Tumor microenvironment in Hodgkin lymphoma: novel prognostic factors for assessing disease evolution.

Hodgkin lymphoma (HL) has become one of the most curable hematological neoplasia. Clinical and biological factors remain the main pillars guiding therapeutic strategies in HL. Recent studies have improved our understanding of the phenotype, the characteristics of histogenesis, and other possible mechanisms of lymphomagenesis, including the role of Epstein-Barr virus (EBV) infection. Tumor cells manipulate the microenvironment, allowing them to develop their malignant phenotype and evade the attack of the host's immune response so that the interaction between tumor cells and the reactive microenvironment determines not only the histological features but also the clinical-pathological characteristics and prognosis of these patients - essential for the development of future therapies targeting various other cellular components of the tumor microenvironment. This article aimed to evaluate the characteristics of the tumor microenvironment and malignant cells using histopathology and immunohistochemistry (IHC) techniques to highlight the association of EBV and to study the expression of characteristic antigens in malignant and non-malignant cells within the tumor mass (overexpression of BCL2 (B-cell lymphoma 2) in malignant cells, presence of PD1 (Programmed cell death Protein 1) on T lymphocytes, CD68+ macrophages in the tumor microenvironment, and presence of EGFR (epidermal growth factor receptor). The analysis of the data collected in this paper highlights several key parameters with prognostic value and statistical significance: the EBV infection at diagnosis, its association with low-intensity BCL2(+), the presence of CD68 with rosette formation, and the identification of specific vascularization patterns. The development of prognostic systems that take into account the integration of biological prognostic markers seems essential for a better risk stratification.

A Review of FLT3 Kinase Inhibitors in AML.

Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6-8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient's condition and susceptibility.

Perioperative Trajectory of Haemoglobin, Predictors of Blood Transfusion and Tailoring Targets for Patient Blood Management Interventions: A Single-centre, Retrospective Study of Non-emergent Cardiac Surgery Patients.

Background: Anaemia and blood transfusion are two independent contributing factors to perioperative morbidity in cardiac surgery. While preoperative treatment of anaemia has been shown to improve outcomes, in real life, logistical difficulties remain substantial, even in high-income countries. The adequate trigger for transfusion in this population remains controversial, and there is a wide variability in transfusion rates among centres. Objectives: To assess the impact of preoperative anaemia on perioperative transfusion in elective cardiac surgery,todescribe the perioperative trajectory of haemoglobin (Hb), to stratify outcomes based on preoperative presence of anaemia and to identify predictors of perioperative blood transfusion. Materials: and Methods: We included a retrospective cohort of consecutive patients who underwent cardiac surgery with cardiopulmonary bypass in a tertiary centre of cardiovascular surgery. Recorded outcomes included hospital and intensive care unit (ICU) length of stay (LOS), surgical re-exploration due to bleeding, packed red blood cell (PRBC) transfusion pre-, intra- and postoperatively. Other record perioperative variables were preoperative chronic kidney disease, duration of surgery, use of rotation thromboelastometry (ROTEM) and cell saver, and fresh frozen plasma (FFP) and platelet (PLT) transfusion. Hb values were recorded at four distinct time points: Hb1 - at hospital admission, Hb2 - last Hb recorded preoperatively, Hb3 - first Hb recorded postoperatively and Hb4 - at hospital discharge. We compared the outcomes between anaemic and non-anaemic patients. Transfusion was decided by the attending physician on a case-by-case basis. Results: Of the 856 patients operated during the selected period, 716 underwent non-emergent surgery and 710 were included in the analysis. Also, 40.5% (n = 288) of patients were anaemic preoperatively (Hb <13 g/dl); 369 patients (52%) were transfused PRBCs, with differences found between anaemic and non-anaemic patients regarding the percentage of transfused patients perioperatively (71.5% vs 38.6%, p < 0.001) and in the total median number of units transfused (2 [IQR 0-2] vs 0 [IQR 0-1], p <0.001). We built a multivariate model, and logistic regression analysis showed that preoperative Hb <13 g/dl (odds ratio [OR] 3.462 [95% CI 1.766-6.787]), female sex (OR 3.224 [95% CI 1.648-6.306]), age (1.024 per year [95% CI 1.0008-1.049]), hospital LOS (OR 1.093 per day of hospitalisation [95% CI 1.037-1.151]) and FFP transfusion (OR 5.110 [95% CI 1.997-13.071]) are associated with PRBC transfusion. Conclusions: Untreated preoperative anaemia leads to more transfusion in elective cardiac surgery patients, both as a ratio of transfused patients and as the number of units of PRBCs per patient, and this is associated with an increased use in FFP.

