Vitamin C boosts DNA demethylation in TET2 germline mutation carriers.

BACKGROUND: Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation. METHODS: In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members. RESULTS: We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals. CONCLUSIONS: These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations. TRIAL REGISTRATION: This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019).

Inflammatory Modulation of Hematopoiesis: Linking Trained Immunity and Clonal Hematopoiesis with Chronic Disorders.

Inflammation-adapted hematopoietic stem and progenitor cells (HSPCs) have long been appreciated as key drivers of emergency myelopoiesis, thereby enabling the bone marrow to meet the elevated demand for myeloid cell generation under various stress conditions, such as systemic infection, inflammation, or myelosuppressive insults. In recent years, HSPC adaptations were associated with potential involvement in the induction of long-lived trained immunity and the emergence of clonal hematopoiesis of indeterminate potential (CHIP). Whereas trained immunity has context-dependent effects, protective in infections and tumors but potentially detrimental in chronic inflammatory diseases, CHIP increases the risk for hematological neoplastic disorders and cardiometabolic pathologies. This review focuses on the inflammatory regulation of HSPCs in the aforementioned processes and discusses how modulation of HSPC function could lead to novel therapeutic interventions.

[Hematological neoplasia associated with primary mediastinal germ-cell tumor treated with hematopoietic stem cell transplantation].

The occurrence of a primary mediastinal germ cell tumor and hematological neoplasia provides a poor prognosis that is known to be fatal at a median of 6 months after onset. We report the case of a 15-year-old male who was treated with chemotherapy and hematopoietic cell transplantation based on a report of a surviving case. At diagnosis, the patient had an unresectable mediastinal tumor with elevated alpha-fetoprotein and human chorionic gonadotropin levels and acute megakaryoblastic leukemia. We prioritized treatment with chemotherapy for the tumor owing to the oncological emergency. We then performed leukemia induction therapy and achieved complete remission. Although we used CDDP in combination with intensive therapy, the mediastinal tumor grew too large for it to be safely resected. We transplanted bone marrow from the patient's human leukocyte antigen-haploidentical sibling upon conditioning with busulfan-melphalan. After 44 days, the leukemia recurred in the patient's central nervous system. This was followed by various post-transplant complications, and the patient died of organ failure that was associated with infectious diseases. At necropsy, a poorly engrafted bone marrow was observed. The mediastinal tumor was primarily necrotic, although some immature teratoma components were observed. No leukemic precursor cells were detected. Residual mediastinal tumors may be associated with the recurrence of leukemias. We seek a treatment strategy that enables early tumor resection and high-dose chemotherapy. Further case studies are warranted along with the development of effective treatment methods.

Mieloma múltiple: enfermedad ósea extensa en una paciente joven / Myeloma multiple: extensive bone disease in a young patient

El mieloma múltiple (MM) es un tumor de proliferación clonal de plasmocitos en la médula ósea (MO). Hasta ahora no es curable1,2. Puede presentarse como una enfermedad indolente o con manifestaciones clínicas como insuficiencia renal, anemia y lesiones osteolíticas1. Se presenta el caso de una paciente femenina de 46 años, quien padecía dolor en la región del brazo izquierdo, acompañado por dolores óseos generalizados. Al examen físico se observó en el tercio proximal de la región humeral izquierda y hombro ipsilateral, gran tumoración que deformaba la anatomía local, indurada, inmóvil y dolorosa. Presentaba anemia severa (Hb. 6 g/dL), cuantificación de ß2 Microglobulina 4,23 mg/L (VR 0,80 ­ 3,0 mg/L) y rastreo óseo radiológico con múltiples lesiones líticas. En la muestra de médula ósea se encontró infiltración de 80 % de células plasmáticas mono- clonales kappa. Se le diagnosticó discrasia de células plasmáticas tipo MM monoclonal kappa sintomático, estadio II (ISS), con enfermedad ósea extensa y un gran plasmocitoma humeral izquier- do. Se indicó tratamiento de inducción de la remisión con el esquema VCD (bortezomib, ciclofosfamida y dexametasona). Adicionalmente ácido zoledrónico. Posteriormente se modificó a bortezomib, talidomida y prednisona. Luego del tratamiento antineoplásico, refirió acalmia completa del dolor con mejoría de la movilidad. Este caso clínico se trata de una presentación inusual de MM debido a la edad de la paciente y a la extensa enfermedad ósea. Llamó la atención la ausencia de niveles elevados de la cadena liviana kappa de las inmunoglobulinas libres en suero. Por la edad de la paciente y la ausencia de co-morbilidades significativas, es candidata para trasplante de células progenitoras hematopoyéticas (TCPH)(AU)

