Efficiency and safety analysis of Plerixafor combined with granulocyte colony-stimulating factor on autologous hematopoietic stem cell mobilization in lymphoma / 中华血液学杂志

Objective: To evaluate the advantages and safety of Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) in autologous hematopoietic stem cell mobilization of lymphoma. Methods: Lymphoma patients who received autologous hematopoietic stem cell mobilization with Plerixafor in combination with G-CSF or G-CSF alone were obtained. The clinical data, the success rate of stem cell collection, hematopoietic reconstitution, and treatment-related adverse reactions between the two groups were evaluated retrospectively. Results: A total of 184 lymphoma patients were included in this analysis, including 115 cases of diffuse large B-cell lymphoma (62.5%) , 16 cases of classical Hodgkin's lymphoma (8.7%) , 11 cases of follicular non-Hodgkin's lymphoma (6.0%) , 10 cases of angioimmunoblastic T-cell lymphoma (5.4%) , 6 cases of mantle cell lymphoma (3.3%) , and 6 cases of anaplastic large cell lymphoma (3.3%) , 6 cases of NK/T-cell lymphoma (3.3%) , 4 cases of Burkitt's lymphoma (2.2%) , 8 cases of other types of B-cell lymphoma (4.3%) , and 2 cases of other types of T-cell lymphoma (1.1%) ; 31 patients had received radiotherapy (16.8%) . The patients in the two groups were recruited with Plerixafor in combination with G-CSF or G-CSF alone. The baseline clinical characteristics of the two groups were basically similar. The patients in the Plerixafor in combination with the G-CSF mobilization group were older, and the number of recurrences and third-line chemotherapy was higher. 100 patients were mobilized with G-CSF alone. The success rate of the collection was 74.0% for one day and 89.0% for two days. 84 patients in the group of Plerixafor combined with G-CSF were recruited successfully with 85.7% for one day and 97.6% for two days. The success rate of mobilization in the group of Plerixafor combined with G-CSF was substantially higher than that in the group of G-CSF alone (P=0.023) . The median number of CD34(+) cells obtained in the mobilization group of Plerixafor combined with G-CSF was 3.9×10(6)/kg. The median number of CD34(+) cells obtained in the G-CSF Mobilization group alone was 3.2×10(6)/kg. The number of CD34(+) cells collected by Plerixafor combined with G-CSF was considerably higher than that in G-CSF alone (P=0.001) . The prevalent adverse reactions in the group of Plerixafor combined with G-CSF were grade 1-2 gastrointestinal reactions (31.2%) and local skin redness (2.4%) . Conclusion: The success rate of autologous hematopoietic stem cell mobilization in lymphoma patients treated with Plerixafor combined with G-CSF is significantly high. The success rate of collection and the absolute count of CD34(+) stem cells were substantially higher than those in the group treated with G-CSF alone. Even in older patients, second-line collection, recurrence, or multiple chemotherapies, the combined mobilization method also has a high success rate of mobilization.

Clinical Analysis of Autologous Peripheral Blood Hematopoietic Stem Cells Mobilization and Collection in Lymphoma Patients / 中国实验血液学杂志

OBJECTIVE@#To analyze the factors influencing collection of autologous peripheral blood hematopoietic stem cells in lymphoma patients.@*METHODS@#Clinical data of 74 patients who received autologous peripheral blood hematopoietic stem cells mobilization and collection in the 940th Hospital of Joint Logistic Support Force of PLA from April 2009 to April 2021 were collected. The effects of gender, age, disease type, stage, course of disease, chemotherapy cycle number, relapse, radiotherapy, disease status and blood routine indexes on the day of collection on peripheral blood hematopoietic stem cell collection were analyzed.@*RESULTS@#The success rate of collection was 95.9%(71/74), and the excellent rate of collection was 71.6%(53/74). There was a significantly statistical differentce in the number of CD34+ cells in grafts collected from patients with chemotherapy cycle ≤6 and >6 ［(9.1±5.2)×106/kg vs (6.4±3.7)×106/kg, P=0.031］. The number of CD34+ cells in the first collection was positively correlated with WBC count, hemoglobin, platelet count, neutrophil count, lymphocyte count, monocyte count and hematocrit value on the day of collection ( r value was 0.424,0.486,0.306,0.289,0.353,0.428,0.528, respectively). WBC count, hemoglobin, monocyte count and hematocrit value have higher predictive value for the first collection of CD34+ cells. The area under the receiver operating characteristic was 0.7061,0.7845,0.7319,0.7848, respectively.@*CONCLUSION@#Low dose CTX and VP16 chemotherapy combined with G-CSF can effectively mobilize autologous peripheral blood stem cells. The cycle number of chemotherapy relates to the collection of autologous peripheral blood stem cells. After mobilization, the success of the first collection can be better predicted by the blood routine indexes.

