Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia.

We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective "off-the-shelf" immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.

Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis.

BACKGROUND: The social impact of degenerative diseases is steadily increasing, because of the continued rise in the mean age of the active population. Articular cartilage lesions are generally associated with disability and symptoms such as joint pain and reduced function, and remain a challenge for the orthopaedic surgeon. Several non-invasive solution have been proposed, but the results achieved to date are far from being completely satisfactory. Recently, new therapeutic approaches, such as the use of mesenchymal stem cells, have been developed. Among the many sources, the adipose tissue is nowadays considered one of the smartest, due to its abundance and easy access. The aim of this retrospective study is to explore whether patients affected by symptomatic knee osteoarthritis treated with micro-fragmented adipose tissue associated with a chondral shaving procedure experience an improvement in symptoms and function. METHODS: Thirty-eight patients affected by symptomatic knee osteoarthritis were treated in 2015 with an arthroscopic procedure associated with an injection of autologous and micro-fragmented adipose tissue. Micro-fragmented adipose tissue was obtained using a minimal manipulation technique in a closed system. Clinical outcomes were determined at 1, 3, 6, and 12 months follow-up using Knee Injury and Osteoarthritis Outcome Score questionnaire and direct physical examination. Safety of the procedure, recording type and incidence of any adverse event, was also assessed. RESULTS: A steady and statistically significant improvement of all the clinical scores from pre-operative evaluation to 1, 3, 6, and 12 months follow-up was observed, with KOOS sport and quality of life being the most improved scores. On average, 92% of the patients clinically improved and 100% of them were satisfied with the treatment. No adverse events nor relevant complications were recorded. CONCLUSION: The result of the study pointed to micro-fragmented adipose tissue as a safe and beneficial adjuvant in the surgical treatment of degenerative knee chondropathy. The procedure is simple, sustainable, quick, minimally invasive, one-step, and safe. After one year, the results are very satisfactory and promising. A longer follow-up is needed to draw definitive conclusions and enlarge the indications. TRIAL REGISTRATION: Registered at clinicaltrials.gov as NCT03527693 on 27 April 2018 (retrospectively registered).

Análise conjunta de indicadores na viabilidade econômica do confinamento de novilhos recebendo dietas com diferentes níveis de concentrado / Joint analysis of economic viability indicators of feedlot steers fed diets with different concentrate levels

O objetivo deste estudo foi avaliar a viabilidade econômica, por meio da análise conjunta de indicadores financeiros expressos por animal, da terminação em confinamento de novilhos Aberdeen Angus recebendo dietas com diferentes níveis de concentrado (NC): 25, 40, 55 ou 70% (base na matéria seca). Foram consideradas cotações históricas consecutivas dos anos de 2003 a 2014. A análise univariada caracterizou-se por delineamento inteiramente ao acaso, com quatro tratamentos e quatro repetições, procedendo-se à análise de regressão. A análise multivariada consistiu de agrupamento (cluster). Pela análise univariada, houve similaridade para os indicadores financeiros, com médias para margem bruta de R$ 173,21; margem líquida de R$ 163,73; lucro de R$ 110,61; valor presente líquido de R$ 93,31; índice benefício: custo de 1,048; retorno adicional sobre o investimento de 1,17% a.m.; taxa interna de retorno de 2,04% a.m. e payback descontado de 1,36 mês. Pela análise de cluster, o NC de 55% apresentou maior discrepância em relação aos demais níveis, enquanto 40 e 70% foram os mais próximos. A análise conjunta dos indicadores financeiros indicou viabilidade do confinamento de novilhos, independentemente do nível de concentrado.

The objective of this study was to evaluate the economic viability, through the joint analysis of financial indicators expressed by animal, of the Aberdeen Angus steers feedlot finished fed diets with different levels of concentrate (CL): 25, 40, 55 or 70% (on dry matter basis). Consecutive historical quotes of years 2003 to 2014 were considered. Univariate analysis was characterized by a completely randomized design with four treatments and four replications, proceeding regression analysis. Multivariate analysis consisted of grouping (cluster). The univariate analysis showed similarity to the financial indicators with averages to gross margin of R$ 173.21; net margin of R$ 163.73; income of R$ 110.61; net present value of R$ 93.31; benefit: cost ratio of 1.048; additional return on investment of 1.17% per month; internal rate of return of 2.04% per month and discounted payback of 1.36 months. By cluster analysis, 55% CL presented greater discrepancy in relation to other levels, while 40 and 70% were the nearest. The analysis of the financial indicators indicated feasibility of feedlot steers, regardless of the concentrate level.