Allogeneic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma-Romanian Experience.

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive mature T-cell malignancy caused by the human T lymphoma virus I (HTLV-I) affecting 3-5% of HTLV-1 carriers and is usually diagnosed in endemic regions. Romania is a region with high prevalence of HTLV-1 infection and ATLL and with low median age at diagnosis for aggressive types. We performed a retrospective analysis of post-transplant outcome in the first Romanian patients with ATLL receiving hematopoietic stem cell allotransplant. The study population included eight patients (three males, five females), with median age of 39.5 (range 26-57), with acute (one case) and lymphoma type (seven cases) that received peripheral stem cells (PBSC) from matched related (MRD) and unrelated donors (MUD) after reduced intensity conditioning. Graft versus host disease (GVHD) developed in six patients. Relapse occurred in four cases (50%) at a median time of 5-months post-transplant. Six patients died: four cases with disease-related deaths and two patients with GVHD-related deaths. The median survival post-transplant was 19.5 months (range 2.3-44.2 months). The post-transplant survival at 1-year was 62.5%, at 2-years 50%, and at 3-years 37.5%. In our opinion allogeneic transplant improves outcome in aggressive type ATLL.

Present and Future in Treatment of Hodgkin Lymphoma.

Hodgkin lymphoma is a highly curable malignant hemopathy, using chemotherapy, radiotherapy, target therapies and hematopoietic stem cell transplantation. Current research in this field focuses on identifying prognostic factors associated with the pathogenic characteristics of the tumoral process, enabling the therapy to be adjusted to each patient's degree of risk. The identification of biomarkers associated with the tumoral process is extremely important because these molecules can be targets for new biological therapies.

MRI differential diagnosis: bone metastases versus bone lesions due to malignant hemopathies.

Bone determinations are usually the first sign of disseminated cancers, whether is a hematological malignancy or other type of neoplasia. The aim of this paper is the possibility of differentiating the bone lesions from hematological malignancies by other malignancies that give bone metastases for the purpose to guide the clinician concerning causality of bone lesions. The research involved a retrospective study, which included 309 cases that were investigated by magnetic resonance imaging (MRI) at a segment of the spine, between 2010 and 2014, from which 137 were diagnosed with a form of hematological neoplasia, and the remaining had another form of cancer. Imaging aspect differs in these two study groups. Bone determinations due to malignant hemopathies (MH) were in general hypointense on T1-weighted sequences, iso- or hyperintense on T2-weighted sequences. On the other hand, bone metastases were hypo- or isointense on T1-weighted sequences, and had no specific signal intensity on T2-weighted sequences. In post-contrast images, all lesions showed contrast enhancement, with some differences. In terms of imagistic aspect, there are certain characteristics that can make a clear differentiation between bone determinations due to MH from the bone metastases, and some are found in the majority of the cases studied.

Hemophagocytic lymphohistiocytosis: a rare complication of autologous stem cell transplantation.

Hemophagocytic lymphohistiocytosis (HLH) is a very severe and rare syndrome of pathologic immune activation characterized by cytopenia and clinical signs and symptoms of extreme inflammation. HLH is usually fatal without treatment so that accurate and timely diagnosis is very important. The syndrome occurs as a familial disorder (familial HLH - FLH) or as an acquired condition (secondary - sHLH) in association with a variety of pathologic states: infections, rheumatologic, malignant or metabolic diseases. Malignancy associated HLH is primarily reported in T÷NK (natural killer)-cell malignancies but also in B-cell neoplasms and other types of cancer. HLH has also been reported in rare cases as a highly fatal and difficult to diagnose complication of stem cell transplantation (SCT). In this paper, we present the case of a young male patient who underwent autologous SCT as consolidation therapy for a T÷NK-cell lymphoma, complicated with graft failure due to HLH. The patient was successfully treated with corticosteroids, Etoposide, Cyclosporine and immunoglobulins. As a particularity, he developed a second B-cell neoplasia a few months after SCT.

