Current opinion and consensus statement regarding the diagnosis, prognosis, and treatment of patients with essential thrombocythemia: a survey of the Spanish Group of Ph-negative Myeloproliferative Neoplasms (GEMFIN) using the Delphi method.

The current consensus on the diagnosis, prognosis, and treatment of essential thrombocythemia (ET) is based on experts' recommendations. However, several aspects of the diagnosis of, prognosis of, and therapy for ET are still controversial. The Delphi method was employed with an expert panel of members of the Spanish Group of Ph-negative Myeloproliferative Neoplasms in order to identify the degree of agreement on the diagnosis, prognosis, and treatment of ET. Nine leading experts selected a total of 41 clinical hematologists with well-known expertise in ET. An electronic questionnaire was used to collect the questions rated in a four-step scale. The questions were grouped into four blocks: diagnosis, risk stratification, goals of therapy, and treatment strategy. After the first round consisting of 80 questions, a second round including 14 additional questions focused on the recommendations advocated by experts of the European LeukemiaNet in 2011 was analyzed. The median and mean values for the first and second rounds were calculated. A summary of the conclusions considered as the most representative of each block of questions is presented. The Delphi method is a powerful instrument to address the current approaches and controversies surrounding ET.

Atypical IgM multiple myeloma with deletion of c-MAF.

IgM multiple myeloma (MM) is a rare subtype of myeloma that shares clinical and pathological features with Waldenström's macroglobulinaemia. These are two separate entities that differ both in therapy and prognosis. We report a 57-year-old male, who presented with anaemia, hypercalcaemia, acute renal failure and several vertebral fractures that clinically suggested a multiple myeloma. Further investigations revealed a serum monoclonal component of IgM lambda type and a bone marrow infiltrated by small, lymphoplasmocytic cells. IgM MM was finally diagnosed by means of both inmunophenotypic and immunohistochemistry techniques, stressing the importance of inmunophenotypic evaluation when clinical and morphological features are discordant. Fluorescence in situ hybridization (FISH) studies disclosed a particular combination of deletion 13q14, t(11;14) and monoallelic deletion C-MAF without t(14;16). The clinical evolution after a Bortezomib-containing polychemotherapy and autologous stem cell transplantation (ASCT) conditioned with busulphan and melphalan is also presented. This very uncommon case highlights the impact of immunophenotyping on the differential diagnosis between IgM MM and WM, to choose the best treatment and establish an appropriate outcome.

Rhodotorula mucilaginosa catheter-related fungaemia in a patient with multiple myeloma.

To date, there have been several case reports of Rhodotorula infection in haematological patients, but none affecting patients with multiple myeloma (MM). We describe a 54-year-old man with MM receiving prophylaxis with fluconazole who was using a subclavian Port-A-Cath and presented two episodes of fungaemia caused by Rhodotorula mucilaginosa. The first episode was resolved with oral itraconazole and neutropenia recovery. During the second episode, caspofungin was administered without success; however, liposomal amphotericin B and catheter withdrawal resolved the fungaemia. As far as we know, this is the first case reported of R. mucilaginosa fungaemia in a patient with MM.

Epidemiology and outcome of Rhodotorula infection in haematological patients.

Rhodotorula spp. are emergent opportunistic pathogens, particularly in haematological patients. However, no systematic review of this infection has been undertaken in this high-risk patient group. The aim of this study was to review all reported cases of Rhodotorula infection to determine the epidemiology and outcome of this infection in this high-risk population. The 29 reported cases were fungaemias. The most common underlying haematological disorder was the presence of acute leukaemia (65.5%). Rhodotorula mucilaginosa was the species found more frequently (79.3%). Most cases (58.6%) had several risk factors (≥ 3) simultaneously. The most common predisposing factors were the presence of central venous catheter (CVC, 100%) and neutropenia (62.1%). A substantial number of patients (81.5%) received antifungal treatment with amphotericin B. The overall mortality was higher (13.8%) than that described in non-haematological patients (5.8% in solid-organ neoplasms and 9% in AIDS or other chronic diseases). Patients with acute leukaemia had a higher mortality rate (15.7%) than patients with non-Hodgkin's lymphoma (0%). Our data suggest that patients with acute leukaemia might be managed as high-risk patients and intensive measures might be taken. In addition, it appears that the subgroup of patients without acute leukaemia have a good outcome and might be managed as low-risk patients with a less intensive approach.

Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients.

