Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete. METHODS: To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS). RESULTS: Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively). CONCLUSIONS: Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.

Gestão do Diabetes Tipo 1: necessidades de autocuidado apoiado na transição para adolescência / Type 1 Diabetes management: self-management support needs in the transition to adolescence

Analisar as necessidades de autocuidado apoiado para a gestão do diabetes tipo 1 na transição da infância para adolescência. Pesquisa qualitativa mediada pela entrevista semiestruturada com nove pré-adolescentes atendidos em ambulatório e Unidades de Saúde da Família da Paraíba entre setembro/dezembro de 2016. Os dados foram interpretados pela análise temática. Os pré-adolescentes necessitam além do conhecimento para o manejo e a gestão da doença nos espaços que frequenta cotidianamente, do apoio da família e da rede social na transição do cuidado. A equipe multiprofissional de saúde não tem utilizado o autocuidado apoiado singular na gestão do diabetes e a da atenção primária não tem acolhido suas necessidades, fragilizando vínculos com a rede de cuidados. As necessidades para o autocuidado no diabetes versam sobre conhecimento da doença, e as relações estabelecidas com a rede de apoio social como a família, equipe multiprofissional e a escola.

To analyze the self-management support needs for the type 1 diabetes management in the transition from childhood to adolescence. This qualitative research was mediated by semi-structured interviews with nine prepubescent children attended at an outpatient clinic and Family Health Units in Paraíba between September and December 2016. The data were interpreted by thematic analysis. Prepubescent children need knowledge for the administration and management of the disease in the spaces they audit, in addition to family and social media support in the transition of care. The multidisciplinary health team has not used singular self-management support in the management of diabetes, and that of primary care has not accommodated their needs, weakening bonds with the care network. Diabetes self-management needs refer to knowledge of the disease and relationships established with social support networks such as family, multidisciplinary team, and school.

Neck and waist circumference values according to sex, age, and body-mass index: Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Body fat distribution predicts cardiovascular events better than body-mass index (BMI). Waist circumference (WC) and neck circumference (NC) are inexpensive anthropometric measurements. We aimed to present the conditional distribution of WC and NC values according to BMI, stratified by age and sex, from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline data. We analyzed 15,085 ELSA-Brasil participants with complete data. We used spline quantile regression models, stratified by sex and age, to estimate the NC and WC quantiles according to BMI. To test a putative association between age and median NC or WC values, we built sex-specific median regression models using both BMI and age as explanatory variables. We present estimated 25th, 50th, 75th, and 90th percentiles for NC and WC values, according to BMI, age, and sex. Predicted interquartile intervals for NC values varied from 1.6 to 3.8 cm and, for WC values, from 5.1 to 10.3 cm. Median NC was not associated with age in men (P=0.11) nor in women (P=0.79). However, median WC increased with advancing age in both sexes (P<0.001 for both). There was significant dispersion in WC and NC values for a given BMI and age strata for both men and women. WC, but not NC values, were associated with increasing age. The smaller influence of advancing age on the relationship between BMI and NC (compared to WC) values may be useful in longitudinal studies.

Effects of changes in micro-weather conditions on structural features, total protein and carbohydrate content in leaves of the Atlantic rain forest tree golden trumpet (Tabebuia chrysotricha) / Efeito de alterações nas condições micro-climáticas sobre características estruturais, e proteína e carboidratos histoquimicamente marcados, de folhas da árvore da floresta Atlântica ipê amarelo

Abstract Golden trumpet, Tabebuia chrysotricha, is a native tree from the Brazilian Atlantic rain forest, with a broad latitudinal distribution. In this study, we investigated the potential effects of short-term changes in micro-weather conditions on structural features, and total protein and carbohydrate content of golden trumpet leaves, using structural and histochemical approaches. Leaves were harvested in four different micro-weather conditions: 1. Afternoon, after a hot, sunny day; 2. at dawn, after a previously hot, sunny day; 3. at noon, of a hot, sunny day; and 4. at noon, of a cold, cloudy day. Leaflets exposed to low light irradiance showed flattened chloroplasts, uniformly distributed within the cells, throughout the palisade parenchyma. Conversely, leaflets exposed to high light irradiance presented flattened and rounded chloroplasts, in the upper and lower palisade parenchyma cells, respectively. The strongest protein staining was found for leaves harvested at the coldest period, whereas the weakest protein staining was found for leaves harvested after a hot, sunny day. The largest and most numerous starch grains were found for leaves harvested in the afternoon, after a hot, sunny day. Conversely, the smallest and less numerous starch grains were found for leaves harvested at dawn. Analysis of the data reported herein suggests that the leaflet responses to transient changes in micro-weather conditions are likely to contribute to the golden trumpet successful establishment in the broad latitudinal distribution in which the species is found.

