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Purpose:The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937).Patients and Methods:We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC.Results:Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood.Conclusions:Our findings suggest that while patients with highly infiltrated, “hot” EOCs benefit from chemotherapy, women with “cold” EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.

Supplementary Figure from An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors

Supplementary Data from An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors

Purpose: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). Patients and Methods: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. Results: Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. Conclusions: Our findings suggest that while patients with highly infiltrated, “hot” EOCs benefit from chemotherapy, women with “cold” EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.

BackgroundMost patients with epithelial ovarian cancer (EOC) relapse despite primary debulking surgery and chemotherapy (CT). Autologous dendritic cell immunotherapy (DCVAC) can present tumor antigens to elicit a durable immune response. We hypothesized that adding parallel or sequential DCVAC to CT stimulates antitumor immunity and improves clinical outcomes in patients with EOC. Based on the interim results of sequential DCVAC/OvCa administration and to accommodate the increased interest in maintenance treatment in EOC, the trial was amended by adding Part 2.MethodsPatients with International Federation of Gynecology and Obstetrics stage III EOC (serous, endometrioid, or mucinous), who underwent cytoreductive surgery up to 3 weeks prior to randomization and were scheduled for first-line platinum-based CT were eligible. Patients, stratified by tumor residuum (0 or + monocytes, pulsed with two allogenic OvCa cell lines (SK-OV-3, OV-90), and matured in the presence of polyinosinic:polycytidylic acid. We report the safety outcomes (safety analysis set, Parts 1 and 2 combined) along with the primary (progression-free survival (PFS)) and secondary (overall survival (OS)) efficacy endpoints. Efficacy endpoints were assessed in the modified intention-to-treat (mITT) analysis set in Part 1.ResultsBetween November 2013 and March 2016, 99 patients were randomized. The mITT (Part 1) comprised 31, 29, and 30 patients in Groups A, B, and C, respectively. Baseline characteristics and DCVAC/OvCa exposure were comparable across the treatment arms. DCVAC/OvCa showed a good safety profile with treatment-emergent adverse events related to DCVAC/OvCa in 2 of 34 patients (5.9%) in Group A and 2 of 53 patients (3.8%) in Group B. Median PFS was 20.3, not reached, and 21.4 months in Groups A, B, and C, respectively. The HR (95% CI) for Group A versus Group C was 0.98 (0.48 to 2.00; p=0.9483) and the HR for Group B versus Group C was 0.39 (0.16 to 0.96; p=0.0336). This was accompanied by a non-significant trend of improved OS in Groups A and B. Median OS was not reached in any group after a median follow-up of 66 months (34% of events).ConclusionsDCVAC/OvCa and leukapheresis was not associated with significant safety concerns in this trial. DCVAC/OvCa sequential to CT was associated with a statistically significant improvement in PFS in patients undergoing first-line treatment of EOC.Trial registration numberNCT02107937, EudraCT2010-021462-30.

Radiation and chemotherapy represent standard‐of‐care cancer treatments. However, most patients eventually experience tumour recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate the molecular mechanisms of resistance to radio‐ and chemotherapy, we exposed human cancer cell lines (HeLa, MCF‐7 and DU145) to clinically relevant doses of 5‐azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations, including low‐adherent stem‐like cells. Stress‐mobilized low‐adherent cell fractions differed from other survivors in terms of deregulation of hundreds of genes, including those involved in interferon response. Exposure of cancer cells to interferon‐gamma but not interferon‐beta resulted in the development of a heterogeneous, low‐adherent fraction comprising not only apoptotic/necrotic cells but also live cells exhibiting active Notch signalling and expressing stem‐cell markers. Chemical inhibition of mitogen‐activated protein kinase/ERK kinase (MEK) or siRNA‐mediated knockdown of extracellular signal‐regulated kinase 1/2 (Erk1/2) and interferon responsible factor 1 (IRF1) prevented mobilization of the surviving low‐adherent population, indicating that interferon‐gamma‐mediated loss of adhesion and anoikis resistance required an active Erk pathway interlinked with interferon signalling by transcription factor IRF1. Notably, a skin‐specific protein suprabasin (SBSN), a recently identified oncoprotein, was among the top scoring genes upregulated in surviving low‐adherent cancer cells induced by 5‐azacytidine or irradiation. SBSN expression required the activity of the MEK/Erk pathway, and siRNA‐mediated knockdown of SBSN suppressed the low‐adherent fraction in irradiated, interferon‐gamma‐ and 5‐azacytidine‐treated cells, respectively, implicating SBSN in genotoxic stress‐induced phenotypic plasticity and stress resistance. Importantly, SBSN expression was observed in human clinical specimens of colon and ovarian carcinomas, as well as in circulating tumour cells and metastases of the 4T1 mouse model. The association of SBSN expression with progressive stages of cancer development indicates its role in cancer evolution and therapy resistance.

