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Background: Small extracellular vesicles (sEVs) in the blood of cancer patients contain higher amounts of tumor markers than those identified as free-circulating. miRNAs have significant biomedical relevance due to their high stability and feasible detection. However, there is no reliable endogenous control available to measure sEVs-miRNA content, impairing the acquisition of standardized consistent measurements in cancer liquid biopsy. Results: In this study, we identified three miRNAs from a panel of nine potential normalizers that emerged from a comprehensive analysis comparing the sEV-miRNA profile of six lung and ovarian human cancer cell lines in the absence of or under different conditions of chemotherapy. Their relevance as normalizers was tested in 26 additional human cancer cell lines from nine different tumor types undergoing chemotherapy or radiotherapy treatment. The validation cohort was comprised of 172 prospective plasma and ascitic fluid samples from three different human tumor types. Variability and normalization properties were tested in comparison to miR-16, the most used control to normalize free-circulating miRNAs in plasma. Conclusion: Our results indicate that miR-151a is consistently represented in small extracellular vesicles with minimal variability compared to miR-16, providing a novel normalizer to measure small extracellular vesicle miRNA content that will benefit liquid biopsy in cancer patients.

The main objective was to analyze the rate of bilateral sentinel lymph node (SLN) detection in endometrial cancer using indocyanine green (ICG) as a unique tracer compared to Technetium99 + ICG. As secondary objectives, we analyzed the drainage pattern and factors that might affect the oncological outcomes. A case-control ambispective study was carried out on consecutive patients at our center. Data on the SLN biopsy with ICG collected prospectively were compared to retrospective data on the use of a double-tracer technique including Technetium99 + ICG. In total, 194 patients were enrolled and assigned to both groups, in which the group with both tracers (controls) included 107 (54.9%) patients and the ICG-alone group (cases) included 87 (45.1%) patients. The rate of bilateral drainage was significantly higher in the ICG group (98.9% vs. 89.7%; p = 0.013). The median number of nodes retrieved was higher in the control group (three vs. two nodes; p < 0.01). We did not find survival differences associated with the tracer used (p = 0.85). We showed significant differences in terms of disease-free survival regarding the SLN location (p < 0.01), and obturator fossa retrieved nodes showed better prognosis compared to external iliac. The use of ICG as a single tracer for SLN detection in endometrial cancer patients seemed to obtain higher rates of bilateral detection with similar oncological outcomes.

Digital, Background: In an effort to contribute to overcoming the platinum resistance exhibited by most solid tumors, we performed an array of epigenetic approaches, integrating next-generation methodologies and public clinical data to identify new potential epi-biomarkers in ovarian cancer, which is considered the most devastating of gynecological malignancies. Methods: We cross-analyzed data from methylome assessments and restoration of gene expression through microarray expression in a panel of four paired cisplatin-sensitive/cisplatin-resistant ovarian cancer cell lines, along with publicly available clinical data from selected individuals representing the state of chemoresistance. We validated the methylation state and expression levels of candidate genes in each cellular phenotype through Sanger sequencing and reverse transcription polymerase chain reaction, respectively. We tested the biological role of selected targets using an ectopic expression plasmid assay in the sensitive/resistant tumor cell lines, assessing the cell viability in the transfected groups. Epigenetic features were also assessed in 189 primary samples obtained from ovarian tumors and controls. Results: We identified PAX9 and FKBP1B as potential candidate genes, which exhibited epigenetic patterns of expression regulation in the experimental approach. Re-establishment of FKBP1B expression in the resistant OVCAR3 phenotype in which this gene is hypermethylated and inhibited allowed it to achieve a degree of platinum sensitivity similar to the sensitive phenotype. The evaluation of these genes at a translational level revealed that PAX9 hypermethylation leads to a poorer prognosis in terms of overall survival. We also set a precedent for establishing a common epigenetic signature in which the validation of a single candidate, MEST, proved the accuracy of our computational pipelines. Conclusions: Epigenetic regulation of PAX9 and FKBP1B genes shows that methylation in non-promoter areas has the potential to control gene expression and thus biological consequences, such as the loss of platinum sensitivity. At the translational level, PAX9 behaves as a predictor of chemotherapy response to platinum in patients with ovarian cancer. This study revealed the importance of the transcript-specific study of each gene under potential epigenetic regulation, which would favor the identification of new markers capable of predicting each patient's progression and therapeutic response., Ciencias Médicas y de la Salud

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study. 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1-mm portion of each lymph node was subjected to semi-serial sectioning at 200-μm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analysed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μl), the sensitivity of the OSNA assay was 92%; specificity was 82%; diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.

