OBJECTIVE: Brachytherapy (BT) boost after radio-chemotherapy (RCT) is a standard of care in the management of locally advanced cervical cancer (LACC). As there is no consensus on high-dose-rate (HDR) BT fractionation schemes, our aim was to report the oncological outcome and toxicity profile of four different schemes using twice-a-day (BID) HDR-BT.
METHODS: This was an observational, retrospective, single institution study for patients with LACC receiving a HDR-BT boost. The latter was performed with a single implant and single imaging done on day 1. The different fractionation schemes were: 7 Gy + 4x3.5 Gy (group 1); 7 Gy + 4x4.5 Gy (group 2); 3x7Gy (group 3) and 3x8Gy (group 4). Local (LFS), nodal (NFS) and metastatic (MFS) recurrence-free survival as well as progression-free survival (PFS) and overall survival (OS) were analyzed. Acute (≤6 months) and late toxicities (>6 months) were reported.
RESULTS: From 2007 to 2018, 191 patients were included. Median follow-up was 57 months [45-132] and median EQD210D90CTVHR was 84, 82 and 90 Gy for groups 2, 3 and 4 respectively (dosimetric data missing for group 1). The 5-year LFS, NFS, MFS, PFS and OS were 85% [81-90], 83% [79-86], 70% [67-73], 61% [57-64] and 75% [69-78] respectively, with no significant difference between the groups. EQD210D90CTVHR < 85 Gy was a prognostic factor for local recurrence in univariate analysis (p = 0.045). The rates of acute/late grade ≥ 2 urinary, digestive and gynecological toxicities were 9%/15%, 3%/15% and 9%/25% respectively.
CONCLUSIONS: Bi-fractionated HDR-BT boost seems feasible with good oncological outcome and slightly more toxicity after dose escalation.

UNASSIGNED: In 2015, new FIGO guidelines for CTG interpretation were presented (FIGO-15). In 2017, the previous Swedish guidelines (SWE-09) were replaced with guidelines adapted to FIGOs (SWE-17). The performance of these three templates had not been scientifically evaluated before its clinical implementation. The objective of this study was to compare the sensitivity and specificity to detect fetal acidosis at birth using these three templates during the second stage of labor.
UNASSIGNED: This case-control study included 295 neonates with cord blood pH < 7.05 and 591 controls with pH ≥ 7.15, born 2012-2017. Tracings from the last 30-80 min of labor were classified independently by three assessors (midwives, residents and obstetricians), blinded to group and outcome.
UNASSIGNED: The classification pathological using FIGO-15 had a sensitivity of 50 % and specificity of 88 % in detecting fetuses with acidosis. For SWE-17, the sensitivity was 62 % and the specificity 85 %. For SWE-09 the sensitivity was 87 % and the specificity 56 %.By combining suspicious and pathological patterns the sensitivity for FIGO-15 increased to 97 %, and for SWE-17 to 83 %, whereas the specificity decreased to 23 % and 68 % respectively.
UNASSIGNED: The FIGO classification seemed to be insufficiently discriminative in the second stage of labor; most patterns in acidotic cases were classified as merely suspicious with this template, and the sensitivity of pathological patterns was low at 50 %. Combined pathological and suspicious patterns detected fetal acidosis at a specificity that was too low to be useful (23 %). SWE-09 showed the best ability to detect acidosis with pathological patterns (sensitivity 87 %). SWE-17 reached almost the same sensitivity (83 %) with the combination of suspicious and pathological patterns, and at a higher specificity (68 %).

Metastatic brain tumors are the rare cause of intracerebral hemorrhage in the young. In this study, we present a case of a 24-year-old woman who suffered from brain and lung metastatic choriocarcinoma with intracerebral hemorrhage as initial presentation. Head computed tomography showed an irregular hematoma of the right frontal lobe and enlarged within 1 month. Chest X ray showed a mass in the right lung. This patient responded well with combined treatment with craniotomy for evacuation of hematoma, multidrug chemotherapy and lobectomy. This case report discusses a rare phenomenon of hemorrhage metastasis in the brain from choriocarcinoma. The better knowledge of this entity would facilitate earlier diagnosis and improve the outcome.