TPS5619 Background: Oregovomab, a murine IgGκ1 monoclonal antibody, has high affinity binding to tumor associated antigen CA125, thus, rendering the target antigen CA125 more immunogenic or “neoantigen-like” through altered and enhanced antigen processing and presentation to specific T cells. This phenomenon is hypothesized to bypass tumor-associated immune suppression when oregovomab is combined with chemotherapy. In a randomized phase II study, oregovomab in combination with paclitaxel and carboplatin (PC) induced tumor immunity and demonstrated significant improvement in median PFS (41.8 months(m) PCO vs 12.2 m PC, HR 0.46, p=0.0027) and median OS (N.E. PCO vs 43.2 m PC, HR O.35, p=0.043) in patients with previously untreated EOC. Oregovomab combined with PC had a favorable toxicity profile. FLORA-5/GOG3035, the definitive confirmatory global registration trial, is currently recruiting patients in the front-line setting. Methods: The study is a phase 3, multicenter, double-blind, placebo-controlled trial. Optimally debulked patients with FIGO III/IV EOC and serum CA125 ≥ 50 U/ml receiving adjuvant (Cohort 1) or patients receiving neoadjuvant chemotherapy post-interval cytoreductive surgery (Cohort 2) will be randomized to PC + oregovomab or placebo (PCO vs. PCP). Patients with germline BRCA1/2 mutations are excluded. Chemotherapy will be administered every 3 weeks in both cohorts. Oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with an additional dose at 12 weeks following cycle 5 in Cohort 1. Neoadjuvant patients will be administered oregovomab/placebo after debulking surgery at cycles 4 and 6 with two additional doses at 6- and 18-weeks following cycle 6 in Cohort 2. No other front-line maintenance therapy is permitted. The primary objective is PFS determined by RECIST 1.1. Cohort 1 will recruit 372 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.65 when 252 PFS events have been observed. Cohort 2 will be analyzed separately recruiting 232 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.60 when 165 PFS events have been observed. An interim futility analysis will be performed. Secondary objectives include OS, frequency and severity of AEs, and QoL. Exploratory objectives include iRECIST, TFST, TSST, PFS2, and evaluation of correlative biomarkers. The study is actively enrolling in the US, Canada, Belgium, Italy, Spain, Czech Republic, Hungary, Poland, Korea, Taiwan, Mexico, Argentina, and Chile. 179 patients were enrolled at time of submission. Clinical trial information: NCT04498117.

Objective 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. Methods 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). Results 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. Conclusions 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.

Simple Summary Despite advances in cancer research in recent years, efficient predictive biomarkers of tumor progression and metastatic spread for ovarian cancer are still missing. Therefore, we critically address recent findings in the field of non-coding RNAs (microRNAs and long non-coding RNAs) and DNA methylation in ovarian cancer patients as promising novel biomarkers of ovarian cancer progression. Abstract Ovarian cancer is one of the most common causes of death among gynecological malignancies. Molecular changes occurring in the primary tumor lead to metastatic spread into the peritoneum and the formation of distant metastases. Identification of these changes helps to reveal the nature of metastases development and decipher early biomarkers of prognosis and disease progression. Comparing differences in gene expression profiles between primary tumors and metastases, together with disclosing their epigenetic regulation, provides interesting associations with progression and metastasizing. Regulatory elements from the non-coding RNA families such as microRNAs and long non-coding RNAs seem to participate in these processes and represent potential molecular biomarkers of patient prognosis. Progress in therapy individualization and its proper targeting also rely upon a better understanding of interactions among the above-listed factors. This review aims to summarize currently available findings of microRNAs and long non-coding RNAs linked with tumor progression and metastatic process in ovarian cancer. These biomolecules provide promising tools for monitoring the patient’s response to treatment, and further they serve as potential therapeutic targets of this deadly disease.