Multiple myeloma (MM) is a tumor of clonal proliferation of plasma cells in the bone marrow (BM). Until now it is not curable1,2. It can present as without symptoms or with clinical manifestations such as renal failure, anemia and osteolytic lesions1. We describe the case of a 46-year-old female patient, who complained of pain in her left arm, and, also, by generalized bone pain. On physical examination a large tumor was present in the proximal third of the left humeral region and ipsilateral shoulder, it was hard, painful and immo- bile. She had severe anemia (Hb 6 g / dL), quantification of ß2 Microglobulin 4.23 mg / L (VR 0.80 - 3.0 mg /L) and the radiological bone survey showed multiple lytic lesions. In the bone marrow sample, an infiltration of 80 % kappa monoclonal plasma cells was found. Her diagnosis was MM-type plasma cell dyscrasia, symptomatic kappa, stage II (ISS), with extensive bone disease and a large left humeral plasmacytoma. Remission induction therapy was indicated with the VCD scheme (bortezomib, cyclophosphamide and dexa- methasone). Additionally zoledronic acid was administered. Subsequently, it was modified to bortezomib, thalidomide and prednisone. After antineoplastic treatment, she referred pain relief with improvement of mobility. This clinical case is an unusual presentation of MM due to the age of the patient and extensive bone disease. The absence of high levels of the kappa light chain of free immunoglobulins in serum attracted attention. Due to the age of the patient and the absence of significant comorbidities, she is a candidate for trans- plantation of hematopoietic stem cells(AU)

Hepatocyte Growth Factor: A Microenvironmental Resource for Leukemic Cell Growth.

Chronic lymphocytic leukemia (CLL) is characterized by the progressive expansion of B lymphocytes CD5+/CD23+ in peripheral blood, lymph-nodes, and bone marrow. The pivotal role played by the microenvironment in disease pathogenesis has become increasingly clear. We demonstrated that bone marrow stromal cells and trabecular bone cells sustain survival of leukemic B cells through the production of hepatocyte growth factor (HGF). Indeed the trans-membrane kinase receptor for HGF, c-MET, is expressed on CLL cells and STAT3 TYR705 or AKT phosphorylation is induced after HGF/c-MET interaction. We have further observed that c-MET is also highly expressed in a peculiar type of cells of the CLL-microenvironment showing nurturing features for the leukemic clone (nurse-like cells: NLCs). Since HGF treatment drives monocytes toward the M2 phenotype and NLCs exhibit features of tumor associated macrophages of type 2 we suggested that HGF, released either by cells of the microenvironment or leukemic cells, exerts a double effect: i) enhances CLL cells survival and ii) drives differentiation of monocytes-macrophages to an oriented immune suppressive phenotype. We here discuss how paracrine, but also autocrine production of HGF by malignant cells, may favor leukemic clone expansion and resistance to conventional drug treatments in CLL, as well as in other hematological malignancies. Novel therapeutic approaches aimed to block HGF/c-MET interactions are further proposed.

Immunohistochemical Biomarkers in Diagnosis of Hematolymphoid Neoplasms of Endocrine Organs.

The hematolymphoid infiltrations are challenging lesions in endocrine organs and tissues. The fourth edition of WHO classification of tumors of endocrine organs and the fourth edition of WHO classification of tumors of hematopoietic and lymphoid tissues are recently published. The updates in both fields include some new disease descriptions and prognostic markers. Our aim in this review article is to give practical diagnostic information about the most frequently seen hematolymphoid involvements of the pituitary gland, thyroid, and adrenal tissue. We designed the text in the order of organs and the contents according to the disease frequency. The pituitary gland and cellar region are the most frequently involved with Langerhans cell histiocytosis. Although it is very rare, Erdheim-Chester disease has recently been included in the classification and still needs more clear diagnostic definitions. Lymphoproliferative thyroid lesions and presentations create diagnostic problems for the pathologists. IGG4-related disease and its relation with thyroiditis is a new concept. There are many unknowns on pathobiology of the disease spectrum and discussion on defined diagnostic criteria of the IGG4-related thyroid diseases. The overlapping features of thyroiditis and primary thyroid lymphomas also create diagnostic difficulties. The frequently recognized primary hematolymphoid lesions of the endocrine organs may not be difficult to diagnose since they are expected lesions. The secondary involvement of hematolymphoid neoplasia may be more difficult to diagnose for an endocrine pathologist. In this review article, we aim to give brief description of the diseases and practical diagnostic approach by using optimum markers guided by the latest WHO classifications.