The frequency of vascular events and evolution to myelofibrosis (MF) in young individuals with essential thrombocythemia (ET) is not well known. The incidence and predisposing factors to such complications was studied in 126 subjects diagnosed with ET at a median age of 31 years (range: 5-40). Overall survival and probability of survival free of thrombosis, bleeding and MF were analyzed by the Kaplan-Meier method and the presence of the Janus Kinase 2 (JAK2) V617F mutation correlated with the appearance of such complications. The JAK2 mutation (present in 43% of patients) was associated with higher hemoglobin (Hb) (P<0.001) and lower platelets at diagnosis. With a median follow-up of 10 years (range: 4-25), 31 thrombotic events were registered (incidence rate: 2.2 thromboses/100 patients/year). When compared with the general population, young ET patients showed a significant increase in stroke (odds ratio 50, 95% CI: 21.5-115) and venous thromboses (odds ratio 5.3, 95% CI: 3.9-10.6). Thrombosis-free survival was 84% at 10 years, with tobacco use being associated with higher risk of thrombosis. Actuarial freedom from evolution to MF was 97% at 10 years. In conclusion, young ET patients have thrombotic events, especially stroke and venous thrombosis, more frequently than generally considered, whereas they rarely transform to MF.

Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukemia.

A 56-year-old woman with an acute promyelocytic leukemia (APL) developed a severe all-trans-retinoic (ATRA) syndrome on day 17 of treatment. Shortly after, she presented a picture of pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome (HPS) were negative. A diagnosis of HPS was made. Treatment with dexamethasone and high-dose immunoglobulins was unsuccessful. Consolidation chemotherapy with idarubicin and ATRA rapidly reversed the HPS. The HPS in this patient could be related to the release of macrophage-stimulating cytokines by APL cells during ATRA syndrome.

Profilaxis de la enfermedad tromboembólica en urología / Prophylaxis of thombo-embolic disease in urology

La enfermedad tromboembólica continúa siendo una importante causa de muerte hospitalaria en pacientes sometidos a cirugía. La incidencia de trombosis se incrementa considerablemente con la edad y la presencia de otros factores de riesgo trombótico. El uso de profilaxis anticoagulante permite reducir el riesgo trombótico un 70 por ciento. La introducción de heparinas de bajo peso molecular con mejor farmacocinética y biodisponibilidad ha extendido el uso de profilaxis tromboembólica en cirugía y, desde luego, en cirugía urológica. La incidencia de complicaciones hemorrágicas leves o serias, es igual o menor que con la HNF en baja dosis. Se recomienda adoptar la pauta de profilaxis, dependiendo del grado de riesgo trombótico Inherente al procedimiento quirúrgico. La profilaxis con heparina debe iniciarse preoperatoriamente y mantenerse durante 7 días o hasta el alta y movilización del enfermo (AU)

HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy.

Hepatitis C virus (HCV) has been proposed as a possible causative agent of chronic thrombocytopenia. We investigated HCV infection in a series of 51 unselected Spanish patients with chronic acquired thrombocytopenia. Anti-HCV and HCV viraemia were detected in 13/51 (22.5%) of cases; this prevalence was particularly significant when compared with HCV seropositivity in age-matched controls (0.4%). Anti-HCV-positive patients, four men and nine women with a median age of 59.3 years (range 36-72), had a mean platelet count of 55.8 x 109/l (range 12-96). Only one of our HCV-positive thrombocytopenic patients had hypersplenism. Platelet-associated IgG (PAIgG) was negative, as measured by immunofluorescent flow cytometric analysis in 11/13 HCV-positive thrombocytopenic patients. Thus, thrombocytopenia in our HCV-positive patients appeared to be non-autoimmune mediated. In six patients, a trial of recombinant alpha2b-interferon (IFN-alpha) given at a dose of 3 MU three times per week for 6-24 months gave a durable (> 1 year) and significant increase in platelet count in all six patients. The maximum increase occurred after 6 months of IFN-alpha therapy. In conclusion, the ability of IFN-alpha to increase platelet counts in HCV-positive thrombocytopenic patients supports mechanisms involving a direct role for HCV inhibiting platelet production.

Defective activity of monocytes from patients with non-Hodgkin lymphoma. The modulatory effect of granulocyte-macrophage-colony stimulating factor.