The standard procedure in cervical cancer is radical hysterectomy (RH) and pelvic lymphadenectomy (PLND). Because of the increasing age of women at childbirth, fertility becomes a major challenge. We present 20 years of experience with two-step less radical fertility-sparing surgery in women with IA1, LVSI positive, IA2 and IB1 (2 cm, infiltration less than half of stromal invasions.Preoperative workout consisted of histopathological diagnosis and magnetic resonance imaging along with ultrasonographic volumetry. We then performed laparoscopic sentinel lymph node mapping (SLNM) with frozen section (FS) followed by PLND and "selective parametrectomy" (removal of afferent lymphatic channels from the paracervix) in case of a negative result. If verified by definitive histopathology, patients were treated by simple trachelectomy (IB1) or large cone (IA1/IA2) biopsy 1 week after primary surgery.From 1999 to 2018, 91 women were enrolled in the study (median age 29.1 years, range 21-40). Of these 91 women, 51 (56.0%) were nulliparous. The detection rate of SLNs was 100% per patient and the specific side detection rate 96.7%. Positive lymph nodes were diagnosed in nine cases (9.8%). These women then underwent RH. Fertility was spared in 80 women but 4 recurred locally (5.0%). The mortality rate was 0.0%. The median follow-up was 149 months.Less radical fertility-sparing surgery with SLNM is safe in cervical cancers2 cm at the largest diameter and infiltrating less than half of the cervical stroma. The recurrence rate is acceptable with no mortality. Morbidity with this procedure is low. Extended and accurate follow-up is necessary and human papillomavirus - high risk (HPV-HR tests seem to be useful in such follow-up assessment.

BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.MethodsRNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.Results1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.ConclusionsImmunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.

BACKGROUND: Awareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes. METHODS: This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log-binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing. FINDINGS: 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1·10, 95% CI 1·05-1·15), mainly related to an increase of chemotherapeutic treatment (1·31, 1·20-1·43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1·04, 95% CI 1·01-1·06) and fewer iatrogenic preterm deliveries (0·91, 0·84-0·98). Our data suggest a relationship between platinum-based chemotherapy and small for gestational age (odds ratio [OR] 3·12, 95% CI 1·45-6·70), and between taxane chemotherapy and NICU admission (OR 2·37, 95% CI 1·31-4·28). NICU admission seemed to depend on cancer type, with gastrointestinal cancers having highest risk (OR 7·13, 95% CI 2·86-17·7) and thyroid cancers having lowest risk (0·14, 0·02-0·90) when compared with breast cancer. Unexpectedly, the data suggested that abdominal or cervical surgery was associated with a reduced likelihood of NICU admission (OR 0·30, 95% CI 0·17-0·55). Other associations between treatment or cancer type and outcomes were less clear. INTERPRETATION: Over the years, the proportion of patients with cancer during pregnancy who received antenatal treatment increased, especially treatment with chemotherapy. Our data indicate that babies exposed to antenatal chemotherapy might be more likely to develop complications, specifically small for gestational age and NICU admission, than babies not exposed. We therefore recommend involving hospitals with obstetric high-care units in the management of these patients. FUNDING: Research Foundation-Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic. ispartof: The Lancet Oncology vol:19 issue:3 pages:337-346 ispartof: location:England status: published

Transmission of human papillomavirus (HPV) is a premise for development of cervical dysplasia and genital warts. This cross-sectional study assesses concordance of HPV types present in genital warts or cervical dysplasia in women and genital infection of their monogamous male partners in conjunction with seroprevalence of HPV-6,-11,-16 and -18 antibodies. Blood was taken from both women and men, as well a smear of the urogenital area of men. HPV DNA detection in women was done in fixed paraffin embedded tissues under histological control. Of 143 couples who agreed to participate in the study, 68 met inclusion criteria. Type-specific concordance was observed in 32.5% (13/40) of couples in which women had genital warts and in 32.1% (9/28) of couples in which women had cervical dysplasia. In multivariate analysis only smoking in women was associated with concordance (p

Currently, three prophylactic HPV vaccines are commercially available to prevent HPV 16/18 infection and associated lesions. The aim of the study was to assess markers of HPV infection in women/girls before vaccination and to ascertain the prevalence and spectrum of post-vaccination HPV types. Three hundred and thirty subjects of which 75 were virgins were enrolled. Before the first dose of the HPV vaccine and 1, 3 and 5 years after the completion of HPV vaccination, the samples for cytology, HPV detection and anti-HPV antibody response were taken. At enrolment, HPV DNA was detected in 38% of sexually active girls/women. At the first, second and third follow-up, HPV DNA was found in 40, 45, and 39% of them. The seroprevalence rates to HPV 6, 11, 16 and 18 in these subjects were 31, 21, 18 and 10%. On the follow-up significantly higher levels of antibodies to HPV 16/18 were found after application of divalent vaccine. Results of the study demonstrate high prevalence of HPV infection in young women. In a substantial number of women, HPV-specific antibodies as well as high-risk HPV types were detected. HPV-specific antibodies were also frequently found in non-sexually active girls. The acquisition of HPV after the onset of sexual life was very fast.