ObjectiveTo evaluate the role of sentinel lymph node biopsy (SLNB) to avoid staging lymphadenectomies by detecting nodal metastasis in intermediate- and high-risk endometrial cancer (EC).MethodsA single institutional retrospective study was performed including all patients with intermediate- and high-risk EC who underwent surgical nodal staging between January 2012 and December 2019. Patients with disseminated disease detected on imaging techniques or at the time of surgery were excluded. Patients were evaluable if they underwent nodal staging with SLNB and pelvic (PLD) and paraaortic (PALD) lymph node dissection. We analyzed the accuracy of the sentinel lymph node technique. Only patients with at least one sentinel lymph node (SLN) detected were included in the sensitivity and negative predictive value (NPV) analyses. The tracers used were technetium 99m, blue dye, and indocyanine green.ResultsEighty-eight patients presented intermediate- and high-risk EC (51 patients and 37 patients respectively) and underwent SLNB with consecutive PLD and PALD. The median (range) number of sentinel nodes retrieved was 2.9 (0–11). The global detection rate of SLN was 96.6% with a bilateral detection of 80.7% when considering all tracers used. However, when combination of indocyanine green and technetium was used the bilateral detection rate was 90.3%. Nodal metastases were detected in 17 (19.3%) cases, 8 (47%) of them corresponded to low volume metastasis (LVM), 7 (87.5%) of them diagnosed at ultrastaging pathologic exam. Finally, we obtained a sensitivity of 90%, a NPV of 97.5%, and a false negative rate (FNR) of 10% in the intermediate-risk EC compared to sensitivity of 85.7%, NPV of 96.6%, and FNR of 14.3% in the high-risk EC group. The only patient with isolated paraaortic nodal metastasis was found at the high-risk group, 1.1%.ConclusionsAccording to our results, full lymphadenectomy could be avoided by performing SLNB in patients with intermediate-risk EC because the only false negative case detected was at the beginning of ICG learning curve. For high-risk EC patients we did not find enough evidence to support the systematic avoidance of staging full lymph node dissection. Nevertheless, SLNB should be performed in all cases of EC as it improves LVM diagnosis substantially.

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 μm intervals and examined by hematoxylin–eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis., El objetivo de este estudio fue evaluar la eficacia de la amplificación de ácido nucleico en un solo paso (OSNA) para la detección de metástasis en el ganglio linfático centinela (GC) en comparación con la ultraestadificación patológica estándar en pacientes con cáncer de endometrio (CE) en estadio temprano. Se incluyeron en el estudio un total de 526 SLN de 191 pacientes con EC, y 379 SLN (147 pacientes) fueron evaluados por ambos métodos, OSNA y ultraestadificación patológica estándar. La porción central de 1 mm de cada ganglio linfático se sometió a un seccionamiento semiserie a intervalos de 200 μm y se examinó mediante hematoxilina-eosina e inmunohistoquímica con CK19; el tejido restante fue analizado por OSNA para ARNm de CK19. El ensayo OSNA detectó metástasis en el 19,7 % de los pacientes (14,9 % micrometástasis y 4,8 % macrometástasis), mientras que la ultraestadificación patológica detectó metástasis en el 8,8 % de los pacientes (3. 4% micrometástasis y 5,4% macrometástasis). Usando el valor de corte establecido para detectar metástasis SLN por OSNA en EC (250 copias/μL), la sensibilidad del ensayo OSNA fue del 92 %, la especificidad fue del 82 %, la precisión diagnóstica fue del 83 % y el valor predictivo negativo fue del 99 % Se registraron resultados discordantes entre ambos métodos en 20 pacientes (13,6%). OSNA resultó en una sobreestadificación en 12 pacientes (8,2%). OSNA podría ayudar en la identificación de pacientes que requieren tratamiento adyuvante en el momento del diagnóstico. Se registraron resultados discordantes entre ambos métodos en 20 pacientes (13,6%). OSNA resultó en una sobreestadificación en 12 pacientes (8,2%). OSNA podría ayudar en la identificación de pacientes que requieren tratamiento adyuvante en el momento del diagnóstico. Se registraron resultados discordantes entre ambos métodos en 20 pacientes (13,6%). OSNA resultó en una sobreestadificación en 12 pacientes (8,2%). OSNA podría ayudar en la identificación de pacientes que requieren tratamiento adyuvante en el momento del diagnóstico.

