Darko Antic

Is there a "gold" standard treatment for patients with isolated myeloid sarcoma?

Isolated myeloid sarcoma is an extramedullary tumor of immature myeloid cells defined by the absence of leukemia history, myelodisplastic syndrome, or myeloproliferative neoplasma with a negative bone marrow biopsy. Myeloid sarcoma is a very rare condition, and few cases have been reported. We reviewed data of 12 patients with isolated myeloid sarcoma managed at a single center to determine the possible prognostic factors affecting patient survival, such as age, sex, type, localization, and treatment options. Patients were mostly men (n=8), with a median age of 39 years. Patients were initially treated with chemotherapy (n=7) or surgery (n=5). In three patients, hematopoietic stem cell transplantation was performed. During the follow-up period, nine patients died. The median overall survival was 13 months, while event-free survival was 8 months. Regarding initial treatment strategy, no significant difference in overall survival was observed. Both chemotherapy and hematopoietic stem cell transplantation independently improved event-free survival. In addition, patients who received chemotherapy combined with hematopoietic stem cell transplantation had significantly longer event-free survival than those treated with chemotherapy alone. Age<40 years together with chemotherapy/hematopoietic stem cell transplantation significant affected event-free survival. Based on our results, the treatment of myeloid sarcoma requires a systemic rather than a localized approach with surgery or radiotherapy. While prospective evaluations are needed, chemotherapy with allogenic hematopoietic stem cell transplantation should be considered as the optimal therapy for isolated myeloid sarcoma.

Spinal epidural granulocytic sarcoma in non-leukemic patient

A previously healthy 24-year-old male presented with a 3-month history of progressive backache and weakness in both legs. Magnetic resonance imaging of the spine showed a large soft tissue mass infiltrating paraspinal musculature of lumbosacral area, sacral laminas, last lumbar and all sacral vertebra, protruding into the spinal canal, and with propagation into pelvis. Baseline laboratory data were normal. Decompressive laminectomy and tumor removal were performed resulting in neurological improvement. Histological examination identified granulocytic sarcoma (GS). Bone marrow biopsy showed normal findings. The patient underwent adjuvant chemotherapy and radiotherapy, resulting in the elimination of residual lesion, followed by autologous transplant. Immediate diagnosis and adequate systematic treatment are essential to achieve optimal results in patients with isolated GS. The patient is alive and free of the disease 14 months from the diagnosis.

Intravascular large B-cell lymphoma of central nervous system - a report of two cases and literature review.

Intravascular large B-cell lymphoma (IVL) is a rare form of diffuse large B cell lymphoma (DBCL) frequently presenting with skin and/or central nervous system (CNS) involvement. IVL involves CNS in 75 - 85% of patients and neurological symptoms include sensory and motor deficits or neuropathies, meningoradiculitis, paresthesia, hypostenia, aphasia, dysarthria, hemiparesis, seizures, transient visual loss, vertigo and impaired cognitive function. Neuroimaging discloses CNS involvement only in half of patients with neurological symptoms because there are no pathognomonic neuroradiological findings for IVL; ischemic foci are the most common presentation pattern and therefore vasculitis is the most common differential diagnosis. According to all mentioned data, diagnosis of CNS IVL requires a histopathological confirmation. Brain biopsy is absolutely indicated in patients with progressive neurological deterioration with unclear abnormalities in cerebral MR imaging. A general policy is that patients with IVL should be considered to have disseminated disease and should be treated with systemic chemotherapy. In younger patients with unfavorable features the high-dose chemotherapy with autologous stem cell transplantation should be used. Nevertheless, the course of IVL is rapidly progressive and ultimately fatal.

