbidity and mortality following gynaecological oncology surgery between HIC and LMIC settings. Study design consisted of a multicentre, international prospective cohort study of women undergoing surgery for gynaecological malignancies (NCT04579861). Multilevel logistic regression determined relationships within three-level nested-models of patients within hospitals/countries. We enrolled 1820 patients from 73 hospitals in 27 countries. Minor morbidity (Clavien–Dindo I–II) was 26.5% (178/672) and 26.5% (267/1009), whilst major morbidity (Clavien–Dindo III–V) was 8.2% (55/672) and 7% (71/1009) for LMICs/HICs, respectively. Higher minor morbidity was associated with pre-operative mechanical bowel preparation (OR = 1.474, 95%CI = 1.054–2.061, p = 0.023), longer surgeries (OR = 1.253, 95%CI = 1.066–1.472, p = 0.006), greater blood loss (OR = 1.274, 95%CI = 1.081–1.502, p = 0.004). Higher major morbidity was associated with longer surgeries (OR = 1.37, 95%CI = 1.128–1.664, p = 0.002), greater blood loss (OR = 1.398, 95%CI = 1.175–1.664, p ≤ 0.001), and seniority of lead surgeon, with junior surgeons three times more likely to have a major complication (OR = 2.982, 95%CI = 1.509–5.894, p = 0.002). Of all surgeries, 50% versus 25% were performed by junior surgeons in LMICs/HICs, respectively. We conclude that LMICs and HICs were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. [ABSTRACT FROM AUTHOR]

Background: Molecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking. Methods: 113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance. Results: The most frequent mutations were detected in genes ARID1A, PIK3CA, TERTp, KRAS, TP53, ATM, PPP2R1A, NF1, PTEN, and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLEmut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3, CTNNB1, DDR2, JAK2, KIT, or PDGFRA (p < 0.00001) was identified. Conclusions: The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLEmut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors. [ABSTRACT FROM AUTHOR]

The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Patients received maintenance olaparib capsules (400 mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability. 177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3 months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3–22.1), 16.6 (12.4–22.2), 19.3 (14.3–27.6) and 16.4 (10.9–19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected. Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC. • Clinical activity of maintenance olaparib in platinum-sensitive relapsed ovarian cancer was seen with any BRCA mutation. • This included activity in patients with somatic BRCA mutations. • Activity was also seen in patients with non-BRCA homologous recombination repair mutations. • Safety and tolerability were consistent with previous studies in this setting. [ABSTRACT FROM AUTHOR]

Background: IMP2 and IMP3 are mRNA binding proteins involved in carcinogenesis. We examined a large cohort of ovarian tumors with the aim to assess the value of IMP2 and IMP3 for differential diagnosis, and to assess their prognostic significance. Methods: Immunohistochemical analyses with antibodies against IMP2 and IMP3 were performed on 554 primary ovarian tumors including 114 high grade serous carcinomas, 100 low grade serous carcinomas, 124 clear cell carcinomas, 54 endometrioid carcinomas, 34 mucinous carcinomas, 75 mucinous borderline tumors, and 41 serous borderline tumors (micropapillary variant). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher's Exact test. Results: We found IMP2 expression (in more than 5% of tumor cells) in nearly all cases of all tumor types, so the prognostic meaning could not be analyzed. The positive IMP3 expression (in more than 5% of tumor cells) was most common in mucinous carcinomas (82%) and mucinous borderline tumors (81%), followed by high grade serous (67%) and clear cell carcinomas (67%). The expression was less frequent in endometrioid carcinomas (39%), low grade serous carcinomas (23%), and micropapillary variant of serous borderline tumors (20%). Prognostic significance of IMP3 could be evaluated only in low grade serous carcinomas in the case of relapse-free survival, where negative cases showed better RFS (p = 0.033). Conclusion: Concerning differential diagnosis our results imply that despite the differences in expression in the different ovarian tumor types, the practical value for diagnostic purposes is limited. Contrary to other solid tumors, we did not find prognostic significance of IMP3 in ovarian cancer, with the exception of RFS in low grade serous carcinomas. However, the high expression of IMP2 and IMP3 could be of predictive value in ovarian carcinomas since IMP proteins are potential therapeutical targets. [ABSTRACT FROM AUTHOR]

Background: Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. Results: The WID™-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case–control) and predictive setting (nested case–control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID™-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WID™-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt−) index sample who were diagnosed with CIN3 1–4 years after sample donation. Conclusion: We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WID™-qCIN, a PCR-based DNAme test. The WID™-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case–control settings and future studies will assess performance and generalisability in a randomised controlled trial. [ABSTRACT FROM AUTHOR]

