Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies.

HER2-positive breast cancer accounts for 15-20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody-drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.

Inter and transgenerational impact of H3K4 methylation in neuronal homeostasis.

Epigenetic marks and associated traits can be transmitted for one or more generations, phenomena known respectively as inter- or transgenerational epigenetic inheritance. It remains unknown if genetically and conditionally induced aberrant epigenetic states can influence the development of the nervous system across generations. Here, we show, using Caenorhabditis elegans as a model system, that alteration of H3K4me3 levels in the parental generation, caused by genetic manipulation or changes in parental conditions, has, respectively, trans- and intergenerational effects on H3K4 methylome, transcriptome, and nervous system development. Thus, our study reveals the relevance of H3K4me3 transmission and maintenance in preventing long-lasting deleterious effects in nervous system homeostasis.

The impact of SWI/SNF and NuRD inactivation on gene expression is tightly coupled with levels of RNA polymerase II occupancy at promoters.

SWI/SNF and NuRD are protein complexes that antagonistically regulate DNA accessibility. However, repression of their activities often leads to unanticipated changes in target gene expression (paradoxical), highlighting our incomplete understanding of their activities. Here we show that SWI/SNF and NuRD are in a tug-of-war to regulate PRC2 occupancy at lowly expressed and bivalent genes in mouse embryonic stem cells (mESCs). In contrast, at promoters of average or highly expressed genes, SWI/SNF and NuRD antagonistically modulate RNA polymerase II (Pol II) release kinetics, arguably owing to accompanying alterations in H3.3 and H2A.Z levels at promoter-flanking nucleosomes, leading to paradoxical changes in gene expression. Owing to this mechanism, the relative activities of the two remodelers potentiate gene promoters toward Pol II-dependent open or PRC2-dependent closed chromatin states. Our results highlight RNA Pol II occupancy as the key parameter in determining the direction of gene expression changes in response to SWI/SNF and NuRD inactivation at gene promoters in mESCs.

Nodal positivity and systemic therapy among patients with clinical T1-T2N0 human epidermal growth factor receptor-positive breast cancer: Results from two international cohorts.

BACKGROUND: The optimal treatment strategy for patients with small human epidermal growth factor receptor 2 (HER2)-positive tumors is based on nodal status. The authors' objective was to evaluate pathologic nodal disease (pathologic lymph node-positive [pN-positive] and pathologic lymph node-positive after preoperative systemic therapy [ypN-positive]) rates in patients who had clinical T1-T2 (cT1-cT2)N0M0, HER2-positive breast cancer treated with upfront surgery or neoadjuvant chemotherapy (NAC). METHODS: Two databases were queried for patients who had cT1-cT2N0M0, HER2-positive breast cancer: (1) the Dana-Farber Brigham Cancer Center (DF/BCC) from February 2015 to October 2020 and (2) the Hospital Clinic of Barcelona and the Hospital Clinico of Valencia (HCB/HCV) from January 2012 to September 2021. The pN-positive/ypN-positive and axillary lymph node dissection (ALND) rates were compared between patients who underwent upfront surgery versus those who received NAC. RESULTS: Among 579 patients from the DF/BCC database, 368 underwent upfront surgery, and 211 received NAC; the rates of nodal positivity were 19.8% and 12.8%, respectively (p = .021). The pN-positive rates increased by tumor size (p < .001), reaching 25% for those with cT1c tumors. The ypN-positive rates did not correlate with tumor size. NAC was associated with decreased nodal positivity (odds ratio, 0.411; 95% confidence interval, 0.202-0.838), but the ALND rates were similar (22 of 368 patients [6.0%] who underwent upfront surgery vs. 18 of 211 patients [8.5%] who received NAC; p = .173). Among 292 patients from the HCB/HCV database, 119 underwent upfront surgery, and 173 received NAC; the rates of nodal positivity were 21% and 10.4%, respectively (p = .012). The pN-positive rates increased with tumor size (p = .011). The ALND rates were equivalent by treatment strategy (23 of 119 patients [19.3%] who underwent upfront surgery vs. 24 of 173 patients [13.9%] who received NAC; p = .213). CONCLUSIONS: Among patients who had cT1-cT2N0M0, HER2-positive breast cancer, approximately 20% who underwent upfront surgery were pN-positive, and the rate reached 25% for those with cT1c tumors. Given the opportunity for tailored therapy among lymph node-positive, HER2-positive patients, these data provide rationale for future analyses investigating the utility of routine axillary imaging in patients with HER2-positive breast cancer.