Epithelial ovarian cancer (EOC) has the highest mortality among gynecological carcinomas. The lack of specific markers for prognostic determination of EOC progression hinders the search for novel effective therapies. The aim of the present study was (i) to explore differences in expressions of ATP-binding cassette (ABC) and solute carrier (SLC) transporter genes, genes associated with drug metabolism and cell cycle regulation between control ovarian tissues (n = 14), primary EOCs (n = 44) and intraperitoneal metastases (n = 29); (ii) to investigate associations of gene expression levels with prognosis of patients with intraperitoneal metastases. In all tissue samples, transcript levels of the above target genes were assessed using quantitative real-time PCR. Gene expression levels were compared between particular tissue types and evaluated with regard to progression-free survival (PFS) and drug-resistance status of patients with metastases. Gene expression of ABCA7 significantly increased and that of ESR2 decreased in the order control ovarian tissues - primary EOCs - metastases. High expressions of ABCA2/8/9/10, ABCB1, ABCC9, ABCG2, ATP7A, SLC16A14, and SOD3 genes were significantly associated with longer progression-free survival of patients. In intraperitoneal metastases, expression of all of these genes highly correlated and indicated prognostic profile. Transporters from the ABCA family, ABCG2, and ESR2 are involved mainly in lipid metabolism, membrane transport, and cell proliferation. These processes are thus probably the most important for EOC progression. Based on these results, we have proposed novel markers of ovarian carcinoma progression and metastatic spread which might be potentially useful as therapeutic targets. Their significance should be further explored on a larger independent set of patients.

Introduction/Background The purpose of the study is to present our clinical experience, pregnancy management and long term obstetrical outcome after less radical fertility sparing surgery SLNM + laparoscopic lymphadenectomy + simple trachelectomy or large recone. Methodology From 1999–2018, 91 women with squamous or adenocarcinoma with tumor less than 20 mm in the largest diameter and infiltration less than half of cervical stroma underwent laparoscopic SLNI and select extirpation of afferent parametrial channel and frozen section (FS) of SLN and laparoscopic pelvic lymphadenectomy or only SLN. Second step is simple trachelectomy without cerclage or large recone. Results Fertility was definitely spared in 76 women. 3 women (3.3%) not plan pregnancy, 9 currently plan pregnancy in future (9.9%), 64 women (84.2%) wish to be pregnant and 53 was pregnant (82.8%). From 76 fertility spared, 53 was pregnant - pregnancy rate 69.7%, 44 women have 50 baby - delivery rate was 57.9%. 37 was term pregnancy (74%), extreme premature 24–27w - 2 baby (4%), premature (28–32w) - 2 baby (4%), premature (33–37w) - 9 baby (18%). 22 unsuccessful pregnancy (5 artericial abortion, 11 spontaneus abortion in 1 trimestr, 4 spontaneus abortion in 2 trimestr, 2 GEU. Two women after hysterectomy have two baby with donor mother. Conclusion SLNM and laparoscopic pelvic lymphadenectomy with simple trachelectomy or large recone in small volume cervical cancer (less than 2cm in the largest diameter and less than half of stromal invasion) have excellent pregnancy result. This work was supported by Charles University research program PROGRES Q 28 (Oncology). Disclosure Nothing to disclose.

