Validation of the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes in chronic myelomonocytic leukaemia: A novel approach for improved risk stratification.

Chronic myelomonocytic leukaemia (CMML) is a rare haematological disorder characterized by monocytosis and dysplastic changes in myeloid cell lineages. Accurate risk stratification is essential for guiding treatment decisions and assessing prognosis. This study aimed to validate the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes (AIPSS-MDS) in CMML and to assess its performance compared with traditional scores using data from a Spanish registry (n = 1343) and a Taiwanese hospital (n = 75). In the Spanish cohort, the AIPSS-MDS accurately predicted overall survival (OS) and leukaemia-free survival (LFS), outperforming the Revised-IPSS score. Similarly, in the Taiwanese cohort, the AIPSS-MDS demonstrated accurate predictions for OS and LFS, showing superiority over the IPSS score and performing better than the CPSS and molecular CPSS scores in differentiating patient outcomes. The consistent performance of the AIPSS-MDS across both cohorts highlights its generalizability. Its adoption as a valuable tool for personalized treatment decision-making in CMML enables clinicians to identify high-risk patients who may benefit from different therapeutic interventions. Future studies should explore the integration of genetic information into the AIPSS-MDS to further refine risk stratification in CMML and improve patient outcomes.

Radiotherapy for Brain Metastases Near the End of Life: Characterizing Patients and Tumor Features.

PURPOSE: Patients with brain metastases are often referred for brain radiotherapy (BrRT) when exclusive palliative management would be more appropriate. To assess the indication of BrRT during end-of-life (EOL) care and evaluate the characteristics of the patients who underwent the treatment. METHODS: This retrospective study comprised patients from four independent oncology centers who had undergone BrRT for metastases. The variables included were Karnofsky performance status (KPS), primary tumor site, metastatic status, neurologic symptomatic status, the number and size of metastases, posterior fossa or meningeal involvement, type of BrRT, having undergone brain metastasectomy, and the availability of systemic therapies after BrRT. Patients were allocated into three subgroups with ≤30, 31-60, and 61-90 days of survival, and a control group of patients who survived >90 days. RESULTS: A total of 546 patients were included in the study. A KPS of <70 (P = .021), the number of brain metastases (P = .001), the lack of brain metastasectomy (P = .006), and the lack of systemic therapies after BrRT (P = .047) were significantly associated with the EOL subgroups. Multivariate analysis showed that a KPS of <70 (P < .001), the lack of brain metastasectomy (P = .015), and the lack of systemic therapies after BrRT (P = .027) were significantly associated with worse survival. In all, 241 (44.1%) patients died within 90 days-120 (22.0%) within 30 days, 75 (13.7%) within 31-60 days, and 46 (8.4%) within 61-90 days of BrRT. Patients with colorectal cancer were significantly more likely to die within 90 days of BrRT than >90 days. CONCLUSION: Considering patients' performance status and whether they are candidates for brain metastasectomy or systemic therapies after BrRT is critical to improving BrRT benefits in scenarios of EOL.

Machine Learning Improves Risk Stratification in Myelodysplastic Neoplasms: An Analysis of the Spanish Group of Myelodysplastic Syndromes.

Myelodysplastic neoplasms (MDS) are a heterogeneous group of hematological stem cell disorders characterized by dysplasia, cytopenias, and increased risk of acute leukemia. As prognosis differs widely between patients, and treatment options vary from observation to allogeneic stem cell transplantation, accurate and precise disease risk prognostication is critical for decision making. With this aim, we retrieved registry data from MDS patients from 90 Spanish institutions. A total of 7202 patients were included, which were divided into a training (80%) and a test (20%) set. A machine learning technique (random survival forests) was used to model overall survival (OS) and leukemia-free survival (LFS). The optimal model was based on 8 variables (age, gender, hemoglobin, leukocyte count, platelet count, neutrophil percentage, bone marrow blast, and cytogenetic risk group). This model achieved high accuracy in predicting OS (c-indexes; 0.759 and 0.776) and LFS (c-indexes; 0.812 and 0.845). Importantly, the model was superior to the revised International Prognostic Scoring System (IPSS-R) and the age-adjusted IPSS-R. This difference persisted in different age ranges and in all evaluated disease subgroups. Finally, we validated our results in an external cohort, confirming the superiority of the Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS) over the IPSS-R, and achieving a similar performance as the molecular IPSS. In conclusion, the AIPSS-MDS score is a new prognostic model based exclusively on traditional clinical, hematological, and cytogenetic variables. AIPSS-MDS has a high prognostic accuracy in predicting survival in MDS patients, outperforming other well-established risk-scoring systems.