Background The trend toward late childbearing has made fertility preservation a major issue for women who face gynecological cancer. New techniques in assisted reproductive medicine enable conception after primary treatment of these cancers. Here, we aimed to review the efficacy and safety of assisted reproductive techniques (ART) after fertility-preserving treatment of gynaecological cancers. Methods We conducted a systematic literature review of both prospective and retrospective studies in the PubMed, EMBASE, CENTRAL and SciSearch databases. In the retrieved studies, we evaluated live births, clinical pregnancies, overall survival and disease-free survival. Results We identified many prospective and retrospective studies on this topic, but no relevant randomized clinical trials. Fertility-sparing treatments with safe oncological outcomes are feasible in endometrial, cervical and ovarian cancer cases. After cancer treatment, ART seem safe and show variable obstetrical outcomes. Conclusions After fertility-preserving treatment for gynaecological cancers, ART can enable pregnancy to be achieved with apparent oncological safety. The success of such procedures should directly impact clinical practice and management of those patients who require fertility-sparing treatment.

Study Objective To compare sentinel lymph node (SLN) mapping in women with cervical cancer stage >IB1 (tumor size >2 cm) using indocyanine green (ICG) versus the standard technique using radioisotope technetium 99m radiocolloid (Tc99 m ) radiotracer with or without blue dye. Design European multicenter, retrospective observational study (Canadian Task Force classification II-2). Setting Four academic medical centers. Patients Ninety-five women with stage IB1 cervical cancer (>2 cm) who underwent SLN mapping with Tc99 m with or without blue dye or ICG and radical hysterectomy. Intervention The detection rate and bilateral mapping rate were compared between ICG and standard Tc99 m radiotracer with or without blue dye. Lymphadenectomy was performed, and the false-negative rate was assessed. Measurements and Main Results Forty-seven patients underwent SLN mapping with Tc99 m with or without blue dye, and 48 did so with ICG. All patients underwent radical hysterectomy with or without bilateral salpingo-oophorectomy between 2008 and 2016. The overall detection rate of SLN mapping was 91.5% for Tc99 m with or without blue dye and 100% for ICG. A 91.7% rate of bilateral migration was achieved for ICG, significantly higher than the 66% obtained with Tc99 m with or without blue dye (p = .025). Nine of the 23 SLN-positive patients (39.1%) were diagnosed exclusively as a result of the ultrastaging used to identify micrometastases or isolated tumor cells only. Conclusions In advanced cervical cancer (stage IB1 >2 cm), the detection rate and bilateral migration rate on real-time fluorescent SLN mapping were higher with ICG than with Tc99 m radiotracer with or without blue dye. SLN mapping and ultrastaging can provide additional information for nodal staging in advanced cervical cancer. In this setting, ICG is a promising tool for mapping, appearing less affected by higher disease stage compared with traditional methods.

Background Ovarian cancer may appear in young women during their reproductive age. As a result of late childbearing nowadays, fertility preservation has become a major issue in young women with gynecological cancer. The aim of this review is to update the current knowledge on conservative treatment and fertility preservation of women affected of early stage epithelial ovarian cancer. Material and methods A web-based search in Medline and CancerLit databases on conservative treatment for early stage ovarian cancer has been carried out. All relevant information has been collected and analyzed. Results Less than 40% of ovarian cancers are diagnosed at early stages. Conservative treatment may be considered in young patients with a relapse rate that ranges from 9% to 29%, and a 5-year survival ranging from 83% to 100%. Recurrences in the controlateral ovary has been reported to be less than 5%, with most of these patients being alive after savage treatments. Moreover, it has been reported good fertility outcomes after conservative treatment with a successful conception rate that ranges from 60% to 100%, with an abortion rate under 30% in all series reported. Conclusions Conservative treatment for early epithelial ovarian cancers could be a safe option for women younger than 40 years who wish to preserve their childbearing potential. We need a strict case selection such as FIGO stage I grade 1 and 2, although grade 3 cases could be considered.

