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1.
Clin Case Rep ; 6(5): 915-916, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29744086

RESUMO

In the context of leukocytosis due to increased number of neutrophils and their precursors, with significant dysgranulopoiesis and no or minimal basophilia and no or minimal monocytosis, the typical feature of "clumped" chromatin, in irregularly coarse compacted nuclei, should lead to suspect the diagnosis of atypical chronic myeloid leukemia.

2.
World J Clin Pediatr ; 6(4): 176-179, 2017 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-29259893

RESUMO

Infantile pyknocytosis (IP) is a rare, self-limited neonatal haemolytic anaemia that may require multiple blood transfusions. Only a little more than 50 cases have been reported in the medical literature, and the great majority of them concerns term infants. The etiology of IP is not well understood; most likely it results from a transient extra-corpuscular factor, whose nature is unknown, transmitted from mother to child or, alternatively, from a deficiency of an anti-oxidative agent. We report the case of two preterm twins, one of which suffered from IP and developed severe anaemia at age 2 wk, while the other was unaffected. Although no specific agent was identified as the cause of anaemia and IP, we speculate that the transmission of an agent from mother to child was unlikely, as only twin one suffered from IP. Smelly greenish diarrhoea occurred just before the presentation of IP, suggesting that the same agent led to both the diarrhoea and the oxidative injury. Because IP may remain underdiagnosed, it should be considered in cases of early unexplained severe hemolytic anemia.

3.
J Forensic Sci ; 61(3): 858-861, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27122433

RESUMO

The need to implement novel techniques, able to support a causal link between exposure and pathology, has been emerged over the recent years. The application of scanning electron microscope coupled with probe X-ray microanalysis (by means of an energy-dispersive spectroscopy) has been developed by our research group for the bone remains investigation. It was aimed to testify the exposure to microsized and nanosized pollutions, due to military activities in the Quirra interforce firing range, of a Sardinian shepherd, died of acute leukemia. Metallic debris with a combustive morphology and with an oncogenic potential has been surely detected inside his bone marrow canal. This novel technique has proved to be able to bring to light a source of past exposure preserved over time within the bone marrow canal. It can be useful for postmortem analyses, delivering a new avant-garde approach to modern forensic science.

4.
Br J Haematol ; 172(4): 561-72, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26684692

RESUMO

Chronic/recurrent behaviour may be encountered in some distinct atypical or malignant lymphoproliferations, while recurrences are not generally observed in reactive/benign lymphadenopathies. We retrospectively analysed a consecutive series of 486 human immunodeficiency virus-negative adults, who underwent lymphadenectomy. Neoplastic and benign/reactive histopathological pictures were documented in 299 (61·5%) and 187 (38·5%) cases, respectively. Of note, seven of the 111 (6·3%) patients with benign lymphadenopathy without well-defined aetiology, showed chronic/recurrent behaviour, without constitutional symptoms. Enlarged lymph nodes were round in shape and hypoechoic, mimicking lymphoma. Reactive follicular hyperplasia and paracortical expansion were observed. Human herpesvirus (HHV)-6B positive staining in follicular dendritic cells (FDCs) was documented in all seven patients. Serological, molecular and immunological examinations suggested HHV-6B reactivation. Among the remaining 104 cases with reactive lymphoid hyperplasia in the absence of well-known aetiology and without recurrences, positivity for HHV-6B on FDCs was found in three cases, whereas in seven further patients, a scanty positivity was documented in rare, scattered cells in inter-follicular regions. Immunohistochemistry for HHV-6A and HHV-6B was invariably negative on 134 lymph nodes, with either benign pictures with known aetiology or malignant lymphoproliferative disorders, tested as further controls. Future studies are warranted to investigate a potential association between HHV-6B reactivation and chronic/recurrent benign lymphadenopathy.


Assuntos
Herpesvirus Humano 6/fisiologia , Doenças Linfáticas/virologia , Infecções por Roseolovirus/complicações , Adulto , Idoso , Doença Crônica , Células Dendríticas/patologia , Feminino , Humanos , Hiperplasia/virologia , Imuno-Histoquímica , Excisão de Linfonodo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/virologia , Recidiva , Estudos Retrospectivos , Ativação Viral
6.
Hematol Oncol ; 33(3): 147-51, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24777784

RESUMO

We conducted a population-based study to establish the outcome of T-cell lymphoma (TCL) patients failing systemic first-line therapy. All TCL patients failing first-line systemic therapy in the province of Modena were identified from Modena Cancer Registry between 1997 and 2010. A total of 53 patients were analysed. Regarding the type of failure, 18 patients relapsed, and 35 progressed during first treatment. Among relapsed patients, the median time from date of response to relapse after first treatment was 6.2 months (range 1.87-102). A total of 18 patients (34%) died before receiving salvage treatment, 21 received platinum or gemcitabine-containing regimens (7 addressed to autologous stem cell transplant (ASCT)), 12 other CT regimens; 2 received radiotherapy (RT). The median survival after relapse (SAR) was 2.5 months. After a median follow-up for living patients after failure of 35 months (range 8-111 months), 44 patients died, and the cause of death was found to be lymphoma progression in all (98%) but one of them. The median SAR was 2.5 months. The 3-year SAR was 19%. Univariate and multivariate Cox regression analyses for SAR were performed. In multivariate analysis, performance status and type of failure were associated with a higher risk of death after relapse. The outcome of TCL patients failing first-line therapy is poor. Only a few cases that could receive ASCT had promising chances of long remission. There is urgent need for novel agents for patients requiring second-line treatment.