Análise conjunta de indicadores na viabilidade econômica do confinamento de novilhos recebendo dietas com diferentes níveis de concentrado / Joint analysis of economic viability indicators of feedlot steers fed diets with different concentrate levels

O objetivo deste estudo foi avaliar a viabilidade econômica, por meio da análise conjunta de indicadores financeiros expressos por animal, da terminação em confinamento de novilhos Aberdeen Angus recebendo dietas com diferentes níveis de concentrado (NC): 25, 40, 55 ou 70% (base na matéria seca). Foram consideradas cotações históricas consecutivas dos anos de 2003 a 2014. A análise univariada caracterizou-se por delineamento inteiramente ao acaso, com quatro tratamentos e quatro repetições, procedendo-se à análise de regressão. A análise multivariada consistiu de agrupamento (cluster). Pela análise univariada, houve similaridade para os indicadores financeiros, com médias para margem bruta de R$ 173,21; margem líquida de R$ 163,73; lucro de R$ 110,61; valor presente líquido de R$ 93,31; índice benefício: custo de 1,048; retorno adicional sobre o investimento de 1,17% a.m.; taxa interna de retorno de 2,04% a.m. e payback descontado de 1,36 mês. Pela análise de cluster, o NC de 55% apresentou maior discrepância em relação aos demais níveis, enquanto 40 e 70% foram os mais próximos. A análise conjunta dos indicadores financeiros indicou viabilidade do confinamento de novilhos, independentemente do nível de concentrado.(AU)

The objective of this study was to evaluate the economic viability, through the joint analysis of financial indicators expressed by animal, of the Aberdeen Angus steers feedlot finished fed diets with different levels of concentrate (CL): 25, 40, 55 or 70% (on dry matter basis). Consecutive historical quotes of years 2003 to 2014 were considered. Univariate analysis was characterized by a completely randomized design with four treatments and four replications, proceeding regression analysis. Multivariate analysis consisted of grouping (cluster). The univariate analysis showed similarity to the financial indicators with averages to gross margin of R$ 173.21; net margin of R$ 163.73; income of R$ 110.61; net present value of R$ 93.31; benefit: cost ratio of 1.048; additional return on investment of 1.17% per month; internal rate of return of 2.04% per month and discounted payback of 1.36 months. By cluster analysis, 55% CL presented greater discrepancy in relation to other levels, while 40 and 70% were the nearest. The analysis of the financial indicators indicated feasibility of feedlot steers, regardless of the concentrate level.(AU)

Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management.

Cerebral cavernous malformations (CCMs) are a diffuse cerebrovascular disease affecting approximately 0.5% of the population. A CCM is characterized by abnormally enlarged and leaky capillaries arranged in mulberry-like structures with no clear flow pattern. The lesion might predispose to seizures, focal neurological deficits or fatal intracerebral hemorrhage. However, a CCM can also remain neurologically silent. It might either occur sporadically or as an inherited disorder with incomplete penetrance and variable expressivity. Due to advances in imaging techniques, the incidence of CCM diagnoses are increasing, and the patient must be managed on a multidisciplinary basis: genetic counselling, treatment if needed, and follow-up. Advances have been made using radiological and pathological correlates of CCM lesions adding to the accumulated knowledge of this disease, although management of these patients is very variable among centers. This review is aimed at providing an update in genetic and molecular insights of this condition. Included are implications for genetic counselling, and possible approaches to prevention and treatment that derive from the understanding of pathogenetic mechanisms.

Miniaturized flow cytometry-based BCR-ABL immunoassay in detecting leptomeningeal disease.

Despite central nervous system (CNS) prophylactic programs limit leptomeningeal involvement in acute lymphoblastic leukemia (ALL), it can still occur in a restricted percentage of cases. The exact risk rate remains still unknown, and several factors are associated with an increased probability to develop CNS involvement. Among them, Philadelphia (Ph)-positive genotype seems to play a relevant role. Recently, a flow cytometric assay to detect BCR-ABL protein has been developed, but little is known about its possible employment in leptomeningeal disease. Here, we show the miniaturized application of the original assay for BCR-ABL oncoprotein detection in cerebrospinal fluid (CSF) samples.