Resumo Ipê amarelo é uma árvore nativa da floresta Atlântica brasileira, encontrada em uma ampla distribuição latitudinal. Neste estudo, nós investigamos os efeitos potenciais de alterações de curto prazo nas condições micro-climáticas sobre características estruturais, proteína e carboidratos histoquimicamente marcados, de folhas de ipê amarelo, usando estratégias de análise estrutural e histoquímicas. As folhas foram marcadas em quatro condições microclimáticas distintas: 1. Tarde, após um dia quente e ensolarado; 2. Amanhecer, após um dia quente e ensolarado; 3. Ao meio-dia, de um dia quente e ensolarado; e 4. Ao meio-dia, de um dia frio e nublado. Folíolos expostos à baixa irradiância luminosa apresentaram cloroplastos achatados, uniformemente distribuídos no interior das células, por todo o parênquima paliçádico, enquanto que folíolos expostos à alta irradiância apresentaram cloroplastos achatados e arredondados, nas células superiores e inferiores do parênquima paliçádico, respectivamente. A marcação mais intensa para proteína foi observada para folhas coletadas no momento mais frio de coleta, enquanto que a marcação mais fraca foi observada para folhas coletadas após um dia quente e ensolarado. Os grãos de amido maiores e mais numerosos foram observados em folhas coletadas durante a tarde de dia quente e ensolarado, enquanto que os menores e menos numerosos grãos de amido foram observados em folhas coletadas ao amanhecer.

Development of Canavalia ensiformis in soil contaminated with diesel oil.

Hydrocarbons are the main components of diesel oil and are toxic for the majority of plants. A few plant species, known as phytoremediators, are tolerant of hydrocarbons and can survive the stressful conditions of soils contaminated with diesel oil. Canavalia ensiformis, a plant species that is well distributed throughout the tropics, possesses advantageous features for a potential resistance to soil contamination, such as fast growth and a deep root system. Thus, the aim of the present study was to evaluate the tolerance of C. ensiformis when it was exposed to soil contaminated with diesel oil. Seedlings were subjected to two treatments: contaminated soil (CS) (95 ml/kg of diesel oil) and non-contaminated soil (NCS) for a period of 30 days; its growth, morphology, anatomy, and physiology were analyzed. Despite the high level of toxicity, some individuals were able to survive in CS. These plants had root apical meristems with high levels of mitosis and were able to issue new roots with more developed aerenchyma tissue. Because the surviving plants presented no marks of cellular damage on the organs formed (root and leaves) during the experiment, the species capacity of growth on CS was confirmed. Although, long-term field experiments, applying different contaminant concentrations, should be considered to infer about the species resistance and use as phytoremediator.

[New melanoma immunotherapies: mechanisms of action, efficiency and management of toxicities]. / Nouvelles immunotherapies du mélanome: mécanismes d'action, efficacité et prise en charge des toxicities.

In recent years the therapy of metastatic melanoma has been revolutionized from a disease with very few efficient treatment options to one with access to multiple therapies which can impact on patient survival. Two main classes of therapies have been developed: 1. Immunotherapy by immune checkpoint inhibitors and 2. Small molecule inhibitors of the MAPK pathway. Immunotherapies achieved by either inhibition of CTLA-4 or the PD1/PD-Ll axes are impacting the overall survival in an important fraction of patients. In addition, the side effects of these immune therapy approaches require early detection by all the specialists involved as well as early management according to precise guidelines for optimal outcome.

Spinal and pelvic parameters in Marfan's syndrome and their relevance to surgical planning.

