Sex differences in Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed sequela of acute pulmonary embolism with varied clinical presentation causing significant morbidity among the affected population. There exist important differences in the occurrence, clinical features and diagnosis of CTEPH between men and women, with women carrying a greater predisposition for the disease. Ongoing studies have also pointed out variations among men and women, in the treatment offered and long-term outcomes including mortality. This focused review article highlights important sex-associated differences in multiple aspects of CTEPH including its epidemiology, clinical features, diagnosis, treatment and outcomes as reported in current literature and highlights the need for future research to facilitate a clearer understanding of these differences.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease where blood clots remain stuck in the lungs after a previous clotting episode which leads to high blood pressure in the lung arteries. One interesting aspect is that CTEPH affects men and women differently. Women show different symptoms and may have better survival rates than men, especially if they receive surgery to remove the clots. The reasons for these differences are not fully understood. Diagnosing CTEPH is challenging because its symptoms are similar to other heart and lung conditions, which can cause treatment delays. It is important to consider referring patients with possible CTEPH to specialists early for accurate diagnosis and treatment. Developing new treatments and collecting data will help improve care for these patients.

Venous Thromboembolism in Pregnancy: Challenges and Solutions.

Venous thromboembolism (VTE) is a serious medical condition that can lead to severe morbidity and mortality, making it a significant public health concern. VTE is a multifactorial condition that results from the interaction of genetic, acquired, and environmental factors. Physiological changes during pregnancy increase the risk of VTE as they express Virchow's triad (increased coagulation factors, decreased fibrinolysis, trauma, and venous stasis). Moreover, pregnancy-related risk factors, such as advanced maternal age, obesity, multiple gestations, and cesarean delivery, further increase the risk of VTE. Managing VTE in pregnancy is challenging due to the complexity of balancing the risks and benefits of anticoagulant therapy for both the mother and the fetus. A multidisciplinary approach involving obstetricians, hematologists, and neonatologists, is necessary to ensure optimal outcomes for both the mother and baby. This review aims to discuss the current challenges associated with VTE in pregnancy and identify potential solutions for improving outcomes for pregnant women at risk for VTE.

The Intricate Interplay between Cancer Stem Cells and Oncogenic miRNAs in Breast Cancer Progression and Metastasis.

Complex signaling interactions between cancer cells and their microenvironments drive the clonal selection of cancer cells. Opposing forces of antitumor and tumorigenic potential regulate the survival of the fittest clones, while key genetic and epigenetic alterations in healthy cells force them to transform, overcome cell senescence, and proliferate in an uncontrolled manner. Both clinical samples and cancer cell lines provide researchers with an insight into the complex structure and hierarchy of cancer. Intratumor heterogeneity allows for multiple cancer cell subpopulations to simultaneously coexist within tumors. One category of these cancer cell subpopulations is cancer stem cells (CSCs), which possess stem-like characteristics and are not easily detectable. In the case of breast cancer, which is the most prevalent cancer type among females, such subpopulations of cells have been isolated and characterized via specific stem cell markers. These stem-like cells, known as breast cancer stem cells (BCSCs), have been linked to major events during tumorigenesis including invasion, metastasis and patient relapse following conventional therapies. Complex signaling circuitries seem to regulate the stemness and phenotypic plasticity of BCSCs along with their differentiation, evasion of immunosurveillance, invasiveness and metastatic potential. Within these complex circuitries, new key players begin to arise, with one of them being a category of small non-coding RNAs, known as miRNAs. Here, we review the importance of oncogenic miRNAs in the regulation of CSCs during breast cancer formation, promotion and metastasis, in order to highlight their anticipated usage as diagnostic and prognostic tools in the context of patient stratification and precision medicine.

miRNA-Guided Regulation of Mesenchymal Stem Cells Derived from the Umbilical Cord: Paving the Way for Stem-Cell Based Regeneration and Therapy.