[Metabolic syndrome: from insulin resistance to adipose tissue dysfunction]. / Sindrome metabolica: dall'insulino-resistenza alla disfunzione del tessuto adiposo.

Recently the definition, the pathophysiology and even the clinical utility of metabolic syndrome (MS) have been discussed. The risk induced by each component of the metabolic syndrome is higher than the risk induced by MS alone. MS alone is, in fact, a weaker predictor of cardiovascular disease than diabetes. New criteria to define the metabolic syndrome have been proposed, as adipokines, CRP and PAI-1. IGFBP-1 is related to hyperinsulinemia/insulin resistance and to the risk of diabetes and fatal ischemic heart disease development. IGF/IGFBP system could be a link between insulin resistance and cardiovascular disease. RBP-4 can attenuate insulin signalling in skeletal muscle and induce hepatic gluconeogenesis. The belief that insulin-resistance is the main cause of MS could change in favour of the adipose tissue dysfunction. The most common cause of a reduced capacity of the adipose tissue to store fats is the increased dietary intake, also present in lipodistrophy, type 1 diabetes mellitus and polycystic ovarian syndrome. The adipose tissue production of adipokines and cytokines (such as IL-6, TNF-alpha and TGF-beta) and the excessive lipid flux towards muscles, heart and liver (Ectopic fat storage syndrome) contribute to the MS genesis and to an increased cardiovascular risk. The comprehension of adipose tissue dysfunction mechanisms offers new possibilities of prevention and therapy.

Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has a dismal prognosis. We prospectively evaluated minimal residual disease (MRD) by measuring BCR/ ABL levels with a quantitative real-time PCR procedure after induction and after consolidation in 45 adults with Ph+ ALL who obtained complete hematological remission after a high-dose daunorubicin induction schedule. At diagnosis, the mean BCR-ABL/GUS ratio was 1.55 +/- 1.78. A total of 42 patients evaluable for outcome analysis were operationally divided into two MRD groups: good molecular responders (GMRs; n = 28) with > 2 log reduction of residual disease after induction and > 3 log reduction after consolidation therapy, and poor molecular responders (PMRs; n = 14) who, despite complete hematological remission, had a higher MRD at both time points. In GMR, the actuarial probability of relapse-free, disease-free and overall survival at two years was 38, 27 and 48%, respectively, as compared to 0, 0 and 0% in PMR (P = 0.0035, 0.0076 and 0.0026, respectively). Salvage therapy induced a second sustained complete hematological remission in three GMR patients, but in no PMR patient. Our data indicate that, as already shown in children, adult Ph+ ALL patients have a heterogeneous sensitivity to treatment, and that early quantification of residual disease is a prognostic parameter in this disease.

Characteristics of secondary acute lymphoblastic leukemia with L3 morphology in adult patients.

Secondary acute lymphoblastic leukemia (sALL) is an uncommon condition and sALL with L3 morphology is still less frequent. Here, we compare the characteristics of available cases of L3 sALL (16 patients, including 12 previously published cases and 4 personal cases) to those of de novo L3 ALL and of non L3 sALL. Two patients with L3 sALL obtained a CR after aggressive treatment of their leukemia. Compared with 24 patients from the literature with de novo L3 ALL, L3 sALL patients were characterized by an older age (median 46 vs. 29.5 years, p = 0.0003) and by a poor prognosis (complete responses: 2/16 vs. 19/24, p = 0.0001, median survival: 0.46 month vs. undetermined, p < 0.0001). In comparison with 19 patients from the literature with non L3 sALL, L3 sALL patients were characterized by a high Male/Female ratio (14/2 vs. 8/11, p = 0.01), a frequent history of Hodgkin's disease (12/16 vs. 7/19, p = 0.04) and, again, by a poor prognosis (complete responses: 2/16 vs. 13/18, p = 0.0001, median survival 0.46 vs. 13 months, p = 0.001). In conclusion, though based on a small group of heterogeneously treated patients, some characteristics of L3 sALL, seem to emerge, compared both with de novo L3 ALL and with non L3 sALL, the most prominent being its extremely poor prognosis.

Partial deletions of long arm of chromosome 6: biologic and clinical implications in adult acute lymphoblastic leukemia.