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.

BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.

Metabolic Biomarkers for the Early Detection of Cancer Cachexia.

Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia. Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia. Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss. Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.

A invisibilidade das pessoas LGBTQIA+ nas bases de dados: novas possibilidades na Pesquisa Nacional de Saúde 2019? / The invisibility of the LGBTQIA+ people in the databases: new possibilities in the 2019 National Health Research?

Resumo A disponibilidade de informações a respeito das minorias populacionais, nesse caso, da população LGBTQIA+ (Lésbicas, Gays, Bissexuais, Travestis e Transexuais, Queers, Intersexuais e Assexuais) e a possibilidade de cruzamentos com demais variáveis em bases populacionais é imprescindível para a compreensão das similaridades e especificidades da realidade vivenciada por estes grupos, bem como para a criação de políticas públicas focalizadas. Nesse sentido, buscamos refletir nesse artigo sobre os problemas relativos à investigação sobre as orientações/performances de sexo e gênero e, por consequência, a falta de informação sobre tal temática disponível nas bases de dados populacionais. A partir da inclusão da pergunta sobre orientação sexual na base de dados da Pesquisa Nacional de Saúde (PNS), de 2019, apesar das limitações, apresentamos algumas das possíveis oportunidades de investigações sobre o tema a partir de diferentes óticas.

Abstract The availability of information about population minorities, in this case, the LGBTQIA+ population (Lesbians, Gays, Bisexual, Transvestite/Transsexual, Queer, Intersex, and Asexual), and the possible intersections with other variables on population bases is essential for understanding the similarities and specificities of the reality experienced by these groups, and the establishment of focused public policies. In this sense, this paper aims to reflect on the problems related to research about the sex and gender orientations/performances and, consequently, the lack of information on this topic available in population databases. From the inclusion of the question about sexual orientation in the 2019 National Health Survey database, despite the limitations, this paper presents possible opportunities for investigations on the topic from different perspectives.

[Consensus document for the diagnosis and treatment of pyruvate kinase deficiency]. / Documento de consenso para el diagnóstico y tratamiento del déficit de piruvato quinasa.

Pyruvate kinase (PK) deficiency is the second most frequent enzymopathy and the most common cause of chronic hereditary non-spherocytic haemolytic anaemia. Its global prevalence is underestimated due to low clinical suspicion of mild cases, associated with difficulties in the performance and interpretation of PK enzymatic activity assays. With the advent of next generation sequencing techniques, a better diagnostic approach is achieved. Treatment remains based on red blood cell transfusions and splenectomy, with special attention to iron overload, not only in transfusion-dependent patients. Nowadays, allogeneic hematopoietic stem cell transplantation is the only curative treatment, recommended only in selected cases of severely affected patients with an HLA-identical donor. Novel pharmacological and gene therapies are in clinical trials, with promising results. In this article, the Spanish Erythropathology Group reviews the current situation of PK deficiency, paying special attention to the usefulness of different diagnostic techniques and to actual and emerging treatments.

Sensitivity of the Nipple-Areola Complex in Reduction Mammaplasty Following Periareolar Dermis Section.