Spinal deformities are a common feature of Marfan's syndrome and can be a significant cause of morbidity. The morphology of the scoliosis associated with this condition was previously described by Sponseller, but no correlation with the pelvic parameters has been seen. We performed a retrospective radiological study of 58 patients with scoliosis, secondary to Marfan's syndrome and related the findings in the thoracolumbar spine to the pelvic parameters, including pelvic version (tilt), pelvic incidence and sacral slope. Our results showed marked abnormalities in the pelvic values compared with those found in the unaffected population, with increased retroversion of the pelvis in particular. In addition we found a close correlation between the different patterns of pelvic parameters and scoliosis morphology. We found that pelvic abnormalities may partially dictate the spinal disorders seen in Marfan's syndrome. Our results supplement the well-established Sponseller classification, as well as stressing the importance of considering the orientation of the pelvis when planning surgery.

Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases.

OBJECTIVE: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice. METHODS: 866 rheumatology and internal medicine practitioners were contacted by e-mail to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated. RESULTS: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjogren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease. CONCLUSIONS: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis.

[Primary cutaneous malignant melanoma: retrospective studyfrom 1963 to 1997 at Hospital do Servidor Público Estadual de São Paulo]. / Melanoma maligno cutâneo primário: estudo retrospectivo de 1963 a 1997 no Hospital do Servidor Público Estadual de São Paulo.

OBJECTIVES: A retrospective study on the Primary Cutaneous Malignant Melanoma in the Hospital do Servidor Público Estadual de São Paulo (HSPE-SP) analyzing its distribution according to age, sex, race and cutaneous site. METHODOLOGY: We studied 222 patients with Primary Cutaneous Malignant Melanoma as diagnosed at Hospital do Servidor Público Estadual de São Paulo, Brazil between the period from 1963 to 1997. A retrospective study was performed. Data were expressed as inance of caucasians (98.19%) over afro-americans (1.81) and of the female sex (69.36%) over the male sex (30.63%) was found. The predominant age on the occasion of the diagnosis was between 50 and 60 years for the women (25.32%) and between 60 and 69 years for the men (22.52%). The most frequent site of the cancer in men was the back region (29.41%) and in the lower members in the women (38.31%). The most frequent level of the tumor invasion (Clark) was IV (39.77%), and the average of tumor thickeness (Breslow) was < 0.75 mm (28.4%). A 5 years survival was observed in 73.3% of the patients. CONCLUSIONS: At our Hospital the incidence of Primary Cutaneous Malignant Melanoma has shown an increase in recent years; these results are compatible with the most recent international surveys.

Melanoma maligno cutâneo primário: estudo retrospectivo de 1963 a 1997 no Hospital do Servidor Público Estadual de Säo Paulo / Primary cutaneous malignant melanoma occurence diagnosed at Hospital do Servidor Público Estadual de Säo Paulo between the period from 1963 through 1997

Objetivo. Estudar retrospectivamente a ocorrência do melanoma maligno cutâneo primário no nosso Hospital, objetivando analisar os dados referentes a sua distribuiçao pela idade, sexo, raça, localizaçao cutânea, sobrevida em cinco anos, nível de Clark, índice de Breslow e a taxa de incidência. Casuística e Método. Foram estudados 222 pacientes com melanoma maligno cutâneo primário, diagnosticados no Hospital do Servidor Público Estadual (FMO)-SP, entre os anos de 1963 a 1997. Elaborou-se um estudo do tipo retrospectivo. A descriçao dos dados foi expressa na forma de porcentagens. Para os cálculos dos dados epidemiológicos foram utilizados: Para taxa de incidência anual o número de casos novos no ano (numerador) e o número de consultas ambulatoriais em todo o Hospital no mesmo ano (denominador). Os dados restantes foram calculados por proporçao. A comparaçao entre as diferentes categorias se efetuou pelo teste de x2 e considerou-se significativo em p < 0,05. Resultados. Encontrou-se um predomínio de caucasóides (98,19 por cento) sobre negróides (1,81 por cento) e do sexo feminino (69,36 por cento) sobre o masculino (30,63 por cento). A idade predominante encontrada à época do diagnóstico foi entre 50 e 60 anos para as mulheres (25,32 por cento) e entre 60 a 69 anos para os homens (22,52 por cento). A localizaçao mais freqüente da neoplasia nos homens foi a regiao torácica posterior (29,41 por cento) e os membros inferiores nas mulheres (38,31 por cento). O nível de invasao tumoral (Clark) mais encontrado foi IV (39,77 por cento) e a espessura dos tumores (Breslow) mais freqüente foi <0,75mm (28,4 por cento). Tiveram sobrevida de cinco anos 73,3 por cento dos pacientes. Conclusoes. Evidenciou-se o aumento da ocorrência do melanoma maligno cutâneo primário ao longo destes anos no Hospital, sendo estes resultados compatíveis com os mais recentes trabalhos internacionais.

