Loss of MTAP expression is a negative prognostic marker in Ewing sarcoma family of tumors.

AIM: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. METHODS: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival(OS). RESULTS: Loss of MTAP expression was significantly associated with lower OS in both univariate and multivariate analyses. CONCLUSION: Loss of MTAP expression is an independent negative prognostic biomarker in ESFT.Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP) and CNPq grants to RM Reis. WP Menezes is recipient of a FAPESP fellowship (2016/06833–2). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.info:eu-repo/semantics/publishedVersio

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Association between clinicopathological variables and the immunohistochemical expression of Ezrin and CD44 in patients with osteosarcoma

Metástase é o fator prognóstico mais importante em pacientes com osteossarcoma. A identificação de genes que são cruciais para disseminação metastática é de grande interesse não só para o entendimento básico dos processos moleculares e celulares envolvidos, mas também por prover um potencial de novos alvos terapêuticos. No osteossarcoma tem sido relatado que o gene Ezrin, membro da família ERM (Ezrin- Radixin-Moesin) é importante para que ocorra metástase. Consiste em um componente do citoesqueleto que tem sido responsavel por muitas funções, como, por exemplo, como condutor de sinais entre superfície celular associada à metástase e tradução do sinal. Isto sugere que o gene Ezrin têm a chave da coordenação de sinais e do complexo celular que são necessários para o sucesso da ocorrência de metástases. CD44 é conhecida como a primeira proteína de superfície que demonstrou interação com as proteínas do complexo ERM. Formam um complexo que exerce diversos papéis em células normais e particularmente nas células do câncer. Aumento na expressão de CD44 potencialmente leva a um aumento funcional da ativação do Ezrin e tem sido correlacionada com aumento da invasão do osteossarcoma. Objetivo: A proposta deste estudo é correlacionar a expressão da proteína Ezrin e CD44 com fatores clínicos, identificar fatores prognósticos, sugerindo uma estratificação dos pacientes de risco, para que possa ser proposta no futuro uma terapêutica mais efetiva e com menor toxicidade. Casuística e Métodos: Foram revistos 52 pacientes com osteossarcoma tratados no Hospital de Câncer de Barretos entre 2000 e 2005. O tumor ósseo é uma das neoplasias sólidas mais freqüentes em nossa Instituição, representando aproximadamente 15% dos casos novos/ano. Devido a algumas particularidades, como atendimentos de pacientes em âmbito nacional, tivemos 46,2 % de pacientes metastáticos ao diagnóstico, 37,3 % de tumores maiores que 15 cm, 30,2 % de amputações e 11,5 % de recaídas locais em cirurgias conservadoras. Não demonstramos associação da duração dos sintomas com o tamanho do tumor, presença de metástases. O nível de expressão da proteína Ezrin e CD44H foi avaliado por imunoistoquimica na biópsia inicial em 34 amostras. O nível de expressão pela coloração imunoistoquímica foi classificada em 1+ (1 - 25%), 2+ (26 - 50%), 3+ (51 - 75%), 4+ (76 - 100%) para a proteína Ezrin e o CD44 foi classificada como negativa (até 10%), 1+ (até 50%) e 2+ (até 100%). Foi realizado um escore para classificar a expressão do Ezrin em baixa e alta expressão (levando em consideração a intensidade e a proporção de células coradas) e interação da expressão de ezrin com grau de responsividade à quimioterapia. A associação entre as variáveis foi realizada usando o teste de quiquadrado. O cálculo dos estimadores da probabilidade de sobrevida foi realizado pelo técnica de Kaplan-Meier e as comparações entre as curvas foi realizado pelo teste de log rank. Resultados: A imunorreatividade da proteína Ezrin foi detectada na maioria dos pacientes com osteossarcoma (76%), com igual distribuição em citoplasma e membrana (38,2%). Quanto à intensidade de coloração, tivemos 58,9% forte. Na escala semiquantitativa metade dos casos apresentou mais de 50% das células coradas. No escore que associa intensidade de coloração e proporção de células coradas tivemos 50,0% com alta expressão. Cinqüenta por cento dos pacientes apresentaram CD44H positivo, sendo predominante no citoplasma (38,2%). Na escala semiquantitativa 20,6 % apresentava coloração em mais de 50% das células. Ambos os marcadores não mostraram associação a nenhuma variável clínico-patológicas estudada. Entre os pacientes que apresentaram imunoreatividade de ezrin positivos a taxa de sobrevida apresentada em 5 anos foi de 12,8% versus com 41,7% dos pacientes com ezrin negativo.