Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma.

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities.

[Multiple Myeloma Treatment Guidelines by the Portuguese Group of Multiple Myeloma]. / Recomendações do Grupo Português do Mieloma Múltiplo para Tratamento do Mieloma Múltiplo.

The treatment of multiple myeloma has profoundly changed with the introduction of several innovative therapies. The optimization of therapeutic sequencing through the combined use of the various drugs developed in recent years and the attention given to the characteristics of patients have allowed the reduction of toxicities and increased survival and quality of life of patients with multiple myeloma. These treatment recommendations from the Portuguese Multiple Myeloma Group offer guidance for first-line treatment and progression/relapse situations. These recommendations are given highlighting the data that justify each choice and referring to the respective levels of evidence that support these options. Whenever possible, the respective national regulatory framework is presented. These recommendations constitute an advance towards the best treatment of multiple myeloma in Portugal.

O tratamento do mieloma múltiplo tem sido amplamente alterado com introdução de várias terapêuticas inovadoras. A otimização da sequenciação terapêutica através do uso combinado dos vários fármacos desenvolvidos nos últimos anos e a atenção dada às características dos doentes têm permitido diminuir toxicidades e aumentar a sobrevivência dos doentes, bem como aumentar a sua qualidade de vida. As presentes recomendações terapêuticas do Grupo Português do Mieloma Múltiplo oferecem orientações para o tratamento de primeira linha e progressão/recaída. As recomendações são fundamentadas evidenciando os dados que justificam cada escolha e referindo os respetivos níveis de evidência que suportam essas opções. Sempre que possível é apresentado o respetivo enquadramento regulamentar nacional. Estas recomendações constituem um avanço para o melhor tratamento do mieloma múltiplo em Portugal.

Interim FDG18-PET SUVmax Variation Adds Prognostic Value to Deauville 5-Point Scale in the Identification of Patients with Ultra-High-Risk Diffuse Large B Cell Lymphoma.

INTRODUCTION: Interim response evaluation by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (iPET) in diffuse large B cell lymphoma (DLBCL) could be important to rule out disease progression and has been suggested to be predictive of survival. However, treatment guidance by iPET is not yet recommended for DLBCL in clinical practice. We aimed to compare the predictive value of iPET when utilizing the visual Deauville 5-point scale (DS) and the semiquantitative variation of maximum standardized uptake value (ΔSUVmax). MATERIALS AND METHODS: We included 85 patients diagnosed with DLBCL and uniformly treated with standard protocols. iPET with DS of 1-3 and/or ΔSUVmax ≥66% was defined as negative. Univariable and multivariable Cox regression analyses were performed to determine the independent factors affecting progression free survival (PFS) or overall survival (OS) and to estimate PFS and OS. RESULTS: iPET positivity, measured by DS or ΔSUVmax, showed predictive value of disease refractoriness, improved by combining DS and ΔSUVmax. After a median follow-up of 50.1 months, iPET was an independent predictor for both PFS and OS when interpreted by DS, but only for PFS by ΔSUVmax. Combined visual and semiquantitative analysis (D4-5 & ΔSUVmax<66%) was an independent predictor of PFS and OS, and allowed to identify an ultra-high-risk subgroup of patients with very dismal outcome, increasing the discriminating capacity for iPET. CONCLUSION: Our study suggests that combined DS and ΔSUVmax in iPET assessment predicts refractory disease and distinguishes ultra-high-risk DLBCL patients with a very dismal prognosis, who may benefit from PET-guided therapy adjustment.