The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes.

Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.

Role of SALL4 in HER2+ Breast Cancer Progression: Regulating PI3K/AKT Pathway.

Treatment for the HER2+ breast cancer subtype is still unsatisfactory, despite breakthroughs in research. The discovery of various new molecular mechanisms of transcription factors may help to make treatment regimens more effective. The transcription factor SALL4 has been related to aggressiveness and resistance therapy in cancer. Its molecular mechanisms and involvement in various signaling pathways are unknown in the HER2+ breast cancer subtype. In this study, we have evaluated the implication of SALL4 in the HER2+ subtype through its expression in patients' samples and gain and loss of function in HER2+ cell lines. We found higher SALL4 expression in breast cancer tissues compared to healthy tissue. Interestingly, high SALL4 expression was associated with disease relapse and poor patient survival. In HER2+ cell lines, transient overexpression of SALL4 modulates PI3K/AKT signaling through regulating PTEN expression and BCL2, which increases cell survival and proliferation while reducing the efficacy of trastuzumab. SALL4 has also been observed to regulate the epithelial-mesenchymal transition and stemness features. SALL4 overexpression significantly reduced the epithelial markers E-cadherin, while it increased the mesenchymal markers ß-catenin, vimentin and fibronectin. Furthermore, it has been also observed an increased expression of MYC, an essential transcription factor for regulating epithelial-mesenchymal transition and/or cancer stem cells. Our study demonstrates, for the first time, the importance of SALL4 in the HER2+ subtype and partial regulation of trastuzumab sensitivity. It provides a viable molecular mechanism-driven therapeutic strategy for an important subset of HER2-overexpressing patients whose malignancies are mediated by SALL4 expression.

Variations in consumer acceptance, sensory engagement and method practicality across three remote consumer-testing modalities.

In the context of the COVID-19 pandemic, it has become challenging for sensory scientists to conduct in-person sensory tests, particularly large central location tests. Sensory literature comparing central location and home use tests shows no clear consensus about how each methodology affects sample ratings and panelist engagement. Research on instructional delivery suggests that the most effective method of increasing engagement involves interactive video conferencing. The objective of this study was to compare three methods of remote consumer testing regarding sample acceptance, sensory engagement, and method practicality. Eighty-four participants rated five chocolate-chip cookie products on a 9-pt hedonic scale in each of three methods: 1) a live (synchronous) Zoom session, 2) an asynchronous video-guided session, and 3) a fully written protocol session. Results showed no significant differences in sample liking pattern across the methods used. Engagement scores approached the limit of significance for the Active Involvement dimension, indicating panelists were least likely to feel distracted, zoned out or lose interest in the written protocol method. There were no significant differences in the time spent on the test by the panelists across the three methods. Asynchronous methods showed to be most suitable in terms of the convenience of the time of day at which the tests were completed, but showed no significant differences in other aspects of method practicality. Overall, a written protocol method of remote consumer testing is recommended, as it is less time-consuming for researchers while providing similar acceptance and engagement as other methods.

Immunological Landscape of HER-2 Positive Breast Cancer.

Understanding the biological aspects of immune response in HER2+ breast cancer is crucial to implementing new treatment strategies in these patients. It is well known that anti-HER2 therapy has improved survival in this population, yet a substantial percentage may relapse, creating a need within the scientific community to uncover resistance mechanisms and determine how to overcome them. This systematic review indicates the immunological mechanisms through which trastuzumab and other agents target cancer cells, also outlining the main trials studying immune checkpoint blockade. Finally, we report on anti-HER2 vaccines and include a figure exemplifying their mechanisms of action.

Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation : In memoriam Professor Niels Borregaard.

Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues, and requires the coordinated induction of lineage-specific transcriptional programs and cell cycle withdrawal. To understand the underlying regulatory mechanisms of this fundamental process, we investigated how the tissue-specific transcription factors, CEBPA and CEBPE, coordinate cell cycle exit and lineage-specification in vivo during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-specification by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with differentiation through the use of distinct gene regulatory elements.

H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway.

Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here, we demonstrate that the H3K9me3 histone methyltransferase (HMT) suppressor of variegation 3-9 homolog 1 (SUV39H1) is required for the proliferation of acute myeloid leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occurs via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs, G9A and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes, and interference with the activities of G9A/GLP largely phenocopied loss of SUV39H1. Last, we demonstrate that inhibition of G9A/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker for the response to hypomethylation treatment. Collectively, we uncovered a clinically relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway.

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective.

Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients' future landscape.

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.

Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) gene produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 drives leukemogenesis through direct binding and inducing the aberrant overexpression of key genes, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC However, studying direct binding alone does not incorporate possible network-generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1-driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq, and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors such as RUNX1 that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified a KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1-driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.

Context effect of environmental setting and product information in acceptability testing of tea and cola: A study comparing sensory engagement in a traditional sensory booth and a study commons.

Sensory evaluation of food relies heavily on the eating context. The objective of this study was to determine how the context effect, created from differences in environmental setting and product information, affects consumer's acceptability of two types of beverages. Participants of this study rated five ready-to-drink tea products and five diet cola products on a 9-point hedonic scale. Environmental setting differences were created by altering testing locations, and product information differences were created by serving the same samples with or without product name and image. Self-reported sensory engagement was measured in each location. Tea samples showed significantly higher appearance liking ratings in the sensory booth location as well as higher flavor liking ratings when product information was provided. Cola samples did not show a significant effect of testing location but did show a significant product information by sample interaction, where well-established brands received higher ratings when product information was provided. Overall, results were product-specific; testing location does not appear to have a large influence on hedonic scores for certain beverages, and the impact of product information varies largely depending on the product type and brand. The laboratory sensory booth setting provided higher panelist engagement overall. Additional research on the combination of external context and meal, sample, or social context is needed to fully explore the effect of eating context in sensory tests. PRACTICAL APPLICATION: Findings from this study can help the food industry comprehend how test location may impact results of acceptability testing of different beverage products, both in terms of hedonic scores and sensory engagement. Results of this study also evidence the influence of sample information on product acceptability and how this influence differs based on the type of beverage and the popularity of the brand tested.

BET inhibition disrupts transcription but retains enhancer-promoter contact.

Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.

Carcinoma sebáceo extraocular de vulva: Reporte de caso / Extraocular sebaceous carcinoma of the vulva: A case report

Sebaceous carcinoma is a rare malignant tumor of the skin that usually appears in the head and neck region. Its clinical course is aggressive and local recurrences distant metastases are common. Some cases of sebaceous carcinoma of the female genital tract have been reported. Although sebaceous glands are prominent in the vulva, sebaceous carcinomas rarely occur in this location. Little is known about the behavior and prognosis of this type of cancer. We present a case of a 69-year-old patient with a history of a 3 x 2-centimeter tumor for 9 months in the left labium majus. She had no medical or family history of malignant neoplasms. Increases in size was observed during this period, but otherwise, she was asymptomatic. Lesion was completely excised. The tumor was composed of lobes of tumor cells with sebaceous differentiation. Histopathological report revealed vulvar sebaceous carcinoma. It must be differentiated from other vulvar carcinomas that are morphologically similar but biologically different.

