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In the FIL MCL0208 phase III trial, lenalidomide maintenance (LEN) after transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell surface receptors might predict drug efficacy. Genotypes were obtained by real-time polymerase chain reaction (RT-PCR) in peripheral blood (PB) germ line DNA. Polymorphisms of either ABCB1 or VEGF were found in 69% and 79% of 278 patients and predicted favorable PFS vs homozygous wild type (WT) in the LEN arm: 3-year PFS 85% vs 70% (p < 0.05) and 85% vs 60% (p < 0.01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (OS, 76%): in fact, in these patients LEN did not improve PFS vs OBS (3-year PFS 44% vs 60%, p = 0.62). Moreover, CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL. This trial is registered at eudract.ema.europa.eu as 2009-012807-25.

Submitted by Filipa Silva (filipa.silva@escolasjoaodeus.pt) on 2021-06-28T11:05:45Z No. of bitstreams: 1 RELATORIO pós defesa Telma Bragança.pdf: 1747056 bytes, checksum: f821e9f692271bbfd633346e297b17a0 (MD5) Approved for entry into archive by Filipa Silva (filipa.silva@escolasjoaodeus.pt) on 2021-06-28T11:05:58Z (GMT) No. of bitstreams: 1 RELATORIO pós defesa Telma Bragança.pdf: 1747056 bytes, checksum: f821e9f692271bbfd633346e297b17a0 (MD5) Made available in DSpace on 2021-06-28T11:05:58Z (GMT). No. of bitstreams: 1 RELATORIO pós defesa Telma Bragança.pdf: 1747056 bytes, checksum: f821e9f692271bbfd633346e297b17a0 (MD5) Previous issue date: 2021-05-31

Supplemental Digital Content is available in the text, While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6–182), 5-year progression-free survival (PFS) was 45% (95% CI: 35–54) and 5-year overall survival (OS) was 71% (95% CI: 62–79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.

Allogeneic stem cell transplantation is an established procedure for a variety of diseases of the hematopoietic system. Our transplant program started in 1987 and since then advances have been made in the care of patients undergoing transplantation. We conducted a study to evaluate whether the changes implemented over time have improved the outcomes of transplantation.We analyzed changes in patients, cell source, transplantation and outcome among 682 consecutive patients receiving their first transplant between 1987 and 2016. We compared overall survival, progression-free survival, the incidence of nonrelapse mortality and relapse in 10-year cohorts over the three decades of the study.The median age of transplanted patients, the use of peripheral blood and unrelated donors all increased very significantly. There was an increase in the number of high-risk patients when comparing the first decade with the two subsequent ones. The 3-year non-relapse mortality decreased significantly from 29% to 20% (p = 0.045), while the overall survival, progression free survival and cumulative incidence of relapse remained stable.Allogeneic hematopoietic stem cell transplantation has evolved considerably since its introduction in clinical practice. In the present study, we evaluated how these changes affected our practice along 30 years of activity and compared the results with those published in the literature.Despite increasing age, higher risk patients and the increasing use of unrelated donors our results show a continuous significantly reduced non-relapse mortality, with stable overall survival, progression free survival and relapse rate.Introdução: A transplantação alogénica de células hematopoiéticas é utilizada regularmente no tratamento de uma grande variedade de doenças hematológicas. O nosso programa de transplantação teve início em 1987 e desde então têm sido numerosos os avanços nesta área. Este estudo foi conduzido para avaliar se as alterações introduzidas ao longo de 30 anos melhoraram os resultados obtidos. Material e Métodos: Analisámos os resultados numa população de 682 doentes submetidos consecutivamente a um primeiro transplante alogénico entre 1987 e 2016. Para tal, os doentes foram divididos em intervalos de 10 anos e comparámos a sobrevida global, a sobrevida livre de progressão, a mortalidade não associada a recaída e as recaídas em cada década do estudo. Resultados: A mediana de idades dos doentes transplantados, a utilização de células progenitoras provenientes do sangue periférico e a transplantação com dadores não familiares aumentaram muito significativamente ao longo do estudo. Verificou-se, comparativamente com a primeira década, um aumento do número de doentes de alto risco nas duas décadas subsequentes. A mortalidade não relacionada com recidiva, avaliada aos três anos pós-transplante, diminuiu significativamente de 29% para 20% (p = 0,045), mantendo-se estáveis a sobrevida global e a sobrevida livre de progressão, assim como a incidência cumulativa de recaídas. Discussão: A transplantação alogénica hematopoiética tem evoluído consideravelmente desde a sua introdução na prática clínica. No presente trabalho são avaliados os reflexos dessa evolução ao longo de 30 anos sendo analisados os resultados obtidos e comparados com os referidos na literatura. Conclusão: Apesar das características mais desfavoráveis verificadas ao longo das três décadas (doentes mais idosos, doenças de risco mais elevado, aumento do número de dadores não familiares) foi possível reduzir significativamente a mortalidade associada ao procedimento, mantendo-se estáveis a sobrevida global e livre de progressão, assim como a incidência de recaídas.

