SLPI overexpression in hMSCs could be implicated in the HSC gene expression profile in AML.

Acute myeloid leukaemia (AML) is a severe haematological neoplasm that originates from the transformation of haematopoietic stem cells (HSCs) into leukaemic stem cells (LSCs). The bone marrow (BM) microenvironment, particularly that of mesenchymal stromal cells (hMSCs), plays a crucial role in the maintenance of HSCs. In this context, we explored whether alterations in the secretome of hMSCs derived from AML patients (hMSC-AML) could impact HSC gene expression. Proteomic analysis revealed that the secretome of coculture assays with hMSC-AMLs and HSC from healthy donor is altered, with increased levels of secretory leukocyte protease inhibitor (SLPI), a protein associated with important processes for maintenance of the haematopoietic niche that has already been described to be altered in several tumours. Increased SLPI expression was also observed in the BM plasma of AML patients. Transcriptome analysis of HSCs cocultured with hMSC-AML in comparison with HSCs cocultured with hMSC-HD revealed altered expression of SLPI target genes associated with the cell cycle, proliferation, and apoptosis. Important changes were identified, such as increased expression levels of CCNA2, CCNE2, CCND2, CD133 and CDK1 and decreased levels of CDKN2A and IGFBP3, among others. Overall, these findings suggest that the altered secretome of coculture assays with hMSC-AMLs and HSC from healthy donor, particularly increased SLPI expression, can contribute to gene expression changes in HSCs, potentially influencing important molecular mechanisms related to AML development and progression.

Primary colorectal diffuse large B-cell lymphoma: A report of eighteen cases in a tertiary care center.

Primary colorectal diffuse large B-cell lymphoma (DLBCL) is very rare colon malignancy. It is important to know the main demographic and clinical characteristics of these patients. We conducted a retrospective analysis of 18 patients diagnosed with primary colorectal DLBCL during a 17-year period at the National Cancer Institute of Brazil (INCA) between 2000 and 2018. Demographic characteristics, tumor localization, HIV status, lactate dehydrogenase (LDH) levels, treatment modality and follow-up status were obtained from medical records. Survival was estimated from the date of diagnosis until death. There were 11 male and seven female patients in our cohort, the median age at diagnosis was 59.5 years and four patients were HIV positive. Tumor was mainly localized in the right colon. Patients were treated with chemotherapy (CT) and/or surgical resection. Eleven patients died during a median follow-up of 59 months and the median survival time was 10 months. Six or more cycles of CT (HR=0.19; CI 95% 0.054-0.660, p = 0.009), LDH levels below 350 U/L (HR=0.229; CI 95% 0.060-0.876, p = 0.031) and surgical resection (HR=0.23; CI 95% 0.065-0.828, p = 0.030) were associated with reduced risk of death in univariate analysis. Patient's age and DLBCL right colon localization should be considered at diagnosis to distinguish between DLBCL and other diseases for differential diagnosis. Six cycles of CT, LDH levels below 350 U/L and surgical resection were associated with better survival. Our results are consistent with previous publications and address the importance of correct colorectal DLBCL diagnosis and treatment.

Primary diffuse large B-cell lymphoma of the head and neck in a Brazilian single-center study.

OBJECTIVES: Lymphomas represent around 10% of head and neck neoplasms, among which the diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype. In the present study, we characterized demographic parameters, anatomical sites, and survival rates of patients in a Brazilian cancer center. MATERIALS AND METHODS: Single-center retrospective epidemiological study of 243 head and neck DLBCL patients. Demographic characteristics, tumor localization, HIV status, lactate dehydrogenase (LDH) activity, and treatment modality were obtained from electronic medical records. RESULTS: The most common primary head and neck tumor location in patients with DLBCL was Waldeyer's ring. Interestingly, age above 80 years, male gender, high LDH levels, and HIV positivity were significantly associated with shorter overall survival (OS) rates and increased risk of death. We further demonstrated that treatment had a protective effect, improving OS, and reducing risk of death. Notably, we found no benefit of combination of chemotherapy and radiotherapy versus isolated treatment modalities. CONCLUSION: The study showed that primary head and neck DLBCL is more incident in middle age and elderly patients with a small male patients' majority in a Brazilian population. Moreover, we observed a 3-year OS rate of almost 60% and multivariate analysis showed that treatment was the only protective factor.

