Systematic Review of Nomograms Used for Predicting Pathological Complete Response in Early Breast Cancer.

Pathological complete response (pCR) is an important surrogate outcome to assess the effects of neoadjuvant chemotherapy (NAC). Nomograms to predict pCR have been developed with local data to better select patients who are likely to benefit from NAC; however, they were never critically reviewed regarding their internal and external validity. The purpose of this systematic review was to critically appraise nomograms published in the last 20 years (2010-2022). Articles about nomograms were searched in databases, such as PubMed/MEDLINE, Embase and Cochrane. A total of 1120 hits were found, and seven studies were included for analyses. No meta-analysis could be performed due to heterogeneous reports on outcomes, including the definition of pCR and subtypes. Most nomograms were developed in Asian centers, and nonrandomized retrospective cohorts were the most common sources of data. The most common subtype included in the studies was triple negative (50%). There were articles that included HER2+ (>80%). In one study, scholars performed additional validation of the nomogram using DFS and OS as outcomes; however, there was a lack of clarity on how such endpoints were measured. Nomograms to predict pCR cannot be extrapolated to other settings due to local preferences/availability of NAC. The main gaps identified in this review are also opportunities for future nomogram research and development.

Vagal electrostimulation in postoperative thoracic surgery reduces the systemic inflammatory response and cardiopulmonary complications: an experimental study in pigs.

Background: Conventional thoracotomy (CT) often leads to systemic inflammatory response syndrome (SIRS), which induces several clinical complications. CT remains widely used in low-income institutions. Although minimally invasive surgical procedures, such as robotic surgery (RS), have been used to prevent many of the complications inherit from the surgical procedure. Here, we investigated the protective effect of vagus nerve stimulation (VNS) in a pre-clinical model during CT or RS and postoperative period (POP) relative to clinical complications and inflammatory control. The objective was to compare hemodynamic features and cytokine levels in the blood, lung, and bronchoalveolar lavage (BAL) fluids of animals subjected to CT or RS with or without VNS. Methods: Twenty-four minipigs were subjected to 12 animals CT and 12 animals RS, with or without VNS, and accompanied 24 h later by pulmonary lobectomy. Blood samples for evaluating the hemodynamic parameters were collected before the surgical preparation, immediately after the beginning of VNS, and every 4 h until 24 h after the lobectomy. BAL fluid and lung tissue were collected at the end of the experiment. Cytokine levels were evaluated in the blood, BAL fluid, and lung tissues. Results: VNS maintained a more stable heart rate during POP and decreased the incidence of overall cardiac complications while preventing increase in IL-6 levels 12 h after lobectomy, compared to sham animals. No differences were found in cytokine expression in the BAL fluid and lung tissue in any of the studied groups. Conclusions: Taken together, our data suggested that VNS should be considered a non-pharmacological tool in the prevention of the exacerbated inflammatory response responsible for severe clinical complications, especially in more aggressive surgical procedures.

Real-world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: Correlation of pathological complete response with overall survival.

OBJECTIVES: We aimed to evaluate the pCR rate in patients receiving NAC for the treatment of breast cancer (BC) in a multicenter cohort in Brazil. Additionally, we aimed to use RWD to assess the impact of pCR on OS and DFS. METHODS: This was a retrospective, multicenter cohort study that included female patients over 18 years of age who were diagnosed with nonmetastatic breast cancer and received NAC. OS and DFS at five years were estimated by the Kaplan‒Meier method. Additionally, we conducted a multivariate analysis to identify factors that were significantly associated with pCR and OS. RESULTS: From 2011 to 2020, 1891 patients were included in the study, and 421 (22,3%) achieved pCR (ypT0 ypN0). Considering the presence of residual DCIS, pCR was achieved in 467 patients (23,5%). The pCR rate varied between the subtypes: HER-2+ (p = 0,016) and clinical stage IIIA and IIIB (p < 0,001). Among HER-2+ patients, those who received trastuzumab had a significantly higher pCR rate than those who did not receive trastuzumab (p < 0.0001). Similarly, patients with TNBC who received treatment with platinum-based regimens also showed higher pCR rates (p < 0.0001). OS was grouped according to pCR status, and the OS rate was 88,3% in the pCR group and 58.1% in the non-pCR group (p < 0.0001). The five-year DFS was 92.2% in the pCR group and 64.3% in the non-pCR group (p < 0.0001). CONCLUSION: The pCR rate and its prognostic value varied across BC subtypes. In our study, pCR could be used as a surrogate of favorable clinical outcome, as it was associated with higher OS and DFS rates.