Efficacy and Safety of Plerixafor Combined with G-CSF for Autologous Peripheral Blood Hematopoietic Stem Cell Mobilization in Lymphoma Patients / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of plerixafor combined with granulocyte colony-stimulating factor (G-CSF) in mobilizing peripheral blood hematopoietic stem cells in patients with lymphoma.@*METHODS@#The clinical data of lymphoma patients who received autologous hematopoietic stem cell mobilization using plerixafor combined with G-CSF from January 2019 to December 2021 were retrospectively analyzed. The patients received 3 kinds of mobilization regimens: front-line steady-state mobilization, preemptive intervention, and recuse mobilization. The acquisition success rate, excellent rate of collection, and incidence of treatment-related adverse reaction were counted. The influence of sex, age, disease remission status, bone marrow involvement at diagnosis, chemotherapy lines, number of chemotherapy, platelet count and number of CD34+ cells on the day before acquisition in peripheral blood on the collection results were analyzed to identify the risk factors associated with poor stem cell collection.@*RESULTS@#A total of 43 patients with lymphoma were enrolled, including 7 cases who received front-line steady-state mobilization, 19 cases who received preemptive intervention, and 17 cases who received recuse mobilization. The overall acquisition success rate was 58.1% (25/43) after use of plerixafor combined with G-CSF, and acquisition success rate of front-line steady-state mobilization, preemptive intervention, and recuse mobilization was 100%, 57.9%(11/19), and 41.2%(7/17), respectively. The excellent rate of collection was 18.6%(8/43). A total of 15 patients experienced mild to moderate treatment-related adverse reactions. The number of CD34+ cells < 5 cells/μl in peripheral blood on the day before collection was an independent risk factor affecting stem cell collection.@*CONCLUSIONS@#Plerixafor combined with G-CSF is a safe and effective mobilization regimen for patients with lymphoma. The number of CD34+ cells in peripheral blood on the day before collection is an predictable index for the evaluation of stem cell collection.

Studies on the recombinant production and anticancer activity of thermostable L- asparaginase I from Pyrococcus abyssi / Estudos sobre a produção recombinante e atividade anticancerígena da L asparaginase I termoestável de Pyrococcus abyssi

L-Asparaginase catalysing the breakdown of L-Asparagine to L-Aspartate and ammonia is an enzyme of therapeutic importance in the treatment of cancer, especially the lymphomas and leukaemia. The present study describes the recombinant production, properties and anticancer potential of enzyme from a hyperthermophilic archaeon Pyrococcus abyssi. There are two genes coding for asparaginase in the genome of this organism. A 918 bp gene encoding 305 amino acids was PCR amplified and cloned in BL21 (DE3) strain of E. coli using pET28a (+) plasmid. The production of recombinant enzyme was induced under 0.5mM IPTG, purified by selective heat denaturation and ion exchange chromatography. Purified enzyme was analyzed for kinetics, in silico structure and anticancer properties. The recombinant enzyme has shown a molecular weight of 33 kDa, specific activity of 1175 U/mg, KM value 2.05mM, optimum temperature and pH 80°C and 8 respectively. No detectable enzyme activity found when L-Glutamine was used as the substrate. In silico studies have shown that the enzyme exists as a homodimer having Arg11, Ala87, Thr110, His112, Gln142, Leu172, and Lys232 being the putative active site residues. The free energy change calculated by molecular docking studies of enzyme and substrate was found as ∆G – 4.5 kJ/mole indicating the affinity of enzyme with the substrate. IC50 values of 5U/mL to 7.5U/mL were determined for FB, caco2 cells and HepG2 cells. A calculated amount of enzyme (5U/mL) exhibited 78% to 55% growth inhibition of caco2 and HepG2 cells. In conclusion, the recombinant enzyme produced and characterized in the present study offers a good candidate for the treatment of cancer. The procedures adopted in the present study can be prolonged for in vivo studies.

A L-asparaginase, que catalisa a degradação da L-asparagina em L-aspartato e amônia, é uma enzima de importância terapêutica no tratamento do câncer, especialmente dos linfomas e da leucemia. O presente estudo descreve a produção recombinante, propriedades e potencial anticancerígeno da enzima de Pyrococcus abyssi, um archaeon hipertermofílico. Existem dois genes que codificam para a asparaginase no genoma desse organismo. Um gene de 918 bp, que codifica 305 aminoácidos, foi amplificado por PCR e clonado na cepa BL21 (DE3) de E. coli usando o plasmídeo pET28a (+). A produção da enzima recombinante foi induzida sob 0,5mM de IPTG, purificada por desnaturação seletiva por calor e cromatografia de troca iônica. A enzima purificada foi analisada quanto à cinética, estrutura in silico e propriedades anticancerígenas. A enzima recombinante apresentou peso molecular de 33 kDa, atividade específica de 1.175 U / mg, valor de KM 2,05 mM, temperatura ótima de 80º C e pH 8. Nenhuma atividade enzimática detectável foi encontrada quando a L-glutamina foi usada como substrato. Estudos in silico mostraram que a enzima existe como um homodímero, com Arg11, Ala87, Thr110, His112, Gln142, Leu172 e Lys232 sendo os resíduos do local ativo putativo. A mudança de energia livre calculada por estudos de docking molecular da enzima e do substrato foi encontrada como ∆G – 4,5 kJ / mol, indicando a afinidade da enzima com o substrato. Valores de IC50 de 5U / mL a 7,5U / mL foram determinados para células FB, células caco2 e células HepG2. Uma quantidade de enzima (5U / mL) apresentou inibição de crescimento de 78% a 55% das células caco2 e HepG2, respectivamente. Em conclusão, a enzima recombinante produzida e caracterizada no presente estudo é uma boa possibilidade para o tratamento do câncer. Os procedimentos adotados na presente pesquisa podem ser aplicados para estudos in vivo.