Primary peritoneal malignant tumors are exceptional. Among them, clear cell carcinoma is extremely rare, being only thirteen cases previously reported in the literature since 1990. We report a case of a 48-year-old Caucasian woman who was treated at the University General Hospital of Alicante. She consulted because of progressive abdominal pain over the last seven months, with the initial diagnosis of renal-ureteral colic. Ultrasound and computed tomography of the abdomen and pelvis revealed a 25 × 15 cm, well-defined cystic lesion with papillary projections, centrally located in the abdomen. The radiology report suggested a primary ovarian tumor versus peritoneal implant as the first option. The patient underwent an exploratory laparotomy showing a large cystic mass located in the urinary bladder peritoneum, firmly attached to the mesentery. The entire abdominal tumor was completely excised, and total hysterectomy with bilateral salpingo-oophorectomy and infra-colical omentectomy were performed. The final histological study revealed a new case of primary peritoneal clear cell carcinoma located in the urinary bladder peritoneum, firmly attached to the mesentery. Grossly, it was well-circumscribed and multicystic with papillary growth involving part of the inner wall. Microscopically, it showed tubulocystic and papillary patterns with highly atypical tumor cells. After an extensive immunohistochemical analysis, the most relevant finding was an ARID1A loss that was corroborated by molecular analysis showing an ARID1A deletion. The patient received systemic chemotherapy with carboplatin and paclitaxel protocol (Å ~ 4 cycles). Patient follow-up after the eighth month showed peritoneal implants predominantly in the right diaphragmatic cupule that were histologically confirmed as recurrence. She has just received another six cycles of chemotherapy with carboplatin and paclitaxel. Recognition of primary peritoneal clear cell carcinoma in this uncommon location, and exclude metastasis from the ovary, represents a diagnostic challenge.

Immunotherapy has been proven effective in several tumours, hence diverse immune checkpoint inhibitors are currently licensed for the treatment of melanoma, kidney cancer, lung cancer and most recently, tumours with microsatellite instability. There is much enthusiasm for investigating this approach in gynaecological cancers and the possibility that immunotherapy might become part of the therapeutic landscape for gynaecological malignancies. Cervical cancer is the fourth most frequent cancer in women worldwide and represents 7.9% of all female cancers with a higher burden of the disease and mortality in low- and middle-income countries. Cervical cancer is largely a preventable disease, since the introduction of screening tests, the recognition of the human papillomavirus (HPV) as an etiological agent, and the subsequent development of primary prophylaxis against high risk HPV subtypes. Treatment for relapsed/advanced disease has improved over the last 5 years, since the introduction of antiangiogenic therapy. However, despite advances, the median overall survival for advanced cervical cancer is 16.8 months and the 5-year overall survival for all stages is 68%. There is a need to improve outcomes and immunotherapy could offer this possibility. Clinical trials aim to understand the best timing for immunotherapy, either in the adjuvant setting or recurrent disease and whether immunotherapy, alone or in combination with other agents, improves outcomes.

Ovarian cancer is a silent killer and, due to late diagnosis, the primary cause of death amongst gynecological cancers, killing approximately 376 women annually in Denmark. The discovery of a specific and sensitive biomarker for ovarian cancer could improve early diagnosis, but also treatment, by predicting which patients will benefit from specific treatment strategies. The Mermaid III project is consisting of 3 parts including \"Early detection, screening and long-term survival,\" \"Biomarkers and/or prognostic markers\" and \"The infection theory.\" The present paper gives an overview of the part regarding biomarkers and/or prognostic markers, with a focus on rationale and design. The study described has 3 major branches: microRNAs, epigenetics and Next Generation Sequencing. Tissue and blood from ovarian cancer patients, already enrolled in the prospective ongoing pelvic mass cohort, will be examined. Relevant microRNAs and DNA methylation patterns will be investigated using array technology. Patient exomes will be fully sequenced, and identified genetic variations will be validated with Next Generation Sequencing. In all cases, data will be correlated with clinical information on the patient, in order to identify possible biomarkers. A thorough investigation of biomarkers in ovarian cancer, including large numbers of different markers, has never been done before. Besides from improving diagnosis and treatment, other outcomes could be markers for screening, knowledge of the molecular aspects of cancer and the discovery of new drugs. Moreover, biomarkers are a prerequisite for the development of precision medicine. This study will attack the ovarian cancer problem from several angles, thereby increasing the chance of successfully contributing to saving lives.