Relatório de Prática profissional Supervisionada apresentado à Escola Superior de Educação de Lisboa para obtenção de grau de mestre em Educação Pré-Escolar O presente relatório estabelece a chegada a um lugar de mudança e, simultaneamente, de continuidade. Mudança, porque afirma o final do meu processo de formação inicial como educadora de infância; continuidade, porque representa apenas mais uma etapa na minha construção profissional que se desenvolverá para sempre. Está organizado de acordo com esse percurso, incidindo sobre os processos concretizados durante a prática profissional supervisionada, o papel do educador, a relevância de uma atitude investigativa e os diferentes contributos para a construção do perfil do educador. Assim, aborda-se o papel do educador, com referência à necessidade de este desenvolver competências relacionadas com o saber, o ser e o fazer, para responder à multiplicidade de dimensões que compõem a educação de infância. Acima de tudo, o educador deverá assumir-se como um elemento que, integrado no meio que o rodeia, coopera com a comunidade, a equipa educativa, as famílias e as crianças, para as apoiar de modo pertinente no seu processo de aprendizagem. O seu principal dever é construir espaços desafiantes às crianças, que as incentivem a participar efetivamente e, assim, se constituam como possibilidades de alcançar a autonomia. Sobre a prática profissional supervisionada, no contexto de creche e de jardim-de-infância, relata-se como esta permite iniciar a construção das competências do educador, numa vivência constante entre a teoria e a prática, a ação e a reflexão, a intervenção e a avaliação. No que se refere à investigação nos contextos educativos, estabelece-se esse processo igualmente como uma ferramenta de reconhecimento e reflexão acerca da infância, impelindo a constante procura do conhecimento e da adaptação das práticas. A investigação desenvolvida em jardim-de-infância encara o conflito entre crianças como um impulsionador do seu desenvolvimento socio-emocional e define a mediação do educador, nesses momentos de conflito interpessoal, como um forte contributo para a construção da autonomia na sua resolução. Conclui-se que estes aspetos, de relação com o outro e de indagação constante acerca da infância e da criança, resultam, no fundo, do modo como o educador encara os princípios éticos da sua profissão. Além disso, são influenciados também pelo processo de construção do seu perfil como profissional da educação. ABSTRACT This report establishes the arrival to a place of change, and simultaneously, of continuity. Change, because it declares the final of my initial formation process as a kindergarten teacher. Continuity, because it represents only another step on my professional construction that I will develop forever. It is organized accordingly to this route, focusing on the processes accomplished during professional supervised practice, the educator’s role, the relevance of an investigative attitude and the different contributes to the educator’s profile construction. Thus, the educator’s role is discussed, including references to his/her necessity of developing competences related with knowing, being and doing, to respond to the multiplicity of dimensions that compose childhood education. Above all, the educator should be an element that, integrated on the environment that surrounds him, cooperates with the community, the educational team, the families and the children, to support them in a meaningful way during their learning process. His/Her main duty is to construct challenging spaces for children, which encourage them to participate effectively and, thus, constitute possibilities to achieve autonomy. Professional supervised practice, in day care and kindergarten contexts, is reported as an opportunity for him/her to initiate the constructions of these competences, based on experiences that constantly enforce either theory and practice, action and reflection, intervention and evaluation. Regarding research on educative contexts, this process establishes itself also as a tool to recognize and reflect about childhood, impelling continuous demand of knowledge and practice appropriation. The research developed on kindergarten faces conflict between children as a booster of their socioemotional development and defines educator’s mediation, on those moments of interpersonal conflicts, as a strong contribute to build children’s autonomy on their resolution. Concluding, these aspects, of relationships with others and constant quest about children and childhood, result, actually, from the way the educator faces his profession’s ethical principles. Furthermore, they are influenced by the construction process of his profile as an education professional. N/A