Does Pink October really impact breast cancer screening?

Objective: This study aims to evaluate the impact of the Pink October Campaign on the increase in mammographic screening in Brazil. Study design: Ecological observational study, based on retrospective data. Methods: Brazilian national screening database (DATASUS/SISMAMA/Information System on Breast Cancer) was used as a data source and is publicly available for download and analysis. We report screening numbers and outcome rates from January 2017 to December 2021 comparing statistically (ANOVA test, post-Tukey test), age groups, regions of Brazil, and the four quarters of the year. Results: During the study period, the average number of exams performed monthly over the five years was 137,400.117. An increase in the number of mammograms performed in October was identified, as well as in the two following months, respectively 33%, 39%, and 22%, with statistical significance (p = 0.000) in relation to the three quarters of the year. In addition, in the other months, we found values below the monthly average. Statistical difference was not found in the increase in mammograms considering age groups (p = 0.5) and different regions of the country (p = 0.6). Conclusions: This study showed an increase in mammographic screening in the three months following the Pink October Campaign, so we should intensify similar actions throughout the year and not just in October.

MicroRNAs and exosomes: promising new biomarkers in acute myeloid leukemias?

Despite advances in understanding of carcinogenesis and of treatment of acute myeloid leukemia, this neoplasm still has a lethality of at least 30%. The search for biomarkers that can predict the response to treatment in the early stages of the disease is still necessary. In recent years, a new form of cellular communication between tumor and non-neoplastic cells has been discovered: the exchange of information through extracellular vesicles. These are small vesicles released by membrane-coated cells that carry proteins, lipids, messenger RNAs, microRNA and DNA, which can be internalized and promote biological changes in target cells. Exosomes are qualified as a type of extracellular vesicle and, in tumors, carry immunoinhibitory signals that promote the escape of immune control. Recent studies have showed their involvement in communication with the cells of the tumor microenvironment and with chemoresistance in several tumors. To date, there is no information about immunoregulatory microRNAs transported by exosomes and their correlation with clinical evolution during chemotherapy for acute myeloid leukemia. Knowledge about immunomodulatory microRNAs obtained by leukemic cells and transported by exosomes can direct us towards the design of new diagnostic and treatment tools in this type of leukemia.

MicroRNAs and exosomes: promising new biomarkers in acute myeloid leukemias?

ABSTRACT Despite advances in understanding of carcinogenesis and of treatment of acute myeloid leukemia, this neoplasm still has a lethality of at least 30%. The search for biomarkers that can predict the response to treatment in the early stages of the disease is still necessary. In recent years, a new form of cellular communication between tumor and non-neoplastic cells has been discovered: the exchange of information through extracellular vesicles. These are small vesicles released by membrane-coated cells that carry proteins, lipids, messenger RNAs, microRNA and DNA, which can be internalized and promote biological changes in target cells. Exosomes are qualified as a type of extracellular vesicle and, in tumors, carry immunoinhibitory signals that promote the escape of immune control. Recent studies have showed their involvement in communication with the cells of the tumor microenvironment and with chemoresistance in several tumors. To date, there is no information about immunoregulatory microRNAs transported by exosomes and their correlation with clinical evolution during chemotherapy for acute myeloid leukemia. Knowledge about immunomodulatory microRNAs obtained by leukemic cells and transported by exosomes can direct us towards the design of new diagnostic and treatment tools in this type of leukemia.

Comparative analysis between screening mammography performed in patients at usual risk and at high risk for breast cancer

Breast cancer is currently considered as a public health issue. To avoid late diagnosis, there is an attempt to use appropriate screening programs addressed to the early detection by testing the asymptomatic population in order to identify preclinical stage lesions. Methods: This is a retrospective, analytical, cross-sectional study of the notifications available in the cancer information system. The incidence of notifications from the reports of the BI-RADS™ notification system (Breast Imaging Reporting Data System) was compared between women at high and usual risk for breast cancer. Results: In the analyzed period, from 2013 to 2021, 16,065,383 screening mammographies were performed and notified in Brazil. Of these, 13,167,259 were performed in usualrisk women, whereas 2,898,124 were performed in high-risk women. To analyze the difference between reports of women at usual and high risk, the relative risk between them was calculated, as well as the necessary number to causa damage; the relative risk we found was of 0.5412 (95%CI 0.5341­0.5483) in B4 and relative risk of 0,433 (95%CI 0.4203­0.4462). As to the necessary number to cause damage, we observed 203 (95%CI 198­209) for B4 and 788 (95%CI 754­825) for B5. Despite the well-established need for breast cancer screening programs to reduce mortality, some aspects of screening do not have such a consensus. In this study, the incidence of reports that are suggestive of malignant breast lesions was higher among women at high risk.