•Neuroendocrine tumors (NETs) frequently occur in the lungs or the gastrointestinal tract; they are uncommon in the ovary.•The mammalian target of rapamycin (mTOR) pathway has been reported as a treatment for advanced NETs.•We describe a patient with an aggressive primary ovarian NET, successfully treated with everolimus (an mTOR inhibitor).

BACKGROUND: Tumor interstitial fluid (TIF) rather than plasma should be used in cancer biomarker discovery because of the anticipated higher concentration of locally produced proteins in the tumor microenvironment. Nevertheless, the actual TIF-to-plasma gradient of tumor specific proteins has not been quantified. We present the proof-of-concept for the quantification of the postulated gradient between TIF and plasma.
METHODS: TIF was collected by centrifugation from serous (n = 19), endometrioid (n = 9) and clear cell (n = 3) ovarian carcinomas with early (n = 15) and late stage (n = 16) disease in grades 1 (n = 2), 2 (n = 8) and 3 (n = 17), and ELISA was used for the determination of CA-125, osteopontin and VEGF-A.
RESULTS: All three markers were significantly up-regulated in TIF compared with plasma (p < 0.0001). The TIF-to-plasma ratio of the ovarian cancer biomarker CA-125 ranged from 1.4 to 24,300 (median = 194) and was inversely correlated to stage (p = 0.0006). The cancer related osteopontin and VEGF-A had TIF-to-plasma ratios ranging from 1 to 62 (median = 15) and 2 to 1040 (median = 59), respectively. The ratios were not affected by tumor stage, indicative of more widespread protein expression.
CONCLUSIONS: We present absolute quantitative data on the TIF-to-plasma gradient of selected proteins in the tumor microenvironment, and demonstrate a substantial and stage dependent gradient for CA-125 between TIF and plasma, suggesting a relation between total tumor burden and tissue-to-plasma gradient.
CONCLUSIONS: We present novel quantitative data on biomarker concentration in the tumor microenvironment, and a new strategy for biomarker selection, applicable in future biomarker studies.

An increased level of interleukin-6 (IL-6) in epithelial ovarian cancer (EOC) is correlated with a worse prognosis. IL-6 stimulates tumor-growth and inflammation. We investigated the intricate interaction between the IL-6 signaling pathway and tumor-infiltrating myeloid cells (TIMs) to determine their prognostic impact in EOC. 160 EOC samples were analyzed for the expression of IL-6, its receptor (IL-6R) and downstream signaling via pSTAT3 by immunohistochemistry. Triple color immunofluorescence confocal microscopy was used to identify myeloid cell populations by CD14, CD33, and CD163. The relationship between these markers, tumor-infiltrating immune cells, clinical-pathological characteristics and survival was investigated. EOC displayed a dense infiltration with myeloid cells, in particular of the CD163+ type. The distribution pattern of all myeloid subtypes was comparable among the different histological subtypes. Analysis of the tumor cells revealed a high expression of IL-6R in 15% and of IL-6 in 23% of patients. Interestingly, tumors expressing IL-6 or IL-6R formed two different groups. Tumors with a high expression of IL-6R displayed low mature myeloid cell infiltration and a longer disease-specific survival (DSS), especially in late stage tumors. High expression of IL-6R was an independent prognostic factor for survival by multivariate analyses (hazard ratio = 0.474, p = 0.011). In contrast, tumors with high epithelial IL-6 expression displayed a dense infiltration of mature myeloid cells and were correlated with a shorter DSS. Furthermore, in densely CD8+ T-cell infiltrated tumors, the ratio between these lymphoid cells and CD163+ myeloid cells was predictive for survival. Thus, IL-6 and IL-6R are opposite markers for myeloid cell infiltration and survival.