Objectives Purpose of study was to determine long term experience of less radical surgery, sentinel lymph node identification (SLNI) with Tc99+blue day with laparoscopic surgery. Methods From 1999 to 2018, 91 women with tumor less than 20 mm in largest diameter, infiltration less than half of cervical stroma underwent SLNI, frozen section (FS) of SLN, extirpation of afferent parametrial lymphatic channel, pelvic lymphadenectomy or only SLN. FS SLN positive patients underwent radical hysterectomy. Seven days after final histopathological processing of dissected nodes, large cone or simple trachelectomy was performed. Results 15 women (16.5%) lost fertility. 9 women had positive lymph nodes (9.9%), 2 close invasive margin (2.2%), so radical hysterectomy was performed. Four cases had SIL in margin or patient decision, had laparoscopic hysterectomy. One patient N1 had recurrence and died of disease. All other are in complete remission. Fertility was save in 76 cases. Three central recurrences (isthmic part of uterus) were observed (3.9%), one died (1.3%), 2 are in CR 15 and 7 years. We have no distant recurrence. 62 of 76 women whose reproductive ability had been maintained tried to conceive (82%). Of these 62 women, 49 became pregnant (79%) in total 76 pregnancies. 43 mothers gave birth to 48 children, two children were by surrogate mothers. Conclusions Less radical fertility sparing surgery in early cervical cancer can be feasible method that yields high, successful pregnancy rate. This work was supported by the Charles University research program PROGRES Q 28 (Oncology).

Multidrug resistance to anticancer drugs, which is often associated with enhanced expression of the ATP‑binding cassette (ABC) transporter P‑glycoprotein (encoded by the ABCB1 gene) may limit the effects of cancer therapy. Epigenetic regulation of ABCB1 expression may thus have a clinical impact. A detailed assessment of ABCB1 promoter methylation is of importance for predicting therapy outcome and prognosis. Thus, validated methods for the analysis of ABCB1 promoter methylation are urgently required. In the present study, high‑resolution melting (HRM) analysis of the CpG island regions covering the distal promoter of the ABCB1 gene was developed and compared with pyrosequencing. In addition, the clinical effects of the methylation status of the ABCB1 promoter were analyzed in patients with breast and ovarian carcinoma prior and subsequent to chemotherapy treatment. HRM analysis of ABCB1 methylation correlated with the results of pyrosequencing (P=0.001) demonstrating its analytical validity and utility. Hypermethylation of the analyzed ABCB1 promoter region was significantly correlated with low levels of the ABCB1 transcript in tumors from a subset of patients with breast and ovarian carcinoma prior to chemotherapy but not following treatment. Finally, high ABCB1 transcript levels were observed in tumors of patients with short progression‑free survival prior to chemotherapy. Our data suggest the existence of functional epigenetic changes in the ABCB1 gene with prognostic value in tumor tissues of patients with breast and ovarian carcinoma. The clinical importance of such changes should be further evaluated.

BackgroundTreatment of cervical cancer during pregnancy is often complex and challenging. This study aimed to analyze current patterns of practice in the management of pregnant patients diagnosed with cervical cancer.MethodsThis was a matched cohort study comprising patients managed for cervical cancer during pregnancy from six European centers. Patient information was retrieved from the dataset of the International Network for Cancer, Infertility and Pregnancy from 1990 to 2012. Each center matched its patients with two non-pregnant controls for age (±5 years) and International Federation of Gynecology and Obstetrics (FIGO) 2009 stage. Information on age, histological type, grade, lymphovascular space invasion, stage, tumor size, method of diagnosis, site of recurrence, delivery, date of recurrence, and date of death was recorded. Progression-free survival was compared using multivariable Cox proportional hazards regression.ResultsA total of 132 pregnant patients and 256 controls were analyzed. The pregnant patients (median age 34 years, range 21–43) were diagnosed at a median gestational age of 18.4 weeks of pregnancy (range 7–39). Stage distribution during pregnancy was 14.4% for stage IA, 47.0% for IB1, 18.9% for IB2, and 19.7% for II-IV. For treatment during pregnancy, 17.4% of the patients underwent surgery, 16.7% received neoadjuvant chemotherapy, 26.5% delayed their treatment, 12.9% had a premature delivery, and 26.5% had their pregnancy terminated. Median follow-up was 84 months (67 months for pregnant and 95 months for non-pregnant patients). The unadjusted hazard ratio of pregnancy for progression-free survival was 1.18 (95% confidence interval 0.74 to 1.88).ConclusionSurgery and chemotherapy is increasingly used in the management of pregnant patients with cervical cancer and prognosis is similar to that of non-pregnant patients.

A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity. Electronic supplementary material The online version of this article (10.1186/s40425-018-0446-3) contains supplementary material, which is available to authorized users.