ObjectiveThe aim of this study was to evaluate the feasibility and the safety of single-port extraperitoneal laparoscopic para-aortic lymphadenectomy for patients with gynecologic cancer.MethodsFrom July 2012 to January 2013, a total of 7 patients with gynecologic cancer underwent a laparoscopic pelvic and para-aortic lymphadenectomy with a single-port device. An extraperitoneal approach was performed for para-aortic lymphadenectomy using only one 2.5-cm incision on the left side. In 6 patients, additionally, hysterectomy and pelvic lymphadenectomy with conventional laparoscopy were performed to complete the treatment.ResultsAortic dissection was complete in all cases without complications. The median age of the patients was 63 years (range, 48–78 years), and the median patient body mass index was 31 kg/m2 (range, 19–38 kg/m2). The median number of para-aortic nodes was 17 (range, 10–25); the median operative time was 204 minutes (range, 120–300 minutes). The median hospital stay was 4 days (range, 3–6 days). No patient encountered postoperative complications.ConclusionsThis study demonstrates the feasibility of single-port laparoscopic extraperitoneal para-aortic lymphadenectomy.

Study Objective To evaluate the surgical outcome of extraperitoneal paraaortic lymph node dissection compared with the traditional transperitoneal approach. Design Retrospective review (Canadian Task Force classification III). Setting University hospital. Patients Women with gynecologic malignancies admitted to our hospital between 2007 and 2011 who underwent laparoscopic paraaortic lymphadenectomy. Interventions Indication, diagnosis, and outcome according to type of surgery were evaluated. Measurements and Main Results Of 47 patients who underwent laparoscopic paraaortic lymphadenectomy because of gynecologic indications, 28 patients underwent extraperitoneal paraaortic lymph node dissection and 19 underwent the same procedure via the classic transperitoneal technique. The most frequent indication for extraperitoneal lymph node dissection was cervical cancer (71.4%), and for the transperitoneal technique was endometrial cancer (47.4%). The mean (SD) duration of surgery was 211 (38) minutes in the transperitoneal approach group, and 173 (51) minutes in the extraperitoneal lymphadenectomy group (p = .009). No significant differences between groups were found in the number of lymph nodes removed (15 [5.9] nodes in the extraperitoneal group vs 17.4 [8.6] in the transperitoneal group; p = .25). However, a higher rate of positive nodes was observed in the extraperitoneal group than in the transperitoneal group (42.8% vs 36.2%, respectively [p = .001]), and a significantly shorter stay in the intensive care unit in the extraperitoneal group (0.59 [0.5] vs 1.1 [0.5] days, respectively; p = .02). No significant differences in complication rate were found between groups. Conclusions Extraperitoneal paraaortic lymph node dissection is a minimally invasive procedure that is an excellent and safe approach to the paraaortic area, with a low complication rate, sufficient number of lymph nodes, and short hospital stay. It seems to be a good alternative to the classic transperitoneal approach.

Intravenous leiomyomatosis (IVL) is a rare benign condition characterized by the proliferation of smooth muscle cells originating from either the uterine venous wall or a uterine myoma. This leiomyomatosis extends most frequently to pelvic vessels, but also occasionally into the inferior vena cava and right cardiac chambers. Preoperative diagnosis is difficult and it should be suspected in the presence of cardiac or pelvic masses in women who have undergone hysterectomy or myomectomy previously. The treatment is hysterectomy, normally associated with a bilateral oophorectomy and removing the mass or metastasis if any. The post-surgical follow-up should be performed at long-term and include exploration and imaging, either ultrasound or MRI. The association of antiestrogenic drugs can be useful for disease control, especially in cases where oophorectomy is not performed and the tumor cannot be removed completely.

Objective To evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the diagnosis of sentinel lymph node (SLN) metastasis compared with histopathological examination in patients with endometrial carcinoma. Methods A total of 94 SLNs from 34 patients with endometrial carcinoma were enrolled. The central 1-mm portion of each node was subjected to semi-serial sectioning, sliced at 200-μm intervals and examined by hematoxylin and eosin and cytokeratin 19 (CK19) immunohistochemical staining, and the remaining tissue was analysed by OSNA using CK19 mRNA. The accuracy of the OSNA assay was evaluated based on histopathological diagnosis. Results Histologically, 89 SLNs were determined to be metastasis negative, and the remaining five SLNs were metastasis positive. Using the breast cancer cutoff value for detecting lymph node metastasis (OSNA criteria for breast cancer, >250copies/μl) the sensitivity of the OSNA assay was 100%; specificity was 87.6%; diagnostic accuracy was 88.3%. Discordant results were recorded for 11 of 94 SLNs. In all 11 cases, a positive result was given by the OSNA assay but not by histopathological examination. In two SLNs from the same patient, histopathological examination revealed the presence of benign epithelial inclusions that were CK19 positive; both SLNs yielded a positive result in the OSNA assay (true–false positive). All remaining nine histologically-negative/OSNA-positive SLNs were classified as micrometastasis (+) by the OSNA assay. Conclusion The OSNA assay shows high sensitivity and specificity, which suggests its utility as a novel tool for the molecular detection of SLN metastasis in patients with endometrial carcinoma.