BACKGROUND: Preservation of the periareolar dermis, after de-epithelization in reduction mammaplasty, may result in reduced nipple-areola complex (NAC) mobility. Consequently, distortion in shape and difficulty correcting the areola position can occur. OBJECTIVES: The aim of this study was to evaluate NAC viability and sensitivity resulting from periareolar dermis section after de-epithelization in patients who underwent reduction mammaplasty surgery. METHODS: This study was a randomized, controlled double-blind clinical trial. A total of 41 patients (82 breasts) were randomly allocated into 2 groups and underwent reduction mammaplasty-involving the superior pedicle-with a final inverted T-shaped scar. A sectioning of the periareolar dermis was performed on the breasts in the experimental group. Semmes-Weinstein monofilaments were used to evaluate NAC sensitivity at the preoperative evaluation, and 3, 6, and 52 weeks after surgery. RESULTS: No cases of partial or total NAC necrosis were noted in either group. The comparison between the groups did not show significant differences regarding NAC sensitivity. However, a statistically significant difference was noted when sensitivity levels at the preoperative evaluation and 3 weeks after surgery were compared in the experimental group. A significant difference was noted when the scores of the sensitivity 3 weeks after surgery were compared between the control and the experiment groups. Nevertheless, after 1 year, no statistical differences were observed in the experimental group or between both groups. CONCLUSIONS: The sectioning of the periareolar dermis does not affect the viability or the pressure sensitivity of the NAC.

Evaluation of the Impact of Oral Hygiene and Chamomile Tea in the Development of Oral Mucositis: Pilot Study / Avaliação do Impacto da Higiene Oral Associada ao Uso do Chá de Camomila no Desenvolvimento de Mucosite Oral: Estudo-Piloto / Evaluación del Impacto de la Higiene Oral y el Té de Manzanilla en el Desarrollo de la Mucositis Oral: Estudio Piloto

Introduction: The oral mucositis (OM) represents a frequent inflammatory condition in cancer patients, and poor oral hygiene has been related as a predisposing factor for its onset. Chamomile tea has been studied as an adjunctive therapy in the management of OM due to its analgesic and anti-inflammatory properties. Objective: The objective of this study was to evaluate the influence of chamomile tea associated with a rigorous oral hygiene in the OM prevention. Method: Randomized pilot clinical study, with 35 patients assigned to two groups. The case-group underwent oral hygiene control associated with the use of chamomile tea before starting the first cycle of chemotherapy, while the control group, there were no previous guidelines and prescriptions. Data about sociodemographic characteristics, the type of neoplasm and the chemotherapy scheme proposed were collected. The variables OM, salivary flow and pain associated to the oral cavity were evaluated, and statistical analysis was performed with significance level p <0.05. Results: It was observed that the majority of the patients had a mean age of 50 years, breast (57%) was the most prevalent tumor site and cyclophosphamide (52%), the most frequently used drug In this sample, no statistically significant result was observed in the two groups for OM, salivary flow and pain variables (p> 0.05). Conclusion: These data suggest that the use of chamomile tea and the accuracy of oral hygiene were not sufficient to prevent OM.

Introdução: A mucosite oral (MO) representa uma condição inflamatória frequente em pacientes oncológicos e uma higiene oral insatisfatória tem sido relacionada como fator predisponente para o seu surgimento. O chá de camomila vem sendo estudado como terapia adjuvante no manejo da MO em razão das suas propriedades analgésicas e anti-inflamatórias. Objetivo: Avaliar a influência do chá de camomila associada a uma rigorosa higiene oral na prevenção de MO. Método: Trata-se de um estudo-piloto clínico randomizado, no qual 35 pacientes foram alocados em dois grupos. O grupo-caso foi submetido ao controle de higiene oral associado ao uso do chá de camomila antes de iniciar o primeiro ciclo de quimioterapia; no grupo-controle, não houve orientações e prescrições prévias. Foram coletados dados referentes às características sociodemográficas, à neoplasia em questão e ao tipo de tratamento quimioterápico proposto. Foram avaliadas as variáveis MO, fluxo salivar e dor associada à cavidade oral, e realizada análise estatística com nível de significância p<0,05. Resultados: Observou-se que a maioria dos pacientes apresentava-se na quinta década de vida, a localização do tumor mais prevalente foi a mama (57%) e a droga mais utilizada por esses pacientes foi a ciclosfamida (52%). Nesta amostra, não foi observado resultado estatisticamente significativo entre os grupos, no que diz respeito às variáveis MO, fluxo salivar e dor (p>0,05). Conclusão: Os dados sugerem que o uso do chá de camomila e o rigor na higiene oral não foram suficientes para a prevenção da MO.

