Papers by Roberto Miranda
Clinical Lymphoma Myeloma and Leukemia, 2015
Acute myeloid leukemia (AML) with specific balanced 5q33 translocations are classified as AML wit... more Acute myeloid leukemia (AML) with specific balanced 5q33 translocations are classified as AML with myelodysplasia-related changes regardless of their morphologic findings or antecedent hematologic disease, but the clinicopathologic features of such cases remain poorly understood. From > 2000 cases of hematological malignancies seen at our institution between 2000 and 2013, we identified 9 AML patients with 5q33 translocations with variable partner loci, t(v;5q33). The study group included 8 men and 1 woman, with a median age of 64 years (range, 19-87 years). Four patients had an antecedent myeloproliferative neoplasm (MPN). Cytogenetic analysis showed t(v;5q33) as a sole chromosomal abnormality in 4 (44%) patients, t(v;5q33) and del(3)(q21;q26.2) in 1 (11%) patient, and a complex karyotype in 4 (44%) patients. Only 1 patient had morphologic features of myelodysplasia in 2 or more lineages. Follow-up was available for 7 patients and the median overall survival (OS) was 12 months. Patients with a history of MPN had a significantly shorter OS compared with those with de novo AML (11 vs. 20 months; P = .0445). There was no correlation between complex karyotype and OS in this small group of AML patients (P = .5904). The t(v;5q33) is a rare cytogenetic aberration in AML. Although associated with a poor outcome, AML with t(v;5q33) usually lacks morphologic evidence of multilineage dysplasia. Patients who have AML with t(v;5q33) after MPN have a worse OS compared with those with de novo AML.
British journal of haematology, Jan 10, 2015
A phase II study was performed to evaluate the efficacy of hyper-fractionated cyclophosphamide, v... more A phase II study was performed to evaluate the efficacy of hyper-fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine (HCVIDD/MA) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL), excluding ALK-positive anaplastic large cell lymphoma. Fifty-three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression (n = 13) or prolonged thrombocytopenia (n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression-free survival (PFS) was 7·5 months. With a median follow-up of 7·6 years, 5-year PFS and overall survival (OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer-cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patien...
British journal of haematology, Jan 30, 2015
Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplas... more Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next-generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 + in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002...
Histopathology, 2015
Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intra-... more Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intra-lysosomal accumulation of immunoglobulin (Ig) as crystals, reported in patients with plasmacytic/ lymphoplasmacytic neoplasms. We report the clinicopathologic features of 13 patients with CSH and describe the proteomic composition of the crystals in 3 cases analyzed by mass spectrometry (MS). There were 7 men and 6 women with a median age of 60 years (range, 33-79). CSH was generalized in 1 (8%) and localized in 12 (92%) patients involving various sites. CSH was associated with a low-grade B-cell lymphoma with plasmacytoid differentiation or a plasma cell neoplasm in all cases. In 10 (77%) cases, CSH represented more than 50% of the neoplastic infiltrate. By immunohistochemical studies, histiocytes were positive for monotypic kappa in 5 (50%), lambda in 4 (40%) cases; in 1 (10%) case, results were equivocal. MS analysis of the histiocyte contents in all 3 tested cases showed predominance of variable-region fragments of Ig light and/or heavy chains. CSH is frequently associated with an underlying lymphoplasmacytic neoplasm. MS findings suggest that Ig alterations and/ or possibly defects in the ability of histiocytes to process Ig play a role in pathogenesis. This article is protected by copyright. All rights reserved.
Journal of hematology & oncology, 2015
Plasmablastic lymphoma (PBL) is a rare aggressive neoplasm with lymphoid and plasmacytic differen... more Plasmablastic lymphoma (PBL) is a rare aggressive neoplasm with lymphoid and plasmacytic differentiation that is commonly associated with immunodeficiency and an unfavorable prognosis. Clinicopathologic features have been largely derived from cases reports and small series with limited outcome analyses. The demographic, clinicopathologic features, and clinical outcomes of a cohort of 61 patients with PBL were reviewed and analyzed. Patients had a median age of 49 years (range 21-83 years) and most (49/61; 80 %) were men. Human immunodeficiency virus (HIV) status was available for 50 patients: 20 were HIV-positive and 30 HIV-negative. Twenty-three patients were immunocompetent. Abdominal/gastrointestinal complaints were the most common presenting symptoms, reported in 14 of 47 (30 %) of patients. At presentation, 24 of 43 (56 %) patients had stage III or IV disease. Epstein-Barr virus (EBV) was detected in 40 of 57 (70 %) cases. MYC rearrangement was identified in 10/15 (67 %) cases ...