The human body is an abundant source of multipotent cells primed with unique properties that can be exploited in a multitude of applications and interventions. Mesenchymal stem cells (MSCs) represent a heterogenous population of undifferentiated cells programmed to self-renew and, depending on their origin, differentiate into distinct lineages. Alongside their proven ability to transmigrate toward inflammation sites, the secretion of various factors that participate in tissue regeneration and their immunoregulatory function render MSCs attractive candidates for use in the cytotherapy of a wide spectrum of diseases and conditions, as well as in different aspects of regenerative medicine. In particular, MSCs that can be found in fetal, perinatal, or neonatal tissues possess additional capabilities, including predominant proliferation potential, increased responsiveness to environmental stimuli, and hypoimmunogenicity. Since microRNA (miRNA)-guided gene regulation governs multiple cellular functions, miRNAs are increasingly being studied in the context of driving the differentiation process of MSCs. In the present review, we explore the mechanisms of miRNA-directed differentiation of MSCs, with a special focus on umbilical cord-derived mesenchymal stem cells (UCMSCs), and we identify the most relevant miRNAs and miRNA sets and signatures. Overall, we discuss the potent exploitations of miRNA-driven multi-lineage differentiation and regulation of UCMSCs in regenerative and therapeutic protocols against a range of diseases and/or injuries that will achieve a meaningful clinical impact through maximizing treatment success rates, while lacking severe adverse events.

DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival.

Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, the disease has a recurrence rate of around 50%, and the prognosis of metastatic patients remains poor. HNCs are characterized by a high degree of genomic instability, which involves a vicious circle of accumulating DNA damage, defective DNA damage repair (DDR), and replication stress. Nonetheless, the damage that is induced on tumor cells by chemo and radiotherapy relies on defective DDR processes for a successful response to treatment, and may play an important role in the development of novel and more effective therapies. This review summarizes the current knowledge on the genes and proteins that appear to be deregulated in DDR pathways, their implication in HNC pathogenesis, and the rationale behind targeting these genes and pathways for the development of new therapies. We give particular emphasis on the therapeutic targets that have shown promising results at the pre-clinical stage and on those that have so far been associated with a therapeutic advantage in the clinical setting.

DNA Methylation as a Diagnostic, Prognostic, and Predictive Biomarker in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is a term collectively used to describe all cancers that develop in the oral and nasal cavities, the paranasal sinuses, the salivary glands, the pharynx, and the larynx. The majority (75%) of all newly diagnosed cases are observed in patients with locally advanced and aggressive disease, associated with significant relapse rates (30%) and poor prognostic outcomes, despite advances in multimodal treatment. Consequently, there is an unmet need for the identification and application of tools that would enable diagnosis at the earliest possible stage, accurately predict prognostic outcomes, contribute to the timely detection of relapses, and aid in the decision for therapy selection. Recent evidence suggests that DNA methylation can alter the expression of genes in a way that it favors tumorigenesis and tumor progression in HNSCC, and therefore represents a potential source for biomarker identification. This study summarizes the current knowledge on how abnormally methylated DNA profiles in HNSCC patients may contribute to the pathogenesis of HNSCC and designate the methylation patterns that have the potential to constitute clinically valuable biomarkers for achieving significant advances in the management of the disease and for improving survival outcomes in these patients.

Suitability of Human Mesenchymal Stem Cells Derived from Fetal Umbilical Cord (Wharton's Jelly) as an Alternative In Vitro Model for Acute Drug Toxicity Screening.

Preclinical toxicity screening is the first and most crucial test that assesses the safety of new candidate drugs before their consideration for further evaluation in clinical trials. In vitro drug screening using stem cells has lately arisen as a promising alternative to the "gold standard" of animal testing, but their suitability and performance characteristics in toxicological studies have so far not been comprehensively investigated. In this study, we focused on the evaluation of human mesenchymal stem cells isolated from the matrix (Wharton's jelly) of fetal umbilical cord (WJSCs), which bear enhanced in vitro applicability due to their unique biological characteristics. In order to determine their suitability for drug-related cytotoxicity assessment, we adopted a high-throughput methodology that evaluated their sensitivity to a selected panel of chemicals in different culture environments. Cytotoxicity was measured within 48 h by means of MTS and/or NRU viability assays, and was compared directly (in vitro) or indirectly (in silico) to adult human mesenchymal stem cells and to reference cell lines of human and murine origin. Our data clearly suggest that human WJSCs can serve as a robust in vitro alternative for acute drug toxicity screening by uniquely combining rapid and versatile assay setup with high-throughput analysis, good representation of human toxicology, high reproducibility, and low cost.

BRCA1/2 Mutation Types Do Not Affect Prognosis in Ovarian Cancer Patients.

BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. METHODS: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1-27.5) and the median OS was 92.9 months (95% CI 69.8-116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. CONCLUSIONS: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

Systemic Therapies for the Management of Non-Clear Cell Renal Cell Carcinoma: What Works, What Doesn't, and What the Future Holds.

Non-clear cell renal cell carcinoma (nccRCC) is a broad term that refers to a diverse group of tumors, each with its own distinct biologic and therapeutic profile. The management of nccRCCs is often based on extrapolating data from clinical trials in the more common clear cell renal cell carcinoma, but our emerging prospective and retrospective clinical experience in nccRCC allows us to make more precise recommendations tailored to each histology. The systemic therapy options for metastatic nccRCC include targeted therapies such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and, for specific rare subtypes, cytotoxic chemotherapy. Each nccRCC histology may respond differently to these regimens, which makes accurate pathologic diagnosis imperative. In the present review, we discuss the available clinical and biological data that can help guide systemic therapy recommendations for specific nccRCC subtypes.

Desfechos após inserção de balão intra-aórtico em pacientes de cirurgia cardíaca / Outcomes after intra-aortic balloon pump insertion in cardiac surgery patients

RESUMO Objetivo: Avaliar se o momento de inserção de um balão intra-aórtico pré-operatório em comparação com o intraoperatório se associa com menor mortalidade em 30 dias ou diminuição do tempo de permanência no hospital entre pacientes que passaram por inserção de um balão intra-aórtico para cirurgia cardíaca. Métodos: Este foi um estudo observacional de pacientes submetidos à inserção de um balão intra-aórtico no período pré-operatório ou intraoperatório de cirurgia cardíaca em nosso departamento entre 2000 e 2012. Avaliamos a associação entre a inserção pré-operatória em comparação com a intraoperatória de um balão intra-aórtico e a mortalidade em 30 dias em uma análise de regressão logística multivariada, incluindo a classificação pré-operatória segundo a New York Heart Association, a presença de fibrilação atrial pós-operatória, a reoperação, a creatinina pós-operatória e a cirurgia de revascularização do miocárdio isolada como cofatores. Utilizamos um modelo linear multivariado para avaliar se a inserção pré-operatória do balão intra-aórtico, em comparação com a intraoperatória, associou-se com o tempo de permanência no hospital após a cirurgia, com ajuste para reoperação, cirurgia de revascularização do miocárdio isolada, cirurgia valvar, sexo, idade, tempo de bypass cardiopulmonar, tempo de oclusão aórtica, condição pré-operatória do paciente (cirurgia eletiva, de urgência ou emergência) e infarto do miocárdio pré-operatório. Resultados: Foram submetidos à cirurgia cardíaca aberta em nosso departamento 7.540 pacientes consecutivos, tendo sido inserido um balão intra-aórtico em momento pré-operatório ou intraoperatório em 322 (4,2%) pacientes. A média de idade foi 67 ± 10,2 anos, e a mortalidade em 30 dias foi de 12,7%. O tempo mediano de permanência no hospital foi de 9 dias (7 - 13). A inserção pré-operatória de balão intra-aórtico, em comparação com a intraoperatória, não afetou a incidência de mortalidade em 30 dias (RC ajustada = 0,69; IC95% 0,15 - 3,12; p = 0,63) e nem o tempo de permanência no hospital após a cirurgia (β = 5,3; IC95% 1,6 - 12,8; p = 0,13). Conclusão: Em comparação com a inserção intraoperatória, a inserção pré-operatória de um balão intra-aórtico não se associou com menor mortalidade em 30 dias nem reduziu o tempo de permanência no hospital.