Risk Factors Analysis of Thromboembolism in Patients with Lymphoma Chemotherapy / 中国实验血液学杂志

OBJECTIVE@#To evaluate the risk factors affecting thromboembolism in lymphoma patients with chemotherapy.@*METHODS@#Three hundred and four consecutive lymphoma patients treated by chemotherapy between January 2012 and July 2019 were enrolled and retrospectively analyzed, consisting of 111 patients with thromboembolism and 193 without thromboembolism. Univariate analysis was used to compare the clinical characteristics and related laboratory examination between the patients, while multivariate Logistic regression analysis were used to identify the risk factors affecting thromboembolism in lymphoma patients with chemotherapy.@*RESULTS@#Univariate analysis showed that the female, BMI <18.5 or >24, ≥60 years old, with abnormal platelets before chemotherapy, prolonged single hospitalization days and patients at Ann Arbor stage III and IV could increase the incidence of thromboembolism in lymphoma patients treated by chemotherapy. Multivariate Logistic regression analysis showed that abnormal platelet count before chemotherapy, patients at Ann Arbor stage III and IV, and female were all the independent risk factors affecting thromboembolism in lymphoma patients thromboembolism after chemotherapy (P<0.05).@*CONCLUSION@#For lymphoma chemotherapy patients, female, abnormal platelet count before chemotherapy and Ann Arbor stages III and IV show a significantly higher risk for thromboembolism. Thus, preventive anticoagulation therapy is recommended.

Primary extraperitoneal rectum lymphoma in AIDS patient / Linfoma primário de reto extraperitoneal em paciente SIDA

ABSTRACT Introduction The gastrointestinal lymphoma can be classified in primary or secondary, and this is important regarding diagnosis and subsequent treatment. Primary gastrointestinal lymphoma of the rectum is rare and therefore lacks data in medical literature. Its incidence has been increasing and that fact may be related to a higher incidence in immunosuppressive therapy and immunosuppressive diseases (such as AIDS). Metodology 19 articles have been reviewed, searched online on the Scielo and PubMed databases. The goal was to increase data available regarding this pathology and improve its therapy. Discussion Primary GI lymphoma of the rectum presents as hematochezia, rectal pain, change in bowel habits. PET/CT is the first choice exam to pursue investigation; however abdominal CT and MRI reveal sufficient information and are much more available in daily practice. Plasmablastyc lymphoma is an aggressive subtype and is usually associated with AIDS patients. There are no available treatment protocols for this specific type of lymphoma and colonic lymphoma's therapy is usually used for this patient (such as ECHOP and CHOP). Conclusion As rare as this pathology is, this article aims to improve the available data and provide useful information regarding diagnosis and therapy.

RESUMO Introdução O linfoma do TGI pode ser dividido entre primário e secundário, com importância diagnóstica e terapêutica. O linfoma primário de reto é patologia rara, pouco relatada em literatura médica. Sua incidência tem aumentado e possivelmente esse fenômeno esteja associado ao aumento no numero de pacientes com imunossupressão (seja por SIDA ou drogas imunossupressoras). Metodologia Foram revisados 19 artigos nas bases de dados Scielo e PubMed, com o objetivo de aumentar o número de relatos dessa patologia e consequentemente expandir o conhecimento disponível, visando melhorar a terapêutica e, principalmente, o diagnóstico desse tipo de linfoma. Discussão Quando o linfoma tem seu sítio primário no reto, as principais manifestações são sangramento, dor retal, tenesmo e mudança nos hábitos intestinais (diarreia ou constipação). O exame de investigação de escolha é o PET/CT, porém a TC e RNM fornecem as informações necessárias e são mais disponíveis na prática clínica. O linfoma plasmablástico é um subtipo bastante agressivo e associado aos pacientes com SIDA. Não existem ainda protocolos definidos para o tratamento do linfoma primário de reto, sendo optado por seguir a mesma terapêutica dos linfomas de cólon com esquemas EPOCH e CHOP. Conclusão Por se tratar de patologia rara e pouco descrita na literatura, espera-se que este relato contribua na formação de protocolos de tratamento específicos.

Metformin and blood cancers

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

Biological therapy and development of neoplastic disease in patients with juvenile rheumatic disease: a systematic review / Uso de imunobiológicos e desenvolvimento de doenças neoplásicas em pacientes com doenças reumáticas juvenis: revisão sistemática

Abstract Juvenile rheumatic diseases affect the musculoskeletal system and begin before the age of 18. These conditions have varied, identifiable or unknown etiologies, but those of an autoimmune inflammatory nature have been associated with an increased risk of development of cancer, regardless of treatment. This study aims to assess, through a systematic review of the literature according to Prisma (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) quality criteria, the risk of cancer in patients with juvenile rheumatic disease, and its association with biological agents. The criteria described by the Strengthening the Reporting of Observational Studies in Epidemiology initiative were used in order to assess the methodological quality of those individual items selected in this study. We analyzed nine publications, from a total of 251 papers initially selected. There was an increase in cancer risk in the population with juvenile rheumatic disease versus the general population. Most specified cancers were of a lymphoproliferative nature. Seven studies did not specify the treatment or not defined an association between treatment and cancer risk. Only one study has suggested this association; in it, their authors observed high risk in patients diagnosed in the last 20 years, a period of the advent of new therapies. One study found an increased risk in a population not treated with biological agents, suggesting a disease in its natural course, and not an adverse effect of therapy. Studies have shown an increased risk of malignancy associated with juvenile rheumatic disease, and this may be related to disease activity and not specifically to the treatment with biological agents.