(p = 0,121). O escore realizado com a imunoreatividade de ezrin também não mostrou papel na sobrevida (p: 0,558). Já a interação da positividade de Ezrin com má resposta histológica para pacientes não metastáticos mostrou associação com sobrevida livre de recaída em 5 anos (100% x 12,7%; p: 0,042). Quanto à taxa de sobrevida global foi semelhante para pacientes com CD44 positivo (21,5%) ou negativo (25,3%) (p: 0,676). Conclusão: Em nossa experiência, a imunoexpressao de CD44H nem Ezrin mostraram ser preditor do prognóstico em pacientes com osteossarcoma. Os resultados sugerem que são necessárias outras investigações para melhor definir a relação entre padrão de expressão de Ezrin e CD44, status funcional e sobrevida em portadores de osteossarcoma.Metastasis is the most important prognostic factor in patients with osteosarcoma. Identification of genes that are crucial for metastatic dissemination is of great interest, not only to gain a basic understanding of the molecular and cellular processes involved, but also to provide the potential for new therapeutic targets. In relation to osteosarcoma, it has been reported that the Ezrin gene, a member of the ERM family (ezrin-radixin-moesin), is important for enabling metastasis. Ezrin is a component of the cytoskeleton that has been implicated in many functions, for example as a conductor of signals between cell surfaces associated with metastasis and signal translation. This suggests that Ezrin holds the key to coordination of the signals and cell complexes needed for successful metastasis to occur. CD44 is known as the first surface protein that was shown to interact with proteins of the ERM complex. It forms a complex that plays various roles in normal cells and particularly in cancer cells. Increased CD44 expression potentially leads to functional increases in Ezrin activation and has been correlated with greater osteosarcoma invasion. Objective: The aim of this study was to correlate the expression of the Ezrin and CD44 proteins with clinical factors and identify prognostic factors, thereby enabling stratification of patients at risk, so that therapy of greater effectiveness and lower toxicity can be proposed in the future. Sample and Methods: Data on 52 patients with osteosarcoma who were treated at Barretos Cancer Hospital between 2000 and 2005 were reviewed. Bone tumors are among the types of solid neoplasia most frequently seen in our institution, accounting for around 15% of the new cases every year. Because of certain special features such as our institution\'s national-level attendance, 46.2% of the patients were metastatic at diagnosis, 37.3% of the tumors were larger than 15 cm, 30.2% of the cases led to amputation and 11.5% of the conservatively operated cases presented local relapse. We did not find any association between symptoms and either tumor size or presence of metastases. The expression levels of the Ezrin and CD44H proteins were evaluated using immunohistochemistry on the initial biopsy, for 34 samples. From the immunohistochemical staining, the Ezrin protein expression level was classified as 1+ (1 - 25%), 2+ (26 - 50%), 3+ (51 - 75%) or 4+ (76 - 100%). CD44 was classified as negative (up to 10%), 1+ (up to 50%) or 2+ (up to 100%). The Ezrin expression was scored to classify it as low or high (considering the intensity and proportion of stained cells) and the interaction of Ezrin expression with the degree of responsiveness to chemotherapy. The chi-square test was used to correlate the variables. Estimators for survival likelihood were calculated using the Kaplan-Meier technique and the curves were compared using the log-rank test. Results: Most patients with osteosarcoma (76%) were immunoreactive for Ezrin protein, equally distributed between cytoplasm and membrane (38.2%). High-intensity staining was found in 58.9%. On the semiquantitative scale, half of the cases presented more than 50% of the cells stained. From the score correlating staining intensity and proportion of cells stained, 50.0% showed high expression. Half of the patients were positive for CD44H, predominantly in cytoplasm (38.2%). On the semiquantitative scale, 20.6% presented staining in more than 50% of the cells. Neither of the markers showed associations with any of the clinicopathological variables studied. Among the patients who were immunoreactive for Ezrin, the five-year survival rate was 12.8%, while it was 41.7% among Ezrinnegative patients (p = 0.121). The score relating to Ezrin immunoreactivity was not shown to have a role in survival (p = 0.558). However, the interaction between Ezrinpositive findings and poor histological response among non-metastatic patients showed an association with five-year relapse-free survival (100% x 12.7%; p = 0.042). The overall survival rates for CD44-positive and negative patients were similar (21.5% and 25.3%, respectively) (p = 0.676). Conclusion: In our experience, neither CD44H nor Ezrin immunoexpression predicted the prognosis for patients with osteosarcoma. The results suggest that further investigations are needed in order to better define the relationships between Ezrin and CD44 expression patterns, functional status and survival among patients with osteosarcoma