ABSTRACT Objective: To assess whether preoperative versus intraoperative insertion of an intra-aortic balloon pump is associated with lower 30-day mortality or reduced length of hospital stay among patients who had an intra-aortic balloon pump inserted for cardiac surgery. Methods: This was an observational study of patients who had an intra-aortic balloon pump inserted in the preoperative or intraoperative period of cardiac surgery in our department between 2000 and 2012. We assessed the association between preoperative versus intraoperative insertion of an intra-aortic balloon pump and 30-day mortality in a multivariable logistic regression analysis, including preoperative New York Heart Association class, postoperative atrial fibrillation, reoperation, postoperative creatinine and isolated coronary bypass grafting as cofactors. We used a multivariate linear model to assess whether a preoperative versus intraoperative intra-aortic balloon pump was associated with length of postoperative hospital stay, adjusting for reoperation, isolated coronary bypass grafting, heart valve surgery, sex, age, cardiopulmonary bypass time, aortic cross-clamp time, preoperative patients' status (elective, urgency or emergency surgery) and preoperative myocardial infarction. Results: Overall, 7,540 consecutive patients underwent open heart surgery in our department, and an intra-aortic balloon pump was inserted pre- or intraoperatively in 322 (4.2%) patients. The mean age was 67 ± 10.2 years old, the 30-day mortality was 12.7%, and the median length of hospital stay was 9 days (7 - 13). Preoperative versus intraoperative intra-aortic balloon pump insertion did not affect the incidence of 30-day mortality (adjusted OR = 0.69; 95% CI, 0.15 - 3.12; p = 0.63) and length of postoperative hospital stay (β = 5.3; 95%CI, -1.6 to 12.8; p = 0.13). Conclusion: Preoperative insertion of an intra-aortic balloon pump was not associated with a lower 30-day mortality or reduced length of postoperative hospital stay compared to intraoperative insertion.

Intrathecal administration of anti-HER2 treatment for the treatment of meningeal carcinomatosis in breast cancer: A metanalysis with meta-regression.

Leptomeningeal Metastases (LM) is a turning point in terms of prognosis and quality of life of patients with breast cancer (BC). Intrathecal therapy is largely used for the treatment of breast cancer LM. In this metanalysis with meta-regression, we gathered data on intrathecal (IT) trastuzumab administration in patients with HER2 positive breast cancer with LM. A total of 24 articles (58 patients) were included in the study and intrathecal trastuzumab was used in all patients. The mean age at IT administration was 50.7 years (SD 11.4, range 24-80) and the mean total dose of IT trastuzumab was 711.9 mg (SD 634.9, median 450). IT trastuzumab was used both alone (n = 20) and in combination with systemic pharmacotherapy (n = 37). No serious adverse events were reported in 87.9% of cases. In this selected population a significant clinical improvement was observed in 55.0% of cases while stabilization was reported in 14% of cases. CSF response was observed in 55.6% of the cases. MRI was improved or stable in 70.8% of the cases. Interestingly, the CNS-PFS was 5.2 months and the median OS was 13.2 months. A clinical improvement (HR 0.13, 95% CI 0.03-0.49) and CSF response (HR 0.13, 95% CI 0.03-0.58) were associated with a longer CNS-PFS. The association of longer CNS-PFS with radio- or neurosurgery prior to the administration of IT trastuzumab did not reach statistical significance. This metanalysis with meta-regression indicates that IT trastuzumab in patients with HER2 positive breast cancer LM might be a safe and effective treatment, but further prospective studies are needed to definitively prove such a point.

Outcomes after intra-aortic balloon pump insertion in cardiac surgery patients. / Desfechos após inserção de balão intra-aórtico em pacientes de cirurgia cardíaca.

OBJECTIVE: To assess whether preoperative versus intraoperative insertion of an intra-aortic balloon pump is associated with lower 30-day mortality or reduced length of hospital stay among patients who had an intra-aortic balloon pump inserted for cardiac surgery. METHODS: This was an observational study of patients who had an intra-aortic balloon pump inserted in the preoperative or intraoperative period of cardiac surgery in our department between 2000 and 2012. We assessed the association between preoperative versus intraoperative insertion of an intra-aortic balloon pump and 30-day mortality in a multivariable logistic regression analysis, including preoperative New York Heart Association class, postoperative atrial fibrillation, reoperation, postoperative creatinine and isolated coronary bypass grafting as cofactors. We used a multivariate linear model to assess whether a preoperative versus intraoperative intra-aortic balloon pump was associated with length of postoperative hospital stay, adjusting for reoperation, isolated coronary bypass grafting, heart valve surgery, sex, age, cardiopulmonary bypass time, aortic cross-clamp time, preoperative patients' status (elective, urgency or emergency surgery) and preoperative myocardial infarction. RESULTS: Overall, 7,540 consecutive patients underwent open heart surgery in our department, and an intra-aortic balloon pump was inserted pre- or intraoperatively in 322 (4.2%) patients. The mean age was 67 ± 10.2 years old, the 30-day mortality was 12.7%, and the median length of hospital stay was 9 days (7 - 13). Preoperative versus intraoperative intra-aortic balloon pump insertion did not affect the incidence of 30-day mortality (adjusted OR = 0.69; 95% CI, 0.15 - 3.12; p = 0.63) and length of postoperative hospital stay (ß = 5.3; 95%CI, -1.6 to 12.8; p = 0.13). CONCLUSION: Preoperative insertion of an intra-aortic balloon pump was not associated with a lower 30-day mortality or reduced length of postoperative hospital stay compared to intraoperative insertion.