Within 285 adult acute lymphoblastic leukemias (ALL) included in the multicenter GIMEMA 0496 trial and prospectively studied by conventional cytogenetics, 18 cases (6%) with long arm deletion of chromosome 6 (6q) were identified. These cases were divided into: (i) del(6q) only (n = 6); (ii) del(6q) plus other numerical and/or structural abnormalities (n = 8); (iii) del(6q) and other 'specific' translocations (n = 4). The biologic and clinical features of the patients carrying this anomaly, as well as their outcome, were compared with those of 267 patients without del(6q). A T cell phenotype was more frequently associated with del(6q) cases in general (P = 0.001) and particularly with cases presenting del(6q) as the isolated abnormality (P = 0.0027). No significant difference with respect to multidrug resistance (MDR)/P glycoprotein expression was observed between the two groups of patients (21% vs 28% of MDR-positive cases, respectively). A BCR-ABL fusion transcript was less frequently detected in cases with del(6q) (11%) compared with those without the anomaly (29%). p15 and p16 deletions were identified by Southern blot analysis in 21% of cases with del(6q) and in 26% of cases without del(6q). In this latter group, a T cell phenotype was less frequently associated with p15 and/or p16 deletion than in the group carrying del(6q) (36% vs 100% of cases, P = 0.011). Overall, patients with ALL and del(6q) had a high complete remission (CR) rate (83%); however, they had a lower 18 month event-free survival (31% vs 41%) and a higher relapse rate (70% vs 37%, P = 0.02) compared with patients without del(6q). To date, this is the largest series of adult ALL cases reported with del(6q) homogeneously treated, which have also been prospectively studied for MDR expression and for the detection of known fusion genes. This anomaly, as an isolated change, identifies a subset of cases with hyperleukocytosis (median WBC count 52 x 10(9)/l) and a strict correlation with a T cell phenotype. Overall, del(6q) seems to be associated with an unfavorable clinical outcome, although this finding will need to be confirmed by extended FISH analysis.

Acute megakaryoblastic leukemia: experience of GIMEMA trials.

The objective of the study was to evaluate the incidence, characteristics, treatment and outcome of acute megakaryoblastic leukemia (AMeL) in patients enrolled in GIMEMA trials. Between 1982 and 1999, 3603 new consecutive cases of AML aged over 15 years were admitted to GIMEMA trials. Of them, 24 were AMeL. The incidence of AMeL among AML patients enrolled in GIMEMA trials was 0.6% (24/3603). Diagnosis was based on morphological criteria. Out of 11 cytogenetic studies performed two presented chromosome 3 abnormalities. Twelve patients (50%) reached a CR, five (21%) died in induction and seven (27%) were unresponsive. The median duration of CR was 35 weeks (range 10-441). Seven patients underwent transplantation procedures (1 BMT, 4 aBMT, 2 aPBSCT). Four patients died in CR due to chemotherapy-related complications. Comparing the CR rate between AMeL and the other cases of AML enrolled in GIMEMA trials, no differences were observed. These results were mirrored for different age groups. The median survival was 40 weeks. At present, after a follow-up of a minimum of 2 years, only two patients are alive in CR, all the others having died. A 5-year Kaplan-Meier curve shows a disease-free survival of 17% and an actuarial overall survival of 10%. AMeL is a rare form of AML. The CR duration and the overall survival in this group of patients are very poor, even if similar to those observed in other AML. Furthermore, a high number of deaths in CR were observed. On the basis of these data, a specific therapeutic approach, possibly with innovative treatments, should be evaluated.

Severe pancytopenia and intrahepatic cholestasis in a patient with a history of Hodgkin's disease. Responsiveness to high-dose pulse steroid therapy and diagnosis of a late relapse.

A 47-year-old male, treated 7 years earlier for Hodgkin's disease (HD), was admitted with persistent fever, liver enlargement, and increased cholestasis parameters. He developed acute bone marrow failure and progressive worsening of his clinical condition and cholestasis markers without showing evidence of HD recurrence or second malignancy. High-dose intravenous pulse methylprednisolone therapy was given, after which resolution of pyrexia and progressive improvement in performance status and in hematological counts and cholestasis parameters were observed. During this phase, a bone biopsy showed HD marrow infiltration. This clinical course may reflect tumor cytokine-induced phenomena, significantly affected by high-dose steroids.