Effects of clinical heterogeneity on Pregnancy-Associated Breast Cancer survival: a systematic review with meta-analysis

Pregnancy-associated breast cancer is defined as a diagnosis of breast cancer during pregnancy or within 1 year of childbirth. Current evidence shows that Pregnancy-associated breast cancer is associated with poor prognosis; however, no systematic review has summarized and explored how baseline characteristics could impact survival. We aimed to explore the impact of breast cancer characteristics on death and disease relapse. A systematic review with meta-analyses was conducted by searching articles in the main databases (Medline, Embase, and Cochrane) and congress abstracts. Summarized death and disease-free survival hazard ratios were recalculated, and all meta-analyses used a random-effects model. Heterogeneity was reported using the I2 method. A total of 7143 studies were identified and only 30 studies were included. Pregnancy-associated breast cancer is associated with a 96% (HR 1.96; 95%CI 1.58­2.35) higher risk of death and 82% (HR 1.82; 95%CI 1.45­2.20) risk of death or disease relapse in comparison to a population of non-pregnancy-associated breast cancer or nulliparous breast cancer. Through sensitivity analyses, we identified that clinical outcomes were impacted, possibly due to Ki-67 levels, poorly differentiated tumors, and triple-negative breast cancer frequency in the study. As relevant sources of inconsistencies, such clinical cancer-related characteristics should be better investigated as potential confounders for upcoming Pregnancy-associated breast cancer therapeutic strategies.

Exosomes from patients with septic shock convey miRNAs related to inflammation and cell cycle regulation: new signaling pathways in sepsis?

BACKGROUND: Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock. METHODS: Blood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array. RESULTS: As compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold). CONCLUSIONS: Exosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.

Integration of miRNA and gene expression profiles suggest a role for miRNAs in the pathobiological processes of acute Trypanosoma cruzi infection.

Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America. Its acute phase is associated with high parasitism, myocarditis and profound myocardial gene expression changes. A chronic phase ensues where 30% develop severe heart lesions. Mouse models of T. cruzi infection have been used to study heart damage in Chagas disease. The aim of this study was to provide an interactome between miRNAs and their targetome in Chagas heart disease by integrating gene and microRNA expression profiling data from hearts of T. cruzi infected mice. Gene expression profiling revealed enrichment in biological processes and pathways associated with immune response and metabolism. Pathways, functional and upstream regulator analysis of the intersections between predicted targets of differentially expressed microRNAs and differentially expressed mRNAs revealed enrichment in biological processes and pathways such as IFNγ, TNFα, NF-kB signaling signatures, CTL-mediated apoptosis, mitochondrial dysfunction, and Nrf2-modulated antioxidative responses. We also observed enrichment in other key heart disease-related processes like myocarditis, fibrosis, hypertrophy and arrhythmia. Our correlation study suggests that miRNAs may be implicated in the pathophysiological processes taking place the hearts of acutely T. cruzi-infected mice.

Simultaneous Quantification of the 8 Human Herpesviruses in Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human herpesviruses may cause severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of some of these infections on transplant outcomes is still unclear. A prospective survey on the incidence and clinical features of herpesviruses infections after HSCT has not yet been conducted in Brazilian patients, and the impact of these infections on HSCT outcome remains unclear. METHODS: We prospectively analyzed the incidence of infection of the eight human herpesviruses simultaneously in 1 045 peripheral blood samples from 98 allogeneic HSCT recipients. Samples were collected weekly starting at the time of transplant until day +100. All herpesviruses were screened and quantified in plasma by quantitative real-time polymerase chain reaction. Median follow up time was 24 months. RESULTS: The incidences of infection for each herpesvirus were as follows: cytomegalovirus (CMV), 44%; human herpesvirus [HHV] 6, 18%; HHV8, 6%; Epstein-Barr virus, 3%; herpes simplex virus 1, 3%; varicella zoster virus, 3%; HHV7, 2%; and herpes simplex virus 2, 1%. The CMV infection was significantly more frequent among adults and was associated with a higher risk of developing acute graft-versus-host disease. The HHV6 infection was significantly more frequent after umbilical cord blood transplant and was associated with an increased risk of platelet engraftment failure. There was no significant impact of these infections on the other transplant outcomes. CONCLUSIONS: Herpesviruses infections were uncommon after HSCT, except for CMV and HHV6, which, although relatively frequent, had no clinically relevant impact on the outcomes.

MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes.

Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.

Pentraxin 3 accelerates lung injury in high tidal volume ventilation in mice.

Mechanical ventilation is the major cause of iatrogenic lung damage in intensive care units. Although inflammation is known to be involved in ventilator-induced lung injury (VILI), several aspects of this process are still unknown. Pentraxin 3 (PTX3) is an acute phase protein with important regulatory functions in inflammation which has been found elevated in patients with acute respiratory distress syndrome. This study aimed at investigating the direct effect of PTX3 production in the pathogenesis of VILI. Genetically modified mice deficient and that over express murine Ptx3 gene were subjected to high tidal volume ventilation (V(T)=45 mL/kg, PEEP(zero)). Morphological changes and time required for 50% increase in respiratory system elastance were evaluated. Gene expression profile in the lungs was also investigated in earlier times in Ptx3-overexpressing mice. Ptx3 knockout and wild-type mice developed same lung injury degree in similar times (156±42 min and 148±41 min, respectively; p=0.8173). However, Ptx3 over-expression led to a faster development of VILI in Ptx3-overexpressing mice (77±29 min vs 118±41 min, p=0.0225) which also displayed a faster kinetics of Il1b expression and elevated Ptx3, Cxcl1 and Ccl2 transcripts levels in comparison with wild-type mice assessed by quantitative real-time polymerase chain reaction. Ptx3 deficiency did not impacted the time for VILI induced by high tidal volume ventilation but Ptx3-overexpression increased inflammatory response and reflected in a faster VILI development.

Avaliação do papel da proteína PTX3 na lesão pulmonar induzida pela ventilação mecânica / Role of pentraxin 3 in ventilator-induced lung injury

Introdução: A ventilação mecânica (VM) é uma terapia indispensável no tratamento da insuficiência respiratória que pode causar como efeito colateral a Lesão Pulmonar Induzida pelo Ventilador (LPIV). Apesar do importante papel da inflamação na patogênese da LPIV, nem todos os mecanismos e vias são claramente conhecidos. O objetivo deste projeto foi investigar a função da proteína Pentraxina 3 (PTX3) na LPIV. Observamos que além de PTX3 ser um dos mediadores inflamatórios envolvidos na LPIV, sua presença em maiores quantidades levou ao desenvolvimento mais rápido da lesão nos animais transgênicos para Ptx3 em relação aos camundongos sem modificações quando submetidos à VM em alto volume corrente. A mesma ação pró-inflamatória de PTX3 não foi observada em condições de ventilação mecânica protetoras ao pulmão, sugerindo que seu impacto seja maior em LPIV mais severas. A fim de modular negativamente a expressão de PTX3 in vivo, investigamos a ação anti-inflamatória da Pentoxifilina na LPIV causada por alto volume corrente. Embora as doses de 50 e 100 mg/kg não tenham retardado o aparecimento da LPIV sua ação ainda deve ser melhor investigada. Nossos dados revelam o importante papel da pentraxina longa PTX3, cuja hiper-expressão acelerou o desenvolvimento da lesão pulmonar nos camundongos submetidos à ventilação mecânica. Os resultados contribuem para um melhor entendimento do processo inflamatório na LPIV e colaboram na elaboração de medidas visando minimizar tais danos...

Mechanical ventilation is an indispensable therapy for respiratory failure that can cause Ventilator-Induced Lung Injury (VILI) as side effect. Although inflammation is known to be involved in the pathogenesis of the ventilatorinduced lung injury (VILI), several aspects and mediators of this process are still unknown. This study aimed at investigating the role of the pentraxin 3 (PTX3) in VILI pathogenesis. In addition to be one of the inflammatory mediators in VILI, Ptx3 over-expression led to a faster development of VILI in Ptx3-transgenic mice in comparison with wild-type when submitted to high tidal volume ventilation. The same PTX3 pro-inflammatory action was not observed in a lung protective ventilation strategy, suggesting that its impact may be worse in more severe VILI. In order to down-regulate PTX3 expression in vivo, we investigated the Pentoxifylline anti-inflammatory action in VILI caused by high tidal volume ventilation. Although 50 and 100 mg/kg doses did not delayed the onset of VILI, its function deserves further investigation. Our data show the important involvement of the long pentraxin PTX3, which hiper-expression accelerated the lung injury development in mice submitted to mechanical ventilation. The results contribute to a better understanding of the inflammatory process in VILI disclosing the involvement of PTX3 in the pathogenesis of this disorder and its potential usefulness as a target for clinical interventions.