Placental immune editing switch (PIES): learning about immunomodulatory pathways from a unique case report.

The hypothesis of this work is that, in order to escape the natural immune surveillance mechanisms, cancer cells and the surrounding microenvironment might express ectopically genes that are physiologically present in the placenta to mediate fetal immune-tolerance. These natural "placental immune-editing switch" mechanisms (PIES) may represent the result of millions of years of mammalian evolution developed to allow materno-fetal tolerance. Here, we introduce genes of the immune regulatory pathways that are either similarly over- or under-expressed in tumor vs normal tissue. Our analysis was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman. Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (in the placenta) and pathologically (in the cancer setting).

The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients.

OBJECTIVE: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. METHODS: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. RESULTS: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.

Consenso cáncer de mama y fertilidad / Consensus on breast cancer and fertility

El Consenso de Cáncer de Mama y Fertilidad de la Sociedad Española de Senología y Patología Mamaria es un documento elaborado por un amplio grupo de expertos de todas las especialidades implicadas en cáncer de mama. El presente documento se concluyó en el Primer Congreso Español de la Mama, celebrado en Madrid en octubre de 2014, y es una actualización del consenso que fue publicado en Revista de Senología y Patología Mamaria en 2009. Los avances que se están produciendo, tanto en el campo de la fertilidad como en la oncología, obligarán sin ninguna duda a una nueva revisión de las recomendaciones en un futuro cercano (AU)

The Consensus on Breast Cancer and Fertility of the Spanish Society of Senology and Breast Pathology (Sociedad Española de Senología y Patología Mamaria) is a document prepared by a wide group of experts in all the specialties involved in breast cancer. This document was finished at the 1st Spanish Congress on Breast Cancer, held in Madrid in October 2014, and is an update of the consensus document published in Revista de Senología y Patología Mamaria in 2009. Because of the advances currently taking place in the fields of both fertility and oncology, a new review of the recommendations will undoubtedly be needed in the near future (AU)

Impact of Surgery on the Evolution of Uterine Sarcomas.

STUDY OBJECTIVE: To identify the characteristics of uterine sarcomas and assess the impact of morcellation on prognosis. DESIGN: Case-control study. (Canadian Task Force classification II-2). SETTING: Hospital Quiron-Dexeus, an academic hospital. PATIENTS: Patients with uterine sarcoma histologically diagnosed and treated in our center between 1987 and 2013. INTERVENTION: All descriptive data, including type of surgery and clinical and pathological data, were reviewed. Survival analysis was performed comparing patients with hysterectomy/myomectomy without any type of morcellation and patients with morcellation during surgery. MEASUREMENTS AND MAIN RESULTS: A total of 37 sarcomas were diagnosed during the study period. The most common symptom was metrorrhagia (50%). The indication for surgery was related to myoma growth in 40% of cases and to metrorrhagia in 37.1% of cases. Open surgery was performed in 23 patients (62.2%), and laparoscopy was performed in 9 (24.3%). Myomectomy was performed in 14 patients (37.8%), and 23 patients (62.1%) underwent hysterectomy as initial surgery. Morcellation for tumor extraction was done in 8 cases (21.6%). Survival analysis by surgical approach showed increased disease-free survival (DFS) in the laparotomy group compared with the laparoscopy group (median, 70.3 months vs 10.4 months; p = .018). Median DFS according to type of surgery was 6.3 months in morcellation cases, 11.9 months in vaginal fragmentation cases, and 149.9 months in nonmorcellated cases (p < .002). The median time to progression was shorter in morcellated cases (laparocopic and vaginal) compared with nonmorcellated cases (11.9 vs 14.9 months; p < .001). No statistically significant differences in prognosis were related to myomectomy versus hysterectomy; however, there were significants difference between morcellation and nonmorcellation cases. CONCLUSION: Taking into account the negative impact of morcellation in sarcomas, the use of this technique should be reconsidered in cases of myoma with atypical clinical presentation or symptomatology. Patients must be informed about the possibility of a nonidentified sarcoma and the possible impact on prognosis resulting from its morcellation.