Pericardial involvement in human immunodeficiency virus infection.

STUDY OBJECTIVES: Previous studies have showed that the pericardium is frequently involved in HIV infection. However, the characteristics and etiology of the pericardial abnormalities that have been found remained poorly defined. We analyzed the features of pericardial involvement in these patients and investigated the clinical variables associated with moderate and severe effusions. DESIGN: Prospective, clinical, and echocardiographic study. SETTING: The service of infectious diseases of a university hospital. PATIENTS: 181 consecutive patients at all stages of HIV infection. RESULTS: Only one patient (0.55%) had acute pericarditis. Seventy-five patients (41%) had an asymptomatic pericardial effusion; in 23 patients (13% of all patients), the effusion was either moderate or severe. Ten cases (5.5% of all patients) of moderate or severe effusions resulted in right atrium diastolic compression, and three of these cases (1.6% of all patients) required pericardiocentesis for the management of tamponade. Six patients (3%) presented with echogenic pericardial masses of undetermined etiology. A moderate or severe effusion was present in a greater number of patients with symptomatic HIV infection than was present in asymptomatic HIV-infected patients, respectively: 17 vs 2% (p = 0.015). The following are variables independently associated with moderate or severe pericardial effusions: heart failure (odds ratio, 20.3; p = 0.0001); Kaposi's sarcoma (odds ratio, 8.6; p = 0.01), tuberculosis (TB; odds ratio, 47.2; p = 0.0006); and other pulmonary infections (odds ratio,15.0; p = 0.02). CONCLUSIONS: Most of these moderate or severe effusions are clinically unsuspected, but they can lead to life-threatening tamponade. This fact seems to justify echocardiographic surveillance in HIV-infected patients, especially in those with heart failure, Kaposi's sarcoma, TB, or other pulmonary infections.

Aspectos anatomicos das cardiopatias congenitas nao cianogenicas / Anatomical findings of acyanotic congenital heart disease

Sao revistas as principais caracteristicas morfologicas das cardiopatias congenitas mais comuns, consideradas primariamente nao cianogenicas. Foram descritos os defeitos septais que condicionam "shunt" da esquerda para a direita, alguns tipos de obstrucao a ejecao do ventriculo esquerdo, a transposicao arterial congenitamente corrigida, a persistencia do canal arterial e, por fim, a anomalia de Ebstein da valvula tricuspide. Alem dos aspectos morfologicos, foram abordados os mecanismos fisiopatologicos mais relevantes e as teorias relativas a embriologia dos temas selecionadas

Results of penetrating keratoplasty for the treatment of corneal perforations.

We retrospectively analyzed 46 consecutive cases of penetrating keratoplasty performed as part of the treatment of corneal perforations; the minimum follow-up time after keratoplasty was 7 months. Predisposing conditions leading to perforation were an infectious keratitis in 26 eyes (57%), trauma in 14 eyes (30%), and corneal melt associated with ocular surface disorder in 6 eyes (13%). The success of penetrating keratoplasty in the treatment of corneal perforation depended on the timing of surgery and the cause of the perforation. If the perforation was traumatic in origin, delaying surgery for at least 3 months significantly improved the chances for graft success. Eighty percent of the penetrating keratoplasties delayed 3 months following primary repair of corneal laceration remained clear, and 50% of these patients had a visual acuity of 20/60 or better. If penetrating keratoplasties were performed for an infectious corneal perforation, grafts had a better chance to remain clear if surgery could be delayed. All grafts performed for corneal perforation associated with melting and ocular surface abnormalities failed.