Introducción: La mucositis oral (MO) representa una afección inflamatoria frecuente en pacientes con cáncer, y la mala higiene bucal se ha relacionado como un factor predisponente para su aparición. El té de manzanilla se ha estudiado como una terapia adyuvante en el tratamiento de la OM debido a sus propiedades analgésicas y antiinflamatorias. Objetivo: El objetivo de este estudio fue evaluar la influencia del té de manzannilla asociado con una hygiene oral rigurosa en la prevención de la MO. Método: Fue un estudio clínico piloto aleatorizado, en el que treinta y cinco pacientes fueron asignados en dos grupos. El grupo de casos se sometió a un control de higiene oral asociado con el uso de té de manzanilla antes de comenzar el primer ciclo de quimioterapia, mientras que en el grupo de control, no había pautas ni recetas previas. Se recopilaron datos sobre las características sociodemográficas, el tipo de neoplasia y el esquema de quimioterapia propuesto. Se evaluaron las variables MO, flujo salival y dolor asociado a la cavidad oral, y se realizó un análisis estadístico con nivel de significancia p<0,05. Resultados: Se observó que la mayoría de los pacientes tenían una edad media de 50 años, el sitio del tumor más prevalente era la mama (57%) y el fármaco utilizado con mayor frecuencia era la ciclofamida (52%). En esta muestra, no se observaron resultados estadísticamente significativos entre los grupos con respecto a las variables MO, flujo salival y dolor (p>0,05). Conclusión: Estos datos sugieren que el uso de té de manzanilla y la precisión de la higiene oral no fueron suficientes para prevenir la MO.

Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles.

Despite recent progress, chemotherapy remains the preferred treatment for cancer. We have shown a link between anticancer drugs and the development of cachexia, i.e., body wasting accompanied by muscle loss. The multi-kinase inhibitors (MKIs) regorafenib and sorafenib, used as second-line treatment for solid tumors, are frequently accompanied by several side effects, including loss of muscle mass and strength. In the present study we aimed to investigate the molecular mechanisms associated with the occurrence of muscle toxicities in in vivo conditions. Hence, we treated 8-week old healthy CD2F1 male mice with MKIs for up to six weeks and observed decreased skeletal and cardiac muscle mass, consistent with muscle weakness. Modulation of ERK1/2 and GSK3ß, as well as increased expression of markers of autophagy, previously associated with muscle atrophy conditions, were shown in skeletal muscle upon treatment with either drug. MKIs also promoted cardiac abnormalities consistent with reduced left ventricular mass, internal diameter, posterior wall thickness and stroke volume, despite unchanged overall function. Notably, different signaling pathways were affected in the heart, including reduced expression of mitochondrial proteins, and elevated AKT, GSK3ß, mTOR, MEK1/2 and ERK1/2 phosphorylation. Combined, our data demonstrate detrimental effects on skeletal and cardiac muscle in association with chronic administration of MKIs, although different mechanisms would seem to contribute to the cachectic phenotype in the two tissues.

Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism.

BACKGROUND: Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer-induced and chemotherapy-induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. METHODS: The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer-induced cachexia. In vivo administration of Folfiri (5-fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy-induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance-based and mass spectrometry-based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. RESULTS: The study involved four groups of CD2F1 male mice (n = 4-5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (-3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (-38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (-47% in CC vs. V; P < 0.001) and depletion of liver glucose (-51% in CC vs. V; P < 0.001) and glycogen (-74% in CC vs. V; P < 0.001). The cancer-induced and chemotherapy-induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and ß-oxidation pathways. Cancer-induced cachexia was uniquely characterized by a dramatic elevation in low-density lipoprotein particles (+6.9-fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001). CONCLUSIONS: The results of this study demonstrated for the first time that cancer-induced and chemotherapy-induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer-induced and chemotherapy-induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.

