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.

Effect of Functional Nanoporous TiO2 Film Obtained on Ti6Al4V Implant Alloy to Improve Resistance in Biological Solution for Inflammatory Conditions.

The metallic titanium-based biomaterials are sensitive to corrosion-induced degradation in biological fluids in the presence of inflammatory conditions containing reactive oxygen species (ROS). Excess ROS induces oxidative modification of cellular macromolecules, inhibits protein function, and promotes cell death. In addition, ROS could promote implant degradation by accelerating the corrosive attack of biological fluids. The functional nanoporous titanium oxide film is obtained on titanium alloy to study the effect on implant reactivity in biological fluid with reactive oxygen species such as hydrogen peroxide, which are present in inflammations. The TiO2 nanoporous film is obtained by electrochemical oxidation at high potential. The untreated Ti6Al4V implant alloy and nanoporous titanium oxide film are comparatively evaluated for corrosion resistance in biological solution by Hank's and Hank's doped with hydrogen peroxide by electrochemical methods. The results showed that the presence of the anodic layer significantly improved the resistance of the titanium alloy to corrosion-induced degradation in biological solutions under inflammatory conditions.

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.

LEAM vs. BEAM vs. CLV Conditioning Regimen for Autologous Stem Cell Transplantation in Malignant Lymphomas. Retrospective Comparison of Toxicity and Efficacy on 222 Patients in the First 100 Days After Transplant, On Behalf of the Romanian Society for Bone Marrow Transplantation.

High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in patients with malignant lymphomas. In Europe over 8,000 ASCTs for lymphoma were performed out of a total of 40,000 transplants according to the European Bone Marrow Transplant (EBMT) activity survey in 2017. ASCT is considered the standard treatment for eligible patients failing to achieve remission after first line chemotherapy or patients with relapsed or refractory lymphomas, including classical Hodkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, as well as consolidation therapy in first remission in mantle cell lymphoma. BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) is the most commonly used conditioning regimen for ASCT in patients with relapsed/refractory (R/R) lymphomas in Europe, whereas the CBV (cyclophosphamide, BCNU, and etoposide) regimen is also widely used in North America. Recently, concerns regarding BCNU toxicity as well as restricted availability of BCNU and melphalan has determined an increasing number of transplant centers to use alternative conditioning regimens. Currently, only a few comparative studies, most of them retrospective, between different conditioning protocols regarding efficacy and toxicity have been published. Thus, in the current manuscript, we report the experience of 2 transplant centers in ASCT in R/R lymphomas with three types of conditioning: BEAM, CLV (cyclophosphamide, lomustine, etoposide) and LEAM (lomustine, etoposide, cytarabine, and melphalan), with the aim to evaluate the results of alternative conditioning regimens using lomustine (LEAM and CLV) and compare them with the standard BEAM regarding early toxicity, engraftment, and transplant related mortality (TRM). All patients developed grade IV neutropenia, anemia with/without transfusion necessity. Severe thrombocytopenia with transfusion requirements is reported in most cases. Median time to platelet engraftment and neutrophil engraftment was 13 days (range) and 10 days (range), respectively. Gastrointestinal toxicity was the most common non-hematologic toxicity after all three conditioning regimens. Oral mucositis in various grades from I to IV was diagnosed in most cases. Other side effects include vomiting, diarrhea, colitis, and skin rash but with low severity grades. For the LEAM arm, one patient died after transplant, before engrafting, one patient didn't achieve platelet engraftment in day 100, one patient developed grade 3 upper gastrointestinal bleeding, one patient died (grade 5 toxicity) with acute renal failure, one patient developed hypoxic events up to grade 4 acute respiratory failure and one patient developed grade 3 itchy skin rash. For the CLV arm, one patient died after transplant, before engrafting, one patient developed grade 3 colitis, one patient with grade 3 hepatic cytolysis, one patient with cardiac toxicity followed by death (grade 5) caused by an acute myocardial infarction with ST elevation and one patient with pulmonary toxicity clinically manifested with grade 3 pleurisy. For the BEAM arm, one patient developed grade 3 cardiac toxicity with sinus bradycardia and afterwards grade 4 with acute pulmonary edema, three patients presented a grade 3 pruritic skin rash and two patients developed grade 3 seizures. In the present study we presented the differences that were observed between BEAM, LEAM, and CLV conditioning regimens offering clinical arguments for an SCT practitioner choice in the ideal situation, but also of choice for alternative regimens in the case that one regimen cannot be used.