Assuntos
Linfoma de Células T/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Humanos , Itália , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Recidiva , Sistema de Registros , Análise de Regressão , Estudos Retrospectivos , Terapia de Salvação , Transplante de Células-Tronco , Resultado do Tratamento , Adulto Jovem , Gencitabina
7.
PLoS One ; 9(6): e98818, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24901342

RESUMO

The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ET(A)R and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ET(A)R axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ET(A)R triggering. Moreover, the blockade of ET(A)R by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ET(A)R via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ET(A)R blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ET(A)R signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ET(A)R inhibition.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Endotelina-1/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Receptor de Endotelina A/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/sangue , Endotelina-1/genética , Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Prognóstico , Receptor de Endotelina A/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
9.
Exp Hematol ; 42(2): 126-36.e1, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24212063

RESUMO

Lenalidomide is an IMID immunomodulatory agent clinically active in patients with chronic lymphocytic leukemia (CLL). We evaluated the activity of lenalidomide inside an in vitro coculture system of endothelial and CLL cells. Lenalidomide was able to inhibit CLL survival advantage mediated by endothelial contact. Moreover, the marked increase of in vitro angiogenesis determined by CLL-derived conditioned media was reduced by lenalidomide. We also analyzed peripheral blood collected from 27 patients with relapsed or refractory CLL being treated with lenalidomide within a phase II trial. Plasma levels of VEGF and THBS-1 decreased, whereas Ang2 and Ang increased during treatment. Patients who respond to lenalidomide showed a more pronounced decrease of VEGF and bFGF than did patients with stable or progressive disease (p = 0.007 and p = 0.005). Furthermore, lenalidomide reduced circulating endothelial cells and endothelial progenitors by increasing the percentage of apoptotic cells. Conversely, for six matched bone marrow biopsies available before and after treatment, we did not detect any modification in vessel density, suggesting a possible mechanism of vessel normalization rather than regression. In conclusion, our study provides further evidence that the anti-CLL effect of lenalidomide is mediated through the alteration of microenvironmental elements, implying the modulation of several angiogenesis-related factors and disruption of CLL crosstalk with endothelial cells.


Assuntos
Indutores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Sobrevivência Celular , Células Endoteliais/patologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Talidomida/análogos & derivados , Feminino , Humanos , Lenalidomida , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Talidomida/uso terapêutico
10.
Future Oncol ; 9(10): 1437-42, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24106895

RESUMO

AIM: We report our experience with eribulin mesylate in a pancytopenic heavily pretreated patient with multiple bone metastases and bone marrow infiltration from breast cancer. METHODS: Eribulin mesylate was given at 1.4 mg/m(2) on day 1 and 8 every 3 weeks for a total of 11 courses. RESULTS: After seven cycles, evaluation with a bone marrow biopsy showed a large decrease of neoplastic involvement with substitution of osteolitic lesions for the osteoaddensant type. No unexpected acute toxicity was observed. CONCLUSION: To our knowledge, this represents the first report of bone marrow metastases from breast cancer treated with eribulin mesylate that obtained an improvement of hematopoietic values with an acceptable profile of tolerability and good compliance for the subject.


Assuntos
Neoplasias da Medula Óssea/secundário , Neoplasias Ósseas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Furanos/uso terapêutico , Cetonas/uso terapêutico , Coluna Vertebral/patologia , Medula Óssea/patologia , Neoplasias da Medula Óssea/diagnóstico , Neoplasias Ósseas/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Haematologica ; 98(7): 1115-23, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23349302

RESUMO

Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792 ± 86 cells/µL versus 485 ± 46 cells/µL, P=0.003). Higher numbers of non-classical CD14(+)CD16(++) and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated "education" of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population.


Assuntos
Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Teste de Cultura Mista de Linfócitos , Monócitos/patologia , Fagocitose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Teste de Cultura Mista de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo
14.
Haematologica ; 97(6): 952-60, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22207686

RESUMO

BACKGROUND: Chronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia. DESIGN AND METHODS: We evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after co-culture. RESULTS: We found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both ß(1)- and ß(2)- integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFß and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of anti-apoptotic molecules such as Bcl2 and Survivin. CONCLUSIONS: Our study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.