BACKGROUND: Mononuclear phagocytic function is not well defined in non-Hodgkin lymphoma patients although, defective function of those cells has been reported in patients with Hodgkin disease and other solid tumors. The potential application of granulocyte-macrophage-colony stimulating factor (GM-CSF) in the prevention and treatment of infections in those patients is being studied. METHODS: Phagocytosis and microbiocidal activity of monocytes in peripheral blood from 10 newly diagnosed patients and 14 healthy donors were tested cytologically against a strain of Candida albicans, and chemotaxis was evaluated in a Boyden chamber using zymosan-activated serum as a chemotactic agent. Cells were assayed under basal conditions and after incubation with GM-CSF (12 ng/mL). RESULTS: The phagocytosis and chemotactic activity of monocytes from non-Hodgkin lymphoma patients was lower than results obtained with cells from healthy donors (P < 0.05), and microbiocidal activity against Candida albicanswas similar in both groups. After exposure to GM-CSF, the functional activity of monocytes from control donors was only slightly modified (P > 0.05); by contrast, the percentage of mononuclear phagocytic cells in non-Hodgkin lymphoma (NHL) patients increased from 41 +/- 3% to 53 +/- 3%, the phagocytic index from 0.6 +/- 0.1 to 0.87 +/- 0.1 (P < 0.05), microbiocidal activity against Candida from 54 +/- 5% to 66 +/- 6% (P > 0.05), and chemotaxis from 43 +/- 8 cells per field to 48 +/- 9 cells per field (P > 0.05). CONCLUSIONS: The results of this study indicate that there is defective phagocytic and chemotactic activity in monocytes from NHL patients at diagnosis. "In vitro" improvement of phagocytic activity was observed after exposure to GM-CSF.

The value of comparative volumetric analysis of urinary and blood erythrocytes to localize the source of hematuria.

PURPOSE: We evaluate comparative volumetric analysis of blood and urinary red blood cells (RBCs) to identify the source of hematuria. Comparative volumetric analysis is defined as the difference between mean corpuscular erythrocyte volume in peripheral blood (MCVB) diluted in urine supernatant after centrifugation and mean corpuscular volume of urinary erythrocytes (MCVU). The potential of MCVB-MCVU to distinguish the origin of hematuria is compared to MCVU alone. The fundamental hypothesis is that RBCs that can go through the glomerulus will be smaller than those from the collecting system or lower urinary tract, thus having a smaller MCVU and larger difference between MCVB and MCVU. MATERIALS AND METHODS: A prospective detailed urological evaluation was performed on 210 patients with glomerular or nonglomerular hematuria detected by urinary sediment, clinical radiological evaluation, endoscopy, cytology and sometimes bladder or renal biopsy. After evaluation 24 cases with an uncertain source of hematuria were excluded from study. Specialized urinalysis, volumetric analysis and clinical investigation were performed in a blind fashion. MCVU and MCVB-MCVU were registered for every patient. The Technicon H-3 system with angle laser scattering dual system allowed measurement of mean corpuscular volume in a minimal number of RBCs, and resuspension of RBC pellets in the same urinary supinate avoided effects of osmolarity and pH on RBC size and shape. Reproducibility in assessing the index was tested in 50 cases in which comparative volumetric analysis was repeated on 2 consecutive days. Unpaired t test was performed, and a threshold value of MCVB-MCVU with maximum sensitivity and specificity to detect glomerular hematuria was identified. The potential of urinary and comparative volumetric analysis to distinguish the source of hematuria was evaluated and compared by receiver operating characteristics curve analysis. RESULTS: Hematuria was nonglomerular in 53 (28.4%) and glomerular in 133 (71.6%) patients. Mean MCVB-MCVU was significantly different for nonglomerular (0.6 fl.) and glomerular (30.5 fl.) sources (p<0.0001). There was a correlation between repeat independent measures of MCVU and MCVB-MCVU. The highest positive predictive value to detect a glomerular origin is desirable so that unnecessary investigation can be obviated without the risk of missing a nonglomerular source. With a limit of 16 fl. specificity and positive predictive value were 98 and 99%, respectively. Receiver operating characteristics curve analysis to localize the source of hematuria revealed significant differences in favor of comparative volumetric analysis versus urinary volumetric analysis alone. CONCLUSIONS: MCVB-MCVU using the Technicon H-3 system is a useful noninvasive and accurate method to locate the source of hematuria. A value of 16 fl. or greater practically rules out a nonglomerular origin and obviates further urological investigation. We have incorporated this investigation in our diagnostic algorithm for hematuria.

Bone marrow transplantation in chronic granulomatous disease.

UNLABELLED: We present a 5-year-old boy with a severe form of X-linked chronic granulomatous disease and hypersensitivity to sulphamides preventing prophylaxis with trimethoprim-sulphomethoxazole. Bone marrow transplantation was performed after preconditioning with busulphan and cyclophosphamide. The immediate post-transplant period was without complications. Complete chimerism was demonstrated and post-transplant oxidative metabolism was normal. The patient is asymptomatic 30 months after the graft. CONCLUSION: Bone marrow transplantation in cases of chronic granulomatous disease is controversial, although it could be useful in selected very severe cases in which prophylactic therapy is problematic.