OBJETIVO: Avaliar se o momento de inserção de um balão intra-aórtico pré-operatório em comparação com o intraoperatório se associa com menor mortalidade em 30 dias ou diminuição do tempo de permanência no hospital entre pacientes que passaram por inserção de um balão intra-aórtico para cirurgia cardíaca. MÉTODOS: Este foi um estudo observacional de pacientes submetidos à inserção de um balão intra-aórtico no período pré-operatório ou intraoperatório de cirurgia cardíaca em nosso departamento entre 2000 e 2012. Avaliamos a associação entre a inserção pré-operatória em comparação com a intraoperatória de um balão intra-aórtico e a mortalidade em 30 dias em uma análise de regressão logística multivariada, incluindo a classificação pré-operatória segundo a New York Heart Association, a presença de fibrilação atrial pós-operatória, a reoperação, a creatinina pós-operatória e a cirurgia de revascularização do miocárdio isolada como cofatores. Utilizamos um modelo linear multivariado para avaliar se a inserção pré-operatória do balão intra-aórtico, em comparação com a intraoperatória, associou-se com o tempo de permanência no hospital após a cirurgia, com ajuste para reoperação, cirurgia de revascularização do miocárdio isolada, cirurgia valvar, sexo, idade, tempo de bypass cardiopulmonar, tempo de oclusão aórtica, condição pré-operatória do paciente (cirurgia eletiva, de urgência ou emergência) e infarto do miocárdio pré-operatório. RESULTADOS: Foram submetidos à cirurgia cardíaca aberta em nosso departamento 7.540 pacientes consecutivos, tendo sido inserido um balão intra-aórtico em momento pré-operatório ou intraoperatório em 322 (4,2%) pacientes. A média de idade foi 67 ± 10,2 anos, e a mortalidade em 30 dias foi de 12,7%. O tempo mediano de permanência no hospital foi de 9 dias (7 - 13). A inserção pré-operatória de balão intra-aórtico, em comparação com a intraoperatória, não afetou a incidência de mortalidade em 30 dias (RC ajustada = 0,69; IC95% 0,15 - 3,12; p = 0,63) e nem o tempo de permanência no hospital após a cirurgia (ß = 5,3; IC95% 1,6 - 12,8; p = 0,13). CONCLUSÃO: Em comparação com a inserção intraoperatória, a inserção pré-operatória de um balão intra-aórtico não se associou com menor mortalidade em 30 dias nem reduziu o tempo de permanência no hospital.

Serum neopterin levels in women with preeclampsia: a systematic review.

OBJECTIVE: Neopterin is a pteridine that is produced following activation of human macrophages upon stimulation with the cytokine interferon-gamma. Several studies suggest its association with preeclampsia and the purpose of the present study is to evaluate this assumption. METHODS: We searched the Medline (1992-2018), Scopus (1993-2018) and Google Scholar (1993-2018) databases. All articles that evaluated serum neopterin levels in patients with preeclampsia were held eligible for inclusion, regardless of the trimester of pregnancy in which the measurement was performed. Case reports, animal studies and previous reviews were excluded. RESULTS: A total of 10 studies were finally included in the present review, with a total number of 3,529 pregnant women. Among them 446 were diagnosed with preeclampsia. The majority of included studies reported that serum neopterin was significantly higher in patients with preeclampsia, compared to normotensive pregnant women (p < .05). One study reported that serum levels seem to correlate with the severity of the disease; as patients with HELLP had significantly higher values of neopterin compared to patients with mild and severe preeclampsia. None of the included studies proposed a cut-off value that would help assess the predictive accuracy of this protein for the detection of preeclampsia. CONCLUSION: Although current data seem to be promising, neopterin remains far from being used in current clinical practice as a biomarker that would help predict and follow-up patients that develop preeclampsia. Future studies are needed, to determine the optimal timing for its measurement and to propose potential cut-off values that would help in this direction.