Reduced Osteogenic Differentiation Potential In Vivo in Acute Myeloid Leukaemia Patients Correlates with Decreased BMP4 Expression in Mesenchymal Stromal Cells.

The osteogenic differentiation potential of mesenchymal stromal cells (hMSCs) is an essential process for the haematopoiesis and the maintenance of haematopoietic stem cells (HSCs). Therefore, the aim of this work was to evaluate this potential in hMSCs from AML patients (hMSCs-AML) and whether it is associated with BMP4 expression. The results showed that bone formation potential in vivo was reduced in hMSCs-AML compared to hMSCs from healthy donors (hMSCs-HD). Moreover, the fact that hMSCs-AML were not able to develop supportive haematopoietic cells or to differentiate into osteocytes suggests possible changes in the bone marrow microenvironment. Furthermore, the expression of BMP4 was decreased, indicating a lack of gene expression committed to the osteogenic lineage. Overall, these alterations could be associated with changes in the maintenance of HSCs, the leukaemic transformation process and the development of AML.

COVID-19 in hematology: data from a hematologic and transplant unit

ABSTRACT During the COVID-19 pandemic, special attention has been addressed in cancer care to mitigate the impact on the patient's prognosis. We addressed our preparation to face COVID-19 pandemic in a Hematological and Stem Cell Transplant Unit in Brazil during the first two months of COVID-19 pandemic and described COVID-19 cases in patients and health care workers (HCW). Modifications in daily routines included a separation of area and professionals, SARS-CoV-2 screening protocols, and others. A total of 47 patients and 54 HCW were tested for COVID-19, by PCR-SARS-CoV-2. We report 11 cases of COVID-19 in hematological patients (including 2 post stem cell transplant) and 28 cases in HCW. Hematological cases were most severe or moderate and presented with several poor risk factors. Among HCW, COVID-19 were mostly mild, and all recovered without hospitalization. A cluster was observed among HCW. Despite a decrease in the number of procedures, the Transplant Program performed 8 autologous and 4 allogeneic SCT during the period, and 49 onco-hematological patients were admitted to continuing their treatments. Although we observed a high frequency of COVID-19 among patients and HCW, showing that SARS-CoV-2 is disseminated in Brazil, hematological patients were safely treated during pandemic times.

COVID-19 in hematology: data from a hematologic and transplant unit.

During the COVID-19 pandemic, special attention has been addressed in cancer care to mitigate the impact on the patient's prognosis. We addressed our preparation to face COVID-19 pandemic in a Hematological and Stem Cell Transplant Unit in Brazil during the first two months of COVID-19 pandemic and described COVID-19 cases in patients and health care workers (HCW). Modifications in daily routines included a separation of area and professionals, SARS-CoV-2 screening protocols, and others. A total of 47 patients and 54 HCW were tested for COVID-19, by PCR-SARS-CoV-2. We report 11 cases of COVID-19 in hematological patients (including 2 post stem cell transplant) and 28 cases in HCW. Hematological cases were most severe or moderate and presented with several poor risk factors. Among HCW, COVID-19 were mostly mild, and all recovered without hospitalization. A cluster was observed among HCW. Despite a decrease in the number of procedures, the Transplant Program performed 8 autologous and 4 allogeneic SCT during the period, and 49 onco-hematological patients were admitted to continuing their treatments. Although we observed a high frequency of COVID-19 among patients and HCW, showing that SARS-CoV-2 is disseminated in Brazil, hematological patients were safely treated during pandemic times.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation.