Resumo As doenças reumáticas juvenis afetam o sistema musculoesquelético e se iniciam antes dos 18 anos. Apresentam etiologia variada, identificável ou desconhecida, porém as de natureza inflamatória autoimune têm sido associadas ao maior risco de desenvolvimento de neoplasias, independentemente do tratamento. Este artigo propõe avaliar, por meio de revisão sistemática da literatura de acordo com os critérios de qualidade Prisma (Preferred Reporting Items for Systematic Reviews and Meta- Analyses), o risco de câncer em pacientes com doenças reumáticas juvenis e sua associação com imunobiológicos. Os critérios descritos pela iniciativa Strengthening the Reporting of Observational Studies in Epidemiology foram usados para avaliar a qualidade metodológica individual dos artigos selecionados no presente estudo. Foram analisadas nove publicações, de 251 incialmente selecionadas. Houve aumento no risco de câncer na população com doença reumática juvenil comparada com a população em geral. A maioria dos cânceres especificados foi de natureza linfoproliferativa. Sete estudos não especificaram a terapêutica ou não definiram associação entre ela e o risco de câncer. Apenas um estudo sugeriu essa associação e observou maior risco em pacientes diagnosticados nos últimos 20 anos, período de advento de novas terapias. Um estudo constatou maior risco em uma população não tratada com imunobiológicos, sugeriu tratar-se da evolução natural da doença, e não do efeito adverso da terapêutica. Os estudos demonstram aumento no risco de malignidade associada a doenças reumáticas juvenis que pode estar relacionada à atividade da doença, e não especificamente ao tratamento com imunobiológicos.

Eficacia y seguridad de brentuximab vedotin en el tratamiento de pacientes con linfoma anaplásico de células T alk negativo con progressión de enfermedad a m´s de 2 líneas de qumioterapia / Efficacy and safety of brentuximab vedotin in the treatment of patients with anaplastic alkaline T-cell lymphoma with progression of disease to more than 2 lines of chemotherapy

INTRODUCCIÓN: Antecedentes: El present dictamen expone la evaluación de tecnología de l eficacia y seguridad de brentuximab vedotin en el tratamiento de pacientes con linfoma anaplásico de células T sistémico ALK negativo con progresión de enfermedad a más de 2 líneas de quimioterapia. Aspectos Generales: El linfoma anaplásico de células grandes (ALCL por "anaplastic large cell lymphoma") es un tipo rato, agresivo y heterogéneo no Hodgkin (LNH) de células T con expresion CD30 en las células tumorales. El ALCL constiuye aproximadamente el 2-3% de todos los LNH y menos del 15% de todos los linfomas periférico de células T. Tecnologia Sanitaria de Interés: Brentuximab vedotin es un conjugado de anticuerpo-medicamento que consiste en tres componentes: (i) el anticuerpo quimérico IgG1 cAC10 específico para CD30 jumano; (ii) el agente bloqueador de microtúbulos MMAE (monomethyl auristatin E); y (iii) un proteasa separable que une covalentemente el MMAE AL Cac10 (11). METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de brentuximab vedotin como tratamiento de pacientes con diagnóstico de linforma anaplásico de celulas T, ALK negativo, con progressión de enfermedad a más de 2 líneas de quimioterapia. Eseta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Helath System Evidence. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de la evidencia cientifica para el sustento del uso de brentuximab vedotin como tratamiento de pacientes con diagnóstico de linfoma anaplásico de célulaas T, ALK negativo, con progressión de enfermedad a más de 2 líneas de quimioterapia. Se presenta la evidencia disponbible según el tipo de publicación en los criterios de inclusión. CONCLUSIONES: Brentuximab vedotin ha sido evaluado en un solo ensayo pequeño, abierto de fase II y sin grupo comparador. El objetivo primario fue determinar la eficacia antineoplásica del agente vedotn (1.8 mg/kg vía E.V cada 3 semanas) en términos de la tasa de respuesta objetiva (TRO) . De manera secundaria se midieron los desenlaces de tiempo hasta a evento como la SG y la SLP. El Instituto de Evaluación de Tecnologías en Salud e Investigación IETSI, no aprueba el uso de brentuximab vedotin para el tratamiento de pacientes con ALCLs, ALK negativo y con progressión a > = 2 líneas de quimioterapia.