Symptom perception and end of life suffering of cancer children and the repercussion on caregivers

Introdução: Apesar do progresso da oncologia pediátrica, ainda existem pacientes que não atingem a cura. Estudos mostram que estes recebem tratamento agressivo no fim da vida, sem controle efetivo dos sintomas, com sofrimento significativo. O cuidador familiar é fonte preciosa de informações conforme a morte da criança se aproxima. No entanto, as impressões parentais podem não refletir precisamente a experiência da criança, pois presenciar sofrimento pressupõe sofrimento. Talvez isso explique a discordância entre o relato dos pais e os registros médicos. A convivência com o sofrimento do filho morrendo permanece gravado na memória dos pais. Acreditar que o filho morreu sofrendo pode levar a morbidade psicológica e interferir no futuro deles. Avaliou-se a percepção dos pais sobre os sintomas que afetaram o bem estar dos seus filhos no fim da vida, comparou-se com os dados da equipe médica e relacionaram-se as circunstâncias em que a morte ocorreu com transtornos de humor e presença de luto complicado. Material e métodos: em 2012 entramos em contato com 250 famílias que perderam o filho no período de 2000 a 2010, em um Hospital especializado, no interior do Brasil, que realiza atendimento através do sistema governamental. A pesquisa foi conduzida através de questionários auto-aplicáveis enviados pelos correios. Resultados: tivemos a participação de 60 cuidadores com tempo de luto variando entre 14 e 80 meses. Esses relataram média de 12 sintomas que afetaram o bem estar dos filhos na última semana de vida, sem concordância quando comparado com os dados registrados pela equipe médica, até mesmo para o sintoma dor. Esses pais apresentam altos níveis de ansiedade e depressão (74,0% e 81,0% respectivamente) e altos níveis de luto complicado (38,0% com luto baixo/ausente, 12,0% com luto adiado e 34,0% como luto prolongado). Os maiores escores de luto atual foram evidenciados entre os cuidadores casados, com idade variando entre 30-39 anos, analfabetos, assalariados, com outras religiões que não a católica, pertencente às classes econômicas C/D/E, que tiveram um filho único, que está há mais de 72 meses de luto, cujo filho tinha no momento do óbito idade entre 12 e 18 anos, era portador de tumor de SNC, estava em tratamento com intenção curativa e faleceu na enfermaria. Evidenciamos correlação entre a carga de sintomas referida pelos médicos com luto passado e luto presente. Analisando as Introdução: Apesar do progresso da oncologia pediátrica, ainda existem pacientes que não atingem a cura. Estudos mostram que estes recebem tratamento agressivo no fim da vida, sem controle efetivo dos sintomas, com sofrimento significativo. O cuidador familiar é fonte preciosa de informações conforme a morte da criança se aproxima. No entanto, as impressões parentais podem não refletir precisamente a experiência da criança, pois presenciar sofrimento pressupõe sofrimento. Talvez isso explique a discordância entre o relato dos pais e os registros médicos. A convivência com o sofrimento do filho morrendo permanece gravado na memória dos pais. Acreditar que o filho morreu sofrendo pode levar a morbidade psicológica e interferir no futuro deles. Avaliou-se a percepção dos pais sobre os sintomas que afetaram o bem estar dos seus filhos no fim da vida, comparou-se com os dados da equipe médica e relacionaram-se as circunstâncias em que a morte ocorreu com transtornos de humor e presença de luto complicado. Material e métodos: em 2012 entramos em contato com 250 famílias que perderam o filho no período de 2000 a 2010, em um Hospital especializado, no interior do Brasil, que realiza atendimento através do sistema governamental. A pesquisa foi conduzida através de questionários auto-aplicáveis enviados pelos correios. Resultados: tivemos a participação de 60 cuidadores com tempo de luto variando entre 14 e 80 meses. Esses relataram média de 12 sintomas que afetaram o bem estar dos filhos na última semana de vida, sem concordância quando comparado com os dados registrados pela equipe médica, até mesmo para o sintoma dor. Esses pais apresentam altos níveis de ansiedade e depressão (74,0% e 81,0% respectivamente) e altos níveis de luto complicado (38,0% com luto baixo/ausente, 