5521 Background: Most patients with EOC relapse despite PDS and CMT. Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to CMT stimulates antitumor immunity and improves clinical outcomes. Methods: Key eligibility criteria were FIGO stage III EOC (serous, endometrioid, or mucinous), post-PDS with < 1 cm maximal residuum, no prior systemic therapy, and ECOG 0-2. In part 1, patients were randomized up to 6 weeks after PDS, 1:1:1, into arm A (A; DCVAC concomitant with CMT), arm B (B; DCVAC sequential after CMT), and arm C (C; CMT). Patients were stratified by tumor residuum (0 or < 1 cm). CMT consisted of 6 cycles of carboplatin (AUC 5-7) and paclitaxel (175 mg/m2). Patients in A and B received up to 10 doses of DCVAC (1×107 DCs/dose). The primary endpoint was radiologically assessed progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Results presented refer to a protocol-defined modified intention-to-treat population (mITT) including patients who received ≥1 CMT dose in C or ≥1 DCVAC dose in A and B. Results: Between November 2013 and March 2016, 99 patients were randomized. At the final analysis, the mITT included 31 patients in A, 29 patients in B, and 30 patients in C. Key baseline characteristics and DCVAC exposure were comparable across treatment arms. Median PFS was 20.3 months in A, not reached in B, and 21.4 months in C, with corresponding HRs (95% CI) compared to C of 0.98 (0.48-2.00) in A and 0.39 (0.16-0.96) in B. The PFS benefit in B was statistically significant (p = 0.034) This was supported by a non-significant trend in OS in A and B. Median OS was not reached in any arm at the time of median follow-up of 66 months (34% of events). Patients with low CD8+ T-cell counts (CD8Lo) in tumor samples in A and B had significantly improved clinical outcomes compared to patients in C with CD8Lo: median PFS gain of 6 months (19 vs 13 months) and a more robust OS gain (median not reached vs 31 months), with minimal difference between A and B. This effect could not be attributed to statistical differences in high CD8+ T-cell counts (CD8Hi) density patients. These findings indicated the best clinical outcome in DCVAC patients with immunologically “cold” tumors in both DCVAC arms. DCVAC showed a good safety profile with only 8 DCVAC-related adverse events (Grade 1-2). Conclusions: DCVAC improved PFS and OS outcomes in patients with newly diagnosed EOC, predominantly in patients with immunologically “cold” tumors, thus representing a promising treatment option in this patient population. Clinical trial information: NCT02107937.

Because of a notable increase in age at delivery, the incidence of malignancy diagnosed during pregnancy has substantially increased. This review aims to summarize the literature and expert knowledge on gynecologic cancers diagnosed in pregnancy regarding epidemiology, examination and staging procedures, description of treatment modalities and management of gynecological malignancies with special interest in cervical and ovarian cancer. Thorough attention is paid to the surgery and chemotherapy administration for early-stage cervical cancer diagnosed during pregnancy.

A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naive HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically relevant anticancer immunity. Citation Format: Iva Truxova, Lenka Kasikova, Michal Hensler, Petr Skapa, Jan Laco, Ladislav Pecen, Lucie Belicova, Ivan Praznovec, Michael J. Halaska, Tomas Brtnicky, Eva Salkova, Lukas Rob, Roman Kodet, Jeremy Goc, Catherine Sautes-Fridman, Wolf Herman Fridman, Ales Ryska, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B76.

A high density of tumor-infiltrating CD8+ T lymphocytes (CTLs), key mediator of anticancer immunity, and CD20+ B cells correlates with positive prognostic value and prolonged survival in patients with a various solid tumors including high-grade serous ovarian carcinoma (HGSC). The majority of HGSCs containing high frequencies of CD8+ CTLs are also robustly infiltrated by CD20+ B cells, and patients whose tumors exhibit abundant coinfiltration have higher survival rates than patients with tumors that only contain high amounts of CD8+ CTLs. However, the cellular mechanism, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. Three independent cohorts of patients with resectable HGSC who did not receive neoadjuvant chemotherapy were involved in the study. Lysosomal-associated membrane protein 3 (DC-LAMP) and its colocalization with CD20+B cells in samples was analyzed by immunohistochemistry (IHC) and cell quantification. Prognostic impact of DC-LAMP+ cells in patient cohort was stratified based on median density of DC-LAMP+ cells in the tumor stroma and nest, followed by retrospective RFS and OS analysis. Comparison of DC-LAMPHi and DC-LAMPLo patients and impact of mature DCs on the composition of the immune contexture characterized by TH1 polarization and cytotoxic activity was performed by biomolecular analyses (flow cytometry, NGS analysis). Patients with high density of DC-LAMP+ cells in the tumor stroma exhibited significantly longer RFS and OS than DC-LAMP- patients. Compared to DC-LAMPLo, DC-LAMPHi tumors exhibited an over-representation of gene sets specifically clustering to the following immunologic functions: T cells, CD8 cytotoxicity, TH1 polarization, T cell activation, NK cells, and plasma cells. Also, a significantly higher percentage of CD3+CD45+ and CD3+CD8+ T cells among live mononuclear cells and higher density of NK cells in the tumor stroma in DC-LAMPHi were observed. We found that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically favorable cytotoxic immune response in HGSC microenvironment. Robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in independent cohorts of chemotherapy-naive HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically relevant anticancer immunity. Citation Format: Iva Truxova, Lenka Kasikova, Michal Hensler, Petr Skapa, Jan Laco, Ladislav Pecen, Lucie Belicova, Sarka Vosahlikova, Ivan Praznovec, Michael Halaska, Tomas Brtnicky, Eva Salkova, Lukas Rob, Roman Kodet, Jeremy Goc, Catherine Sautes-Fridman, Wolf Herve Fridman, Ales Ryska, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A24.