Deletion at 6q24.2-26 predicts longer survival of high-grade serous epithelial ovarian cancer patients.

Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03-0.81; Padj = 0.03). We found that loss at 6q24.2-26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01-0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61-0.90, log-rank P = 0.002) and 675 high-FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61-0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2-26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life.

Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer.

BACKGROUND: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. METHODS: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. RESULTS: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. CONCLUSIONS: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing.

Cáncer de mama asociado al embarazo: estudio analítico observacional / Pregnancy-Associated Breast Cancer: An analytical observational study

Fundamento y objetivo: El cáncer de mama asociado al embarazo se define como aquel que aparece durante la gestación o durante el primer año posparto. Pacientes y método: Estudio retrospectivo analítico observacional en el que se comparan 56 cánceres de mama y embarazo (CME) diagnosticados entre 1976-2008 con 73 pacientes con cáncer de mama no asociado al embarazo (CMNE). Se analizan los diversos datos demográficos, los factores pronósticos, el tratamiento y la supervivencia en ambos grupos. Resultados: La prevalencia de CME en nuestro centro es 8,13/10.000 embarazos. La mayor frecuencia (62%) apareció durante el puerperio. Los estadios son mayores en el CME respecto al CMNE, siendo el 31,3% avanzados en el CME frente al 13,3% en el CMNE (p < 0,05). En cuanto a factores pronósticos, el 27,3% de CME eran grado tumoral iii frente al 15,8% del CMNE. En el grupo CME el 33,3% tenían receptores para estrógeno negativos, el 48,7% receptores para progesterona negativos y el 34,5% eran Her2Neu positivo frente al 22,2, 24,1 y 31%, respectivamente, en CMNE. En el 52,8% de CME aparecieron ganglios afectados frente al 33,8% del CMNE (p < 0,05). En el grupo CME la supervivencia global y libre de enfermedad a 5 años fue del 63,7 y del 74,2%, respectivamente. Conclusiones: El peor pronóstico que se observa en el grupo CME es debido posiblemente a la presencia de factores de pronóstico adversos: metástasis ganglionares, receptores hormonales negativos y grado tumoral tipo iii, así como al diagnóstico tardío, con un porcentaje mayor de cánceres avanzados (AU)

Background and objective: Pregnancy-associated breast cancer is defined as breast cancer diagnosed during pregnancy and up to one year postpartum. Patients and method: A retrospective, analytical, observational study comparing 56 cases of breast cancer and pregnancy (PABC) diagnosed 1976-2008 with 73 patients with breast cancer not associated with pregnancy (non-PABC) was performed. Demographic data, prognostic factors, treatment and survival were reviewed and compared. Results: The prevalence of PABC in our center is 8.3/10,000. The highest frequency (62%) appeared during the postpartum period. The stages are higher in PABC, being 31.3% advanced (EIII and EIV) in PABC versus 13.3% in non-PABC (P < .05). Regarding prognostic factors, 27.3% in PABC had a tumoral grade 3 versus 15.8% of non-PABC. Among women with PABC, 33.3% had negative estrogen receptors, 48.7% negative progesterone receptors and 34.5% positive Her2Neu compared with 22.2, 24.1 and 31%, respectively of non-PABC patients. Finally, positive lymph nodes were found in 52.8% of PABC, versus 33.8% non-PABC (P < .05). Overall and disease-free survival rate at 5 years for PABC was 63.7 and 74.2%, respectively. Conclusions: The poorer survival observed is possibly due to the presence of adverse prognostic features such as lymph node metastases, negative hormone receptors, tumoral grade III, as well as a delay in diagnosis with a higher rate of advanced stages (AU)

[Pregnancy-Associated Breast Cancer: An analytical observational study]. / Cáncer de mama asociado al embarazo: estudio analítico observacional.