12,0% com luto adiado e 34,0% como luto prolongado). Os maiores escores de luto atual foram evidenciados entre os cuidadores casados, com idade variando entre 30-39 anos, analfabetos, assalariados, com outras religiões que não a católica, pertencente às classes econômicas C/D/E, que tiveram um filho único, que está há mais de 72 meses de luto, cujo filho tinha no momento do óbito idade entre 12 e 18 anos, era portador de tumor de SNC, estava em tratamento com intenção curativa e faleceu na enfermaria. Evidenciamos correlação entre a carga de sintomas referida pelos médicos com luto passado e luto presente. Analisando as variáveis relacionadas ao luto presente evidenciou-se forte correlação positiva com o luto passado, com ansiedade e depressão e correlação negativa com o tempo de cuidados paliativos. Como fatores preditores na análise de regressão múltipla evidenciaram-se o luto passado e a depressão. Conclusão: Os pais relataram grande sofrimento dos filhos no fim da vida, sem concordância com os dados da equipe médica. Dois terços dos cuidadores apresentam sintomas de ansiedade e depressão e 84% apresentaram alguma reação de luto complicado. Evidenciou-se forte correlação positiva do luto presente com o luto passado, com ansiedade e depressão e a com a carga de sintomas referida pelos médicos e correlação negativa com o tempo de cuidados paliativosIntroduction: Despite all the progress in pediatric oncology, there are still patients who cannot achieve cure. Studies show that they receive aggressive treatment in the end of life, with no effective control of symptoms, and endure considerable suffering. The family caregiver is a precious source of information as the death of the child approaches. Parental impressions may not reflect accurately the child\'s experience due to the fact that witnessing suffering implies in suffering. This may explain the discrepancy between the parents\' reports and the medical records. Living with a dying child remains engraved in the parents\' memories. Believing that their child died in pain may lead to psychological morbidity and interfere in their future. Parental perception on the symptoms that affected the well- being of the child in the end of life was evaluated and compared with medical data, and the circumstances in which death occurred were related with mood swings and the presence of complicated grief. Material and methods: In 2012, 250 families that had lost a child between the years of 2000 and 2010, in a specialized, public hospital in Brazil, were contacted. A survey was carried out through self- applied questionnaires sent by mail. Results: 60 caregivers with time of mourning ranging between 14 and 80 months reported, on average, 12 symptoms that affected the well-being of their children on their last week of life, and these reports did not agree with the data recorded by the medical team. These parents present with high levels of anxiety and depression (74.0% and 81.0% respectively), as well as complicated grief (38.0% absent/ low grief, 12.0% delayed grief and 34.0% prolonged grief). The highest grief scores were seen among the caregivers who met the following parameters: married, age range between 30 and 39, illiterate, minimum wage and social class C/D/E. They had also been mourning the loss of their only child, who was between 12 and 18 years old at the time of death, had CNS tumor, was treated with curative intention and died in the infirmary. There was evident correlation between the burden of symptoms referred by the doctors with past and present grief. When the variables related to present grief were analyzed, there was strong positive correlation with past grief, showing anxiety and depression; and negative correlation with palliative care time. As predictor factors in the multiple regression analysis, past grief and depression were evident. Conclusion: Parents related great suffering of their children in the end of life, which did not agree with the medical data. Two thirds of the caregivers present symptoms of anxiety and depression and 84.0% present some reaction of complicated grief. There was strong positive correlation between present and past grief with anxiety and depression, and with the burden of symptoms referred by doctors, and negative correlation with palliative care tim