The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

Hodgkin's lymphoma unmet medical needs in Brazil: experts' perspective / Necessidades médicas não atendidas no tratamento de linfoma de Hodgkin no Brasil: perspectiva de médicos

Background: In 2016, Hodgkin's Lymphoma (HL) was responsible for 2,470 new cases in Brazil and, despite recent scientific advances, there are unmet medical needs that affects patients' outcome. Therefore, we aimed to explore the unmet medical needs in the management of HL patients in Brazil, based on experts' perspective. Methods: A questionnaire was developed to address the unmet medical needs including barriers for the diagnosis and treatment of HL in Brazil. The questionnaire results were presented in a panel discussion to validate participants' responses and to collect additional data. Main results: Eight experts participated in the panel. On both healthcare systems, public and private, a slight majority of patients was women and most of them were under 60 yearsold. In addition, the majority of patients were referred from another specialty on both systems. The time from onco-hematologist appointment to diagnosis was different between public and private sector (median of 30 and 12.5 days, respectively). Most patients in the public sector were on stage III (33%) and IV (33%); in the private sector, most patients were on stages II (36%) and III (24%). The most common barriers were the delayed diagnosis and the unavailability of diagnostic procedures and treatment options. Conclusion: According to participants, issues related to infrastructure and healthcare resource allocation affects the management of HL. Improvements in the infrastructure and educational measures for physicians and patients may contribute to minimize the barriers.

Introdução: Em 2016, o Linfoma de Hodgkin (LH) foi responsável por 2.470 novos casos no Brasil e, apesar dos recentes avanços científicos, há necessidades médicas não atendidas que afetam os pacientes. Portanto, o estudo teve como objetivo explorar as necessidades médicas não atendidas no manejo de pacientes com LH no Brasil, com base na perspectiva de especialistas. Métodos: Um questionário foi desenvolvido para abordar as necessidades médicas não atendidas, incluindo as barreiras para o diagnóstico e tratamento do LH no Brasil. Os resultados do questionário foram apresentados em um painel de discussão para validar as respostas dos participantes e coletar dados adicionais. Principais resultados: Oito especialistas participaram do painel. De acordo com os especialistas, em ambos os sistemas de saúde público e privado, uma pequena maioria dos pacientes era mulher e a maioria tinha menos de 60 anos. Além disso, a maioria dos pacientes foi encaminhada por outra especialidade em ambos os sistemas. O tempo entre a consulta com o onco-hematologista até o diagnóstico foi diferente entre o setor público e privado (mediana de 30 e 12,5 dias, respectivamente). A maioria dos pacientes do setor público apresenta estádios III (33%) e IV (33%); no setor privado, a maioria dos pacientes apresenta estádios II (36%) e III (24%). As barreiras mais comuns foram o atraso no diagnóstico e a indisponibilidade de procedimentos diagnósticos, e opções de tratamento. Conclusão: De acordo com os participantes, as questões relacionadas à infraestrutura e à alocação de recursos de saúde afetam o gerenciamento do LH. Melhorias na infraestrutura e medidas educacionais para médicos e pacientes podem contribuir para minimizar as barreiras.

Treatment patterns of Hodgkin's lymphoma in Brazil: experts' perspective / Padrões de tratamento do linfoma de Hodgkin no Brasil: a perspectiva dos especialistas

Background: Hodgkin's Lymphoma (HL) is a curable type of cancer, with a wide variety of therapies, especially for refractory/relapsing cases. Therefore, the study aims to explore the treatment patterns used in the management of HL patients in Brazil. Methods: A survey was developed to explore the treatment patterns in Brazil, addressing topics such as clinical characteristics, lines of therapy, transplant information and cure rates. Then, results were presented in a panel discussion to validate participants' responses and gain additional insights. Main results: The eight experts reported that most patients are women and under 60 years old. In both private and public healthcare systems, ABVD was the most commonly used first-line therapy for patients of all stages. The median cure rates for patients in stages I and II were 80% and 87.5%, and for stages III and IV 60% and 67.5%, respectively, in public and private sectors. For the subsequent lines of therapy, different regimens such as DHAP, GVD, GEV, ICE and allogeneic transplant are used, among others. Brentuximab vedotin was present mainly in the private sector. In the public sector, 70% of the patients are eligible for autologous stem cell transplant; of them, 75% actually receive the transplant. In the private sector, 80% of the patients are eligible, and 100% of them receive the transplant. Conclusion: Similarities were found between the public and private sectors in first-line therapy and cure rates. However, barriers for subsequent lines of therapy are more evident in the public system.