BACKGROUND AND OBJECTIVE: Pregnancy-associated breast cancer is defined as breast cancer diagnosed during pregnancy and up to one year postpartum. PATIENTS AND METHOD: A retrospective, analytical, observational study comparing 56 cases of breast cancer and pregnancy (PABC) diagnosed 1976-2008 with 73 patients with breast cancer not associated with pregnancy (non-PABC) was performed. Demographic data, prognostic factors, treatment and survival were reviewed and compared. RESULTS: The prevalence of PABC in our center is 8.3/10,000. The highest frequency (62%) appeared during the postpartum period. The stages are higher in PABC, being 31.3% advanced (EIII and EIV) in PABC versus 13.3% in non-PABC (P < .05). Regarding prognostic factors, 27.3% in PABC had a tumoral grade 3 versus 15.8% of non-PABC. Among women with PABC, 33.3% had negative estrogen receptors, 48.7% negative progesterone receptors and 34.5% positive Her2Neu compared with 22.2, 24.1 and 31%, respectively of non-PABC patients. Finally, positive lymph nodes were found in 52.8% of PABC, versus 33.8% non-PABC (P < .05). Overall and disease-free survival rate at 5 years for PABC was 63.7 and 74.2%, respectively. CONCLUSIONS: The poorer survival observed is possibly due to the presence of adverse prognostic features such as lymph node metastases, negative hormone receptors, tumoral grade iii, as well as a delay in diagnosis with a higher rate of advanced stages.

Estudio retrospectivo de la hemorragia uterina excesiva en la adolescencia / Retrospective study of heavy uterine bleeding in adolescence

Introducción. El objetivo principal es revisar la casuística de las adolescentes que consultaron por hemorragia uterina excesiva en la Unidad de Ginecología de la Adolescencia del Institut Universitari Dexeus de Barcelona, así como el tratamiento y la evolución de las mismas. Material y métodos. Estudio retrospectivo entre enero del 2005 y diciembre del 2009 en 178 adolescentes. Resultados. Los episodios de hemorragia uterina excesiva observados, clasificados según los niveles de la hemoglobina, fueron leves (53,4%), moderados (11,2%) y graves (2,2%). Se alcanzó una mejoría de la sintomatología en el 43% de las adolescentes que han recibido ferroterapia, un 48% con antiinflamatorios no esteroideos, un 55% con antifibrinolíticos, un 59% con gestágenos, un 54% con estroprogestágenos y un 56% con anticonceptivos hormonales combinados. Conclusión. La hemorragia uterina en exceso es una patología frecuente en la consulta de Ginecología de la Adolescencia. Su manejo y las medidas terapéuticas son de fácil aplicación(AU)

Introduction. The main objective of this study was to review the casuistics of adolescent women who consulted the Unidad de Ginecología de la Adolescencia del Institut Universitari Dexeus in Barcelona, Spain, for heavy uterine bleeding, as well as their treatments and outcomes. Material and methods. We performed a retrospective study of 178 adolescents treated between January 2005 and December 2009. Results. The severity of uterine bleeding was classified according to hemoglobin levels as mild (53.4%), moderate (11.2%) and severe (2.2%). Symptoms improved in 43% of the patients treated with iron therapy, 48% of those treated with non-steroidal anti-inflammatory drugs, 55% of patients who received antifibrinolytic agents, 59% of those treated with progestogens, 54% of patients who received estro-progestogens and 56% of those who received combined hormonal contraceptives. Conclusion. Heavy uterine bleeding is a common gynecological condition in adolescence, whose management and therapeutic measures are easy to apply(AU)

[Oncologic risk counselling unit. Selection of risk groups and results]. / Consulta de riesgo oncológico. Selección de grupos de riesgo y resultados.