Bibliometric analysis of main diseases due to exposure to altitude in the world / Análise bibliométrica das principais doenças decorrentes da exposição à altitude no mundo

Introduction: Around 140 million people in the world live-in high-altitude regions; however, there are few bibliometric studies. Objective: Describe the scientific production of the main diseases due to exposure to altitude in the world. Methods: Observational study, bibliometric type. After a systematic search in Scopus, original articles were included, whose main variable was mountain sickness, high-altitude cerebral edema and high-altitude pulmonary edema. Characteristics of each study were manually extracted and analyzed using descriptive statistics. Results: 2305 articles were found on mountain sickness (n=1531), high-altitude pulmonary edema (n=549) and high-altitude cerebral edema (n=225), respectively, in Scopus. Regarding the most influential journal was High Altitude Medicine and Biology in all three diseases, the country with the highest number of articles was the United States (458, 168 and 75), the most used language was English (91.31%, 85.33% and 84.19%), the author with the highest number of publications was Bartsh P. (2.94%, 18.60% and 3.42%) and most of the articles were open access (41.08%, 42.06% and 76.53%), respectively. Conclusion: The scientific production of original articles on mountain sickness, high-altitude pulmonary edema and high-altitude cerebral edema in Scopus has increased in recent years; however, it is still scarce compared to other diseases.

Introdução: Cerca de 140 milhões de pessoas no mundo vivem em regiões de grande altitude, porém, existem poucos estudos bibliométricos. Objetivo: Descrever a produção científica sobre as principais doenças decorrentes da exposição à altitude no mundo. Métodos: Estudo observacional, do tipo bibliométrico. Após busca sistemática no Scopus, foram incluídos artigos originais, cuja variável principal foi mal da montanha, edema cerebral de altitude e edema pulmonar de altitude. As características de cada estudo foram extraídas manualmente e analisadas por meio de estatística descritiva. Resultados: Foram encontrados 2.305 artigos sobre mal da montanha (n=1.531), edema pulmonar de altitude (n=549) e edema cerebral de altitude (n=225), respectivamente no Scopus. Em relação ao periódico mais influente foi High Altitude Medicine and Biology nas três doenças, o país com maior número de artigos foi os Estados Unidos (458, 168 e 75), o idioma mais utilizado foi o inglês (91,31%, 85,33% e 84,19%), o autor com maior número de publicações foi Bartsh P. (2,94%, 18,60% e 3,42%) e a maioria dos artigos foi de acesso aberto (41,08%, 42,06% e 76,53%), respectivamente. Conclusão: A produção científica de artigos originais sobre mal da montanha, edema pulmonar de altitude e edema cerebral de altitude em Scopus tem aumentado nos últimos anos, porém ainda é escassa em comparação com outras doenças

Methotrexate-Associated Lymphoproliferative Disorder in a Patient with Psoriasis: A Case Report and Review of the Literature.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs) are heterogeneous clinicopathological entities developing in patients receiving immunosuppression. Outside the posttransplant setting, methotrexate (MTX), a drug commonly used for the treatment of autoimmune diseases, is an immunosuppressive agent frequently reported to be associated with LPD. MTX-associated LPD (MTX-LPD) includes a spectrum of lymphocytic proliferations, ranging from polyclonal hyperplasia to malignant lymphoma. MTX-LPD diagnosis can be challenging, as signs and symptoms are often nonspecific and may overlap with those of several other conditions, including exacerbation of the underlying autoimmune disease. Spontaneous regression of LPD after MTX discontinuation is characteristic of MTX-LPD, therefore avoiding chemotherapeutic intervention in a significant proportion of patients. Other cases, however, should receive chemotherapy.

Genomic characterisation of multiple myeloma: study of a Portuguese cohort.

Multiple myeloma (MM) genomic complexity reflects in the variable patients' clinical presentation. Genome-wide studies seem to be a reasonable alternative to identify critical genomic lesions. In the current study, we have performed the genomic characterisation of a Portuguese cohort of patients with MM by array comparative genomic hybridisation. Overall, the most frequently detected alterations were 13q deletions, gains of 1q, 19p, 15q, 5p and 7p and trisomy 9. Even though some identified genomic alterations were previously associated with a prognostic value, other abnormalities remain with unknown, but putative significance for patients' clinical practice. These genomic alterations should be further assessed as possible biomarkers.

