Slobodanka Ostojić Kolonić

Serum levels of VEGF and bFGF in hypoxic patients with exacerbated COPD

Hypoxia frequently complicates the course of chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the two most potent angiogenic factors and may play a role in adaptation to hypoxia. The aims of the study were to assess the serum levels of VEGF and bFGF and to evaluate their mutual relationship in hypoxic patients with exacerbated COPD. The study group consisted of 50 hypoxic (PaO(2) 53 mmHg) patients with exacerbated COPD. Control groups were 30 stable COPD patients with PaO(2) 70 mmHg, and 30 healthy blood donors. The serum concentrations of VEGF and bFGF were measured using commercial enzyme-linked immunoassay kits. Patients with exacerbated COPD had significantly higher serum VEGF levels (1,089.16 +/- 1,128.03 pg/mL) compared to those with stable COPD (197.68 +/- 178.06 pg/mL) (p < 0.0001) and healthy blood donor group (257.69 +/- 170.4 pg/mL) (p < 0.0001). Serum bFGF levels were significantly higher in the exacerbated COPD group (6.15 +/- 2.56 pg/mL) compared to control groups (p = 0.0001). Basic FGF was undetectable in the stable COPD and blood donor groups. Since VEGF and bFGF correlated significantly with the majority of factors investigated in COPD patients, multivariate analysis was performed. According to the step-wise regression analysis, VEGF was best determined by PaO(2), WBC and IL-6. Basic FGF was best determined by PaO(2) and pH. The highly significant, simple correlation between VEGF and bFGF was lost in multivariate analysis. This suggests that their correlation is not independent, but due to factors that remain in the model after step-wise regression. These are essentially linked to the level of hypoxia. Results of our study suggest that VEGF and bFGF production is stimulated in hypoxic patients with exacerbated COPD. Elevated levels of VEGF and bFGF may activate the process of neoangiogenesis, which may lead to increased perfusion and an improvement in tissue oxygenation in this group of patients.

Bone marrow renin-angiotensin system expression in polycythemia vera and essential thrombocythemia depends on JAK2 mutational status

Recent observations raise possibility for constitutively active, mutated Jak2 to modulate expression of RAS genes in CMPD. We analyzed the expression of AGT, renin, AT2R1 and ACE genes in normal and bone marrows of PV and ET patients with the respect to the presence of V617F JAK2 mutation. PV and ET had different expression patterns of major RAS components compared to normal BM which was primarily associated with the JAK2V617F mutation and less with PV or ET disease phenotype. However, AT2R1 was exclusively markedly upregulated only in PV, while ET showed moderate expression irrespective of the JAK2 mutational status.

Primary mediastinal large B-cell lymphoma: a single-center study of clinicopathologic characteristics.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a subset of LBCL with unique clinicopathologic features. Some studies have raised the question of differences in biological features and clinical course among patients from different parts of the world. We conducted a retrospective clinicopathologic analysis of 24 patients with PMLBCL from a single center in Croatia. We also conducted the first investigation of the frequency of lymphotropic viruses human herpesvirus 6 (HHV-6) and HHV-8 in lymphoid lesions of this disease.The clinical characteristics of the patients were as expected, with high International Prognostic Index scores, elevated serum lactate dehydrogenase (LDH) levels, and bulky disease being adverse prognostic factors. Only 6 patients (25%) showed CD30 expression, and Bcl-6 protein expression was, in our series, prognostically favorable (P = .0401). One patient’s tumor had detectable HHV-6 genome sequence, but no HHV-8 sequences were detected in any tumors. Two thirds of the patients received CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone) with a relatively low complete remission rate (43.8%; median follow-up, 33.8 months). This study confirmed the moderate preponderance among PMLBCL patients of young females with B symptoms and elevated LDH levels.The CHOP regimen proved effective as first-line therapy only in patients with limited disease. Therefore, other third-generation chemotherapy protocols may be considered for treatment, especially in patients with bulky and advanced disease.