Haemostatic abnormalities in treatment-naïve patients with Type 1 Gaucher's disease

There is a paucity of data on the effects of enzyme replacement therapy (ERT) on the coagulation abnormalities and platelet function of patients with Gauchers disease (GDPs) and much of this data are controversial. This study investigates the haemostatic parameters in treatment-naïve GDPs and the effects of ERT. 31 Serbian treatment-naïve type 1 GDPs (M/F 17/14; median age 49 years, splenectomized 9/31) were studied. The complete blood count, prothrombin time (PT), activated partial tromboplastin time (aPTT) and coagulation factors were measured using the standard methods. Platelet aggregation was assessed with a whole-blood aggregometer. Splenic volumes were assessed using computer tomography. Twenty-one patients were treated with ERT (Imiglucerase). The haemostatic parameters were assessed after 6, 12 and 24 months (ERT6, 12, 24). Initially bleeding episodes were registered in 10/31 GDPs. Median platelet count was 108 × 109/L; 22/31 GDPs were thrombocytopenic. The PT and aPTT values were abnormal in 16/31 and 13/31 GDPs, respectively. Platelet aggregation abnormalities were recorded in 19/31GDPs. Median platelet aggregation was reduced in response to adenosine-diphosphate 5 µmol/L (ADP5 0.46) and collagen 5 µmol/L (Col5 0.47). Splenic volume inversely correlated with the platelet count and a reduced response to arachidonic acid (AA), Col5 and ADP5 (p < 0.05). The splenectomized GDPs had a significantly lower platelet aggregation to Col10 (p < 0.05). Bleeding GDPs had a significantly lower platelet count, higher chitotriosidase levels and a greater splenic volume compared to non-bleeding patients (p < 0.01). ERT: The number of bleeding GDPs had significantly decreased by ERT6 (1/10; p < 0.01). The platelet count had significantly increased by ERT6 (ERT6 180 × 109/L, p < 0.01). The PT increased significantly from ERT0 to ERT24 (PT0 65%, PT24 81%; p < 0.05). The von Willebrand factor had increased significantly by ERT6 and ERT24 (ERT0 56%, ERT6 70%, ERT12 70%, ERT24 86%; p < 0.01). The number of GDPs with abnormal platelet aggregation had decreased significantly by ERT6 (10/19; p < 0.05). Platelet aggregation on ADP10 and AA significantly increased by ERT6 (ADP10: ERT0 0.75, ERT6 0.8 p < 0.01; AA: ERT0 0.7, ERT6 0.8 p < 0.05). In conclusion, platelet dysfunction and coagulation abnormalities were found in a considerable number of our GDPs. The absence of severe bleeding episodes suggests that the haemostatic system is sufficiently balanced and therefore the exact mechanism of the etiology of these abnormalities need to be fully clarified. ERT resulted in the cessation of bleeding and marked increase in platelet count, PT, vWF and platelet aggregation.

Unusual presentation of gastric plasmablastic lymphoma in HIV-negative patient

Plasmablastic lymphoma (PBL) has initially been described as a rapidly progressive and almost invariably fatal diffuse large-cell lymphoma with plasmablastic features, exclusively involving the jaw and oral mucosa in HIV-positive patients. Although its clinical features may help in differential diagnosis, an extra-oral localization in a patient without HIV makes it more difficult to suspect clinically. We describe a very rare case of gastric PBL primarily involving stomach in a middle age man without an HIV infection. A biopsy was performed and its findings revealed a diffuse, monomorphous proliferation of the tumor cells with features of immunoblasts, MUM-1, EMA, and lambda light chains positive. Serology was negative for the human immunodeficiency virus (HIV), HBsAg, and hepatitis C virus infection. The patient started treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, but unfortunately died before the second cycle was given. To our knowledge, this is the second case of gastric PBL presented in HIV-negative patients. The findings in this case suggest that PBL should be included in the differential diagnosis of gastrointestinal tumors.

Prognostic effect of comorbidity indices in elderly patients with multiple myeloma.