Implementation de un protocolo de seguridad en la administración de quimioterapia En el servicio de Hematología de un hospital de cuarto nivel / Implementation of a security protocol in the administration of chemotherapy in the hematology Department of a fourth level hospital

Resumen Objetivo: evaluar el conocimiento del personal e implementación del protocolo de seguridad en la administración de la quimioterapia en el servicio de Hematología del Hospital de San José. Material y métodos: la implementación fue evaluada por medio de listas de chequeo en cada proceso del protocolo y la evaluación del conocimiento por un cuestionario de 15 preguntas. Marco de referencia: servicio de Hematología del Hospital de San José, de Bogotá. Unidades de análisis: ciclos de quimioterapia administrados a pacientes adultos con diagnóstico de neoplasias hematológicas. Participantes: personal del servicio implicado en procesos de administración de quimioterapia. Mediciones: con las historias clínicas se describieron las características demográficas de los pacientes, los incidentes del proceso de administración de quimioterapia y la adherencia al protocolo por parte del personal de salud. El cuestionario de evaluación fue diseñado por los autores. Resultados: en 291 ciclos de quimioterapia (129 pacientes) se presentaron 214 incidentes del proceso de administración de quimioterapia de un total de 4074 posibles (5.2%), de estos, 16 están directamente relacionados con el uso de los medicamentos. La adherencia a los procesos del protocolo oscilo entre 40.5 y 100%. El conocimiento del personal tuvo una mejoría leve al comparar las dos evaluaciones realizadas. Conclusiones: aunque no se alcanzó la adherencia esperada al protocolo, se logró una disminución de los incidentes en comparación con estudios previos institucionales. Se requiere un nuevo plan de mejoramiento para aumentar la adherencia e impactar en la seguridad de los pacientes. (Acta Med Colomb 2017; 42: 112-120).

Abstract Objective: assess staff knowledge and implementation of the security protocol in the administration of chemotherapy in the hematology department at the San Jose Hospital, Bogota. Material and methods: the implementation was evaluated through checklists in each protocol process and the knowledge evaluation by a15 questions questionnaire. Reference frame: hematology department of the San Jose Hospital, Bogota. Units of analysis: chemotherapy cycles administered to adult patients with diagnosis of hematologic malignancies. Participants: service personnel involved in chemotherapy administration processes. Measurements: the patient's demographic characteristics, the incidents of the chemotherapy administration process and adherence to the protocol by the health personnel were described with the medical records. Authors designed the evaluation questionnaire. Results: in 291 chemotherapy cycles (129 patients) there were 214 incidents of the chemotherapy administration process out of a total of 4074 possible (5.2%), of which 16 are directly related to the use of the drugs. Adherence to protocol processes ranged from 40.5 to 100%. Staff knowledge had a slight improvement when comparing the two evaluations performed. Conclusions: although the expected adherence to the protocol was not achieved, a decrease in incidents was obtained compared to previous institutional studies. A new improvement plan is required to increase adherence and achieve greater impact on patient safety. (Acta Med Colomb 2017; 42: 112-120).

Trend reversal in the frequency of mycoses in hematological neoplasias: autopsy results from 1976 to 2005.

INTRODUCTION: Fungal infections of internal organs are a major complication for patients with hematological neoplasias. For more than 20 years, the frequency of such mycoses has been increasing with the aggressiveness of tumor treatment. METHODS: Autopsy findings over a 30-year period (1976 to 2005) from a single institution (Institute of Pathology, University of Essen) were retrospectively classified according to basic disease, frequency of mycoses, kind of mycoses, organs involved, hematopoietic transplantation, and cause of death. RESULTS: 340 of 1591 autopsied patients with hematological neoplasias (21.4%) revealed an invasive mycosis. The proportion increased from about 10% before 1980 to some 30% in the 1990s but fell to 21% by 2005. The frequency of mycoses decreased significantly both for transplanted patients (from 47.5% to 30.3%) and for non-transplanted patients (from 29.8% to 16.4%). The rate of deaths due to mycosis also decreased. The relative frequency of candidal mycoses went down, while aspergilloses predominated. The organ most frequently involved was the lung. DISCUSSION: The autopsy results signal a trend reversal in the leading complication of the treatment of hematological neoplasias and lend support to the assumption that antimycotic strategies are having a positive effect.