Epidemiología de neutropenia febril en pacientes adultos con leucemia aguda y linfoma: Estudio de cohorte en hospitales público y privado de Santiago, Chile / Epidemiology of febrile neutropenia in adult patients with acute leukemia and lymphoma: Cohort study of public and private hospital of Santiago, Chile

Introduction: Febrile neutropenia (FN) is a common complication of patients undergoing chemotherapy (QMT). Clinical presentation is varied, from mild fever to severe sepsis with invasive bacterial infection (IBI) or invasive fungal infection (IFI), with great impact on prognosis and patient mortality. Patients and Methods: Prospective cohort study of FN episodes in adult patients with acute leukemia (AL) or lymphoma (L), diagnosed and treated at the Hospital Clínico Universidad Católica and Hospital Dr. Sótero del Río in Santiago from April 2010 to January 2012. Results: 130 patients were included with 105 episodes of NF, with an incidence of 0.65 per 100 days of observation, higher in AL than L (1.31 vs 0.25, p = 0.001). Etiology or clinical focus was documented in 67 (63.8%) episodes, with IBI in 33 (31.4%) and IFI in 21 (20%) cases. Mortality related to infection occurred in 4 (6.2%) patients. Conclusions: This study reports that the FN incidence and frequency of IBI and IFI during episodes are higher in AL vs. L. It is necessary to evaluate the impact of interventions to reduce its incidence, including the benefit and risk of using antibacterial and antifungal prophylaxis in high-risk subgroups.

Introducción: La neutropenia febril (NF) es una complicación frecuente de pacientes sometidos a quimioterapia (QMT). Su presentación clínica es amplia, desde cuadros leves a sepsis grave con infección bacteriana invasora (IBI) o infección fúngica invasora (IFI), con gran impacto en el pronóstico y mortalidad de los pacientes. Pacientes y Métodos: Estudio prospectivo de episodios de NF en cohorte de pacientes adultos con leucemia aguda (LA) o linfoma (L) diagnosticados y tratados en el Hospital Clínico Pontificia Universidad Católica de Chile y Hospital Dr. Sótero del Río en Santiago, desde abril de 2010 hasta enero de 2012. Resultados: Se reclutaron 130 pacientes que presentaron 105 episodios de NF, con incidencia de 0,65 por 100 días de observación, mayor en LA que en L (1,31 vs 0,25, p: 0,001), documentándose etiología o foco infeccioso en 67 (63,8%) de los episodios, con 33 (31,4%) IBI y 21 (20%) IFI. Hubo mortalidad relacionada a infección en 4 (6,2%) pacientes. Conclusiones: Se define la incidencia de NF (LA > L) y frecuencia de IBI e IFI durante el episodio (LA > L). Es necesario evaluar el impacto de intervenciones destinadas a disminuir la incidencia de NF, entre las que se debe incluir el beneficio y riesgo del uso sistemático de profilaxis antibacteriana y antifúngica en los subgrupos de mayor riesgo.

Chlorambucil and ascorbic acid-mediated anticancer activity and hematological toxicity in Dalton's ascites lymphoma-bearing mice.

Chlorambucil is an anticancer drug with alkylating and immunosuppressive activities. Considering various reports on the possible antioxidant/protective functions of ascorbic acid (vitamin C), it was aimed at to explore the modulatory effect of ascorbic acid on therapeutic efficacy and toxicity induced by chlorambucil. Dalton’s ascites lymphoma tumor serially maintained in Swiss albino mice were used for the present experiments. The result of antitumor activity showed that combination treatment with ascorbic acid and chlorambucil exhibited enhanced antitumor activity with 170% increase in life span (ILS), which is significantly higher as compared to chlorambucil alone (ILS 140%). Analysis of apoptosis in Dalton’s lymphoma tumor cells revealed a significantly higher apoptotic index after combination treatment as compared to chlorambucil alone. Blood hemoglobin content, erythrocytes and leukocytes counts were decreased after chlorambucil treatment, however, overall recovery in these hematological values was noted after combination treatment. Chlorambucil treatment also caused morphological abnormalities in red blood cells, majority of which include acanthocytes, burr and microcystis. Combination treatment of mice with ascorbic acid plus chlorambucil showed less histopathological changes in kidney as compared to chlorambucil treatment alone, thus, ascorbic acid is effective in reducing chlorambucil-induced renal toxicity in the hosts. Based on the results, for further devel­opment, hopefully into the clinical usage, the administration of ascorbic acid in combination with chlorambucil may be recommended.

A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience

BACKGROUND/AIMS: The widespread use of cytotoxic chemotherapy and immunosuppressants has resulted in reactivation of hepatitis B virus (HBV) recently becoming an issue. Although rituximab (an anti-CD20 monoclonal antibody) has revolutionized the treatment of lymphoma, recent reports have suggested that rituximab therapy increases the risk of viral-mediated complications, and particularly HBV reactivation. This study analyzed real clinical practice data for rituximab-related HBV reactivation. METHODS: Between January 2005 and December 2011, 169 patients received treatment with rituximab. Screening status of the HBV infection and frequency of preemptive therapy were determined in these patients, and the clinical features of HBV reactivation were analyzed. RESULTS: Seventy-nine of the 169 patients with chronic or past HBV infection were selected for evaluation of HBV reactivation. Of the 90 patients who were excluded, 22 (13.0%) were not assessed for HBsAg and anti-HBc, and 14 (8.3%) were not assessed for anti-HBc due to seronegativity for HBsAg. The selected patients were divided into those with chronic HBV infection (n=12) and those with past HBV infection (n=67); six patients (7.6%) experienced HBV reactivation. Eight patients received preemptive therapy, but three patients (37.5%) underwent HBV reactivation. Although HBsAg seropositivity was an independent risk factor for HBV reactivation (P=0.038), of the six patients with HBV reactivation, two (33.3%) had past HBV infection and three (50%) died of liver failure. CONCLUSIONS: The findings of this study demonstrate that adherence to guidelines for screening and preemptive therapy for HBV reactivation was negligent among the included cohort. Attention should be paid to HBV reactivation in patients with past as well as chronic HBV infection during and after rituximab therapy.