BACKGROUND Consideration of comorbidity, disability, and frailty represents a significant part of the treatment of elderly multiple myeloma (MM) patients. The aim of study was to analyze the effect of the Charlson Comorbidity Index (CCI) and scale of Instrumental Activities of Daily Living (IADL) on the course of disease. PATIENTS AND METHODS The study included 110 newly diagnosed MM patients older than 65 years of age. According to the CCI most patients had at least 1 comorbidity (CCI score of 1) and most of them (51 of 110 patients; 46.4%) had an age-adjusted CCI (aaCCI) score of 5 to 6. Most of our patients were capable of performing routine daily activities (IADL ≥ 6). Patients were treated with thalidomide- and bortezomib- based combinations, or with conventional chemotherapy. RESULTS International Staging System (ISS) score 3 correlated with high scores of CCI or aaCCI (R = 0.314, P < .003; R = .317, P < .002, respectively), and lower IADL (R = 0.259, P < .007). The probability of adverse events was 70% greater for CCI score ≥ 2 (odds ratio [OR], 1.72); 28% for aaCCI ≥ 5 (OR, 1.28) and 22% higher for IADL < 3 (OR, 2.25). The patients with a CCI score of 0 to 1 had significantly longer overall survival (OS; log rank, 6.538; P < .011). The patients with aaCCI ≥ 5 had significantly shorter OS (log rank, 4.209; P < .040), and the patients with IADL > 3 had significantly longer OS (log rank, 6.62; P < .001). In the proposed model, aaCCI ≥ 5 and IADL > 3 scores had a major effect on the OS (χ(2), 8.46; P = .037). CONCLUSION CCI, aaCCI, and IADL scale are clinical parameters of prognostic significance. A proposed model for a personalized treatment approach is based on variables such as scores for aaCCI ≥ 5 and IADL > 3.

Patients with early stage chronic lymphocytic leukemia: new risk stratification based on molecular profiling.

Abstract We investigated molecular and biological parameters reflecting the biology of chronic lymphocytic leukemia (CLL) that may help us to predict the time to first treatment (TTT). A group of 33 patients with newly diagnosed CLL (Binet stage A) were analyzed. We developed a new scoring system based on the serum levels of β2-microglobulin (β2M) and vascular endothelial growth factor (VEGF) and the expression of lipoprotein lipase (LPL). Patients with a score of 0 had a TTT of 58.4 months, while patients with a score of 3 (increased levels of β2M, LPL, and VEGF) had a significantly shorter TTT of only 10.6 months (p < 0.0001).

Assessment of bone marrow microvessel density in chronic lymphocytic leukemia.

IntroductionAngiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called proangiogenic and antiangiogenic factors. Enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) has been recognized more recently. Our study assesses CD34 and von Willebrand factor (vWf) expression and microvessel density (MVD) in the bone marrow of patients with CLL. Aims(1) To assess bone marrow MVD in CLL using 2 different monoclonal antibodies, CD34 and vWf; and (2) To examine the possible association of marrow MVD and clinical course, pattern of marrow infiltration, Rai stage, CD38 positivity, and cytogenetic abnormalities detected by fluorescence in situ hybridization. Materials and MethodsBone marrow specimens from 33 patients with CLL and 10 controls were studied. A single microvessel was defined as any vessel with a clear lumen. The screening of the slides was carried out by hotspot method. The slides were initially screened at low power to identify the areas with highest number of microvessel or vascularity hotspot. The count of microvessel in a sufficiently extended field (40× objective lens, 10× ocular lens) was then performed. The mean value of 10 most vascularized areas at 400× field was considered as MVD for a sample. ResultsThere was a significant difference between MVD counts according to the antibody used. MVD was higher using CD34 versus vWF (CD34: mean ± SD, 35.91±15.7; 95% confidence interval of mean, 30.34-41.48 vessels/field versus vWF: 8.15±4.65; 95% confidence interval of mean, 4.11-12.44 vessels/field; P<0.0001]. Bone marrow MVD detected by CD34 was significantly higher in patients with CD38 expression more than 30% (P=0.006) and in patients with unfavorable cytogenetic abnormalities. However, no significant MVD differences were detected between CLL subgroups with regard to clinical course, pattern of marrow infiltration, and Rai stage. Bone marrow MVD in patients with CLL was significantly higher than that in controls (P<0.0001). ConclusionsMVD assessment using anti-CD34 resulted in higher MVD counts than when using anti-vWF antibody. However, no MVD differences were detected between CLL subgroups subdivided according to the above-mentioned prognostic factors except CD38 expression and genetic abnormalities.