Abstract: Post-graduate training in oncogynecological surgery should be based on a comprehensive system with three main components: training centers, trainers and trainees. For each of these components, clearly defined requirements should be established. An international consensus on classification, terminology, and performance of standard procedures in gynecological oncology would further improve postgraduate training. One of the key features of this system should be continuous assessment of surgical and non-surgical skills that would make possible the evaluation of individual trainees'' progress, as well as the quality of training centers and trainers. Special attention should be paid to the development of tailored educational tools. Internet databases of video presentations should be available to trainees, demonstrating standard procedures as well as atypical situations, including the management of complications. In Europe, the already available programs for postgraduate training and accreditation of centers developed by the European Society of Gynecological Oncology (ESGO) should become the basis for harmonization of postgraduate training in gynecological oncology. [Copyright &y& Elsevier]

Abstract: The abdominal radical trachelectomy is one of the available fertility-sparing techniques in the treatment of early-stage cervical cancer. The procedure follows the steps of the standard radical hysterectomy and therefore does not require special training. A radical abdominal trachelectomy allows for the adjustment of radicality of the parametrial resection according to prognostic factors and is not limited by distorted cervicovaginal anatomy. The key limitation for the procedure remains the cranial extent of the tumor towards the internal cervical os. Only a limited number of successful pregnancies have been reported to date. Poor fertility outcome, however, may partially be attributed to the selection of patients, requiring more extensive procedure, for the abdominal approach. The abdominal radical trachelectomy is a technique of choice, especially in centers with limited experience with vaginal radical surgery, and in certain specific indications, such as pediatric patients, distorted vaginal anatomy, bulky exophytic tumor, or cervical cancer in the first half of pregnancy. In this article, we describe the standard technique of this procedure along with alternatives, including a nerve-sparing modification of the parametrectomy. [Copyright &y& Elsevier]

Background: Metastatic affection of pelvic lymph nodes is the most important prognostic parameter in early stages cervical cancer. Still, serious number of patients with negative pelvic nodes experience recurrence, majority of them are local in pelvis. High frequency positivity of DNA of the most common high risk (HR) genotypes HPV-16 and 18 was shown in histopathology-negative pelvic nodes, and is considered as subclinical metastatic spread. Limited data are available concerning presence of different HR genotypes and correlation between HR HPV DNA in sentinel lymph nodes (SLN), other pelvic nodes and the primary tumor. Prognostic significance of such findings is still uncertain. Objectives: Main objective of the study was to evaluate the presence of HR HPV DNA including 13 genotypes in pelvic SLN, other pelvic non-SLN nodes and in the tumor. Material and Methods: Enrolled were patients with early-stage cervical cancer referred for surgical treatment including systematic pelvic lymphadenectumy. During the surgery, samples for HR HPV assesment were taken from tumor tissue, sentinel node and the pelvic nodes. All samples were evaluated for the presence of HR HPV and genotyped for the main 13 genotypes. Results: The study included 49 patients (FIGO IA2 - 2B) who underwent radical hysterectomy with systematic pelvic lymphadenectomy and sentinel lymph node biopsy. 91.8% patients had HR HPV DNA in their primary tumors, 49,9% patients in SLN and other pelvic nodes. In 1 case we found HR HPV DNA in pelvic nodes without positivity of SLN. We found 9 different genotypes of HR HPV in the examinated tissue. There were 6 cases with histopatologically confirmed nodal metastases, all of them were also HR HPV DNA positive with agreement between genotype in the primary tumor, SLN and other pelvic nodes. Conclusions: Our results show that the presence of HR HPV DNA in pelvic lymph nodes is an early sign of disease progression to the pelvis. Concordance between HPV genotype in the primary tumor and the involved pelvic lymph nodes is necessary. [ABSTRACT FROM AUTHOR]

The term 'out-of-the-box surgery' in gynecologic oncology was recently coined to describe the resection of tumor growing out of the endopelvic cavity. In the specific case of pelvic sidewall involvement, a laterally extended pelvic resection may be required. As previously defined by Höckel, this resection requires the en bloc removal of structures including the pelvic sidewall muscles, bones, nerves, and/or major vessels. This complex radical procedure leads to tumor-free margins in more than 75% of the patients, with reliable functional results. The rate of recurrence and overall survival are directly correlated with clear resection margins. Progress in imaging, surgical techniques, and perioperative care currently offer the opportunity to attempt surgical curative resection in selected patients for whom palliative therapy was the only alternative. However, the procedure is associated with a high rate of major postoperative complications affecting up to 60% of patients. Multidisciplinary expert centers are the most likely to achieve this complex surgery with favorable oncological outcomes. The aim of this review is to summarize the key issues of out-of-the-box surgery in gynecologic cancer. • The term 'out-of-the-box surgery' is employed for the resection of tumor growing out of the endopelvic cavity. • The rate of recurrence and overall survival are directly correlated with clear resection margin status. • In selected patients, tumor-free margins may be obtained in more than 75% of the cases. • This ultraradical surgery is associated with major postoperative complications affecting up to 60% of patients. • Multidisciplinary expert centers are the most likely to achieve optimal oncological outcomes. [ABSTRACT FROM AUTHOR]