[Blast differentiation in a patient with chronic myeloid leukemia in blast crisis using retinoic acid]. / Diferenciación de los blastos de un paciente con leucemia mieloide crónica en crisis blástica con ácido retinoico.

Clonal proliferation in agar, cell maturation and cell cycle characteristics were studied on peripheral blood cells from a patient with chronic myeloid leukaemia (CML) in blast crisis. Studies were performed in normal conditions and after incubation with all-trans retinoic acid 10(-6) M. At the time of the study the patients showed 300 x 10(9)/leukocytes/L (40% blast and promyelocytes). Cytogenetic studies showed 90% metaphases with t (9; 22) and t (18; 21). DNA index was 1.36. In agar cultures 450 CFU/2 x 10(5)/L cells, plus abnormal clusters were obtained, in the presence of conditioned media, and 115 normal CFU-GM after addition of all-trans retinoic acid 10(-6)M. Addition of retinoic acid to cellular suspension in liquid cultures decreased the number of immature cells from 20 to 2% in 5 days and decreased the number of cells in "S" phase from 33 to 11% after 8 days. These results show cytodinamic abnormalities in patients with CML in blast crisis and potential reversibility of these alterations by all-trans retinoic acid.

Effect of granulocyte-macrophage colony-stimulating factor on leukocyte function in cirrhosis.

BACKGROUND: Cirrhotic patients have been reported to have leukocyte impaired function as well as a high incidence of infectious diseases. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the number and function of phagocytic cells, and clinical applications are under study. We tested in vitro effects of GM-CSF on phagocytosis, phagocytic index, and chemotaxis in polymorphonuclear leukocytes from 21 cirrhotic patients (12 with compensated cirrhosis and 9 with spontaneous bacterial peritonitis). METHODS: Polymorphonuclear leukocyte functions were tested under basal conditions and after incubation with GM-CSF (10 ng/mL). Phagocytosis was tested against a clinical strain of Candida albicans, and chemotaxis was evaluated using a Boyden chamber. Results were compared with those obtained from 14 healthy donors. RESULTS: Leukocytes from cirrhotics displayed lower basal functional activity than control cells in phagocytosis (P < 0.01) and chemotaxis (P < 0.01). After GM-CSF stimulation, the percentage of phagocytic polymorphonuclear leukocytes in noninfected patients increased from 60% +/- 2.5% to 69.9% +/- 2.42% (P < 0.01), phagocytic index from 0.79 +/- 0.07 to 1.02 +/- 0.07 (P < 0.001), and chemotaxis from 61.2 +/- 12.6 to 82.3 +/- 10.2 cells/high power field (P < 0.05). In patients with peritonitis, the phagocytic index increased from 0.87 +/- 0.08 to 1.08 +/- 0.05 (P < 0.01), phagocytosis from 57.8 +/- 3.57 to 64.7 +/- 2.34 and chemotaxis from 83.3 +/- 17.8 to 110.2 +/- 24.1. CONCLUSIONS: Our results indicate that a defective leukocyte function is present both in compensated and infected cirrhotic patients. An in vitro improvement was observed after GM-CSF stimulation.

Amylase-producing Bence Jones multiple myeloma with pancreatitis-like symptoms.

Amylase-producing tumors are mainly adenocarcinomas and, in rare instances, multiple myelomas. We describe here a first case of amylase-producing Bence Jones type myeloma with pancreatitis-like symptoms and the second in a Caucasian patient. The finding of salivary-type hyperamylasemia in a 72-year-old female with a possible pancreatitis made us suspect the diagnosis. Amylase production was observed in bone marrow cultures in which 96% of cellularity was composed of plasmablasts. Serum amylase level decreased when chemotherapy was given.

Enhancement of human neutrophil functions by a monoclonal antibody directed against a 19-kDa antigen.