Avaliação da sensibilidade do complexo areolopapilar após mamoplastia redutora com liberação dérmica versus volume ressecado de tecido mamário / Evaluation of the nipple­areola complex after reduction mammoplasty with dermal release versus resected volume of the breast tissue

Introdução: O complexo areolopapilar (CAP) desempenha grande importância tanto na amamentação quanto na vida sexual das pacientes, consequentemente, devemos ressaltar que uma complicação potencial da mamoplastia redutora é a alteração ou até a perda da sensibilidade do CAP. Método: Estudo prospectivo, randomizado, controlado e duplo-cego para avaliar a relação entre a sensibilidade do complexo areolopapilar após mamoplastia redutora com liberação dérmica e o volume ressecado de tecido mamário. O estudo ocorreu no período de agosto de 2013 a agosto de 2015, no Hospital das Clínicas da Universidade Federal de Pernambuco (HC-UFPE). Resultados: O estudo totalizou 39 pacientes. A média de idade da amostra foi de 31,7 anos, índice de massa corporal (IMC) médio de kg/m2 e nenhuma das pacientes era tabagista. A taxa de comorbidade foi de 5,1% da amostra. O índice de complicações foi de 41%, composto de 7 casos de cicatriz inestética, 6 de hematoma e 4 de deiscência. Não houve caso de sofrimento ou necrose do CAP e todas as pacientes se mostraram satisfeitas com o resultado cirúrgico final. Não houve diferenças estatisticamente significantes em nenhuma das ocasiões entre os pacientes do grupo experimento e controle, tanto no grupo de ressecção de até 300 gramas quanto acima de 300gramas. Conclusões: A manobra de liberação dérmica não provocou diferença na sensibilidade do complexo areolopapilar, independentemente da quantidade de tecido mamário ressecado.

Introduction: The nipple­areola complex (NAC) plays an important role both in breastfeeding and sexual lives of the patients. Because of this, we must mention possible complications of reduction mammoplasty, such change or even loss of sensitivity of the NAC. Method: This was a prospective, randomized, controlled, double-blind study to evaluate the relationship between the sensitivity of the NAC after reduction mammoplasty with dermal release and the resected volume of breast tissue. This study was conducted between August 2013 and August 2015 at the Hospital das Clínicas of the Federal University of Pernambuco (HC-UFPE), in Recife City, Brazil. Results: The study involved 39 patients. The mean age and body mass index (BMI) of the patients were 31.7 years and 25.5 kg/m2, respectively. None of the patients was a smoker. The complication rate was 41%, including 7 cases of non-aesthetic scars, 6 cases of hematoma (bruises), and 4 cases of dehiscence. No patient had pain or NAC necrosis, and all the patients expressed being satisfied with the final surgical result. No statistically significant differences were found between the patients of the experimental and control groups, both in the group with resection of up to 300 g and those with resection >300 g. Conclusions: The maneuver of dermic release did not result in any differences in the sensitivity of the NAC, regardless of the quantity of resected breast tissue.

Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia.

BACKGROUND: Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. METHODS: Nod SCID gamma mice (n = 6-10) were injected intraperitoneally with 1 × 107 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. RESULTS: In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (-12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour-bearing mice (approximately -35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (-34%, P < 0.01) and muscle weakness (-50%, P < 0.001). Body composition assessment by dual-energy X-ray absorptiometry revealed decreased bone mineral density (-8%, P < 0.01) and bone mineral content (-19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho-AKT (-44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (-16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. CONCLUSIONS: Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.

Disparidades no tratamento do infarto agudo do miocárdio entre usuários dos Sistema de Saúde Público e Privado em Sergipe / Disparities in acute myocardial infarction treatment between users of the public and private healthcare System in Sergipe

Com a criação do SUS, todos teriam acesso universal, integral e equânime à assistência de saúde de qualidade. Entretanto, existe grande lacuna de estudos escrutinizando o SUS no tocante à qualidade assistencial praticada. Esse fato é especialmente crítico para vítimas de infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCSST), sendo a responsividade do sistema e o uso da reperfusão em tempo hábil fatores cardinais para obtenção de melhores resultados. Descrever a metodologia empregada no Registro VICTIM que tem como objetivo caracterizar e comparar o acesso e o uso de terapias efetivas e desfechos entre os pacientes com IAMCSST usuários do SUS e do sistema privado atendidos nos hospitais com capacidade de realizar angioplastia em Sergipe, tentanto identificar e mensurar eventuais disparidades na qualidade da assistência.O Registro VICTIM é um estudo observacional, iniciado em dezembro de 2014, e ainda em fase de coleta, com a intenção de investigar a epidemiologia do IAMCSST em Sergipe, os cursos temporal e geográfico dos pacientes até sua admissão em uma instituição com capacidade de realizar angioplastia, uso de terapias de reperfusão, qualidade assistencial recebida durante a linha de cuidado, bem como a mortalidade de 30 dias, comparando-se os resultados obtidos pela população usuária do SUS e do sistema privado.O registro VICTIM é um esforço interinstitucional para identificar oportunidades de melhoria na linha de cuidado para IAMCSST de usuários do SUS e do sistema privado. Com isso, espera-se municiar os gestores públicos de informações técnicas que embasem novas políticas de saúde mais eficientes e equânimes