Multiple myeloma in elderly patients-a Portuguese multicentric real-life study.

Patients older than 75 years old with multiple myeloma (MM) have shorter survival and are usually treated differently from what features in clinical trials. In this study, the authors characterized the Portuguese population of MM patients above 75 years old, treated between 2009 and 2016. We compared the outcomes obtained with bortezomib-based protocols (BBP), thalidomide-based protocols (TBP), and chemotherapy (CT) using univariate and multivariate controlling for age, performance status, International Staging System score, renal impairment, and number of comorbidities. We retrieved data from 386 patients, treated in 12 hospitals. Three hundred thirty-one cases were analyzed: 119 patients treated with BBP, 65 with TBP, 147 with CT. Median age was 79 years; CT-treated patients were older, had a worse performance status, and have more comorbidities. The median follow-up was 25 months. The 2-year OS was 58% and the median OS was 29.5 months. Patients treated with BBP had more frequently very good partial response (VGPR) or better response, and the subgroup of more fit patients had a significantly longer progression-free survival (PFS) and OS. The most frequently grade 3-4 toxicities were hematologic, infectious, and neurologic and were significantly lower in TBP and CT groups vs BBP. The most common second line was CT, followed by lenalidomide. Patients treated with lenalidomide had a higher probability of VGPR or better and a superior 1-year PFS. Despite the limitations of a retrospective study, our cohort represents the reality of older patients with MM in a western country. The hazard of death or progression was higher for old, fit patients treated, in first line, with CT and with TBP compared with that of BBP.

Quantification and phenotypic characterization of peripheral blood Vδ1 + T cells in chronic lymphocytic leukemia and monoclonal B cell lymphocytosis.

BACKGROUND: Vδ1+ T cells, a subset of γδ T cells, are responsible for innate-like immune responses. Recently, an anti-tumor function mediated by MHC-unrestricted recognition of lipid and stress molecules, has also been described in these cells. This study aimed to quantify and phenotypically characterize circulating Vδ1+ T cells in B cell Chronic Lymphocytic Leukemia (CLL) and Monoclonal B cell lymphocytosis (MBL). METHODS: This study enrolled 58 individuals distributed in five groups: Binet B and C CLL (n = 9), Binet A CLL (n = 26), High count-MBL (n = 10), Low count-MBL (n = 5), and a control group (n = 8). The phenotypic characterization of Vδ1+ T cells, as well as the other T cell subpopulations (CD4+ , CD8+ , CD4+ /CD8+ , and Vδ1- γδT cells), were assessed by flow cytometry, evaluating the frequency of each subset expressing CD27, CD69, and cytoplasmic granzyme B. RESULTS: We observed an increasing percentage of Vδ1+ T cells belonging to CD27- compartment from controls to advanced stages of the disease, which was accompanied by an increasing percentage of these cells expressing granzyme B, a phenotypic pattern that was also observed in the other T cell subpopulations under study since earlier stages of the disease. Moreover, a striking expansion of Vδ1+ T cells in Binet B and C CLL was observed. CONCLUSIONS: These experiment findings point to an expansion of CD27- Vδ1+ T cells with a cytotoxic profile, from controls to advanced stages of the disease, which points to a role of Vδ1+ T cells in the host's anti-tumor responses against clonal B-cells in MBL and CLL. © 2018 Clinical Cytometry Society.

The complete mitogenome of the invasive Japanese mud snail Batillaria attramentaria (Gastropoda: Batillariidae) from Elkhorn Slough, California, USA.

