Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial

Background: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multi centre, 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. Methods: 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). Results: 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. Interpretation: 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. (C) 2020 The Author(s). Published by Elsevier Ltd

Central Pathology Review in SENTIX, a Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2)

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review

Uloha HPV v cervikalni kancerogenezi a prinos metodik detekce HPV pro vcasnou diagnostiku a terapii neoplazii delozniho hrdla.

Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Matrix metalloproteinase-26 (MMP-26) and Tissue inhibitor of metalloproteinases-4 (TIMP-4) in normal, hyperplastic, and malignant endometrium.

The aim of the thesis was to study matrix metalloproteinase-26 (MMP-26) and tissue inhibitor of metalloproteinases-4 (TIMP-4) in normal, hyperplastic, and malignant endometrium. Most importantnly, both these molecules may be ivolved in the implantation process. Trophoblast tissue from human as well as mouse embryos produces pro-MMP-9. Active MMP-9 (gelatinase B) is a proteolytic enzyme with a broad substrate specificity. MMP-26 is an effective activator of pro-MMP-9, and TIMP-4 is a strong inhibitor of MMP-26. We found that endometrial expression of MMP-26 mRNA and TIMP-4 mRNA is elevated during the proliferative phase, is maximal in the early, decreases in the mid-, and is low in the late secretory phases (I, III). The expression pattern of both genes suggests their up-regulation by estrogen, and down-regulation by progesterone. This is supported by our findings of potential estrogen response elements upstream the coding sequences of both genes (II, III). In situ hybridization localised MMP-26 mRNA in epithelial and TIMP-4 mRNA in stromal cells (I, III). As expected, using immunohistochemistry we found MMP-26 protein in the epithelium (II). However, the same technique showed only occasional staining for TIMP-4 in the stroma (V). Instead, TIMP-4 protein was localised in granules of the apical part of epithelial cells. This finding suggests that TIMP-4 is produced in and secreted by the stromal cells, taken up by the epithelial cells, stored in apical granules, and finally secreted to the uterine fluid. Analysis of uterine fluid with Western blot technique demonstrated presence of TIMP-4, but not MMP-26 (V). So far, very few proteins of stromal origin have been demonstrated in the uterine fluid. Furthermore, using different antibodies, we have shown that MMP-26 is stored in epithelial cells in its active form, is not released spontaneously, and when released it is controlled by TIMP-4 in both stroma and uterine fluid. Examination of endometrial tissue obtained from IVF patients in an estrogen and progesterone substitution protocol showed that the estrogen sensitive genes MMP-26 and TIMP-4 are over-stimulated by both estrogen and progesterone. Analysis of MMP-26 and TIMP-4 expression in endometrial hyperplastia showed that both localization and amount of mRNA corresponded to that of the proliferative phase. This is in agreement with estrogen mediated regulation of these genes, as well as hyperplasia being the result of estrogen over-stimulation. The expression of MMP-26 and TIMP-4 decreases with loss of histological differentiation in endometrial cancer. This is also in agreement with the general loss of differentiated functions during progression to poorly differentiated, and more malignant tumors

Prospective comparison of cervical ripening with double balloon Cook catheter, misoprostol or dinoprostone in term singleton pregnancies

Objectives: Induction of labor is indicated if the risk of continuing pregnancy is higher (either for fetus or mother) than the risk associated with the induction itself. The purpose of the present study was to compare the effectiveness of the double balloon Cook catheter and pharmacological preparations — prostaglandins (PGE), in our case it was misoprostol (PGE1) or dinoprostone (PGE2) for cervical ripening in pregnant women with gestational age at term. Material and methods: The prospective observational study was conducted from March 2017 to December 2018. We used mechanical and pharmacological methods for cervical ripening. We compared the efficiency of methods and time to delivery from start of cervical ripening. We also evaluated the neonatal complications by Apgar score and neonatal intensive care unit admission in three different groups. Results: Two hundred and nine women were chosen for cervical ripening. Double balloon Cook catheter and misoprostol were equally efficient in achieving vaginal delivery (76%). The shortest time for cervical ripening and successful vaginal delivery was shown in misoprostol (PGE1) group. In conclusion, no significant differences were found between groups in all neonatal outcomes. Conclusions: Currently, many methods of delivery preinduction exist and the prevalence of their usage varies considerably between countries. As yet, there is no literature comparing these three methods for the preparation of cervix