A mouse IgG mAb termed P1C3 was raised against A23187-treated human peripheral blood neutrophils and has been shown to recognize an Ag with an apparent molecular mass of 19 kDa, herein named p19. This p19 Ag was weakly expressed at the cell surface of resting human peripheral blood neutrophils and monocytes, but its cell surface expression was dramatically increased upon activation of these cell types with different secretagogues, including FMLP, PMA, and the calcium ionophores A23187 and ionomycin. A large latent pool of p19 molecules became accessible by immunofluorescence flow cytometry after cell permeabilization of resting neutrophils. A practically total translocation of the intracellular pool of this p19 molecule to the plasma membrane was achieved under appropriate cell stimulation, which induced an almost total degranulation of neutrophil secretory granules. The p19 Ag was absent from platelets, PBL, as well as from the human promyelocytic cell line HL-60, the human promonocytic cell line U937, and the human lymphoid cell lines Daudi and Jurkat. The p19 Ag was also expressed by circulating and/or interstitial neutrophils and monocytes in distinct tissues examined. The mAb P1C3 was found to enhance several neutrophil responses, such as chemotaxis, cell adhesion, phagocytosis, and respiratory burst. These data indicate that the mAb P1C3 recognizes an intracellular Ag in human resting mature neutrophils and monocytes, which upon cell activation is translocated to the cell surface and is able to affect cell functionality.

[The effect of clindamycin on intraphagocytic Staphylococcus aureus in leukocytes from patients with chronic osteomyelitis]. / Efecto de clindamicina sobre Staphylococcus aureus intrafacogíticos en leucocitos de pacientes con osteomielitis crónica.

BACKGROUND: Osteomyelitis are infections difficult to be completely cured, and its optimal therapy had not clearly been established. METHODS: We study the bactericidal activity of polymorphonuclear leukocytes and also of serum from 13 patients with Staphylococcus aureus chronic osteomyelitis. We also studied the activity of clindamycin against intraphagocytic S. aureus. The study was done in vitro using control S. aureus strain ATCC 25923 and also microorganisms recovered from infected bone. RESULTS: S. aureus two hours survival rates in polymorphonuclear leukocytes were 13.5 +/- 4.4 x 10(6), 10.5 +/- 4.0 x 10(6), 11.0 +/- 4.0 x 10(6), using polymorphonuclear leukocytes from controls and patients, with control and autologous sera respectively (p greater than 0.05). We have observed a bactericidal activity defect in polymorphonuclear leukocytes from one patient and in the sera of 7 other patients. The incubation with clindamycin (10 MIC) reduces the number of cfu/ml to 2.1 +/- 0.9 x 10(6), 1.1 +/- 0.7 x 10(6) y 1.9 +/- 1.1 x 10(6), and we also detected and additional inhibition of 81.7 +/- 7%, 70.7 +/- 17% and 79.0 +/- 4% respectively. CONCLUSION: The results of our study confirm that clindamycin has an intracellular action against intraphagocytic S. aureus and also showed the ability of this antimicrobial agent to cover defects in defensive mechanism of the host. Both statements give support the potential usefulness of clindamycin as therapy for bone infections due to S. aureus.

Hematological abnormalities in hemophilic patients with human immunodeficiency virus infection.

Hematological abnormalities are common in patients with AIDS or AIDS-related complex. We studied cytological characteristics in peripheral blood and bone marrow samples of 33 hemophilic patients with HIV Infection and in six HIV negatives. The HIV-positive patients presented leukopenia (60.6%), thrombocytopenia (69.9%), and anemia (57.5%). Bone marrow showed abnormalities of maturation in one or more cell lines similar to those described in other HIV-infected groups of patients. These findings were more prominent in megakaryocytes and granulocytic series. Lymphocytosis, plasmocytosis, and increased hemophagocytosis were also common. These alterations do not appear in HIV-negative patients and seem related to a direct effect of HIV on bone marrow cells or to alterations in T-cell regulatory functions.

[Neutropenia secondary to cefotaxime use]. / Neutropenia secundaria a cefotaxima.

Agranulocytosis is an uncommon complication of beta-lactam antibiotic therapy. Two patients who developed absolute neutropenia and anemia after having received 168 g of cefotaxime are reported. There was fever and rash, and hematologic recovery too place 10 and 6 days after withdrawal of the drug. The bone marrow culture showed that the incubation of cells with cefotaxime (10 micrograms/ml) induced a 26 +/- 1% inhibition of the formation of granulocytic colonies (CFU-GM) in controls and a 47% and 48% inhibition, respectively, in the two patients with neutropenia. When serum was added to the culture, the control serum improved the in vitro granulopoietic response, while the serum from the first patient inhibited in 77 +/- 1.5% the formation of CFU-CM in the control marrow. The need for the monitoring of peripheral blood cells in patients receiving long term treatment with beta-lactam antibiotics emphasized, as we have shown the suppressor effect of cefotaxime on the hematopoietic precursors and the effect of an autoimmune mechanism in some cases.