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Abstract Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the “teloscore” in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36–2.11; P = 2.97 × 10−6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86–0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

Non-Hodgkin lymphoma (NHL) is characterized by a great variability in patient outcomes, resulting in the critical need for identifying new molecular prognostic biomarkers. This study aimed to identify novel circulating prognostic biomarkers based on an miRNA/lncRNA-associated ceRNA network for NHL. Using bioinformatic analysis, we identified the miRNA-lncRNA pairs, and using RT-qPCR, we analyzed their plasma levels in a cohort of 113 NHL patients to assess their prognostic value. Bioinformatic analysis identified SNHG16 and SNHG6 as hsa-miR-20a-5p and hsa-miR-181a-5p sponges, respectively. Plasma levels of hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNG6 were significantly associated with more aggressive disease and IPI/FLIPI scores. Moreover, we found that patients with risk expression profiles of hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNHG6 presented a higher risk of positive bone marrow involvement. Moreover, hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNHG6 pairs’ plasma levels were associated with overall survival and progression-free survival of NHL patients, being independent prognostic factors in a multivariate Cox analysis. The prediction models incorporating the ceRNA network expression analysis improved the predictive capacity compared to the model, which only considered the clinicopathological variables. There are still few studies on using the ceRNA network as a potential prognostic biomarker, particularly in NHL, which may permit the implementation of a more personalized management of these patients.

Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy with variable patient outcomes. There is still a lack of understanding about the different players involved in lymphomagenesis, and the identification of new diagnostic and prognostic biomarkers is urgent. MicroRNAs and long non-coding RNAs emerged as master regulators of B-cell development, and their deregulation has been associated with the initiation and progression of lymphomagenesis. They can function by acting alone or, as recently proposed, by creating competing endogenous RNA (ceRNA) networks. Most studies have focused on individual miRNAs/lncRNAs function in lymphoma, and there is still limited data regarding their interactions in lymphoma progression. The study of miRNAs’ and lncRNAs’ deregulation in NHL, either alone or as ceRNAs networks, offers new insights into the molecular mechanisms underlying lymphoma pathogenesis and opens a window of opportunity to identify potential diagnostic and prognostic biomarkers. In this review, we summarized the current knowledge regarding the role of miRNAs and lncRNAs in B-cell lymphoma, including their interactions and regulatory networks. Finally, we summarized the studies investigating the potential of miRNAs and lncRNAs as clinical biomarkers, with a special focus on the circulating profiles, to be applied as a non-invasive, easy-to-obtain, and reproducible liquid biopsy for dynamic management of NHL patients.

Introduction: To perform a cost-effectiveness analysis of follicular lymphoma maintenance treatment after first-line induction with rituximab compared to observation in Portugal. Methods: A Markov follicular lymphoma model was developed with four health states: progression free survival on first and second lines, progression and death. The transition probabilities between health states were obtained from the PRIMA and EORTC20981 clinical trials and the health states utilities from the literature. The analysis considered the Portuguese National Health Service perspective and includes only direct costs. Resource consumption was estimated by a Portuguese clinical expert panel. The unit costs (€ in 2014) were estimated using Portuguese official databases. Deterministic and probabilistic analyses were performed. Results: In the base case, for a time horizon of 10 years, the cost per life year gained and per quality-adjusted life-year were € 10,634 and € 10,664, respectively. The sensitivity analyses confirmed the stability of the base case for time horizons of 20 and 30 years, varying between € 7,430 and € 7,155. Maintenance with rituximab is cost-effective for a time horizon of 5.5 years (cost per quality-adjusted life-year gained of € 23,616). Conclusion: According to the present model rituximab maintenance treatment of follicular lymphoma patients that respond to first line induction therapy in comparison with observation is cost-effective in Portugal.

A pneumonia organizativa fibrinosa aguda é uma entidade histológica, incluída no grupo das doenças pulmonares intersticiais, com múltiplas etiologias, incluindo a toxicidade farmacológica. Os autores descrevem o caso de um homem de 73 anos, com diagnóstico de linfoma linfoplasmocítico, sob tratamento de manutenção com rituximab após quimioterapia. O doente desenvolveu um quadro clínico insidioso caracterizado por tosse não produtiva, dispneia e astenia. A integração dos aspetos imagiológicos e da histologia de biópsia pulmonar conduziram ao diagnóstico de pneumonia organizativa fibrinosa aguda. Após suspensão do fármaco e instituição de corticoterapia o doente apresentou evolução clínica e imagiológica favorável. Dada a utilização crescente de terapêuticas-alvo em oncologia, o presente caso pretende contribuir para o reconhecimento desta entidade como potencial evento adverso. Recebido: 07/06/2017 - Aceite: 30/08/2017

A pneumonia organizativa fibrinosa aguda é uma entidade histológica, incluída no grupo das doenças pulmonares intersticiais, com múltiplas etiologias, incluindo a toxicidade farmacológica. Os autores descrevem o caso de um homem de 73 anos, com diagnóstico de linfoma linfoplasmocítico, sob tratamento de manutenção com rituximab após quimioterapia. O doente desenvolveu um quadro clínico insidioso caracterizado por tosse não produtiva, dispneia e astenia. A integração dos aspetos imagiológicos e da histologia de biópsia pulmonar conduziram ao diagnóstico de pneumonia organizativa fibrinosa aguda. Após suspensão do fármaco e instituição de corticoterapia o doente apresentou evolução clínica e imagiológica favorável. Dada a utilização crescente de terapêuticas-alvo em oncologia, o presente caso pretende contribuir para o reconhecimento desta entidade como potencial evento adverso. Recebido: 07/06/2017 - Aceite: 30/08/2017