Clinical Lymphoma Myeloma and Leukemia, 2015
Primary myelofibrosis (PMF) is a rare myeloproliferative stem cell disorder. The genomic features... more Primary myelofibrosis (PMF) is a rare myeloproliferative stem cell disorder. The genomic features in PMF are poorly understood. Characterization of genomic alternations in PMF helps to determine their association with clinicopathologic features for further therapeutic implications. In this retrospective study, we investigated genomic changes using array-based comparative genomic hybridization (aCGH) in 17 PMF patients with isolated del(13q) and confirmed our aCGH findings with quantitative polymerase chain reaction (PCR) assay. We also compared the clinicopathologic features of patients with del(13q) (n = 17) with those of patients with a normal karyotype (NK) (n = 26). Clinicopathologically, del(13q) PMF patients had significantly higher blast counts (P = .03) than did NK patients, who had significantly higher marrow cellularity (P = .02). The degree of bone marrow fibrosis of PMF-3 was higher in the del(13q) group than in the NK group. Splenomegaly was present significantly more often in the del(13q) PMF group than in the NK group (P = .03). Genomically, the Janus Kinase 2 V617F mutation was observed less often in del(13q) PMF patients (P = .07). The common deleted region in del(13q) was confined to 13q13-13q14.3 according to G-band karyotyping, demonstrating a minimal deleted region (MDR) of 15.323 Mb, identified using aCGH. The tumor suppressor genes, Retinoblastoma, Forkhead box protein O1, and Succinyl -CoA ligase [ADP-forming] subunit beta in the MDR were deleted, confirmed using real-time PCR to confirm our aCGH findings. Accurate molecular characterization of del(13q) in PMF using aCGH and quantitative PCR provided further insight to define the MDR and analyze the genomic changes in del(13q) PMF patients.
Human pathology, 1999
The cell of origin of parafollicular (monocytoid) B cell lymphoma (PBCL), splenic marginal zone l... more The cell of origin of parafollicular (monocytoid) B cell lymphoma (PBCL), splenic marginal zone lymphoma (SMZL), and hairy cell leukemia (HCL) is controversial. To better understand the relationship between these low-grade B-cell neoplasms, we analyzed the nucleotide sequences of the rearranged immunoglobulin heavy (IgH) chain variable (V) region of the clonal population of cells in five cases of PBCL, four cases of SMZL, and seven cases of HCL to determine whether these neoplasms could be differentiated by the degree of somatic mutation in the IgH V gene or by the IgH V gene family usage. DNA was extracted from diagnostic material and clonality confirmed by PCR. The DNA was reamplified using V heavy chain family specific primers, and the amplicons were sequenced. Sequences were compared with germline IgH V gene sequences, and base changes were determined to be silent or to represent amino acid replacements by using three different methods. Four of five (80%) cases of PBCL, three of...
Oncotarget, Jan 8, 2015
CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBC... more CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5+ DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5+ DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell-like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5+ DLBCL patients had significantly worse overall survival (median, 25.3 months vs. not reached, P< .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P< .0001) than CD5- DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression aboli...
Resumo A monitorização residencial da pressão arterial (MRPA) é um método relativamente novo, mas... more Resumo A monitorização residencial da pressão arterial (MRPA) é um método relativamente novo, mas que tem sido alvo de interesse crescente, tanto na prática diária como em pesquisas clínicas envolvendo fármacos anti-hipertensivos. Os diversos métodos de medida de PA não se excluem, mas se complementam. Em relação à medida de consultório, a MRPA disponibiliza um número maior de medidas, não está sujeita ao efeito placebo ou ao efeito do avental branco, levando à menor variabilidade e maior precisão. Em comparação com a monitorização ambu-latorial da pressão arterial (MAPA), apresenta menor custo e maior praticidade, podendo ser utilizada por períodos mais longos. Porém, não fornece informações sobre a PA durante o sono, nem determina a relação vale-Palavras-chave: Hipertensão arterial; Monitorização residencial da pressão arterial; Tratamento da hipertensão arterial. pico do anti-hipertensivo. A MRPA permite apenas a avaliação do efeito residual de um fármaco, calculando-se a taxa de...
Blood, Jan 11, 2014
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoi... more The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report o...
Resumen: Rhipicephalus sanguineus es una de las especies más relacionadas con la salud pública, d... more Resumen: Rhipicephalus sanguineus es una de las especies más relacionadas con la salud pública, debido a que transmite varios patógenos a perros y humanos. A pesar de que es una garrapata común, existen pocos datos sobre sus enemigos naturales, especialmente en América Central. En este trabajo se presentan datos de especies de arañas de las familias Filistatidae, Oecobiidae, Pholcidae y Theridiidae y tres morfoespecies de avispas parasitoides del género Ixodiphagus atacando R. sanguineus en Panamá. Palabras clave: Ixodida, Ixodidae,Ixodiphagus, arañas, Micropholcus, Panamá.