The Brazilian Unified Health System (SUS) was created to ensure universal, integral and equitable access to quality healthcare to Brazilians. However, studies scrutinizing the quality of the healthcare provided by the SUS are scarce. This is especially critical for patients with ST-elevation myocardial infarction (STEMI), who depend on healthcare system responsiveness and timely reperfusion to achieve better outcomes. To describe the methodology of the VICTIM Registry aimed at characterizing and comparing the access to effective therapies and the outcomes of patients with STEMI, who use the SUS and the private healthcare system at hospitals capable of performing angioplasty in Sergipe. In addition, that registry aimed at identifying and measuring possible disparities in the quality of the care provided. The VICTIM Registry is an observational study, launched in December 2014, being still in the data collection phase, to investigate: the epidemiology of STEMI in Sergipe, the temporal and geographic courses of the patients up to their admission to one of the hospitals capable of performing angioplasty, the reperfusion therapy rates, the quality of the healthcare provided during the event, and the 30-day mortality. It compares the results obtained in the SUS with those of the private healthcare system. The VICTIM Registry is an interinstitutional effort to identify opportunities for healthcare improvement for SUS and private healthcare system patients with STEMI. It is expected to provide healthcare managers with information to support new, more efficient and equitable healthcare policies

ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass.

Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.

Incidencia de lesiones en la práctica deportiva del motocross / Incidence of injuries in the sport practice of motocross

Antecedentes: Estudiar la incidencia de lesiones que involucran a atletas profesionales de Motocross de diferentes categorías en niveles de carreras estatales, nacionales e internacionales y evaluar las le-siones más comunes dentro de los atletas de Motocross y las áreas más frecuentemente afectadas por la práctica del deporte. Métodos: El estudio incluyó un cuestionario respondido por 45 atletas entre 16 y 46 años de edad, hombres y mujeres, de diferentes nacionalidades y lugares de nacimiento, en carreras para el Campeonato de Motocross de Brasil. Resultados: Las fracturas son las lesiones más comunes entre los corredores de Motocross (17.55 %), seguido de dislocaciones (13.05%). Los hom-bros y las rodillas son los sitios anatómicos más afectados. Las pruebas de chi- cuadrado mostraron que el diagnóstico tiene una relevancia significativa sobre la influencia y la definición del tratamiento de las lesiones (p = 0.001). El diagnóstico tuvo significación estadística en relación con el regreso de los corredores a los deportes con el mismo nivel físico anterior a la lesión (p = 0.001). Conclusión: Los hombros fueron los más afectados por las lesiones y las fracturas la lesión más común en la práctica de Motocross y debido a su naturaleza de alto impacto, el Motocross tiene una alta tasa de lesiones.

Background: To study the incidence of injuries involving professional Motocross athletes from diffe-rent categories in state, national and international racing levels and to evaluate the most common inju-ries within Motocross athletes and the most frequently affected areas by the sport's practice. Methods: The study included a questionnaire answered by 45 athletes aged between 16 and 46 years old, male and female, of different nationalities and places of birth, racing for the Brazilian Motocross Champion-ship. Results: Fractures are the most common injuries among Motocross racers (17.55%), followed by dislocations (13.05%). The shoulders and knees are the most affected anatomical sites. The chi- square tests showed that the diagnosis has significant relevance over the influence and definition of the inju-ries' treatment (p=0.001).The diagnosis had statistical significance in relation to the racers' return to sports with the same physical level prior to the injury (p=0.001). Conclusion: The shoulders were the most affected by injuries and the fractures the most common lesion in Motocross practice and because of its high impact nature, Motocross has a high rate of injuries.

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia.

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.

Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways.

Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; -1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs.

Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFß-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.