Introdução: O linfoma de Hodgkin (LH) é um tipo de câncer curável, com ampla variedade de terapias, especialmente para casos refratários/recidivantes. Portanto, o estudo visa explorar os padrões de tratamento utilizados no manejo de pacientes com LH no Brasil. Métodos: Uma pesquisa foi desenvolvida para explorar os padrões de tratamento no Brasil, abordando tópicos como: características clínicas, linhas de terapia, informações sobre transplantes e taxas de cura. Em seguida, os resultados foram apresentados em um painel de discussão para validar as respostas dos participantes e coletar os insights adicionais. Principais resultados: Os oito especialistas relataram que maioria dos pacientes é composta por mulheres com idade menor de 60 anos. Em ambos os sistemas de saúde, privado e público, ABVD foi a terapia de primeira linha mais comumente usada para pacientes de todos os estágios. As medianas das taxas de cura para pacientes nos estágios I e II foram de 80% e 87,5%, e para os estádios III e IV, de 60% e 67,5%, nos setores público e privado, respectivamente. Para as linhas subsequentes de terapia, diferentes regimes como DHAP, GVD, GEV, ICE e transplante alogênico são utilizados, entre outros. Brentuximabe vedotina estava presente principalmente no setor privado. No setor público, 70% dos pacientes são elegíveis para transplante autólogo de células-tronco; deles, 75% recebem o transplante. No setor privado, 80% dos pacientes são elegíveis e 100% recebem o transplante. Conclusão: Foram encontradas semelhanças entre o setor público e privado na terapia de primeira linha, bem como nas taxas de cura. No entanto, as barreiras para as linhas subsequentes de terapia são mais evidentes no sistema público.

Centroblastic diffuse large B cell lymphoma displays distinct expression pattern and prognostic role of apoptosis resistance related proteins.

Centroblastic diffuse large B cell lymphoma (DLBCL) samples were analyzed by immunohistochemistry to evaluate the expression of p53, Bcl-2, Survivin, XIAP, and Ki-67. Survivin was the only protein which expression exhibited a trend for impact in progression-free (p = .077) and overall survival (p = .054). In the Mann-Whitney test, Survivin expression correlated with a negative overall survival (p = .045). These results appeared to be intimately related to Survivin cytoplasmic localization. Moreover, the anti-apoptotic proteins Bcl-2 and Survivin were less frequent in centroblastic DLBCL. Our results indicate that centroblastic DLBCL may be a disease with characteristic biology and clinical course and, therefore, specific prognostic factors.

O transplante de células-tronco hematopoéticas no tratamento dos linfomas não Hodgkin / Hematopoietic stem cell transplantation for non-Hodgkin lymphomas

No final da década de 70, ocorreu o primeiro relato de sucesso com a utilização de quimioterapia de alta dose, seguida de transplante de células-tronco hematopoéticas autólogo (TCTH auto), em pacientes com linfoma não Hodgkin (LNH). Desde então, o TCTH autólogo vem se constituindo em um importante instrumento na estratégia de tratamento dos LNH. Inúmeros estudos, em vários subtipos de linfomas, têm consolidado o papel do TCTH autólogo, principalmente como resgate em recidivas de doença. O melhor momento para a incorporação desta estratégia depende do subtipo do linfoma, do status de doença previamente ao transplante (sensível ou resistente) e de fatores clínico-biológicos associados à doença. Em recidiva sensível de linfoma difuso de grandes células, o TCTH autólogo é a terapia de escolha. Nestes pacientes, o transplante promove taxas de resposta completa em até 50 por cento dos casos, comparado a aproximadamente 15 por cento, quando esse resgate é realizado com protocolos quimioterápicos convencionais. O seu papel como parte da terapia de indução de remissão não está totalmente estabelecido. Em linfomas indolentes, principalmente folicular, é a terapia de escolha nas recidivas sensíveis à quimioterapia de resgate. Em linfomas de células do manto, o TCTH autólogo tem se incorporado à terapia de primeira linha, como consolidação de remissão. As indicações de TCTH alogênico em LNH têm se limitado aos casos de refratariedade ao tratamento convencional e recidiva pós-transplante autólogo, em pacientes jovens e sem comorbidades, em decorrência da alta toxicidade associada à utilização de regimes de condicionamento mieloablativos. A utilização de regimes de condicionamento de intensidade reduzida tem reduzido a toxicidade e ampliado o seu uso nos LNH recidivados ou refratários.