El carcinoma sebáceo es un tumor maligno poco frecuente de la piel que generalmente aparece en la región de cabeza y cuello. Su curso clínico es agresivo y las recidivas locales / metástasis a distancia son habituales. Se han notificado algunos casos de carcinoma sebáceo del tracto genital femenino. Aunque las glándulas sebáceas son prominentes en la vulva, los carcinomas sebáceos rara vez ocurren en esta ubicación. Poco se conoce sobre el comportamiento y pronóstico de este tipo de cáncer. Se presenta un caso de paciente de 69 años con antecedentes de un tumor de 3 × 2 centímetros por 9 meses, en el labio mayor izquierdo. No tenía antecedentes médicos o familiares de neoplasias malignas. Se observó aumento de tamaño durante este período; por lo demás, estaba asintomático. La lesión fue extirpada totalmente. El tumor estaba compuesto por lóbulos de células tumorales con diferenciación sebácea. El informe histopatológico reveló carcinoma sebáceo de vulva. Debe diferenciarse de otros carcinomas vulvares morfológicamente similares, pero biológicamente distinto.

Soluble E-selectin in the second trimester and risk of developing preeclampsia / Selectina E soluble en el segundo trimestre y riesgo de desarrollo de preeclampsia

Objective: To establish the association between soluble E-selectin concentrations in the second trimester and the risk of developing preeclampsia. Material and methods: A case-control study was conducted at Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela. The study population comprised 504 nulliparous women with singleton pregnancies (17-20 weeks) who attended the antenatal clinic. General characteristics, soluble E-selectin concentrations, and prognostic efficacy were evaluated. Results: A total of 41 pregnant women developed preeclampsia (cases, group A). The remaining 463 women were considered controls (group B). No statistically significant differences were found in maternal age, gestational age, or systolic and diastolic blood pressure at the time of the ultrasound examination (p = NS). Gestational age at the time of diagnosis of preeclampsia in group A was 35.0 (3.2) weeks. Statistically significant differences were found in the concentrations of soluble E-selectin among pregnant women in group A (15.5 (2.8) ng / mL) and pregnant women in group B (11.8 (2.3) ng / mL; p < 0.0001). The relative risk for developing preeclampsia was significant for patients with very high concentrations (relative risk = 2.212; 95% CI, 1.879-2.605; p < 0.0001). The difference in relative risk between patients with low concentrations and patients with moderate and high concentrations was not statistically significant (p = NS). Conclusion: There is a significant association between an increase in soluble E-selectin concentrations in the second trimester and risk of preeclampsia

Objetivo: Establecer la asociación entre las concentraciones de selectina E soluble en el segundo trimestre y el riesgo de desarrollo de preeclampsia. Material y métodos: Se realizó un estudio de casos - controles en el Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela con 504 pacientes nulíparas con embarazos simples entre 17 y 20 semanas que acudieron a la consulta pre-natal. Se evaluaron las características generales, concentraciones de selectina E soluble y eficacia pronóstica. Resultados: Los casos fueron 41 embarazadas que desarrollaron preeclampsia (grupo A) y 463 embarazadas fueron consideradas como controles (grupo B). No se encontraron diferencias estadísticamente significativas en la edad materna, edad gestacional y presión arterial sistólica y diastólica al momento de la realización de la ecografía (p = ns). La edad gestacional al momento del diagnóstico de preeclampsia en el grupo A fue de 35,0 +/- 3,2 semanas. Se encontraron diferencias estadísticamente significativas en las concentraciones de selectina E soluble entre las embarazadas del grupo A (15,5 +/- 2,8 ng/mL) y las embarazadas del grupo B (11,8 +/- 2,3 ng/mL; p < 0,0001). El riesgo relativo para el desarrollo de preeclampsia fue significativo para los grupos que presentaron concentraciones muy altas (riesgo relativo = 2,212; IC 95%, 1,879 - 2,605; p < 0,0001). El grupo de pacientes con concentraciones moderadas y altas no mostraron riesgos relativos significativos comparado con aquellas pacientes con concentraciones bajas (p = ns).Conclusiones: Existe una asociación significativa entre el aumento de las concentraciones de selectina E soluble en el segundo trimestre y el riesgo de preeclampsia

Furosemida en el control de la hipertensión arterial posparto en preeclámpticas severas / Furosemide in the control of postpartum hypertension in severe preeclamptic women