Linfoma primário de cólon / Prymary limphoma of large bowell

O linfoma colorretal primário é uma doença rara (0,2 a 0,6% de todas as neoplasias colônicas), apresentando pior prognóstico quando comparado com o linfoma gástrico primário ou com o adenocarcinoma do cólon. É uma doença com sintomatologia inespecífica, o que dificulta o diagnóstico precoce. A importância deste caso é mostrar as variadas formas de apresentação macroscópica do linfoma de células do manto (MCL), uma variante do linfoma não-Hodgkin de células B, de ocorrência rara no cólon.

Tumor blástico a células dendríticas plasmocitoides / Blastic neoplasm of plasmocytoid dendritic cells

El tumor blástico a células dendríticas plasmacitoides (TBCDP) es una malignidad hematopoyética rara, altamente agresiva, derivada de las células dendríticas plasmocitoides; se caracteriza por su alta incidencia de compromiso cutáneo, que a menudo termina en una fase leucémica de mal pronóstico. La primera manifestación de la enfermedad pueden ser placas y tumores solitarios o múltiples, de manera que la biopsia cutánea es crucial para el diagnóstico. En la histopatología se observa un infiltrado difuso, monomorfo, no epidermotrópico de células de tamaño mediano con núcleos redondos, cromatina finamente dispersa, CD4 + CD56 + CD 123 +. Presentamos el caso de una paciente de sexo femenino de 48 años con un tumor plasmocitoide de células dendríticas. Al examen dermatológico se observaron lesiones cutáneas en cara externa de la pierna izquierda y mama derecha, acompañados de adenopatías inguinales palpables. No se halló compromiso de médula ósea y el hemograma fue normal. La paciente fue tratada con metotrexato, L-asparaginasa y dexametasona con buena respuesta clínica. El trasplante alogénico fue propuesto después del tercer ciclo.

Blastic neoplasm of plasmacytoid dendritic cells (BNPDC) is a rare hematopoietic malignancy, highlyaggressive, derived from plasmacytoid dendritic cells, and is characterized by a high incidence of cutaneousinvolvement, common leukemic dissemination and poor prognosis. Solitary or multiple skin plaques andtumors are often the first clinical manifestations of the disease; thus, cutaneous biopsies are crucial tocorrectly classify the patients. Histopathologic features are characterized by diffuse, monomorphous, nonepidermotropic infiltrates of medium-sized cells with round nuclei, finely dispersed chromatin CD4+CD56+ CD123+. We describe a 48-year-old woman who presented BNPDC. Clinically, two isolated bruiselikelesions arising on her left leg and right breast were detected, with palpable inguinal lymph nodes.Peripheral blood smear was normal, and the bone marrow was not involved. The patient was treatedwith methotrexate, L- asparaginase and dexametasone before entering in an allogenic bone marrowtransplantation program.

Antitumoral activity of allicin from garlic / Actividad antitumoral de alicina de ajo

Epidemiological studies link increased garlic consumption with a reduced incidence of cancer in various human populations. Experimental carcinogenesis studies in animal models and in cell culture systems indicate that several allium-derived compounds exhibit inhibitory effects. To provide a better understanding of the effects of allium derivatives on the prevention of cancer, we examined allicin, the major component of garlic, for their effects on antitumoral activity in vitro and in L5178Y lymphoma bearing mice. We found that allicin decreased the growth of tumor cells whereas in vivo, the compound shown an antitumor effect in murine L5178Y lymphoma. Allicin enhanced the secretion of IL-2, IFN-gamma and TNF-alpha cytokines from mouse plasma. These cytokines are associated with the beneficial Th1 antitumor response, which is characteristic of effective cancer immunotherapies.

Los estudios epidemiológicos relacionan el aumento del consumo de ajo con una disminución en la incidencia de cáncer en diferentes poblaciones humanas. Los estudios experimentales de carcinogénesis en modelos animales y en los cultivos de células tumorales indican que varios compuestos derivados del ajo tienen efectos inhibitorios. A fin de proporcionar una mejor comprensión de los efectos de derivados del ajo en la prevención del cáncer, se evaluó la alicina el principal componente del ajo, en la actividad antitumoral in vitro y en ratones con linfoma. Se encontró que la alicina disminuyó el crecimiento de células tumorales, mientras que in vivo, el compuesto muestra un efecto antitumoral en el linfoma murino L5178Y. La alicina incrementó la secreción de las citocinas IL-2, interferón-gamma y TNF-alfa obtenidas de plasma de ratón con linfoma. Estas citocinas están asociadas con la respuesta antitumoral benéfica Th1, que es característica de inmunoterapias efectivas para el cáncer.