BACKGROUND AND OBJECTIVE: We evaluated the patients' selection and the results of the detection of mutations as well as the follow-up of families at a genetic counselling unit. PATIENTS AND METHOD: One hundred and fifty three patients were visited corresponding to 137 families: 77 of them were classified as high-risk group, 35 as moderate-risk and 25 as low-risk. The classification of patients in each group was made according to the recommendations of the guidelines and the "Oncoguia de càncer familiar" of the Departament de Salut de la Generalitat de Catalunya. RESULTS: With regard to familiar antecedents, patients of the high-risk group had an average (standard deviation) of 2.80 (1.5) cases of breast and/or ovarian cancer, while it was 1.82 (0.75) in the moderate-risk group, and 1.05 (0.80) in the low-risk group. Thirty seven families of high-risk (51.9%) were studied for the detection of deleterious mutations in BRCA1/2. Of 37 completed studies, 5 were positive (one BRCA1 and one BRCA2), 3 had variants of unknown significance in BRCA2 and 25 (83.4%) had no deleterious mutation in BRCA1/2. CONCLUSIONS: A correct selection of patients was performed, because 16.6% of BRCA's studies was positive. This fact allows us to adapt a planning of screening.

Ovulation induction treatment and risk of borderline ovarian tumors.

AIM: Research has suggested an association between the use of ovulation induction drugs and the risk of ovarian cancer. It has also been proposed that there may be pre-cancerous alterations in the ovary which themselves are the cause of infertility. The aim of the present study was to evaluate the relationship between the use of ovulation induction drugs and the appearance of borderline ovarian tumors. MATERIAL AND METHODS: This was a case-control study in which the study group comprised 42 women with a borderline ovarian tumor and the control group comprised 257 women with benign ovarian pathology. RESULTS: No differences were found between the borderline tumor and control groups (14.3% vs. 27.2%, respectively) in terms of infertility history. Nor were there any differences between the groups with respect to the type of drug used, whether clomiphene citrate (9.5% vs. 6.2%, respectively) or gonadotropins (7.1% vs. 10.1%, respectively). Analysis in terms of the number of cycles administered also failed to reveal any differences. The mean number of cycles with clomiphene citrate/gonadotropins was 2.50 +/- 1.00 and 3.00 +/- 2.64 in the borderline tumor group and 2.44 +/- 1.75 and 3.27 +/- 2.25 in the control group. CONCLUSIONS: Our series produced no evidence that ovulation induction treatment predisposes women to the development of borderline ovarian tumors.

Results of the national survey of borderline ovarian tumors in Spain.

MATERIAL AND METHODS: Retrospective multi-center analysis of women diagnosed with borderline ovarian tumor and treated between January 1990 and December 1997. A national survey was conducted, in which 457 patients from 27 centers corresponding to ten of Spain's autonomous communities were analyzed. RESULTS: Four hundred fifty-seven women with borderline ovarian tumor were analyzed. The mean age of patients was 45.5+/-16.9 years. Of these, 390 patients (85.3%) were at stage I, 8 (1.8%) were at stage II and 36 (7.9%) at stage III. A bilateral tumor was observed in 63 women (13.8%). The mean tumor size was 14.2 cm and in 88 cases (19.3%) the tumor was on the surface of the ovary. Microinvasion was observed in 25 (5.5%) cases, and 29 women (6.3%) showed a micropapillary pattern. Study of the factors related to the appearance of peritoneal implants revealed positive tumor markers (OR 15.02: 1.9-32.9) and a tumor on the ovarian surface (OR 8.0: 1.8-127) to be independent risk factors. With respect to recurrence, the presence of peritoneal implants at the time of initial surgery (OR 3.4: 1.1-10.4) and signs of microinvasion in the anatomicopathological study (OR 5.5: 1.5-17.8) were found to be independent risk factors. The overall survival rate in our series was 97% with a mean follow-up of 88.3 months. The survival rate by stage was 97% for stage I, 100% for stage II and 97% for stage III. CONCLUSIONS: Although borderline ovarian tumors have an excellent prognosis, they are not exempt from a risk of recurrence. Characterization of patients with borderline ovarian tumor is essential in order to prevent their evolution. Likewise, the taking on board of risk factors will enable more selective treatments to be offered in each case.