Influence of the JAK2 V617F Mutation and Inherited Thrombophilia on the Thrombotic Risk among Patients with Myeloproliferative Disorders.

BACKGROUND: A number of studies showed that the JAK2 V617F mutation increases the thrombotic risk in patients with myeloproliferative disorders (MPN) while others did not reveal this correlation, and it is unknown whether inherited thrombophilia is an additive risk factor in mutated subjects. Our aim was to clarify the contribution of JAK2 V617F to a hypercoagulable state, as well as its interaction with other thrombophilic factors in patients with thrombosis and myeloproliferative disorders. METHOD: We studied 192 patients with myeloproliferative disorders, 90 with Essential thrombocytemia (ET), 42 with Polycythemia vera (PV) and 60 with Primary or idiopathic myelofibrosis (PMI). From these patients a subgroup of only 62 patients underwent laboratory screening for thrombophilia. RESULTS: The JAK2 V617F mutation was present in 62.8% patients with myeloproliferative disorders, 97.6% with PV, 54.5 % with ET and 53.44% patients with PMI. The mutated patients had a relative risk (RR) for thrombosis at any time of 2.94 in comparison with "wild-type" patients which was 0.93; in those patients having both the mutation and thrombophilia the RR was 3.56 (95% CI 2.41-7.34) compared to patients with neither the mutation nor thrombophilia, suggesting an additive interaction between the two risk factors. CONCLUSION: In patients with myeloproliferatives neoplasias, the thrombotic risk is higher in the JAK2 V617F-mutated subgroup and it is further increased by the presence of inherited thrombophilia (especially by the presence of mutated F V Leiden and lupus anticoagulant).

The Impact of 2-(18) Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in Treatment Strategy of Hodgkin Lymphoma-Current Hematologic Concepts.

Positron emission tomography/computed tomography (PET/CT) is useful in staging of Hodgkin lymphoma (HL), for early response - adapted therapy and choosing an individualized therapy, and is useful in determination of disease extent in relapsed and refractory Hodgkin lymphoma. Interim PET using 2-(18) fluoro-2-deoxyglucose(FDG) and low dose CT performed in one scanning session (FDG-PET/ CT) helps to predict outcome in Hodgkin lymphoma and to asses therapeutic stratification.

Composite diffuse large B-cell lymphoma and follicular B-cell lymphoma - case report and review of literature.

Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma.

Onset risk factors and treatment response features of refractory hodgkin lymphoma.

BACKGROUND: The International Prognostic Factors Project on Advanced Hodgkin lymphoma (HL) developed a seven factor prognostic score consisting of gender, age, stage, serum albumin, hemoglobin, leukocytosis and lymphocytopenia for the newly diagnosed Hodgkin disease patients in advanced stages, who receive chemotherapy. OBJECTIVES: The purpose of this study was to determine whether this prognostic score would also be useful for refractory Hodgkin lymphoma patients in monitoring response to treatment. MATERIAL AND METHOD: In the period 2000-2012, we performed a study on a group of 91 patients to show that the prognostic factors identified by the International Prognostic Factors (IPF) score affect the event- free survival (EFS) and the overall survival (OS). Our study also intends to show that the results of these factors change with the treatment response in patients with HL included in the category of patients with refractory disease. RESULTS: B symptoms, onset lymph node, more than 3 areas involved, bulky disease, extranodal involvement, low serum albumin, erythrocytes sedimentation rate (ESR), C reactive protein (CRP), lactic dehydrogenase (LDH) and anemia were associated with poorer EFS and OS. Male gender, stage, histological type, age (>45 years) and leukocytosis were not associated with significantly poorer outcomes. CONCLUSIONS: the prognostic score for advanced disease is also useful in predicting relapse in patients with HL and early detection of response in patients with refractory HL.

Secondary Acute Lymphoblastic Leukemia after Hodgkin's Lymphoma or a Coincidental Association of Two Hematological Malignancies?

ABSTRACT: Secondary acute lymphoblastic leukaemia (sALL), defined as acute lymphoblastic leukaemia following another malignancy, irrespective of previous treatment, is a rare disease, and its biological characteristics have not been accurately described. We report the case of a 24-year old patient followed for Hodgkin's lymphoma at our clinic, who develops and is diagnosed, less than a year after obtaining complete remission, as having pro-B acute lymphoblastic leukaemia This case has been a real diagnostic and treatment challenge, as sALL following another haematological malignancy is quite rare. CONCLUSION: It is necessary to better identify the prognostic factors of haematological malignancies in order to prevent the appearance of sALL.