Introdução: Realizar uma análise de custo-efetividade de rituximab no tratamento de manutenção do linfoma folicular após indução em primeira linha, em comparação com observação, em Portugal. Métodos: Desenvolveu-se um modelo de Markov para o linfoma folicular com quatro estados de saúde: sobrevivência livre de progressão, após primeira e segundas linhas, progressão e morte. As probabilidades de transição entre estados de saúde foram obtidas a partir dos ensaios clínicos PRIMA e EORTC20981 e as respetivas utilidades a partir da literatura. A perspetiva da análise foi a do Serviço Nacional de Saúde português e incluiu apenas os custos diretos. O consumo de recursos foi estimado por um painel de peritos constituído por clínicos portugueses. Os custos unitários (€ em 2014) foram estimados usando bases de dados oficiais portuguesas. Realizaram-se análises determinísticas e probabilísticas. Resultados: No cenário base, para um horizonte temporal de dez anos, os custos por ano de vida ganho e por ano de vida ajustado pela qualidade foram de € 10 634 e € 10 664, respetivamente. As análises de sensibilidade confirmaram os resultados do cenário-base para horizontes temporais de 20 e 30 anos, variando entre € 7430 e € 7155. O tratamento de manutenção com rituximab é custo-efetivo para um horizonte temporal de 5,5 anos (custo por ano de vida ajustado pela qualidade ganho de € 23 616). Conclusão: De acordo com o atual modelo, o tratamento de manutenção com rituximab em doentes com linfoma folicular que responderam à terapêutica de indução em primeira linha, em comparação com a observação, é custo-efetivo em Portugal.

Evaluate costs and benefits of rituximab in combination with cyclophosphamide/vincristine/prednisolone chemotherapy regimen (R-CVP), in previously untreated patients with indolent non-Hodgkin lymphoma (NHL), compared to CVP alone from a Portuguese National Health System (NHS) perspective.Cost-effectiveness (Life Years Gained--LYG) and cost-utility analysis (Quality Adjusted Life Years--QALYs) were performed for a time horizon of 10 years, according to a Markov economic model with three health states (progression free survival, progression and death) and monthly cycles for a population of previously untreated patients with indolent NHL. Data from a phase III clinical trial was used and expanded to include unpublished 53-month median follow-up data. Survival after first-line therapy was estimated from the Scotland and Newcastle Lymphoma Group registry data and utilities were derived from a study in the UK performed in patients with follicular lymphoma. Resource consumption was estimated by a Portuguese expert panel (Delbecq Panel). Costs were calculated from the Portuguese NHS perspective through official data with prices updated to 2008. Only direct medical costs were considered. Costs and clinical outcomes were discounted at 5% per annum. Deterministic and probabilistic sensitivity analysis were performed around assumptions on the time horizon, costs, utilities and excess mortality rate due to progression applied in the base-case analysis.The 10-year base-case analysis showed a lower total cost per patient with CVP alone (€ 85,838) in comparison with R-CVP (€ 87,774). Life expectancy and Quality adjusted life expectancy per patient were higher with R-CVP (6.361 and 4.166, respectively) than with CVP alone (5.557 and 3.438, respectively), representing increases of 0.804 in LYG and 0.728 (8.7 months) in QALYs gained. The incremental cost per LYG was € 2,407 and the incremental cost per QALY gained was € 2,661. The probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results.This study demonstrates that the combination R-CVP in previously untreated indolent NHL patients improves life expectancy and is a cost-effective alternative to CVP in Portugal.

Indeterminate cell histiocytosis (ICH) is a rare proliferative disorder, in which the predominant cells share morphologic and immunophenotypic features from both Langerhans and non-Langerhans cell histiocytosis. We describe a 62-year-old man presenting a 2-month history of firm nodular lesions on the upper lip. Histopathology, immunohistochemical, and ultrastructural analysis showed typical findings of ICH. The patient was treated with thalidomide and almost complete regression of the lesions was reached within 7 months. Nevertheless, one month after remission, he developed an acute myeloid leukemia of the subtype monocytic leukemia (M5). The patient's condition rapidly worsened and he died due to a respiratory failure four weeks later. We present this case because apart of being rare it joins the effectiveness of thalidomide and the association with an acute monocytic leukemia. A review of the literature is made.

Chronic Myeloid Leukemia (CML) is a clonal stem cell disease characterized by the expression of the fusion protein bcr-abl1, which has deregulated tirosine-kinase activity. Tyrosine kinase inhibitors (TKIs), and in particular imatinib, introduced fundamental changes in the treatment of CML, becoming, in most cases, the first-line treatment of choice in the chronic phase of this disease. Compared to other available therapies imatinib results in a marked increase in overall survival, tolerability and quality of life. The introduction of second generation TKI, with increased potency against bcr-abl1, expanded the number of therapeutic options for this disease and offers an alternative for patients resistant or intolerant to imatinib or who have progressed to the accelerated phase under this therapy. In order to achieve optimal outcomes, TKI therapy must be managed rigorously, requiring a careful monitoring of treatment response in pre-established time periods, thus permitting disease evaluation and safe decision of the most adequate option. Despite the definition of the criteria for imatinib treatment response, the therapeutic strategies to adopt according to the responses obtained are less clear. The objective of this paper is to review the criteria for CML diagnosis, treatment and monitoring, with recommendations as to the most adequate therapeutic choice according to the response to TKI therapy. The paper also focuses the current lines of investigation and debate areas that in the short term can significantly change the therapeutic scenario in this disease. These recommendations, supported by published scientific evidence and by the clinical practice of the expert panel involved in their elaboration, may constitute an important instrument for a better understanding and standardisation of the treatment and monitoring of CML in Portugal.