RESUMEN OBJETIVO: Establecer la utilidad de la furosemida en el control de la hipertensión arterial posparto en preeclámpticas severa. MÉTODOS: Se realizó un estudio de casos y controles en el Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela. Se incluyeron pacientes con preeclampsia severa, las cuales durante el posparto fueron asignadas al azar para ser tratadas con furosemida, alfametildopa y cloruro de potasio oral (grupo A) o alfa-metildopa oral (grupo B) por 48 horas. Los parámetros evaluados fueron: variaciones en los valores de presión arterial y frecuencia cardiaca, persistencia de hipertensión, parámetros de laboratorio y efectos adversos. RESULTADOS: Para el análisis final estaban disponibles los datos de 198 pacientes en el grupo A y 197 pacientes en el grupo B en cada uno de los grupos. Luego de 48 horas de tratamiento se observaron disminuciones estadísticamente significativas en los valores de presión arterial sistólica y diastólica entre las pacientes tratadas con furosemida y las pacientes del grupo control (p < 0,0001). Se observó persistencia de la hipertensión en 52 pacientes (26,3 %) del grupo A y en 134 pacientes (68,0 %) del grupo B (p < 0,0001). No se encontraron diferencias entre los grupos en la frecuencia cardiaca, valores de laboratorio y efectos adversos (p = ns). CONCLUSIÓN: La furosemida produce disminuciones significativas en los valores promedios de presión arterial sistólica y diastólica, al igual que en la frecuencia de persistencia de hipertensión postparto en preeclámpticas severas.

ABSTRACT OBJECTIVE: To establish the utility of furosemide in the control of postpartum blood pressure in severe preeclamptic patients. METHODS: A case-control study was conducted at the Central Hospital "Dr. Urquinaona", Maracaibo, Venezuela. Patients diagnosed with severe preeclampsia were included, who during the postpartum period were randomized to be treated with furosemide, alpha-methyldopa and oral potassium chloride (group A) or oral alpha-methyldopa (group B) for 48 hours. The parameters evaluated were: variations in blood pressure and heart rate values, the persistence of hypertension, laboratory parameters and adverse effects related to treatment. RESULTS: Data of 198 patients in group A and 197 patients in group B in each of the groups were available for the final analysis. After 48 hours of treatment, statistical significant decreases were observed in the values of systolic and diastolic blood pressure between patients treated with furosemide and patients in the control group (p <0.0001). Persistence of hypertension was observed in 52 patients (26.3 %) of group A and in 134 patients (68.0 %) of group B (p < 0.0001). No differences were found between the groups in heart rate, laboratory values and adverse effects (p = ns). CONCLUSION: Furosemide produces significant decreases in the mean values of systolic and diastolic blood pressure, as well as in the frequency of persistence of postpartum hypertension in severe preeclamptic patients.

Laparoscopia en el tratamiento de endometriosis moderada y severa en mujeres infértiles / Laparoscopy in the treatment of moderate and severe endometriosis in infertile women

El objetivo de este estudio fue evaluar la eficacia de la laparoscopia en el tratamiento de endometriosis moderada y severa en mujeres infértiles. La investigación fue de tipo prospectivo realizado en el Hospital Central Dr. Urquinaona, Maracaibo, Venezuela, en el periodo de enero de 2012 a diciembre de 2017. Se incluyeron 118 pacientes con diagnóstico de endometriosis moderada a severa. El diagnóstico de endometriosis se planteó sobre los hallazgos encontrados durante la laparoscopia y la evaluación histopatológica de las muestras de las biopsias de tejido. El éxito del tratamiento y el porcentaje de embarazos se analizaron en todas las pacientes. Durante la laparoscopia secundaria en pacientes con endometriosis estadios III y IV, se encontró la resolución en 54,9 % y reaparición de la enfermedad en 45,1 % de los pacientes. El grupo de las pacientes con endometriosis estadio I y II tratadas y con terapia hormonal se descubrió regresión en 30,7 % y recurrencia en 69,2 % de las pacientes. La incidencia total de embarazos en pacientes con endometriosis estadio I y II sometidas a tratamiento médico fue del 23,8 % y 18,1 %, respectivamente. Las pacientes con endometriosis estadio III y IV presentaron una tasa de embarazo de 23,5 %. Se concluye que las pacientes con diagnóstico de endometriosis estadios III y IV deben ser tratadas con extirpación laparoscópica de los focos de endometriosis, seguido por tratamiento médico.