screening intervalCarcinoma of the uterine cervix is the fourth most common malignant tumor in women worldwide. It is estimated that in 2012 there will be 528,000 new cases and 266,000 deaths in the world. A large majority of the global burden occurs in developing countries, where 445,000 cases and 230,000 deaths from cervical cancer take place annually

Background Tregs play a suppressive role in the control of antitumour immunity. In this study we evaluated the relevance of prospective monitoring of peripheral blood regulatory T cells (Tregs) as a potential prognostic marker of future outcome of epithelial ovarian cancer in patients with or without a metronomic chemotherapy. Methods 46 patients diagnosed with the ovarian cancer were enrolled in the study and divided into groups according to the stage of the disease, outcome of the surgery and treatment received. Proportions of Tregs in the peripheral blood samples were evaluated using flow cytometry. Results We show that the early stage of the disease and absence of the tumor residuum after radical surgery are the most important factors predicting a favourable clinical outcome in the ovarian cancer. We did not show any significant effect of consolidation chemotherapy with metronomic doses of etoposide or cyclophosphamide on the peripheral blood Tregs and on the clinical outcome. The slope of the Tregs trend line was a significant predictor of an early relapse, even after controlling for stage and tumor residuum after the surgical debulking by using the Cox proportional hazard model. Conclusions This study shows that the faster kinetics of Tregs increase in the peripheral blood, expressed as the slope of the Tregs trend line, is a significant predictor of ovarian cancer early relapse hazard. However, due to its relatively low specificity, the informative value of regular monitoring of Tregs kinetics in the peripheral blood for the subsequent clinical outcome is limited.

ObjectiveThe aim of this study was to prospectively monitor the patients’ quality of life (QoL) after vulvar cancer surgery.DesignThe design was prospective clinical study.SettingThe study was set in the Department of Obstetrics and Gynecology, 2nd Medical Faculty of the Charles University and University Hospital Motol, Prague, Czech Republic.MethodsA group of 36 patients underwent vulvar cancer surgery: 24 patients were subject to inguinofemoral lymphadenectomy (RAD) and 12 to sentinel lymph node biopsy. To evaluate QoL, the European Organisation for Research and Treatment of Cancer, QoL questionnaires (QLQ-C30 and QLQ-CX24) were administered to patients before and 6 and 12 months after surgery.ResultsIn patients with vulvar cancer after inguinofemoral lymphadenectomy, increased fatigue and impaired lymphedema were observed. In the group of patients after sentinel lymph node biopsy, none of the QoL variables worsened postoperatively. Comparing both groups 12 months after surgery, the RAD group had significantly worse outcomes in body image and cognitive functioning than the sentinel lymph node biopsy group.Patients in the RAD group, who received adjuvant radiotherapy (n = 13), had worse QoL in symptom experience (P < 0.05) at 6 and 12 months after the surgery than patients without radiotherapy (n = 11).ConclusionsLess radical surgery showed objectively better QoL results.

Incidence nadorových onemocněni v těhotenstvi stoupa vzhledem ke starnouci populaci rodicek. Onkologicka prognoza těchto pacientek se nelisi oproti netěhotným. Diky aktualnim poznatkům je ve velkem procentu připadů možne pokracovat v graviditě a soucasně zahajit protinadorovou lecbu. Tato prace shrnuje zakladni fakta týkajici se diagnostiky a lecby nadorových onemocněni v těhotenstvi vcetně podavani chemoterapie v graviditě.