BackgroundPelvic exenteration is an ultraradical surgery involving the en bloc resection of the pelvic organs, including the internal reproductive organs, the distal urinary tract (ureters, bladder, urethra), and/or anorectum. It is mainly applied as a salvage surgery for recurrent gynecologic tumors of any origin (vulva, vagina, cervix, uterine, and also ovary). Our aim was to establish the most favorable cases for this type of surgery by means of a review of our institution experience.MethodsRetrospective analyses of all patients treated with pelvic exenteration for recurrent gynecologic cancer from 2008 to 2014 at La Paz University Hospital.ResultsTen patients underwent pelvic exenteration for recurrent gynecologic cancers including uterine, cervical, vaginal, vulvar, and ovarian cancer. All patients had received prior treatment: surgery, radiotherapy, and/or chemotherapy. Eight patients underwent total pelvic exenteration, one anterior and one posterior pelvic exenteration. Urinary diversions technique consisted of ileal conduits in all cases. Permanent colostomy was performed in all cases. Postoperative complications were related to the urinary diversion in 50% of the cases, to the reconstructive technique in 30%, and to systemic or pelvic infections in 20%.ConclusionsDespite the high morbidity and mortality rates, pelvic exenteration is feasible, and in selected cases of cancer recurrence is the last possible treatment.

Study Objective To show the removal of an intramyometrial fetus after uterine curettage using laparoscopy as a safe surgical technique that offers excellent results and fewer complications than laparotomy. Design Presentation of the clinical case and step-by-step explanation of the technique. Settings Uterine curettage is a frequently performed gynecologic abortion procedure. Dilatation and curettage is considered to be a safe surgical technique, with a low percentage of complications. The most common is uterine perforation, with higher risks in advanced gestational age, retroflexed uterus, or uterine leiomyomas. Interventions After institutional review board approval, we present the case of a 29-year-old women referred to our hospital from another clinic with a suspected uterine perforation after an elective curettage for a 14-week pregnancy. She presented with moderate abdominal pain. Vaginal ultrasound revealed intramyometrial fetal parts on isthmus and right parametrium and minimal free fluid in the pouch of Douglas. A laparoscopic approach was chosen. After a complete revision of the abdominal cavity, the right paravesical space was dissected, confirming no right uterine artery or ureter injury. One cavity was objectified in the posterior leaf of the broad ligament related to a uterine perforation and containing fetal bone parts, which were removed. The myometrial defect and the peritoneum were closed with intracorporeal sutures. The removal of fetal parts was done with a surgical glove thimble. After the procedure, the patient was treated with clindamycin and gentamycin, with a satisfactory recovery. Conclusion The presence of an intramyometrial fetus is not a common complication of curettage. The use of laparoscopy is feasible and offers excellent results and advantages versus laparotomy regarding its treatment.

Objective To analyze the prognostic factors related to the recurrence rate of vulvar cancer. Methods Retrospective study of 87 patients diagnosed of vulvar squamous cell carcinoma diagnosed at a tertiary hospital in Madrid between January 2000 and December 2010. Results The pathological mean tumor size was 35.1±22.8 mm, with stromal invasion of 7.7±6.6 mm. The mean free margin after surgery was 16.8±10.5 mm. Among all patients, 31 (35.6%) presented local recurrence (mean time 10 months; range, 1 to 114 months) and 7 (8%) had distant metastases (mean time, 5 months; range, 1 to 114 months). We found significant differences in the mean tumor size between patients who presented a relapse and those who did not (37.6±21.3 mm vs. 28.9±12.1 mm; p=0.05). Patients with free margins equal or less than 8 mm presented a relapse rate of 52.6% vs. 43.5% of those with free margin greater than 8 mm (p=0.50). However, with a cut-off of 15 mm, we observed a local recurrence rate of 55.6% vs. 34.5%, respectively (p=0.09). When the stromal invasion cut-off was >4 mm, local recurrence rate increased up to 52.9% compared to 37.5% when the stromal invasion was ≤4 mm (p=0.20). Conclusion Tumor size, pathologic margin distance and stromal invasion seem to be the most important predictors of local vulvar recurrence. We consider the cut-off of 35 mm of tumor size, 15 mm tumor-free surgical margin and stromal invasion >4 mm, high risk predictors of local recurrence rate.