Characterization of two novel cell lines, DERL-2 (CD56+/CD3+/Tcry5+) and DERL-7 (CD56+/CD3-/TCRgammadelta-), derived from a single patient with CD56+ non-Hodgkin's lymphoma.

Two novel IL2-dependent cell lines, DERL-2 and DERL-7, were established from a patient with hepatosplenic gammadelta T cell lymphoma. This patient presented, at diagnosis, two discrete populations of CD56+ cells, one TCRgammadelta+, the second lacking T cell-restricted antigens. The cell lines derived displayed features corresponding to the two cellular components of the disease: DERL-2 was CD56+/CD3+/TcRgammadelta+ while DERL-7 was CD56+/CD3-/TcRgammadelta-. Along with CD56, the two cell lines shared the expression of CD7, CD2, CD158b and CD117. Karyotype analysis showed that both cell lines were near-diploid, with iso-7q and loss of one chromosome 10. In addition, DERL-2 showed 5q+ in all metaphases analyzed, while DERL-7 revealed loss of one chromosome 4. Genotypically, both cell lines shared the same STR pattern at nine loci and demonstrated an identical rearranged pattern of the T cell receptor genes beta, gamma and delta, with respect to the original tumor cells. These data indicated that both cell lines and the original neoplastic populations were T cell-derived and arose from a common ancestor. Among a large panel of cytokines tested, only SCF was able to substitute IL2 in supporting cell proliferation. Moreover, SCF and IL2 acted synergistically, dramatically enhancing cell growth. These cell lines may represent a model to further analyze the overlap area between T and NK cell malignancies, and may provide new information about the synergistic action of IL2 and SCF on normal and neoplastic T/NK cells.

Endoscopic management of foreign bodies in the upper gastrointestinal tract: report on a series of 414 adult patients.

BACKGROUND AND STUDY AIMS: Ingestion of foreign bodies is a common occurrence. Few papers in the literature report experience and outcome at tertiary centers. The aim of this paper is to report the management and the outcomes in 414 patients admitted for suspected ingestion of foreign body between May 1995 and December 1999. METHODS: A plain radiographic film of the neck, chest or abdomen was obtained in the case of radiopaque objects, and in order to rule out suspected perforation: in such cases a computed tomography (CT) study was also performed. All patients were asked to give their informed consent, which was refused by three patients. Anesthesia was always used, either conscious sedation (86.8 %), or general anesthesia in the case of poor patient tolerance (13.2 %). All patients underwent an endoscopic procedure within six hours of admission. A flexible scope was used in all patients and a wide range of endoscopic devices was employed. RESULTS: Foreign bodies were found in 64.5 % of our patients. Almost all were found in the esophagus. The types of foreign body were very different, but they were chiefly food boluses, bones or cartilages, dental prostheses or fish bones. In three patients (1.1 %) it was impossible to endoscopically remove the foreign body, which was located in the cervical esophagus: all these three patients required surgery. No complications relating to the endoscopic procedure were observed, but 30.7 % of patients had an underlying esophageal disease, such as a stricture. Only eight patients required a second endoscopic procedure, performed by a more experienced endoscopist. CONCLUSION: Foreign body ingestion represents a frequent reason for emergency endoscopy. The endoscopic procedure is a successful technique which allows the removal of the foreign bodies in almost all cases without significant complications. Surgery is rarely required.

Prevalence of thyroid disorders in untreated adult celiac disease patients and effect of gluten withdrawal: an Italian multicenter study.