Nove matrix metaloproteinazy v cyklickem endometriu

OBJECTIVE: To examine the expression pattern of some novel matrix metalloproteinases (MMPs) in cycling endometrium. DESIGN: Experimental study. SETTING: Department of Obstetrics and Gynecology of the Palacky University Medical School and University Hospital, Olomouc, Czech Republic, Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden. METHODS: We studied MMP-12, -16, -17, -19 and -26 mRNA in 39 normal endometrial samples obtained across the menstrual cycle. Based on histological examination, all specimens were classified according to an ideal 28 day menstrual cycle as early (n=8), mid (n=6) and late (n=7) proliferative phase, early (n=4), mid (n=4) and late (n=8) secretory phase and menstrual (n=3) phase. Cycle variation was examined in frozen samples using in situ hybridization. RESULTS: Three distinct pattern of MMP mRNA expression were detected in cycling endometrium. MMP-12 was expressed predominantly in perimenstrual period, MMP-16, -17 and 19 were expressed throughout the cycle and MMP-26 was found to be maximal in periovulatory period. CONCLUSION: Different endometrial expression patterns of novel MMPs during menstrual cycle may indicate their specific roles for menstruation, endometrial growth and remodelling and implantation

Exprese MMP-26 v endometrialnich explantech pod vlivem estradiolu a progesteronu

OBJECTIVE: To examine possible estrogen dependent endometrial expression of MMP-26 in vitro. DESIGN: Experimental study. SETTING: Department of Obstetrics and Gynecology of the Palacky University Medical School and University Hospital, Olomouc, Czech Republic, Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden. METHODS: We studied MMP-26 mRNA in 14 normal endometrial samples obtained from the proliferative phase of the menstrual cycle. Samples were cultured for five days either with estradiol alone or in combination with progesterone. Samples cultured with ethanol represented control groups. MMP-26 mRNA expression was examined in frozen samples using in situ hybridization. Immunohistochemistry was used to study the presence of estrogen and progesterone receptors in endometrial explants. RESULTS: MMP-26 mRNA expression was highest in fresh (non cultured) samples. Signal intensity decreased during the first two days of culture and was negligable in the following days. Nuclear intensity for estrogen and progesterone receptor was high after five days of culture. CONCLUSION: We did not find MMP-26 mRNA in vitro expression to be directly estrogen dependent

Profily endometrialni exprese mRNA u vybranych matrix metaloproteinaz a tkanoveho inhibitoru metaloproteinaz-1

OBJECTIVE: To examine the endometrial expression pattern of messenger RNA (mRNA) for selected matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases-1 (TIMP-1). DESIGN: Experimental study. SETTING: Department of Obstetrics and gynecology of the Palacky University Medical School and University Hospital, Olomouc, Czech Republic, Department of Obsterics and Gynecology, University Hospital, Luna, Sweden. METHODS: We studied MMP-1, -3, -7, -10, -11, -12, -13, -14, -16, -26 and TIMP-1 mRNA in 39 normal endometrial samples obtained across the menstrual cycle. Based on histological examination, all specimens were classified according to an ideal 28 day menstrual cycle as early (n=8), mid (n=6) and late (n=7) proliferative phase, early (n=4), mid (n=4) and late (n=8) secretory phase and menstrual (n=3) phase. mRNA extracted from frozen tissue samples was quantitated using real time PCR. RESULTS: Four distinct patterns of MMP mRNA expression were detected in cycling endometrium. MMP-1, -3, -10, and -12 were expressed predominantly in perimenstrual period, MMP-7 and -11 had highest levels in proliferative phase, MMP-13, -14 and -16 were expressed throughout the cycle and MMP-26 was found to be maximal in periovulatory period. Levels of TIMP-1 mRNA remained unchanged during the cycle. CONCLUSION: The specific endometrial expression profiles of MMPs during menstrual cycle point to their specific biologic roles during the cycle. MMP-26 exhibits a unique expression pattern