Complete remission of Sweet's syndrome after azacytidine treatment for concomitant myelodysplastic syndrome

Sweet's syndrome is a rare condition with potentially disabling implications, characterized by painful skin lesions due to neutrophilic dermal infiltration and systemic inflammatory symptoms. A significant proportion of cases is malignancy associated. Hematologic neoplasms, particularly acute myeloid leukemia and myelodysplastic syndromes, are the most commonly associated malignant conditions. Here, we describe the first case of clinical remission of refractory Sweet's syndrome following hypomethylating therapy with azacytidine in a patient with myelodysplastic syndrome who concurrently obtained a complete hematologic response

Molecular cytogenetic lesions in chronic lymphocytic leukemia

Molecular cytogenetic lesions in CLL

Erratum to: Circulating endothelial cells in patients with chronic lymphocytic leukemia: Clinical-prognostic and biologic significance (Cancer (2010) 116, (1926-37))

[No abstract available

CLINICAL AND BIOLOGICAL CHARACTERIZATION OF CIRCULATING ENDOTHELIAL CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

Background. Several studies have shown that bone marrow-derived endothelial cells (EC) may contribute to tumor angiogenesis and that in the peripheral blood of cancer patients there is an increased amount of circulating ECs (CECs) that may participate to new vessel formation. Recent data also showed that in B-cell neoplasms ECs are in part tumorrelated reflecting a novel aspect of tumor angiogenesis. All together these observations suggest that tumors can elicit the sprouting of new vessels from existing capillaries through the secretion of angiogenic factors and that, in some cases, cancer cells can also mimic the activities of ECs by participating in the formation of vascular-like networks. Aims. To characterize the clinical and biological role of CECs in a series of 85 chronic lymphocytic leukemia (CLL) patients. Methods. CEC levels were evaluated by multiparameter flow cytometry and correlated with known clinical and biological parameters. For biological studies, CECs were first isolated by immunomagnetic sorting and then characterized by phenotypic studies with antibodies recognizing endothelial and CLL antigens, by FISH analyses with specific probes and by gene expression profiling comparing CLL CECs with CECs from normal subjects, and with monocytes and lymphocytes from the same CLL patient. Results. CEC levels were significantly higher in CLL patients in comparison to normal healthy subjects (p=0.037). Higher CEC levels were associated with advanced disease stage (p=0.012) and with lack of response to treatment or progressive disease (p=0.005). No association was demonstrated with CD38/ZAP70 expression and FISH/cytogenetic abnormalities. In all experiments more than 95% of immunomagnetically sorted cells were of EC origin as demonstrated by phenotypic analyses (VEGFR2+, vWF+, CD144+, UEA1 lectin+, CD45–, CD14–, CD5–, CD19–). FISH analysis showed that a significant proportion of sorted CECs was tumorderived because they harbored the same genetic lesion as observed in neoplastic CLL cells. The fraction of CECs showing cytogenetic aberrations averaged 40.7% (range, 20-78%). More then 85% of CECs presented features of EPCs because they expressed CD133, a marker gradually lost during EC differentiation and absent in mature ECs. CLL CEC had a similar gene expression pattern for several genes characterizing CEC function such as CD144, CD34, CD133, CD146, CD31, VEGFR2, VEGFR3, VWF, and TIE2. Moreover, CLLCEC showed a strongly different gene expression pattern compared to normal CEC characterised by increased cell survival and proliferation including activation of Wnt and inhibition of Notch signalling pathways, reduction of cell adhesion to extracellular matrix and enhanced pro-angiogenic function. Gene expression profiling analysis also suggested that similarities exist with clonal CLL lymphocytes. Conclusions. These findings suggest that in CLL CECs are in part tumor related and with a gene expression profile that may indicate their contribution to tumor neovasculogenesis and possibly to the spreading and progression of the disease

CLINICAL AND BIOLOGICAL CHARACTERIZATION OF CIRCULATING ENDOTHELIAL CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