he aim of this study was to evaluate the efficacy of laparoscopy in the treatment of moderate and severe endometriosis in infertile women. The research was prospective in the Central Hospital Dr. Urquinaona, Maracaibo, Venezuela in the period from January 2012 to December 2017. We included 118 patients diagnosed with moderate to severe endometriosis. The diagnosis of endometriosis was raised on the findings found during laparoscopy and the histopathological evaluation of tissue biopsy samples. The success of the treatment and the percentage of pregnancies were analyzed in all patients. During secondary laparoscopy in patients with endometriosis stages III and IV, resolution was found in 54,9 % and reappearance of the disease in 45,1 % of patients. The group of patients with stage I and II endometriosis treated and with hormone therapy, regression was found in 30.7% and recurrence in 69,2 % of patients. The total incidence of pregnancies in patients with stage I and II endometriosis undergoing medical treatment was 23,8 % and 18,1 %, respectively. Patients with stage III and IV endometriosis had a pregnancy rate of 23,5 %. It is concluded that patients diagnosed with stage III and IV endometriosis should be treated with laparoscopic excision of the endometriosis foci, followed by medical treatment.

Culdoplastía de Mayo o colposacropexia abdominal en la corrección del prolapso de la cúpula vaginal poshisterectomía / Mayo culdoplasty or abdominal colposacropexy in correction of post-hysterectomy vaginal vault prolapse

El objetivo de este estudio fue comparar los resultados de la culdoplastía de Mayo con la colposacropexia abdominal en la corrección del prolapso de la cúpula vaginal poshisterectomía. Se revisaron las historias clínicas de 155 pacientes con prolapso de cúpula vaginal poshisterectomía en las que se procedió a la corrección quirúrgica entre febrero 2013 y noviembre 2017. Se realizó seguimiento para evaluar la satisfacción del paciente y el resultado a largo plazo. La edad promedio de las pacientes al momento de la cirugía fue de 67,1 +/- 5,6 años y 69,0 % de las pacientes tenían antecedentes de haber sido sometidas a histerectomía abdominal. El tiempo medio entre la histerectomía y la cirugía de corrección fue de 16,9 +/- 3,6 años. Ciento diecinueve pacientes se sometieron a abordaje vaginal utilizando la técnica de culdoplastía de Mayo (grupo A) y 36 pacientes se sometieron a colposacropexia abdominal (grupo B). Durante la cirugía se produjeron tres casos (2,5 %) de lesión vesical inadvertida en el grupo A. En el grupo A se observaron 2 casos de recurrencia comparado con un solo caso en las pacientes del grupo B (p = ns). Al analizar la satisfacción de la cirugía, 84,9 % de las pacientes del grupo A y 77,7 % de las pacientes del grupo B se declararon satisfechas con los resultados quirúrgicos. Se concluye que la corrección del prolapso de la cúpula vaginal mediante colposacropexia abdominal y culdoplastía de Mayo son procedimientos seguros y efectivos.

The aim of this study was to compare the results of the Mayo culdoplasty with abdominal colposacropexy in the correction of post-hysterectomy vaginal vault prolapse. Medical records of 155 patients with post-hysterectomy vaginal vault prolapse were reviewed in which the surgical correction was carried out between February 2013 and November 2017. Follow-up was performed to evaluate the patient's satisfaction and the long-term result. The average age of the patients at the time of surgery was 67.1 +/- 5.6 years and 69.0% of the patients had a history of having undergone an abdominal hysterectomy. The mean time between hysterectomy and correction surgery was 16.9 +/- 3.6 years. One hundred and nineteen patients underwent vaginal access using the Mayo culdoplasty technique (group A) and 36 patients underwent abdominal colposacropexy (group B). During surgery there were three cases (2,5 %) of inadvertent bladder injury in group A. In group A, 2 cases of recurrence were observed compared with a single case in patients in group B (p = ns). When analyzing the satisfaction of the surgery, 84,9 % of the patients of group A and 77,7 % of the patients of group B declared themselves satisfied with the surgical results. It is concluded that the correction of vaginal vault prolapse by abdominal colposacropexy and Mayo culdoplasty are safe and effective procedures.