Lenalidomide induced good clinical response in a patient with multiple relapsed and refractory Hodgkin's lymphoma

BackgroundA 24-year-old female patient was diagnosed with classic Hodgkins lymphoma in clinical stage II, and combination chemotherapy followed by radiotherapy was initiated. During the following 5 years, the disease progressed despite several standard therapeutic approaches, including autologous and allogeneic stem cell transplantation.MethodsLenalidomide (25 mg daily) treatment was then initiated in a continuous dosing schedule. Positron emission tomography scans were performed before and during lenalidomide treatment. Hematologic and laboratory values, as well as physical condition were also assessed before and during lenalidomide treatment.ResultsFour months after continuous lenalidomide treatment, tumor load was significantly reduced, B symptoms had resolved, and the patients physical condition had improved, allowing her to resume normal daily-living activities. Evaluations after 15 months of lenalidomide treatment indicated limited disease progression. Nevertheless, the patient was feeling well and maintaining a normal active life. Treatment was well tolerated, allowing the patient to remain on continuous dosing, which has now been maintained for 18 months.ConclusionDaily, long-term lenalidomide treatment provided clinical benefit and was well tolerated in a patient with relapsed, advanced classic Hodgkins lymphoma.

Atypical blast morphology of primary plasma cell leukemia with renal involvement and plasmablasts in urine

Primary plasma cell leukemia (PCL) is a rare and aggressive variant of plasma cell (PC) myeloma characterized by high levels of circulating PCs. Clinical presentation is like other acute leukemia, with extramedullary infiltration of various tissues and organs being a frequent complication. The disease has a fulminant course and poor prognosis. Morphology of PCs in PCL includes a spectrum of maturity, with most cases having lymphoplasmacytoid or plasmablastic morphology. Presentation as more primitive cells that do not resemble PCs is even rarer and requires additional morphological and immunophenotypic studies. We present a case of 79‐year‐old woman who presented with severe pancytopenia and lobar pneumonia. Laboratory and clinical evaluation revealed primary, nonsecretory PCL with atypical, immature blast morphology, extramedullary renal involvement, and plasmablasts in urine. Despite therapeutic efforts the patient succumbed to the disease. Detection of PCs in the urine indicates extramedullary spread of disease, especially without accompanying hematuria, and may contribute to impairment of renal function, what is already a frequent complication in these patients. Diagn. Cytopathol. 2015;43:158–162.

Meningeal Infiltration of Chronic Myelomonocytic Leukemia

Chronic Myelomonocytic Leukemia (CMML) is a hematologic malignancy considered a subtype of Myelodysplastic Syndrome (MDS)/Myeloproliferative Disease (MPD). According the World Health Organization (WHO) two subtypes of CMML, CMML-1 and CMML-2 are defined depending on the percentage of blasts in Bone Marrow (BM) and Peripheral Blood (PB). The clinical presentation is variable, but the majority of patients present with fatigue, weight loss, fever, night sweats and splenomegaly, less often skin infiltration or serous effusions. Meningeal leukemic involvement is rarely a presenting feature of CMML. We are reporting a case of 67-year old male with central nervous system involvement of CMML.

Acute leukemia in patients with untreated chronic lymphocytic leukemia: A report of two cases with remarkably similar time cluster