High-dose chemotherapy (HDT) followed by autologous bone marrow transplantation (ABMT) has proved to provide significant advantage regarding event-free and overall survival in patients with chemosensitive relapses of aggressive non-Hodgkin's lymphoma (NHL) after conventional therapy. These results encouraged many investigators to use HDT as part of first-line therapy but the results are contradictory. There is no consensus regarding management of relapsed or refractory DLBCL. In follicular lymphomas, autologous stem cell transplantation (SCT) is considered the treatment of choice for young patients with relapsed disease. Autologous SCT has also been evaluated in prospective trials as first-line treatment for high risk patients at diagnosis, but the results are not yet conclusive. In mantle cell lymphoma, autologous stem cell transplantation has been employed as part of first-line therapy. Allo-SCT for patients with lymphoma was first performed in the mid-1980s. The high transplant-related mortality, seen after myeloablative conditioning, discouraged broader interest in this approach and made further research difficult. The generally lower relapse rates after allo-SCT, the association of GvHD with reduced relapse rates, the increase of relapse rates after ex vivo or in vivo T-cell depletion, and the frequent responses to DLIs all support the existence of a graft-vs.-lymphoma effect. However, further data analysis supports the view that not all lymphomas are equal. While slowly proliferating diseases such as follicular lymphoma seem particularly sensitive targets for allogeneic T-cells, results of allo-SCT with aggressive B-cell lymphomas have been less convincing. Patients with these latter diseases obviously need vigorous debulking of their tumor prior to conditioning. Reduced-intensity conditioning fueled a renaissance of allo-SCT as treatment of lymphoma because the lower expected TRM was highly attractive for a patient population where...

CD26/DPPIV cell membrane expression and DPPIV activity in plasma of patients with acute leukemia.

CD26/DPPIV (dipeptidil peptidase IV) displays an array of diverse functional properties, with a role in the development of several human cancers. This enzyme is found mainly anchored in the membrane of cells although it also has an enzymatically active plasma isoform. The regulation of biological activities of cytokines by DPP IV activity has a potential role in the homeostatic regulation of hematopoiesis. In this study, we analyzed the CD26 antigen cell membrane expression by flow cytometry and the DPPIV activity in plasma of patients of acute leukemia. The results showed that the plasma DPPIV activity is significantly higher in leukemia patients and could be 100% inhibited by Januvia (Merck Sharp & Dohme) a selective DPPIV inhibitor. Although CD26 expression on immune cells were not leukemia-dependent the analysis of the correlation between CD26 expression and the DPPIV plasma activity were statistically significant (p < 0.01) in acute lymphoid leukemia (B-ALL and T-ALL).

Bisphosphonates induce apoptosis in CLL cells independently of MDR phenotype.

PURPOSE: The anti-tumoral activity of bisphosphonates (BPs) has been reported in leukemia. In this study, we attempted to evaluate the apoptotic effects of the BPs pamidronate (PAM) and zoledronic acid (ZOL) in chronic lymphocytic leukemia (CLL) samples, and to correlate it with clinical parameters and multidrug resistance (MDR) phenotype (P-glycoprotein and multidrug resistance-related protein expression and/or their functional activity). RESULTS: Both BPs were able to induce apoptosis significantly. No correlation was observed between BP-induced apoptosis and clinical parameters or MDR phenotype. CONCLUSION: Our data suggest that concurrent or sequential administration of BPs with conventional chemotherapeutic drugs may have significant therapeutic potential for CLL patients.