Right atrial myeloid sarcoma causing superior vena cava syndrome.

A 37-year-old male presented in March 2007 with facial oedema. Quincke oedema was suspected and the patient was treated with parenteral corticosteroids and antihistamines. In spite of the therapy, his condition deteriorated. He developed breathing difficulties and cyanosis of his earlobes. Blood gas analysis showed mild hypoxemia and hypocapnia. A thoracic computed tomography (CT) scan showed collateral circulation and a large mass in the right atrium, extending into and obstructing the superior vena cava. The patient was referred urgently to the Cardiosurgery Department, where the tumour was partially resected. It was 50 · 50 · 40 mm in size, weighed 46 g and was covered with an incomplete thin, fibrous, elastic, solid light-brown to greenish membrane. It contained two dark-brown thrombotic masses, 30 · 15 · 10 mm and 25 · 18 · 8 mm in size. Microscopy of the tumour showed blastlike cells with round, irregular or elongated nuclei, finely granulated chromatin, large nucleoli and scanty basophilic cytoplasm. Mitotic and apoptotic indexes were high. There were numerous macrophages involved in phagocytosis of apoptotic debris, creating a ‘starry sky’ appearance. Immunohistochemical analysis showed cells clearly positive for CD45, CD34, CD117 and myeloperoxidase. Cells were negative for epithelial membrane antigen, cytokeratin, vimentin, S100, neurone-specific enolase, chromogranin A, synaptophysin, desmin, Myo D1, CD99, terminal deoxynucleotidyl transferase, CD15, CD68, lysozyme, CD31, CD79a, CD20, CD10, CD1a, CD3, CD4, CD5, CD7, CD8, CD43, CD45RO, CD56, CD57, CD30 and ALK-1. Proliferative activity was high (up to 40% of cells were Ki67+). A diagnosis of extramedullary myeloblast proliferation without maturation (myeloid sarcoma) was made. The patient was then admitted to our institute for further tests. Morphology and flow cytometry did not show any leukaemic infiltration of the bone marrow. Repeated CT scanning showed the right atrium to be completely filled with a solid, avascular tumour mass, with irregular contours, measuring 44 · 67 · 82 mm (top left), that did not spread into the right ventricle or left side of the heart (top right). There was a well-developed collateral circulation (bottom) between the inferior vena cava and the jugular vein. Combination chemotherapy with daunorubicin and cytarabine was commenced.

Development and validation of multivariable predictive model for thromboembolic events in lymphoma patients.

Lymphoma patients are at increased risk of thromboembolic events but thromboprophylaxis in these patients is largely underused. We sought to develop and validate a simple model, based on individual clinical and laboratory patient characteristics that would designate lymphoma patients at risk for thromboembolic event. The study population included 1,820 lymphoma patients who were treated in the Lymphoma Departments at the Clinics of Hematology, Clinical Center of Serbia and Clinical Center Kragujevac. The model was developed using data from a derivation cohort (n = 1,236), and further assessed in the validation cohort (n = 584). Sixty‐five patients (5.3%) in the derivation cohort and 34 (5.8%) patients in the validation cohort developed thromboembolic events. The variables independently associated with risk for thromboembolism were: previous venous and/or arterial events, mediastinal involvement, BMI>30 kg/m2, reduced mobility, extranodal localization, development of neutropenia and hemoglobin level < 100g/L. Based on the risk model score, the population was divided into the following risk categories: low (score 0‐1), intermediate (score 2‐3), and high (score >3). For patients classified at risk (intermediate and high‐risk scores), the model produced negative predictive value of 98.5%, positive predictive value of 25.1%, sensitivity of 75.4%, and specificity of 87.5%. A high‐risk score had positive predictive value of 65.2%. The diagnostic performance measures retained similar values in the validation cohort. Developed prognostic Thrombosis Lymphoma – ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis in cancer patients. Am. J. Hematol. 91:1014–1019, 2016.