A pilot study on parvovirus B19 infection in paediatric haematological malignancies.

Background & objectives: Leukaemia and lymphoma are common paediatric haematological malignancies acquiring human parvovirus B19 (B19) infection. In some studies anaemia has been found in children with acute lymphoblastic leukaemia (ALL) during maintenance therapy and rarely in lymphoma. We studied frequency of B19 infection and its implications in new onset acute leukaemia (mostly ALL) and lymphoma in children. Methods: Seventy serum samples from 35 children (age <12 yr, 29 males) newly diagnosed with haematological malignancies (on induction therapy) were collected together with 34 controls (solid tumours). Children were examined clinically and for anti-B19 IgM antibodies by quantitative ELISA and B19 DNA by PCR (VP1-VP2) and nested-PCR (VP1 unique). Bone marrow aspirates were examined histopathologically, whenever possible. Results: Of the 35 children, 22 had acute leukaemia while 13 had lymphoma. B19 infection was seen in six (17.1%) of 35 children (5 ALL, 1 NHL), two at diagnosis and four during follow up compared to none in the control. Among five B19 IgM positive ALL (n=18) children, two had B19 genome and two had giant pronormoblasts (lantern cells; but one lacked B19 DNA). Of the 70 serum samples tested, eight (11.4%) had anti-B19 IgM as two children had persistent B19 infection and one showed atypical maculopapular rashes (lower limbs) while 12 (34.3%) had anti-B19 IgG antibodies. B19 infected children had unexplained anaemia (80%), required more blood transfusions (6.6 ± 4.8 Units vs 3.0 ± 2.6 Units) besides induction chemotherapy was delayed (60%) and required longer duration of therapy (29.2 ± 20 vs 6.3 ± 7.8 days) (P<0.02). Five children (2 ALL, 2 AML, 1 NHL) died but none were infected with B19. Interpretation & conclusions: B19 infection should be considered in children with ALL as it frequently caused unexplained anaemia and delay in induction chemotherapy.

Combination Therapy with Rituximab and Temozolomide for Recurrent and Refractory Primary Central Nervous System Lymphoma

High-dose methotrexate-based chemotherapy has extended survival in patients with primary central nervous system lymphoma (PCNSL). However, although salvage treatment is necessary in recurrent and refractory PCNSL, this has not been standardized. We herein describe the efficacy of a combination of rituximab and temozolomide (TMZ) in two consecutive patients with recurrent and refractory PCNSL. Based on the immunohistochemical study, case 1 had a non-germinal center B-cell-like (non-GCB) subtype, was positive for bcl-2 and negative for O6-methylguanine-DNA methyltransferase (MGMT). Case 2 was GCB subtype, bcl-2-, and MGMT+. Because of the positive expression of MGMT, interferon-beta was additionally given in case 2. Complete responses and partial responses were obtained after the third and fourth cycles of combination therapy, respectively. This was maintained for 12 months, with acceptable toxicity. The combination of rituximab and TMZ was effective in tumors with different immunohistochemical profiles. This combination therapy warrants further study in a larger population.

Factors Influencing the Response to High Dose Methotrexate-based Vincristine and Procarbazine Combination Chemotherapy for Primary Central Nervous System Lymphoma

The authors investigated objective response rate to high dose methotrexate (HDMTX)-based combination chemotherapy in primary central nervous system lymphoma (PCNSL), and sought to identify factors that influence response to HDMTX-based combination therapy. Prospective observational analysis was performed on 52 PCNSL patients. All patients received HDMTX (3.5 g/m2) and vincristine (1.4 mg/m2/day) for one day during weeks 1, 3, 5, 7, and 9, and procarbazine (100 mg/m2/day) for one week during weeks 1, 5, and 9. Forty-one patients (78.8%) achieved complete or partial remission. Higher objective response rates were observed for patients with: 1) age < 60 yr; 2) Eastern Cooperative Oncology Group (ECOG) performance score of < 2; 3) low risk status as defined by the International Extranodal Lymphoma Study Group; 4) p53 positivity; 5) XBP-1 negativity; 6) MUM-1 negativity; and 7) homogenous gadolinium enhancement in MR images. Multivariate analysis showed that ECOG performance score of < 2, low risk, negativity for XBP-1, homogenous gadolinium enhancement by MRI, and response to chemotherapy were associated with longer overall survival. In particular, it is interesting to note that patients with a PCNSL that is homogenously enhanced by gadolinium have a higher objective response rate, and a longer progression-free survival and overall survival.