Characterization, survival analysis, and expression of IGFR in tumor samples from patients diagnosed with Ewing family tumors treated at the Barretos Cancer Hospital

ABSTRACT OBJECTIVES: Study the clinical characteristics of patients diagnosed with Ewing family tumors (EFTs) and survival analysis based on risk criteria and expression of the surface protein known as insulin-like growth factor (IGFR). METHODS: This was a retrospective cohort study based on clinical data from 77 patients diagnosed with EFTs treated by the Department of Pediatric Oncology at the Barretos Cancer Hospital in a period between 2003 and 2012. Biological samples of patients were examined for the presence of the surface receptor IGFR. RESULTS: The overall survival rate (OSR) of patients included in the study was 45% at five years, and EFS was 30% at five years. Metastasis at diagnosis was present in 44.2% of the sample; 88.2% of the sample was male (p < 0.001). The evaluation of the expression of IGFR in biological samples of patients was associated with the variable metastasis at diagnosis (p < 0.001). Worse prognosis was observed in patients with extrapulmonary metastasis (p = 0.009). The local treatment of neoplasia presented better prognosis in patients undergoing local surgical treatment (p < 0.001). CONCLUSIONS: These results showed a higher incidence of metastasis at diagnosis in patients with EFTs treated at the Barretos Cancer Hospital (BCH). Extrapulmonary metastases were a negative prognostic factor in this study. Surgical treatment of the primary tumor was a factor for better prognosis. Strong expression of IGFR was more frequent in patients with metastases at diagnosis, but did not represent a prognostic factor for EFTs

Evaluation of quality of life related to i-131 therapy in patients with well-differentiated thyroid cancer and emphasis in salivary morbidity: a follow up study after treatment

To evaluate the impact of iodine-131 therapy received during childhood and adolescence and correlate it with the quality of life in these patients. Methods: We studied 19 patients diagnosed with cancer in childhood or adolescence who underwent thyroidectomy and supplemental therapy with I-131. We also recruited a control group of healthy subjects with the same demographic parameters. All patients were subjected to a scintigraphy examination of the salivary glands, and were also asked to complete a questionnaire in order to assess their overall quality of life. In addition, a more specific questionnaire for patients with head and neck cancer was also given to all study participants. Results: The quantitative and qualitative analyses of the salivary glands showed functional deficits with greater involvement of the parotid gland for volume, concentration and excretion. The right submandibular gland showed significant changes for volume in the patient group. The questionnaires made it possible to observe significant differences between the patient and control groups for symptoms such as thick saliva, dry mouth and speech problems. Conclusion: In spite of being very effective and widely used, iodine radionuclide therapy is correlated with a lower quality of life in young people

An explainable machine learning model to solid adnexal masses diagnosis based on clinical data and qualitative ultrasound indicators