Several studies have shown that bone marrow-derived endothelial cells (EC) may contribute to tumor angiogenesis and that in the peripheral blood of cancer patients there is an increased amount of circulating ECs (CECs) that may participate to new vessel formation. Recent data also showed that in B-cell neoplasms ECs are in part tumor-related reflecting a novel aspect of tumor angiogenesis. All together these observations suggest that tumors can elicit the sprouting of new vessels from existing capillaries through the secretion of angiogenic factors and that, in some cases, cancer cells can also mimic the activities of ECs by participating in the formation of vascular-like networks. In this study we aim to characterize the clinical and biological role of CECs in a series of 85 chronic lymphocytic leukemia (CLL) patients. CEC levels were evaluated by multiparameter flow cytometry and correlated with known clinical and biological parameters. For biological studies, CECs were first isolated by immunomagnetic sorting and then characterized by phenotypic studies with antibodies recognizing endothelial and CLL antigens, by FISH analyses with specific probes and by gene expression profiling comparing CLL CECs with CECs from normal subjects, and with monocytes and lymphocytes from the same CLL patient. We found that CEC levels were significantly higher in CLL patients in comparison to normal healthy subjects (p=0.037). Higher CEC levels were associated with advanced disease stage (p=0.012) and with lack of response to treatment or progressive disease (p=0.005). No association was demonstrated with CD38/ZAP70 expression and FISH/cytogenetic abnormalities. In all experiments more than 95% of immunomagnetically sorted cells were of EC origin as demonstrated by phenotypic analyses (VEGFR2+, vWF+, CD144+, UEA1 lectin+, CD45–, CD14–, CD5–, CD19–). FISH analysis showed that a significant proportion of sorted CECs was tumor-derived because they harbored the same genetic lesion as observed in neoplastic CLL cells. The fraction of CECs showing cytogenetic aberrations averaged 40.7% (range, 20-78%). More then 85% of CECs presented features of EPCs because they expressed CD133, a marker gradually lost during EC differentiation and absent in mature ECs. CLL CEC had a similar gene expression pattern for several genes characterizing CEC function such as CD144, CD34, CD133, CD146, CD31, VEGFR2, VEGFR3, VWF, and TIE2. Moreover, CLLCEC showed a strongly different gene expression pattern compared to normal CEC characterised by increased cell survival and proliferation including activation of Wnt and inhibition of Notch signalling pathways, reduction of cell adhesion to extracellular matrix and enhanced pro-angiogenic function. Gene expression profiling analysis also suggested that similarities exist with clonal CLL lymphocytes. In conclusion these findings suggest that in CLL CECs are in part tumor related and with a gene expression profile that may indicate their contribution to tumor neovasculogenesis and possibly to the spreading and progression of the disease

Electrically conductive thermal interface materials based on vertically aligned carbon nanotubes mats

In power microelectronics, the trends towards miniaturization and higher performances result in higher power densities and more heat to be dissipated. In most electronic assembly, thermal interface materials (TIM) help provide a path for heat dissipation but still represent a bottleneck in the total thermal resistance of the system. VA-CNTs mats are typically grown on HR silicon substrate with Al2O3 diffusion barrier layer using Thermal CVD process. In many cases, 'die attach' thermal interface materials need to be electrically conductive and the growth of dense VA-CNT mats on an electrically conductive substrate remains a challenge. This paper presents the growth of dense VA-CNT mats on doped silicon with Al2O3 and TiN diffusion barrier layer. Processes, thermal and electrical characterization of VA-CNTs based thermal interface materials are studied and reported

Delirium in acute promyelocytic leukemia patients: two case reports.

BACKGROUND: Delirium is a frequently misdiagnosed and inadequately treated neuropsychiatric complication most commonly observed in terminally ill cancer patients. To our knowledge this is the first report describing delirium in two patients aged less than 60 years and enrolled in an intensive chemotherapeutic protocol for acute promyelocytic leukemia. CASE PRESENTATION: Two female Caucasian acute promyelocytic leukemia patients aged 46 and 56 years developed delirium during their induction treatment with all-trans retinoic acid and idarubicin. In both cases symptoms were initially attributed to all-trans retinoic acid that was therefore immediately suspended. In these two patients several situations may have contribute to the delirium: in patient 1 a previous psychiatric disorder, concomitant treatments with steroids and benzodiazepines, a severe infection and central nervous system bleeding while in patient 2 steroid treatment and isolation. In patient 1 delirium was treated with short-term low-doses of haloperidol while in patient 2 non-pharmacologic interventions had a beneficial role. When the diagnosis of delirium was clear, induction treatment was resumed and both patients completed their therapeutic program without any relapse of the psychiatric symptoms. Both patients are alive and in complete remission as far as their leukemia is concerned. CONCLUSIONS: We suggest that patients with acute promyelocytic leukemia eligible to intensive chemotherapy should be carefully evaluated by a multisciplinary team including psychiatrists in order to early recognize symptoms of delirium and avoid inadequate treatments. In case of delirium, both pharmacologic and non-pharmacologic interventions may be considered

CYTOGENETIC ABERRATIONS IN THE CD38 POSITIVE FRACTION OF CD38 NEGATIVE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS: A MARKER OF AGGRESSIVENESS?