OBJECTIVES: Many afflictions have been associated with celiac disease, but chance associations may exists. The aim of this study was to establish, by means of a multicenter prospective study, the prevalence of thyroid impairment among adult patients with newly diagnosed celiac disease and to evaluate the effect of a 1-yr gluten withdrawal on thyroid function. METHODS: A total of 241 consecutive untreated patients and 212 controls were enrolled. In 128 subjects a thorough assessment, including intestinal biopsy, was repeated within 1 yr of dietary treatment. Thyroid function was assayed by measuring the levels of TSH, free T3, free T4, thyroperoxidase, and thyroid microsome antibodies. RESULTS: Thyroid disease was 3-fold higher in patients than in controls (p < 0.0005). Hypothyroidism, diagnosed in 31 patients (12.9%) and nine controls (4.2%), was subclinical in 29 patients and of nonautoimmune origin in 21. There was no difference regarding hyperthyroidism, whereas autoimmune thyroid disease with euthyroidism was present in 39 patients (16.2%) and eight controls (3.8%). In most patients who strictly followed a 1-yr gluten withdrawal (as confirmed by intestinal mucosa recovery), there was a normalization of subclinical hypothyroidism. Twenty-five percent of patients with euthyroid autoimmune disease shifted toward either a subclinical hyperthyroidism or subclinical hypothyroidism; in these subjects, dietary compliance was poor. In addition, 5.5% of patients whose thyroid function was normal while untreated developed some degree of thyroid dysfunction 1 yr later. CONCLUSIONS: The greater frequency of thyroid disease among celiac disease patients justifies a thyroid functional assessment. In distinct cases, gluten withdrawal may single-handedly reverse the abnormality.

Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia.

Between July 1992 and June 1996, 3934 new cases of acute leukaemia were registered in the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Archive of Adult Acute Leukaemia. Two hundred cases (5.1%) presented with a history of primary malignancy (PM), 179 of which were acute myeloid leukaemia (AML). The median age of these cases was significantly higher than that of other primitive AML (63 years vs. 57 years; P < 0.001). The number of men was significantly lower than the number of women [74/1544 (4.8%) vs. 105/1420 (7.4%); odds ratio (OR) 0.63, 95% confidence interval (CI) 0.46-0.87; P < 0.002], as was the number of patients aged <65 years [104/1963 (5.3%) vs. 75/1001 (7.5%); OR 0.69, 95% CI 0.50-0.95; P < 0.01]. An increased incidence of cancer was observed among first-degree relatives of patients with AML occurring after a PM (secondary AML; sAML) [66/179 (36.9%) sAML vs. 757/2785 (27.2%) de novo AML, age adjusted; OR 2.62, 95% CI 1.07-6.42; P < 0.005]. Prevalent types of PM were breast cancer, lymphoma and Hodgkin's disease. sAML occurred after a median latency of 52 months (range 2-379). Of the 122 patients who received chemotherapy for sAML, 67 patients (55%) achieved a complete remission (CR), three a partial remission, 15 (12%) died in induction and 37 (30%) were unresponsive. The median duration of CR was 30 weeks (range 4-250). The median overall survival was 7 months (range 1-196). Comparing acute promyelocytic leukaemia with all other French-American-British (FAB) groups, a significant increase in CR achievement was observed [14/18 (77.7%) vs. 53/101 (52.4%), P < 0.046] as well as in median CR duration (55 vs. 24 months, P < 0.02). The analysis of our data suggests that not only previous chemotherapy but also genetic predisposition could play a role in the pathogenesis of sAML.

Coexistence of two distinct cell populations (CD56(+)TcRgammadelta(+) and CD56(+)TcRgammadelta(-)) in a case of aggressive CD56(+) lymphoma/leukemia.

BACKGROUND AND OBJECTIVE: Large granular lymphocytes derive from two major lineages: one expressing the CD3 surface antigen (T-lymphocytes), and the other lacking this marker (NK-cells). Although developmental overlaps between natural killer cells and T-cells have been described, malignancies derived from these two cell types are considered as distinct lymphoid disorders. DESIGN AND METHODS: We report the case of a 30-year old man affected by a lymphoma/leukemia syndrome presenting with hepatosplenic lymphoma which rapidly transformed into aggressive NK-leukemia. Extensive flow cytometry studies and molecular analysis were repeated during the course of the disease, and showed an unexpected changing pattern. RESULTS: At diagnosis, flow cytometry analysis showed the co-existence of two cell populations, one CD56(+), CD3(+), TcRgd(+), and the other CD56(+), CD3(-) and TcRgd(-). Molecular analysis showed that the TcR genes had the same clonally rearranged pattern involving b, g and d genes in both populations. At disease relapse and during the terminal refractory phase, only CD3(-) cells were present. INTERPRETATION AND CONCLUSIONS: This is an unusual case of CD56(+) aggressive lymphoma/leukemia characterized by the clonal expansion of two phenotypically different cell populations, variably balanced during the course of the disease. The presence of the same TcR genomic rearrangement suggests the origin from a common progenitor able to differentiate along both T- and NK-pathways.