Genomic analysis of the invasive marine snail Batillaria attramentaria from Elkhorn Slough, Moss Landing, California, USA using 150 bp paired-end Illumina sequences resulted in the assembly of its complete mitogenome. The mitogenome is 16,095 bp in length and contains 2 rRNA, 13 protein-coding, and 22 tRNA genes (GenBank Accession MN557850). Gene content and organization of B. attramentaria are identical to the Turritellidae and Pachychilidae. The phylogenetic analysis of B. attramentaria resolves it in a fully supported clade with these same two families in the superfamily Cerithioidea. Nucleotide BLAST searches of the Elkhorn Slough cox1 gene of B. attramentaria yielded identical sequences from invasive populations from California and British Columbia, and native populations from northeastern and central Japan. These data show that mitogenome sequencing is a useful tool for studying the classification and phylogenetic history Cerithioidea.

Plantas utilizadas en la medicina tradicional de comunidades campesinas e indígenas de la Selva Zoque, Chiapas, México / Useful plants in traditional medicine of peasant and indigenous communities of Selva Zoque, Chiapas, Mexico

El objetivo fue conocer las plantas utilizadas en la medicina tradicional de cuatro comunidades de la Selva Zoque, Chiapas, México. En cada comunidad, se aplicaron 30 entrevistas semiestructuras. El listado florístico medicinal estuvo conformado por 113 especies, 96 géneros y 50 familias. Asteraceae, Fabaceae y Lamiaceae fueron las más representativas. Se obtuvieron 84 indicaciones de uso medicinal, clasificadas en 13 enfermedades, gastrointestinales, dermatológicas y respiratorias, fueron las más frecuentes. La hoja es la estructura de la planta más empleada (72%). El cocimiento es la manera más común de preparar a las plantas, y la vía oral es la forma más frecuente de administrar la medicina. El uso de plantas medicinales es resultado de la experiencia e íntimo contacto con la naturaleza que la sociedad ha acumulado por generaciones. Este saber ha permitido que sobrevivan comunidades que habitan en lugares apartados, donde hay carencias de servicios médicos.

The objective was to know the useful plants in the traditional medicine of four communities of Selva Zoque, Chiapas. In each community, 30 semi-structured interviews were applied. The medicinal floristic listing consisted of 114 species, 97 genera and 50 families. Asteraceae, Fabaceae and Lamiaceae were the most representative. There were 84 indications for medicinal use, classified in 13 diseases, gastrointestinal, dermatological and respiratory, were the most frequent. The leaf is the structure of the most used plant (72%). Cooking is the most common way to prepare plants, and the oral route is the most frequent way to administer medicine. The use of medicinal plants is the result of experience and intimate contact with nature that society has accumulated for generations. This knowledge has allowed communities that live in remote places to survive, where there are shortages of medical services.

Aberrant p15, p16, p53, and DAPK Gene Methylation in Myelomagenesis: Clinical and Prognostic Implications.

BACKGROUND: Aberrant DNA methylation is considered a crucial mechanism in the pathogenesis of monoclonal gammopathies. We aimed to investigate the contribution of hypermethylation of 4 tumor suppressor genes to the multistep process of myelomagenesis. METHODS: The methylation status of p15, p16, p53, and DAPK genes was evaluated in bone marrow samples from 94 patients at diagnosis: monoclonal gammopathy of uncertain significance (MGUS) (n = 48), smoldering multiple myeloma (SMM) (n = 8) and symptomatic multiple myeloma (MM) (n = 38), and from 8 healthy controls by methylation-specific polymerase chain reaction analysis. RESULTS: Overall, 63% of patients with MM and 39% of patients with MGUS presented at least 1 hypermethylated gene (P < .05). No aberrant methylation was detected in normal bone marrow. The frequency of methylation for individual genes in patients with MGUS, SMM, and MM was p15, 15%, 50%, 21%; p16, 15%, 13%, 32%; p53, 2%, 12,5%, 5%, and DAPK, 19%, 25%, 39%, respectively (P < .05). No correlation was found between aberrant methylation and immunophenotypic markers, cytogenetic features, progression-free survival, and overall survival in patients with MM. CONCLUSIONS: The current study supports a relevant role for p15, p16, and DAPK hypermethylation in the genesis of the plasma cell neoplasm. DAPK hypermethylation also might be an important step in the progression from MGUS to MM.