Background: Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting.Methods: In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m2 on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy). Patients were treated in 21-day or 28-day cycles. The primary endpoint was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations), and then in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all patients who received at least one dose of assigned study treatment. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete, and the study is ongoing.Findings: Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause).Interpretation: Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma.Funding: Clovis Oncology. [ABSTRACT FROM AUTHOR]

In order to define the clinical significance of low-volume metastasis, a comprehensive meta-analysis of published data and individual data obtained from articles mentioning micrometastases (MIC) and isolated tumor cells (ITC) in cervical cancer was performed, with a follow up of at least 3 years. We performed a systematic literature review and meta-analysis, following Cochrane's review methods guide and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome was the disease-free survival (DFS), and the secondary outcome was the overall survival (OS). The hazard ratio (HR) was taken as the measure of the association between the low-volume metastases (MIC+ITC and MIC alone) and DFS or OS; it quantified the hazard of an event in the MIC (+/− ITC) group compared to the hazard in node-negative (N0) patients. A random-effect meta-analysis model using the inverse variance method was selected for pooling. Forest plots were used to display the HRs and risk differences within individual trials and overall. Eleven articles were finally retained for the meta-analysis. In the analysis of DFS in patients with low-volume metastasis (MIC + ITC), the HR was increased to 2.60 (1.55–4.34) in the case of low-volume metastasis vs. N0. The presence of MICs had a negative prognostic impact, with an HR of 4.10 (2.71–6.20) compared to N0. Moreover, this impact was worse than that of MIC pooled with ITCs. Concerning OS, the meta-analysis shows an HR of 5.65 (2.81–11.39) in the case of low-volume metastases vs. N0. The presence of MICs alone had a negative effect, with an HR of 6.94 (2.56–18.81). In conclusion, the presence of MIC seems to be associated with a negative impact on both the DFS and OS and should be treated as MAC. • We performed a meta-analysis of published and individual data to define the significance of low-volume metastasis. • The presence of micrometastases seems to be associated with a negative impact on the disease-free survival. • Patients with isolated tumor cells should be considered like negative lymph node patients. [ABSTRACT FROM AUTHOR]

The accurate harvesting of a sentinel node in gynaecological cancer (i.e. vaginal, vulvar, cervical, endometrial or ovarian cancer) includes a sequence of procedures with components from different medical specialities (nuclear medicine, radiology, surgical oncology and pathology). These guidelines are divided into sectione entitled: Purpose, Background information and definitions, Clinical indications and contraindications for SLN detection, Procedures (in the nuclear medicine department, in the surgical suite, and for radiation dosimetry), and Issues requiring further clarification. The guidelines were prepared for nuclear medicine physicians. The intention is to offer assistance in optimizing the diagnostic information that can currently be obtained from sentinel lymph node procedures. If specific recommendations given cannot be based on evidence from original scientific studies, referral is made to 'general consensus' and similar expressions. The recommendations are designed to assist in the practice of referral to, and the performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for high-quality evaluation of possible metastatic spread to the lymphatic system in gynaecological cancer. The final result has been discussed by a group of distinguished experts from the EANM Oncology Committee and the European Society of Gynaecological Oncology (ESGO). The document has been endorsed by the SNMMI Board. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cervarix® demonstrated, in clinical trials, an overall 93.2% efficacy against CIN3+. [•] This efficacy translates into a large number of lives saved in all countries; an additional 18–34% more lives saved than expected based on protection against HPV-16/18 only. [•] Public health benefit also includes reduction in costs, morbidity and suffering. [ABSTRACT FROM AUTHOR]