Background. Chronic lymphocytic leukemia (CLL) is a disease with a high variability in clinical presentation and outcome. Even though many patients live for long periods with the disease, some cases may show a progression to a more aggressive leukemia which may be characterized by the acquisition of new genetic abnormalities either by clonal evolution or by an expansion of a clone with high risk aberrations. Prognostic parameters that correlate with worse clinical outcome include stage, the expression of CD38 and/or ZAP70, the unmutated configuration of the variable region of the immunoglobulin heavy chain gene (IGHV), the presence of specific chromosome aberrations and/or molecular mutations affecting TP53, NOTCH1, SF3B1 and BIRC3. However in patients with favourable prognostic features the biologic and molecular events leading to disease progression and the occurrence of new molecular cytogenetic lesions are largely unknown. Aims. We studied the biologic and clinical significance of minor cytogenetically abnormal clones in the CD38 positive fraction of untreated CLL patients with good prognostic parameters (CD38 negativity and normal karyotype or del(13)(q14) as single aberration). Methods. Twenty eight consecutive CD38 negative (Cd38 positive cells < 5%) CLL patients with normal karyotype or del(13)(q14) were evaluated in this study. CD38 positive and CD38 negative CLL cells were isolated by sequential immunomagnetic sorting (Dynabeads) following depletion of CD3, CD16, CD14 positive cells (purity > 99%). CD38 positive and negative cells were then analyzed by (i) FISH analysis using commercially available probes for the regions most frequently involved in CLL patients (13q14, 12q13, 11q22/ATM, 17p13/TP53, 14q32) and by (ii) micro-RNA expression. Data were then correlated with clinical parameters. Results. In 16/28 CD38 negative CLL patients, FISH analysis demonstrated the presence of minor (15-34% of the cells) cytogenetically abnormal clones within the CD38 positive fraction: 11q deletion in 7 cases, 17p deletion in 6, trisomy 12 in 5, 14q32 rearrangements in 1 case. According to FISH results patients were therefore classified as CLL with and without subclones in the CD38 positive fraction. By micro-RNA analysis we found that patients with subclones had a distinctive profile, when compared to patients without subclones, characterized by a downregulation of microRNA- 125a-5p (a tumor suppressor in various malignancies) both in the CD38 negative and positive populations. With a median follow-up of 36 months, patients with subclones showed a higher need of treatment ( 9/16 cases vs 1/11 in patients with and without subclones respectively, p=0.0159). Among CLL patients with subclones, 2 cases showed the emergence of a major clone in the peripheral blood sample (45-67% of the cells) with the same genetic lesions previously observed in the CD38 positive subpopulations.ConclusionsOur data showed that genetic instability within the CD38 positive fraction of CLL patients with favourable prognostic features (CD38 negativity and normal karyotype or del13q14) may favour the growth of small clones with poor prognosis cytogenetic aberrations which may be associated with microRNA-125a-5p disregulation, clonal expansion and, in some cases, disease progression

Clonal evolution including 14q32/IGH translocations in chronic lymphocytic leukemia: analysis of clinicobiologic correlations in 105 patients.

To better define the significance of clonal evolution (CE) including 14q32 translocations involving the immunoglobulin heavy chain gene (IGH) in chronic lymphocytic leukemia (CLL), 105 patients were analyzed sequentially by fluorescence in situ hybridization (FISH) with the following panel of probes: 13q14/D13S25, 11q22/ATM, 17p13/TP53, #12-centromere and 14q32/IGH break-apart probe. CE was observed in 15/105 patients after 24-170 months (median 64). Recurring aberrations at CE were 14q32/IGH translocation in seven patients; other aberrations were 17p -, 11q -, biallelic 13q - and 14q32 deletion. CE was detected in 15/58 pre-treated patients; in contrast, none of 47 untreated patients developed CE (p < 0.0001). In two cases the appearance of 14q32/IGH translocation was first detected in the bone marrow (BM) or in the lymph node (LN) and 13-58 months later in the peripheral blood (PB). ZAP70 + and high-risk cytogenetics predicted for the occurrence of CE with borderline statistical significance (p = 0.055 and 0.07, respectively). Shorter time to first treatment (TTT) and time to chemorefractoriness (TTCR) were noted in 15 patients with CE when compared to patients without CE (TTT: 35 vs. 71 months, p = 0.0033 and TTCR: 34 vs. 86 months, p = 0.0046, respectively). Survival after the development of CE was 32 months (standard error 8.5). We arrived at the following conclusions: (i) 14q32/IGH translocation may represent one of the most frequent aberrations acquired during the natural history of CLL and (ii) it may be detected earlier in BM or LN samples; (iii) CE including 14q32/IGH translocation occurs in pre-treated patients with short TTT and TTCR; (iii) survival after CE is relatively short