Factores de riesgo para cáncer de endometrio en premenopáusicas con hemorragia uterina disfuncional / Risk factors for endometrial cancer in pre-menopausal women with dysfunctional uterine hemorrhage

El objetivo de la investigación fue establecer los factores de riesgo para cáncer de endometrio en premenopáusicas con diagnóstico de hemorragia uterina disfuncional. Se realizó un estudio observacional en mujeres con diagnóstico de hemorragia uterina disfuncional. Se evaluaron la asociación entre la histología endometrial y los factores de riesgo para el cáncer de endometrio, de ellos se analizaron: irregularidades del ciclo menstrual, diabetes mellitus, nuliparidad, hipertensión, obesidad y edad mayor de 40 años. La regresión logística se utilizó para investigar la importancia relativa de cada factor de riesgo. El estudio incluyó 266 mujeres con edad promedio de 41 años. La prevalencia de los factores de riesgo fue la siguiente: edad mayor de 40 años (67,2 %), menstruaciones irregulares (22,1 %), nuliparidad (16,9 %), obesidad (10,1 %), hipertensión (8,6 %) y diabetes (2,2 %). Los resultados de la biopsia endometrial incluyeron: 14 casos (5,2 %) de hiperplasia simple, 16 casos (6,0 %) de hiperplasia compleja y 4 casos (1,5 %) de hiperplasia con atipia. No se observaron casos de adenocarcinoma de endometrio. Se encontró que las menstruaciones irregulares eran el único factor de riesgo estadísticamente significativo asociado a alteración de la histología endometrial (p = 0,0132). En el grupo de pacientes con menstruaciones regulares y sin factores de riesgo, la incidencia de biopsia anormal observada fue inferior al 1 %. Las irregularidades del ciclo menstrual aumentan la probabilidad de un resultado anormal de la biopsia a un 14,2 %. Se concluye que las mujeres premenopáusicas diagnosticadas con hemorragia uterina disfuncional cuyos ciclos menstruales son regulares tienen un riesgo insignificante de desarrollar hiperplasia endometrial.

The objective of the research was to establish risk factors for endometrial cancer in pre-menopausal women with a diagnosis of dysfunctional uterine hemorrhage. An observational study was conducted in women with a diagnosis of dysfunctional uterine bleeding. The association between endometrial histology and risk factors for endometrial cancer analyzed were menstrual cycle irregularities, diabetes mellitus, nulliparity, hypertension, obesity and age over 40 years. Logistic regression was used to investigate the relative importance of each risk factor. The study included 266 women with an average age of 41 years. The prevalence of risk factors was the following: age over 40 years (67,2 %), irregular menses (22,1 %), nulliparity (16,9 %), obesity (10,1 %), hypertension (8,6 %) and diabetes (2,2 %). The results of the endometrial biopsy included: 14 cases (5,2 %) of simple hyperplasia, 16 cases (6,0 %) of complex hyperplasia and 4 cases (1,5 %) of complex hyperplasia with atypia. No cases of endometrial adenocarcinoma were observed. It was found that irregular menses were the only statistically significant risk factor associated with alteration of endometrial histology (p = 0.0132). In the group of patients with regular menses and without risk factors, the incidence of abnormal biopsy observed was less than 1 %. The irregularities of the menstrual cycle increases the probability of an abnormal result of the biopsy to 14,2 %. It is concluded that premenopausal women diagnosed with dysfunctional uterine bleeding whose menstrual cycles are regular have a negligible risk of developing endometrial hyperplasia.