Se presenta el parasitismo de Ornithodoros puertoricensis en el sapo común Rhinella marina, a par... more Se presenta el parasitismo de Ornithodoros puertoricensis en el sapo común Rhinella marina, a partir de una observación en la ciudad de David. Adicionalmente se hace una breve revisión del género Ornithodoros parasitando anfibios neotropicales. Este hecho constituye el primer reporte de Argasidae sobre anfibios en Panamá.
Human Pathology, 2011
Fas-associated death domain protein is a key component of the extrinsic apoptotic pathway. In add... more Fas-associated death domain protein is a key component of the extrinsic apoptotic pathway. In addition, in animal models, Fas-associated death domain protein phosphorylation at serine 194 has been shown to affect cell proliferation, especially in T lymphocytes. The importance of Fas-associated death domain protein phosphorylation at serine 194 for the proliferation of B lymphocytes, however, is uncertain. Here we show in reactive lymph nodes that serine 194 phosphorylated Fas-associated death domain protein is expressed predominantly in the dark (proliferative) zone of germinal centers. In B-cell non-Hodgkin lymphoma cell lines, serine 194 phosphorylated Fas-associated death domain protein levels are substantially higher in highly proliferating cells and lower in serum-starved cells. We also used immunohistochemical analysis to assess Fas-associated death domain protein phosphorylation at serine 194 expression in 122 B-cell non-Hodgkin-type lymphomas. The mean percentage of serine 194 phosphorylated Fas-associated death domain protein positive tumor cells was 81% in Burkitt lymphoma, 41% in diffuse large B-cell lymphoma, 18% in follicular lymphoma, 18% in plasma cell myeloma, 12% in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, 11% in mantle cell lymphoma, and 2% in chronic lymphocytic leukemia/small lymphocytic lymphoma (P b .0001, Kruskal-Wallis test). Furthermore, in chronic lymphocytic leukemia/small lymphocytic lymphoma, serine 194 phosphorylated Fas-associated death domain protein was detected predominantly in proliferation centers. In the entire study group, the percentage of cells positive for serine 194 phosphorylated Fas-associated death domain protein correlated significantly with the proliferation index Ki-67 (Spearman R = 0.9, P b .0001). These data provide evidence that serine 194 phosphorylated Fasassociated death domain protein is involved in the proliferation of normal and neoplastic B cells and has features of a novel proliferation marker.
Atherosclerosis Supplements, 2007
Modern Pathology, 2014
Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), a... more Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n=14) or more aggressive chemotherapy regimens (n=17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P=0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P=0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), less frequently expressed CD10 (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), and patients less often had an elevated serum lactate dehydrogenase level (P=0.01). In aggregate, these results support expanding the category of MYC/BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.
Blood, 2015
Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with HIV infection. Ho... more Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with HIV infection. However, PBL can also be seen in patients with other immunodeficiencies as well as in immunocompetent individuals. Due to its distinct clinical and pathological features, such as lack of expression of CD20, plasmablastic morphology, and clinical course characterized by early relapses and subsequent chemoresistance, PBL can represent a diagnostic and therapeutic challenge for pathologists and clinicians alike. Despite the recent advances on the therapy of HIV-associated and aggressive lymphomas, patients with PBL have for the most part poor outcomes. The objectives of this review are to summarize the current knowledge on the epidemiology, biology, clinical and pathological characteristics, differential diagnosis, therapy, prognostic factors, outcomes and potential novel therapeutic approaches in patients with PBL, and also to increase the awareness towards PBL in the medical community.
Human Pathology, 1999
The human myeloid cell nuclear differentiation antigen (MNDA) is a nuclear antigen knova~ to be e... more The human myeloid cell nuclear differentiation antigen (MNDA) is a nuclear antigen knova~ to be expressed in mature myelomonocytic cell fines. An extensive immunocytochemical evaluation of fixed tissues confirmed MNDA expression in normal maturing granulocytes and monocytes and in acute nonlymphocytic leukemias and chronic myelogenous leukemia. MNDA was not detected in normal tissue histiocytes but was found in activated macrophages and foreign body giant cells associated with inflammation. Flow cytometric cell sorting of normal bone marrow established that MNDA is initially expressed in myeloid blast cells. Examination of lymphoid tissues showed a low level of expression in a population of normal mantle B lymphocytes but not in germinal center cells or plasma cells. A subset of B cell neoplasms expressing MNDA included hairy ceil leukemia, parafollicular (monocytoid) B cell lymphoma, mantle cell lymphoma, and small lymphocytic lymphoma. Cell sorting of normal bone marrow showed MNDA expression in CD20+/CD10-/CD5 -B cells. MNDA was not detected in other normal bone marrow or all other nonhematopoietic cells. The hematopoietic cell-specific pattern of MNDA expression was elucidated through a comprehensive analysis of normal and neoplastic tissues, and the results provide further evidence of the coexpression of B-and myeloid cell markers in neoplastic B cells and identify a normal B cell population that might be related to the cell of origin of a subset of B cell neoplasms. HUM PATnOL 30:1040-1049.
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Papers by Roberto Miranda