Abstract Background Accurate characterization of newly diagnosed a solid adnexal lesion is a key step in defining the most appropriate therapeutic approach. Despite guidance from the International Ovarian Tumor Analyzes Panel, the evaluation of these lesions can be challenging. Recent studies have demonstrated how machine learning techniques can be applied to clinical data to solve this diagnostic problem. However, ML models can often consider as black‐boxes due to the difficulty of understanding the decision‐making process used by the algorithm to obtain a specific result. Aims For this purpose, we propose an Explainable Artificial Intelligence model trained on clinical characteristics and qualitative ultrasound indicators to predict solid adnexal masses diagnosis. Materials & Methods Since the diagnostic task was a three‐class problem (benign tumor, invasive cancer, or ovarian metastasis), we proposed a waterfall classification model: a first model was trained and validated to discriminate benign versus malignant, a second model was trained to distinguish nonmetastatic versus metastatic malignant lesion which occurs when a patient is predicted to be malignant by the first model. Firstly, a stepwise feature selection procedure was implemented. The classification performances were validated on Leave One Out scheme. Results The accuracy of the three‐class model reaches an overall accuracy of 86.36%, and the precision per‐class of the benign, nonmetastatic malignant, and metastatic malignant classes were 86.96%, 87.27%, and 77.78%, respectively. Discussion: SHapley Additive exPlanations were performed to visually show how the machine learning model made a specific decision. For each patient, the SHAP values expressed how each characteristic contributed to the classification result. Such information represents an added value for the clinical usability of a diagnostic system. Conclusions This is the first work that attempts to design an explainable machine‐learning tool for the histological diagnosis of solid masses of the ovary

Preventing and Treating Pain and Anxiety during Needle-Based Procedures in Children with Cancer in Low- and Middle-Income Countries

Introduction: Children with cancer experience significant pain and anxiety during needle-based procedures. Undertreated pain in children has long-lasting consequences and reduces the efficacy of subsequent analgesic efforts. A validated quality improvement (QI) intervention, known as the “Children’s Comfort Promise”, includes (1) topical anesthetics, (2) sucrose or breastfeeding for infants, (3) comfort positioning, and (4) distraction techniques, and has been shown to be highly effective in decreasing procedural pain and anxiety in children. However, there is limited data about the adoption, adaptation, and implementation of these interventions in low- and middle-income countries (LMICs). Methods: A QI pilot project utilizing the Model for Improvement of the “Global Comfort Promise” was implemented in four global pediatric cancer hospitals (Lima, Peru; Barretos, Brazil; Pietermaritzburg, South Africa; and Manila, Philippines). Between August 2021 and January 2023, the pilot sites identified a specific aim, co-designed the measurement strategy with St. Jude Children’s Research Hospital, and adopted, adapted, and implemented the project at their individual sites. Results: A total of 2,185 different procedures were recorded in the first year of implementation. Most patients were less than 10 years old (60.5%) and solid tumors (37.9%) were the most common diagnosis. Overall, healthcare professionals (98.3%) were satisfied with the procedures. Parents and patients reported that only 33.7% of patients experienced pain during the procedure. All (100%) parents and patients felt the healthcare teams adequately addressed their child’s pain. Median self-reported adherence to ≥2 interventions was 98.0%. Challenges to the implementation of the QI initiative included lack of training, turnover of the medical staff, maintaining staff enthusiasm, and access to topical anesthetics. Each site had unique change ideas to implement the initiative. Conclusions: This multi-site, multi-country QI initiative was feasible and was successfully adopted, adapted, and implemented in the LMIC context to improve procedural pain in children (Global Comfort Promise). Additionally, this intervention resulted in high satisfaction of both healthcare professionals and patients/families. Further work is needed to overcome the challenges of topical anesthetic access and education of the workforce. Additional plans include modifying the Global Comfort Promise to include high-quality communication and expanding to additional sites with further refinement of the implementation strategy