Background Age is a negative prognostic factor in lymphomas, and elderly patients are often undertreated because of toxicity concerns. The pattern of treatment in elderly patients with diffuse large B-cell lymphoma (DLBCL) in Portugal has not been previously described. Patients and Methods We conducted a multicenter retrospective study including 378 elderly patients with DLBCL receiving alkylating agent–containing regimens between 2003 and 2010. We compared the outcome of patients aged 60 to 79 years with patients > 79 years and analyzed the second group according to treatment. Results R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) was prescribed in only 60% of patients and was prescribed significantly less in patients > 79 years, despite no significant differences being found in comorbidities between the 2 age groups. Similarly, dose reductions frequently were instituted because of chronologic age and not always because of toxicity. When different regimens were compared, multivariate analysis showed an independent beneficial effect of R-CHOP in treatment outcomes. Additionally, treatment with anthracyclines and rituximab predicted a better progression-free survival (PFS) and time to progression (TTP) in patients > 79 years. Conclusion This was the first characterization of the clinical care of elderly Portuguese patients with DLBCL. We showed that R-CHOP is effective even in patients > 79 years, emphasizing that treatment decisions based on age alone can compromise treatment efficacy and outcome in fit patients.

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell neoplasms with aggressive behavior and dismal outcomes. Anthracycline-based chemotherapy is commonly used upfront; hematopoietic stem-cell transplantation (HSCT) is employed as consolidation by some groups. Refractory/relapsed cases (R/R) have a median survival of less than 6 months. Our objective was to analyze the outcomes of all consecutive PTCLs diagnosed and treated in a single center during 16 years according to histological subtype, disease phase (first line and R/R) and treatment strategies. Patients and methods: All adult PTCL patients referred to our center between 2003 and 2019 were included. All cases were locally diagnosed based on the current WHO classification by an expert hemato-pathologist. Initial clinical features, treatment and outcomes were analyzed, as well as salvage strategies. Results: A total of 188 patients were included (118 male, 70 female; median age 62 years). Median OS was 22.7 months, with a median follow up of 54 months. Histological subtypes, initial features, response to treatment and survival are detailed in table 1. Briefly, most cases were diagnosed at advanced stages, with extranodal involvement in 69% and elevated beta-2 microglobulin (B2m) in 77%; half had B symptoms. OS according to different subtypes is shown in figure 1. Of note, anaplastic large cell lymphoma (ALCL)-ALK+ patients had a 5-year OS of 88%. Interestingly, fifteen patients had circulating lymphoma cells (12 PTCL not otherwise specified [NOS], 2 hepatosplenic lymphoma and 1 angioimmunoblastic lymphoma [AITL]), with no impact on outcome. PTCL-NOS was the most prevalent subtype (40%) followed by AITL; unexpectedly, the proportion of PTCL-NOS cases increased while AITL cases decreased after 2008. Seven cases belonging to the recently recognized nodal PTCL with T follicular helper (TFH) phenotype were observed, with baseline characteristics and outcome similar to other PTCLs. IPI score index stratified patients into 4 groups with 24-month OS of 71%, 55%, 42% and 16% for low, int-low, int-high and high risk patients, respectively (P=.049). Only B2m and IPI score maintained independent significance for OS (HR= 3.2 and 1.8, respectively, P Conclusion: Initial features, treatments and outcomes for PTCL have not significantly changed in a 16-year period. Only a minority of cases underwent HSCT or received new agents. Ideal salvage regimens are not defined and, in our experience, single agent Gemcitabine or BV performed better than more aggressive combinations. Although promising new drugs have been recently approved for PTCL, their impact on outcome is still not clear. Recent progresses in molecular characterization of the disease may translate into better outcomes through prospective collaborative efforts in the near future. Disclosures Silva: Gilead Sciences: Consultancy, Other: Travel support, Research Funding; Janssen Cilag: Consultancy, Other: Travel support; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support.

Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous disease, with no standard treatment. We present the outcome of ten patients diagnosed with CMML and treated with AZA in our institutions between 2005 and 2010. All patients were transfusion dependent at the time of initiation of therapy. The overall response rate was 60%. Responses were obtained in 2/3 of the patients with proliferative CMML. The median survival from start of therapy was 20 months. AZA treatment was well-tolerated and associated with a significant response rate in all forms of the disease.

Neonatal cyanosis in healthy newborns can be associated either with methemoglobin due to cytochrome b5 reductase deficiency or to M-hemoglobin, a group of hemoglobin variants resulting from mutations in the globin chain genes. We report the clinical case of a neonate with cyanosis and normal cardiac and respiratory function. At birth the hematological parameters were normal; however, the methemoglobinemia was 16%. Spontaneously, the cyanosis gradually decreased and by the fifth month of age the methemoglobin level was normal. A heterozygous G gamma-globin gene (HBG2) missense mutation 87 C-A (Leu28Met) was identified. His father, with a history of transfusion in the neonatal period, is heterozygous for the same mutation. This hemoglobin variant, not previously described, was called Hb F Viseu and is the sixth G gamma-chain variant reported in association with neonatal cyanosis.