Efeitos toxicogenômicos tardios de terapias antineoplásicas para linfomas / Toxicogenomic late effects of antienoplastic therapies for lymphomas

Os linfomas representam um grupo heterogêneo de tumores que acometem o tecido linfóide nodal e extranodal. O tratamento, baseado na utilização da poliquimioterapia associada ou não à radioterapia, tem proporcionado altas taxas de cura. Entretanto, é sabido que tais terapias podem induzir mutações genéticas que, mais tarde, podem ser responsáveis pelo desenvolvimento de neoplasias secundárias. Assim sendo, o presente estudo objetivou avaliar os efeitos tardios das terapias antineoplásicas para linfomas. Para isso, foram investigados os danos no DNA e a capacidade de reparo da molécula pelo teste do cometa, e a relação entre polimorfismos e expressão de dois genes de reparo do DNA - XRCC1 (codons 280 e 399) e hOGG1 (codon 326) – com os níveis de lesões genotóxicas. A casuística do estudo incluiu 3 grupos de indivíduos: 14 pacientes recém-diagnosticados com linfoma e antes de qualquer tratamento antineoplásístico (grupo pré-terapia); 29 pacientes com história de linfoma e que haviam finalizado o tratamento há no mínimo 2 anos (histopatologicamente negativos para neoplasia; grupo pós-terapia); 29 indivíduos saudáveis pareados por sexo, idade e hábito tabagista (grupo controle). Os resultados mostraram que os pacientes com diagnótico ou história de linfoma (pré e pós-terapia, respectivamente), apresentavam níveis aumentados de danos no DNA quando comparados aos indivíduos saudáveis. Esses dados evidenciam a relação entre a presença da doença e lesões no DNA, e que mesmo com diagnóstico negativo, os indivíduos com história de linfoma apresentam níveis aumentados de genotoxicidade até, em média, sete anos após o término da terapia.

Lymphomas are a heterogenous group of malignancies that arise in nodal sites with or without extranodal involvement. The treatment, based on polychemotherapy associated or not with radiotherapy, has provided high cure rates. However, it is known that such therapies can induce genetic mutations that could be related to development of second malignancies. Therefore, the present study aimed to evaluate the late effects of antienoplastic therapies for lymphomas. DNA damage and repair capability as depicted by the comet assay, and the relationship between DNA repair genes polymorphisms (XRCC1 codons 280 and 399, hOGG1 codon 326) or gene expressions and the levels of DNA lesions were investigated. Three groups were included in this study: pre-therapy, with 14 patients newly diagnosed with lymphoma and before any antienoplastic; post-therapy, with 29 patients with history of lymphoma and who had finished treatment at least three years before blood collection (histopathologically negative for neoplasia); control, with 29 healthy subjects matched for age, sex and smoking habit. The results showed that patients from pre- and post-therapy groups presented higher amount of DNA damage than the healthy subjects. These data first indicated that individuals with lymphoma have high frequency of primary DNA lesion in lymphocytes, then, that even with negative histopathological diagnostic, patients with history of lymphoma presented increased DNA damage until the average of 7 years after the end of therapy. The reduced DNA repair capability and the low XRCC1 and hOGG1 expression observed in the post-therapy group could explain such findings. Furthermore, higher DNA repair capability was observed in those subjects with XRCC399arg/arg, XRCC1280arg/his and hOGG1326ser/ser genotypes.

Estudio comparativo: prevalencia patologías bucales en pacientes pediátricos oncológicos 1997-2007 / Comparative study: oral pathologies prevalence in pediatric oncology patients 1997- 2007

Los pacientes pediátricos oncológicos con frecuencia presentan lesiones orales debido a su neoplasia o como efecto colateral del tratamiento. El objetivo de este estudio fue comparar la prevalencia de patologías de la mucosa oral en niños con cáncer que fueron hospitalizados y tratados con quimioterapia en el Hospital Regional de Concepción, en los años 1997 y 2007. Se realizó un estudio descriptivo retrospectivo longitudinal en datas de 148 pacientes (74 cada año) con patologías neoplásicas en tratamiento con quimioterapia (Leucemias, linfomas, tumores del Sistema Nervioso Central y otros), registrando sus datos generales y la patología bucal (mucositis (M), candidiasis (C), lesiones por Virus Herpes tipo 1 (VHS) y síndromes hemorragíparos (H) . Los datos se resumieron en tablas anuales y fueron sometidos a análisis estadísticos. Se encontró una disminución significativa del número de pacientes con patologías bucales en el año 2007 en relación al año 1997 (P<0.05, Tet de Fisher). Además se encontró una tendencia a la baja en los pacientes con candidiasis y con mucositis en el año 2007 en comparación con 1997. Es necesario seguir estudiando medidas para prevenir, diagnosticar y/o tratar tempranamente las patologías orales de los pacientes en tratamiento antineoplásico.

Pediatric oncology patients frequently have oral lesions due to malignancy or as a side effect of treatment. The aim of this study was to compare the prevalence of oral pathologies in oncology patients hospitalized and treated at the Regional Hospital of Concepción, Chile, in the years 1997 and 2007. A retrospective study was carried out in 74 patients each year. Patients suffered from acute lymphoblastic leukemia, acute myeloblastic leukemia, central nervous system tumors, lymphomas and other neoplasms. General data (age, gender, oncologic disease) and presence of oral pathologies (candidiasis, mucositis post-chemotherapy, herpetic lesions and hemorrhage) were obtained from their clinical records. Data was analyzed for statistical differences. A significant reduction in the number of patients with oral pathologies was found in 2007 in comparison to 1997 (P<0.05, Fisher´s test). In addition, candidiasis and oral mucositis showed less prevalence in 2007 as compared to 1997, although no significant differences were found. For the relevance of oral pathologies in the chemotherapy it´s important to continue studies about prevention, early detection and treatment of oral pathologies.