The association of chronic lymphocytic leukemia (CLL) and acute leukemia (AL) is rare [1]. In most cases, AL develops after treatment of CLL; thus, previous chemotherapy or radiotherapy is usually considered to be a leukemogenic event [2]. We report two cases of acute leukemia occurring in patients with untreated chronic lymphocytic leukemia with remarkably similar time cluster. These two ALs had the same morphological but distinct immunophenotypic features. The first patient was a 55-year-old woman. A diagnosis of CLL was made in 1998 when hematologic work-up was consistent with B-cell CLL, Rai stage 1 [3], and a low tumor burden by total tumour mass classification [4]. The clinical course was stable, and the patient was observed without therapy. She was admitted to University Hospital ‘Merkur’ in June 2002 for evaluation of a newly developed leukocytosis. Laboratory studies revealed a white blood cell (WBC) count of 1276 10/l (myeloblasts 49%, promyelocytes 19%, lymphocytes 18%, monocytes 9%, promonocytes 5%), hemoglobin of 77 g/l, platelet count of 866 10/l, and lactate dehydrogenase of 1013 U/l. A cytological bone marrow smear revealed approximately 10% atypical blasts type I and approximately 80% blasts type II and III, with numerous granules, some basophile-like, and some Auer rods (Figure 1A). Two cell populations were found by flow cytometric analysis; one with phenotypic characteristics of B-cell CLL [CD5/CD19þ, CD5/CD23þ, monoclonal CD19/kappaþ (with a weak expression of light chains)] and a blasts population (MPOþ, CD2þ, CD13þ, CD33þ, CD117þ, HLA D/DR – /þ, CD 34 – ). The results were consistent with a mixed cell population within the lymphocyte gate (Table I). Approximately 20% of cells in the lymphocyte ‘window’ had the immunophenotypic characteristics of B-cell CLL (18.67% CD19/kappaþ versus 0.67% CD19/ lambdaþ, showing imbalance and supporting clonality) whereas approximately 80% of the cells in that gate had characteristics of blasts (MPOþ), and most likely corresponded to a subpopulation of smaller blasts which fitted the window. By contrast, all the cells in the blasts ‘window’ had the immunophenotypic characteristics of acute leukemia blasts whereas the B-cell CLL clone was not present (Table I). The cytogenetic analysis from the bone marrow sample did not show any chromosomal abnormalities, and the karyotype was 46,XX [10]. The second patient was a 59-year-old woman. A previous diagnosis of B-CLL was also made in 1998 with a stable clinical course, and was observed without therapy. She referred to University Hospital ‘Merkur’ in May 2002 for evaluation of a progressive leukocytosis. WBC count was 104.56 10/l (atypical blasts 45%, promyelocytes 9%, band neutrophiles 1%, lymphocytes 41%, prolymphocytes 3%, plasma cells 1%), hemoglobin 50.6 g/l, platelet count 246 10/l. A cytological smear of bone marrow

Fine-needle aspiration cytology yield as a basis for morphological, molecular, and cytogenetic diagnosis in alk-positive anaplastic large cell lymphoma with atypical clinical presentation.

ALK positive anaplastic large cell lymphoma is a T‐cell lymphoma usually occurring in children and young adults. It frequently involves lymph nodes and extranodal sites and is associated with favorable prognosis. A 20‐year old man was admitted for painful mass in the left axilla with overlying skin redness. Clinical presentation and US findings were highly suspicious for sarcoma. Definitive diagnosis was established cytolologically and using ancillary technologies from cytological samples. Fine needle aspiration cytology of tumor mass (lymph node conglomerate and surrounding tissue) show predominance of large, pleomorphic, atypical cells with large nuclei and vacuolised cytoplasm. Atypical cells immunocytochemically were positive for LCA, CD30, CD3, EMA, and ALK; negative for CD15 and CD56. NPM‐ALK transcript was detected by reverse transcriptase‐polymerase chain reaction (RT‐PCT). Molecular analysis of TCRß and TCRγ genes demonstrated clonal TCR genes rearrangement. Complex karyotype with multiple numerical and structural changes was found on conventional cytogenetics. These findings excluded sarcoma and corroborated the diagnosis of ALK positive ALCL. Cutaneous involvement in ALCL can clinically mimic sarcoma, especially in cases with localized disease without B symptoms. In those cases, immunostaining, PCR, and conventional cytogenetics are helpful to exclude sarcoma. Diagn. Cytopathol. 2017;45:51–54.

Rituximab Maintenance Strategy in Advanced Follicular Lymphoma: Facts and Controversies

Rituximab is a chimeric monoclonal CD20 antibody used in the treatment of CD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hematologic malignancies in the last decade. The main aim of this review is to present data on the use of rituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenance strategies in the first and second line treatment. This approach has improved the outcome in FL patients with better progression-free survival in all patients and better overall survival in relapsed setting. Regardless of good results, this strategy has generated controversies in medical community in the range from the lack of overall survival benefit in first line setting, adverse effects of possible overtreatment and toxicities to its unknown role in the era of novel agents. The existing data suggest that rituximab maintenance should be a rational therapeutic option for all patients with FL responding to fi rst line therapy and transplant-ineligible patients responding to reinduction.