Combined procedure of vascularized bone marrow transplantation and mesenchymal stem cells graft - an effective solution for rapid hematopoietic reconstitution and prevention of graft-versus-host disease.

Hematopoietic stem cell transplantation (HSCT) is a a standard therapeutic option for several diseases. The success of the procedure depends on quality and quantity of transplanted cells and on stromal capacity to create an optimal microenvironment, that supports survival and development of the hematopoietic elements. Conditions associated with stromal dysfunction lead to slower/insufficient engraftment and/or immune reconstitution. A possible solution to this problem is to realize a combined graft of hematopoietic stem cells along with the medular stroma in the form of vascularized bone marrow transplant (VBMT). Another major drawback of HSCT is the risk of graft versus host disease (GVHD). Recently, mesenchymal stromal cells (MSC) have demonstrated the capacity to down-regulate alloreactive T-cell and to enhance the engraftment. Cotransplantation of MSC could be a therapeutic option for a better engraftment and GVHD prevention.

Prognostic factors in myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cell and are characterized by ineffective hematopoiesis with normo- or hyper cellular bone marrow and cytopenia(s).The natural evolution of the disease consists of bone marrow failure (leading to infectious and hemorrhagic episodes or anemia related complications) and transformation to acute myeloid leukemia. Because MDSs display remarkable clinical, pathologic, and cytogenetic heterogeneity, with variable evolution and survival ranging from months to years, the predictive factors of prognosis have a key role in optimal therapeutic decisions.The purpose of this paper is to analyze prognostic factors within a group of patients diagnosed with myelodysplastic syndromes. The prognostic factors taken into account are: the number and depth of cytopenias, percentage of bone marrow blasts, cytogenetic abnormalities, intensity of anemia and transfusional dependence. These factors are related to overall survival, leukemia free survival, bone marrow failure complications, leukemic evolution, treatment decisions and the response to treatment. MATERIAL AND METHOD: The study group comprises of 119 patients diagnosed with de novo MDS, between 2008 and 2011 in the Hematology Department of Coltea Clinical Hospital. In this monitoring period the patients were stratified according to the FAB (French-American-British) morphologic classification. RESULTS: This study revealed that the outcomes of patients with MDS is influenced by the percentage of bone marrow blasts at diagnosis, the number and severity of hematopoietic lineage affected by cytopenia and by the presence of chromosomal abnormalities. CONCLUSIONS: The studied prognostic factors have predictive value in terms of survival, leukemic transformation, treatment response and development of bone marrow failure-related characteristic complications.

Immunotherapy with rituximab in follicular lymphomas.

BACKGROUND: Non-Hodgkin Lymphomas (NHL) represent a recent and fascinating domain of hemato-oncology, in which remarkable progress has been made. The conventional treatments of indolent lymphomas do not extend the survival rate, nor do they cure. Recent directions are centered on using several new drugs that are capable of overcoming the mechanisms that are resistant to recovery. The initiation of immunotherapy (Rituximab in 1997) seems to have changed the natural evolution of follicular lymphomas (FL). It is possible that resistance to healing in follicular lymphomas may be neutralized with Rituximab by suppressing STAT-1 positive macrophages that are present in the cellular microenvironment.Thereinafter, the re-evaluation of recent models of prognostic and therapeutic paradigmas that were used in FL became compulsory.The purpose of the paper is to compare the evolution of patients with follicular lymphoma and the period of response, according to the treatments. MATERIAL AND METHOD: The study group consisted of the 71 patients diagnosed with follicular lymphoma, out of a total of 767 malignant lymphatic proliferations with B cells, for a period of 7 years (2002-2008), at the Hematology Department, Hospital Coltea, Bucharest and Hematology Department, Universitary Hospital, BucharestResults and conclusions: Combining chemotherapy with Rituximab had better results compared to the same chemotherapy, administered alone, both in induction and in case of relapse. The overall response rate in our study group was 74.7%, out of which 42.3% complete remissions. The overall response rate was 84.61% in the Rituximab group, compared to 68.88% in patients without Rituximab.