Assuntos
Linfócitos B/metabolismo , Antígenos CD18/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Integrina beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/patologia , Antígenos CD18/genética , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Integrina beta1/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Cultura Primária de Células , Transdução de Sinais/genética , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Vidarabina/análogos & derivados , Vidarabina/farmacologia
17.
Leuk Res ; 34(3): 312-21, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19616847

RESUMO

Emerging evidence suggests that angiogenic signalling pathways play important role in the patho-biology of chronic lymphocytic leukemia (CLL). Our goal was to investigate: (i) the spontaneous and hypoxia-induced production of pro-angiogenic factors, VEGF and Ang2, by Real-time PCR and ELISA, (ii) the degree of vascularization in CLL-infiltrated bone marrow (BM) compartment by CD34 immunohistochemical staining of microvessels and (iii) the direct angiogenic effect of CLL-derived VEGF and Ang2 by function-blocking experiments in Matrigel assays. The results demonstrated that CLL cells spontaneously express both VEGF and Ang2 and are able to secrete these factors in surrounding microenvironment. Full-length Ang2 mRNA and truncated form Ang2(443) were detectable. Moreover, CLL cells were shown to enhance secretion of both VEGF and Ang2 proteins when subjected to hypoxic condition. Furthermore, increased in vivo and in vitro angiogenesis was induced by CLL cells. Enhanced BM vascularity correlated with Ig-unmutated CLL subset and increased expression of Ang2. Then, we demonstrated that supernatants obtained from CLL cells significantly increase the HUVEC tube formation in Matrigel assays and that this enhanced angiogenic capacity is mediated by both CLL-derived VEGF and Ang2. Taken together, these results suggest that several simultaneous mechanisms may be involved in the CLL capacity to induce the disruption of pre-existing vessel structures to give rise to tumor neoangiogenesis. The preliminary studies in solid tumors, showing that the disruption of Ang2 function can inhibit tumor vessel density and growth, are encouraging and suggest the possibility of new future therapeutic options targeting CLL microenvironment.


Assuntos
Angiopoietina-2/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Medula Óssea/irrigação sanguínea , Medula Óssea/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Leuk Res ; 32(4): 593-7, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17928052

RESUMO

We measured the angiopoietin-2 (Ang-2) expression in early chronic lymphocytic leukemia (CLL) patients, pointing our attention on the association with immunoglobulin (IgV(H)) mutational status, CD38 expression and clinical outcome. Our results indicate that Ang-2 expression is heterogeneous among Binet stage A CLL patients. CLL patients can be divided into two subgroups (Ang-2 positive and Ang-2 negative CLL) with 30% of them displaying Ang-2 RNA levels above the cut off. A shorter progression-free survival was observed in Ang-2 positive CLL subset (p=0.032). Abnormal Ang-2 expression was also associated with unmutated IgV(H) genes (p<0.0001) and increased bone marrow angiogenesis (p=0.028), suggesting a role of Ang-2 in disease-progression of early CLL patients.


Assuntos
Angiopoietina-2/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia Linfocítica Crônica de Células B/genética , Linfoma de Células B/genética , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiopoietina-2/metabolismo , Medula Óssea/irrigação sanguínea , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Cadeias Pesadas de Imunoglobulinas , Região Variável de Imunoglobulina , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Células B/patologia , Masculino , Microcirculação , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Hematol Oncol ; 25(4): 189-97, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17654762

RESUMO

We conducted a population-based study of peripheral lymphomas (PL) that had been diagnosed between 1997 and 2003 in the province of Modena, Italy, with the aim of providing updated incidence, clinical and survival data for these cancers. We evaluated the incidence patterns and time trends of 1582 cases of PL that had been reclassified according to the WHO classification of hematological malignancies. Data regarding clinical characteristics, treatment and outcome were also collected for each case. The World Age-Standardized Rate (ASR) was calculated as 13.4, 2.2 and 3.4 per 100,000 people for B-cell non-Hodgkin's lymphoma (NHL), T-cell NHL and Hodgkin's Lymphoma (HL), respectively, with an increase of 1.62% per year during the study period. The lymphoma subtype showing the highest incidence was found to be diffuse large B-cell lymphoma (DLBCL) with an ASR of 4.8. Compared with reports from other western countries, our series is characterized by a higher incidence of HL and indolent B-NHL in general, and of CLL/SLL (ASR = 3.3) and marginal zone NHL (ASR = 1.5), in particular, and also by a lower incidence of FL (ASR = 2). After a median follow-up of 54 months, the 5-year relative survival for the whole series was found to be 70% with a statistically significant improvement for cases diagnosed during 2002-2003 (from 66 to 74%; p = 0.03). Survival improvement within the study period was also evident for patients with DLBCL, HL and T-NHL. Our study provides a comprehensive description of both the epidemiological and clinical features of PL cases in Modena and our data also reflect the major advances in the curability of some histological subtypes of this disease. The usefulness of a population-based approach to better characterizing different lymphoma subtypes is also demonstrated.


Assuntos
Linfoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Doença de Hodgkin , Humanos , Incidência , Itália/epidemiologia , Linfoma/classificação , Linfoma/mortalidade , Linfoma/patologia , Linfoma/terapia , Linfoma de Células B , Linfoma de Células T , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida
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