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.

Perioperative Patient Blood Management Programme. Multidisciplinary recommendations from the Patient Blood Management Initiative Group.

Patients with untreated anaemia or iron deficiency who undergo surgical procedures have an increased risk for mortality and morbidity. Patient Blood Management programmes address this issue worldwide and try to improve patient outcomes through a complex set of measures targeting anaemia correction, minimisation of bleeding and improvement of anaemia tolerance, in all phases of perioperative care. The Patient Blood Management Initiative Group is a multidisciplinary team of physicians from specialties including anaesthesiology, nephrology, surgery, orthopaedics, haematology, gastroenterology and transfusion medicine. The team has elaborated ten recommendations, divided into five categories, in order to implement a Patient Blood Management programme in Romania, using the most recent and relevant evidence. The document was discussed during three meetings which took place during October 2016 and May 2017 and the result was modified and updated via e-mail.

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.

2016 WHO Clinical Molecular and Pathological Criteria for Classification and Staging of Myeloproliferative Neoplasms (MPN) Caused by MPN Driver Mutations in the JAK2, MPL and CALR Genes in the Context of New 2016 WHO Classification: Prognostic and Therapeutic Implications.

The 2016 WHO-CMP classification proposal defines a broad spectrum of JAK2 V617F mutated MPN phenotypes: normocellular ET, hypercellular ET due to increased erythropoiesis (prodromal PV), hypercellular ET with megakaryocytic-granulocytic myeloproliferation and splenomegaly (EMGM or masked PV), erythrocythemic PV, early and overt classical PV, advanced PV with MF and post-PV MF. ET heterozygous for the JAK2 V617F mutation is associated with low JAK2 mutation load and normal life expectance. PV patients are hetero-homozygous versus homozygous for the JAK2 V617F mutation in their early versus advanced stages with increasing JAK2 mutation load from less than 50% to 100% and increase of MPN disease burden during life long follow-up in terms of symptomatic splenomegaly, constitutional symptoms, bone marrow hypercellularity and secondary MF. Pretreatment bone marrow biopsy in prefibrotic MPNs is of diagnostic and prognostic importance. JAK2 exon 12 mutated MPN is a distinct benign early stage PV. CALR mutated hypercellular thrombocythemia show distinct PMGM bone marrow characteristics of clustered larged immature dysmorphic megakaryocytes with bulky (bulbous) hyperchromatic nuclei, which are not seen in JAK2 mutated ET and PV. MPL mutated normocellular thrombocythemia is featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei without features of PV in blood and bone marrow. Myeloproliferative disease burden in each of the JAK2, CALR and MPL MPNs is best reflected by the degree of anemia, splenomegaly, mutation allele burden, bone marrow cellularity and myelofibrosis.

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.

Indolent lymphoma: diagnosis and prognosis in medical practice.

INTRODUCTION: Non-Hodgkin lymphomas represent malignant tumors of lymphoid cells. These chronic lymphoproliferative disorders stand for malignancies with varied histological aspects, clinical features, evolution, prognosis and aggressiveness. Follicular lymphomas are the most frequent form of indolent lymphomas and they represent around 25% of all malignant lymphomas in adults. MATERIAL AND METHOD: Between 2011 and 2012, we have retrospectively observed, analyzed and described a group of 24 patients diagnosed with follicular lymphomas in the Department of Hematology from Coltea Hospital. The admittance criteria were: age, gender, hemoglobin and LDH levels, number lymph nodes affected and the Ann Arbor lymphoma staging system. Also used as patient study parameters were the following immunohistochemical criteria: CD20, UCHL1, CD79a, expression of Bcl 2 and Bcl 6, CD10 and the proliferative index (Ki-67). RESULTS: Multiple studies have shown that prognosis depends far more on clinical and histology parameters, including age, the presence of extra-node diseases and the performance status. In our study, regarding the ratio between the two genders, the male patients were more numerous than the female patients. The impairment of the male patients is associated with an unfavorable prognosis. From the age perspective, most of the diagnosed patients were part of the age group over 60. The age exceeding 60 is considered a negative prognosis factor. The serum lactate dehydrogenase (LDH) level is also considered an unfavorable prognosis factor. In our study, stage III and IV were frequently and this represents a poor prognosis factor. CONCLUSIONS: Although it was a small number of patients, the results obtained correspond to the results existing in literature.

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.