Abstract: Background: More than 90% of cases of anal cancers are caused by high-risk human papillomavirus (HR HPV) infection and a history of cervical intraepithelial neoplasia (CIN) is established as possible risk factor. Objectives: To demonstrate relationship between anal and cervical HPV infection in women with different grades of CIN and microinvasive cervical cancer. Study design: A total of 272 women were enrolled in the study. The study group included 172 women who underwent conization for high-grade CIN or microinvasive cervical cancer. The control group consisted of 100 women with non-neoplastic gynecologic diseases or biopsy-confirmed CIN 1. All participants completed a questionnaire detailing their medical history and sexual risk factors and were subjected to anal and cervical HPV genotyping using Cobas and Lynear array HPV test. Results: Cervical, anal, and concurrent cervical and anal HPV infections were detected in 82.6%, 48.3% and 42.4% of women in the study group, and in 28.0%, 26.0% and 8.0% of women in the control group, respectively. The prevalence of the HR HPV genotypes was higher in the study group and significantly increased with the severity of cervical lesion. Concurrent infections of the cervix and anus occurred 5.3-fold more often in the study group than in the control group. Any contact with the anus was the only significant risk factor for development of concurrent HPV infection. Conclusions: Concurrent anal and cervical HR HPV infection was found in nearly half of women with CIN 2+. The dominant genotype found in both anatomical locations was HPV 16. Any frequency and any type of contact with the anus were shown as the most important risk factor for concurrent HPV infection. [Copyright &y& Elsevier]

There are multiple classifications in imaging and surgery of endometriosis and in this article, we offer a review of the main evaluation systems. The International Deep Endometriosis Analysis group consensus is the leading document for ultrasound assessment, while magnetic resonance imaging is guided by the European Society for Urogenital Radiology recommendations on technical protocol. In surgery, the revised American Society for Reproductive Medicine classification is the oldest system, ideally combined with newer classifications, such as Enzian or Endometriosis Fertility Index. Recently, The World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project introduced detailed proforma for clinical and intraoperative findings. There is still no universal consensus, so the initial emphasis should be on the uniform reporting of the disease extent until research clarifies more the correlations between extent, symptoms and progression in order to develop a reliable staging system. What is already known on this subject? There have been several reviews of surgical classifications, comparing their scope and practical use, while in the imaging the attempts for literature review has been scarce. What do the results of this study add? This is the first up to date review offering detailed analysis of the main classification systems across the three main areas involved in endometriosis care - ultrasound, MRI and surgery. The mutual awareness of the radiological classifications for surgeons and vice versa is crucial in an efficient multidisciplinary communication and patient care. On these comparisons we were able to demonstrate the lack of consensus in description of the extent of the disease and even further lack of prognostic features (with the exemption of one surgical system). What are the implications of these findings for clinical practice and/or further research? Future attempts of scientific societies should focus on defining uniform nomenclature for extent description. In the second step the staging classification should encompass prognostic value (risk of disease and symptoms recurrence). [ABSTRACT FROM AUTHOR]

Abstract: Despite the extensive research during the last six decades the fundamental questions concerning the role of steroids in the initiation of human parturition and origin and function of some steroids in pregnancy were not definitely answered. Based on steroid metabolomic data found in the literature and our so far unpublished results, we attempted to bring new insights concerning the role of steroids in the sustaining and termination of human pregnancy, and predictive value of these substances for estimation of term. We also aimed to explain enigmas concerning the biosynthesis of progesterone and its bioactive catabolites considering the conjunctions between placental production of CRH, synthesis of bioactive steroids produced by fetal adrenal, localization of placental oxidoreductases and sustaining of human pregnancy. Evaluation of data available in the literature, including our recent findings as well as our new unpublished data indicates increasing progesterone synthesis and its concurrently increasing catabolism with approaching parturition, confirms declining production of pregnancy sustaining 5β-pregnane steroids providing uterine quiescence in late pregnancy, increased sulfation of further neuroinhibiting and pregnancy sustaining steroids. In contrast to the established concept considering LDL cholesterol as the primary substrate for progesterone synthesis in pregnancy, our data demonstrates the functioning of alternative mechanism for progesterone synthesis, which is based on the utilization of fetal pregnenolone sulfate for progesterone production in placenta. Close relationships were found between localization of placental oxidoreductases and consistently higher levels of sex hormones, neuroactive steroids and their metabolites in the oxidized form in the fetus and in the reduced form in the maternal compartment. [Copyright &y& Elsevier]

Background: To compare the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in lean and overweight/obese women with polycystic ovary syndrome (PCOS), with the data from a normal population sample. Methods: PCOS-affected women fulfilling ESHRE diagnostic criteria underwent an oral glucose tolerance test. Prevalence of IGT and T2DM in control sample of white healthy females was extracted from the published data from NHANES II. Results: In 225 women with PCOS, IGT was present in 6/104 (5.8%) lean and in 15/121 (12.4%) overweight/obese women. T2DM was present in 1/104 (1.0%) lean and in 3/121 (2.5%) overweight/obese PCOS women. In a sample of 643 women from NHANES II, the crude rate of IGT was 5.9%. IGT was significantly more common only in the overweight/obese PCOS subgroup as compared to the NHANES II cohort (χ2 = 5.99, p < 0.01). Conclusions: IGT was found significantly more frequently only in overweight/obese PCOS subjects in comparison with healthy controls. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]