ObjectiveThe aim of this study was to develop clinically relevant and evidence-based guidelines as part of European Society of Gynaecological Oncology’s mission to improve the quality of care for women with gynecologic cancers across Europe.MethodsThe European Society of Gynaecological Oncology Council nominated an international development group made of practicing clinicians who provide care to patients with vulvar cancer and have demonstrated leadership and interest in the management of patients with vulvar cancer (18 experts across Europe). To ensure that the statements are evidence based, the current literature identified from a systematic search has been reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group (expert agreement). The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 181 international reviewers including patient representatives independent from the development group.ResultsThe guidelines cover diagnosis and referral, preoperative investigations, surgical management (local treatment, groin treatment including sentinel lymph node procedure, reconstructive surgery), radiation therapy, chemoradiation, systemic treatment, treatment of recurrent disease (vulvar recurrence, groin recurrence, distant metastases), and follow-up.

Objective: The purpose of the study is to present our clinical experience, pregnancy management and long-term obstetrical outcome after less radical fertility sparing surgery SLNM + laparoscopic lymphadenectomy + simple trachelectomy or large recone. Patients and methods: From 1999 till 2018, 91 women with squamous cell carcinoma or adenocarcinoma with tumor less than 20 mm in the largest diameter and infiltrating less than half of cervical stroma underwent laparoscopic SLNI and selective extirpation of afferent parametrial channel and frozen section (FS) of SLN and laparoscopic pelvic lymphadenectomy or only SLN. Second step was simple trachelectomy without cerclage or large recone. Results: Fertility was definitely spared in 76 women. 3 women (3.3%) have no current pregnancy plans, 9 plan pregnancy in the near future (9.9%), 64 women (84.2%) tried to conceive and 53 became pregnant (82.8%). 76 fertility spared resulted in 53 pregnancies u2013 pregnancy rate 69.7%, 44 women delivered 50 babies in totalu2013 delivery rate was 57.9%. 37 were term labors (74%), extreme premature 24-27w - 2 babies (4%), premature (28-32w) u2013 2 babies (4%), premature (33-37w) u2013 9 babies (18%). 22 unsuccessful pregnancies (5 artificial abortions, 11 spontaneous abortions in 1st trimester, 4 spontaneous abortions in 2nd trimester, 2 ectopic pregnancies. Two women after hysterectomy had two babies by donor mother. Conclusion: SLNM and laparoscopic pelvic lymphadenectomy with simple trachelectomy or large recone in small volume cervical cancer (less than 2cm in the largest diameter and less than half of stromal invasion) have excellent pregnancy results. This work was supported by Charles University research program PROGRES Q 28 (Oncology).

Objective 28 women under 35years with early-stage cervical cancer and strong desire for fertility preservation that do not fulfil standard criteria for fertility-sparing surgery (tumour larger than 2cm or with deep of infiltration more than half of stroma) were included in prospective study. Methods Dose-dense neoadjuvant chemotherapy (NAC) was performed on all 28 patients in 10-day intervals: cisplatin plus ifosfamide in squamous cell cancer (15 women—53.6%) or cisplatin plus doxorubicin in adenocarcinoma (13 women—46.3%). Patients underwent laparoscopic lymphadenectomy and vaginal simple trachelectomy after NAC. Patients with positive lymph nodes or inadequate free surgical margins underwent radical hysterectomy. Results No residual disease was found in 6 women (21.4%), microscopic disease was observed in 11 women (39.3%) and macroscopic tumour in was observed in 11 women (39.3%). Ten women (35.7%) lost fertility. Four women (20%) after fertility-sparing surgery recurred, two died of the disease (10%). Fertility was spared in 20 (71.4%) women and 10 of them became pregnant (50%). Eight women delivered ten babies (6 term and four preterm deliveries). There were two miscarriages in second trimester (in one woman) and one in first trimester. One woman underwent four unsuccessful cycles of IVF, one failed to become pregnant and one recurred too early. Two women underwent chemoradiotherapy for recurrence and lost chance for pregnancy. Conclusions Downstaging by NAC in IB1 and IB2 cervical cancer before fertility-sparing surgery is still an experimental procedure, but shows some promise. Long-term results in relation to oncological outcome for this concept are still needed.