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Naturally occurring lymphoblastic leukemia in guinea pigs.

Nine cases of lymphoblastic leukemia were observed in 4,500 guinea pigs from three guinea pig production colonies during a period of 3 years. Seven of the cases occurred in strain 2/N, one in 13/N and one in Dunkin-Hartley/FD. These guinea pigs were 5.5-29 months old and included two males and seven females. Clinically, the animals showed a variety of signs, such as enlargement of peripheral lymph nodes, posterior paralysis and terminal ataxia. Gross lesions were characterized by numerous white spots and enlargement of the lymph nodes and many internal organs. Hematologic examination showed leukocytosis with lymphoblasts predominating. Histologic and cytologic examination of affected tissues and cells revealed generalized infiltration of lymphocytic leukemic cells.

Animals↗

[Transthyretin and albumin in cerebrospinal fluid in patients with acute leukemias or lymphomas of high grade malignancy].

Transthyretin and albumin in lumbar cerebrospinal fluid (CSF) and in serum were repeatedly assessed in 40 patients with acute leukemias or high grade non-Hodgkin's lymphomas. The patients were divided into 3 groups. Group I-5 individuals with clinical manifestations of leukemic or lymphomatous meningosis; Group II-33 cases with no clinical data of central nervous system involvement by neoplasm (leukemia/lymphoma); Group III-2 patients in whom extramedullary solid leukemic or lymphomatous infiltrations were diagnosed. It was revealed that blood-brain-barrier dysfunction due to neoplastic infiltration of leptomeninges went with an increase of albumin blood-CSF barrier dependent- and with decrease of blood-CSF barrier-independent transthyretin concentrations. In patients with extramedullary tumors an evident increase of albumin and total-CSF transthyretin and no blood-CSF barrier-independent transthyretin concentrations below the tumor location were observed. It can betray a complete block of the vertebral canal subarachnoid space below the neoplastic compression of the spinal cord. Cytostatics application, either general or intrathecal, did not influence the CSF albumin and transthyretin levels.

Adolescent↗

Isolated leukemic choroidal relapse in a child with acute lymphoblastic leukemia one year off therapy, diagnosed through transvitreal retino-choroidal biopsy.

A serous retinal detachment and choroidal hemorrhagic infiltration developed in a 17-year-old girl with acute lymphoblastic leukemia one year after cessation of therapy without concurrent bone marrow (BM) or central nervous system relapse. A choroidal biopsy through a sclerotomy with simultaneous release of subretinal fluid revealed no malignant cells. Accordingly, she was treated with prednisone, topical corticosteroid and atropine with normalisation of vision and clinical findings. Five months later the retinal detachment and choroidal infiltration recurred. In order to re-attach the retina once more and obtain a representative choroidal biopsy, a pars plana vitrectomy followed by a retinotomy with removal of subretinal tissue was done revealing leukemic infiltration of the choroid. Simultaneously a BM relapse was diagnosed.

Adolescent↗

Involvement of the central nervous system in rats with acute leukemia L 5222.

Young adult BD-IX rats made leukemic by intravenous infusion of 2 times 10(7) nucleated blood cells from leukemic donors (L 5222), showed lesions in the central nervous system 6 days after transfer when their leukocyte count was between 250,000 and 350,000 cells/mul. The brain was affected in only half of the animals, whereas all showed an infiltration of the meanings. Furthermore, all animals had extensive lesions in the spinal cord. The lesions consisted of nodules of leukemic cells and hemorrhages which were predominant in the lower half of the spinal cord and more abundant in the white than in the gray matter. Paraplegic appeared in some animals shortly before death. Since there is a consistent involvement of the meninges and spinal cord, the L 5222 leukemia seems to be a useful model for the study of leukemic infiltration of the central nervous system and the reaction to chemotherapy.

Acute Disease↗

Leukemic macrocheilia associated with chronic lymphocytic leukemia.

Specific cutaneous infiltrates in chronic lymphocytic leukemia presenting as a tumor or a large nodule on the face, scalp, and upper trunk are rare; involvement of the oral mucosa is extremely rare. We report a case of leukemic macrocheilia that occurred three years before a diagnosis of chronic lymphocytic leukemia was made.

Diagnosis, Differential↗

Childhood acute myeloid leukemia in mice with severe combined immunodeficiency.

Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.

Adolescent↗

CXCR4 chemokine receptors, histone deacetylase inhibitors and acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. The mechanism for selective homing of ALL cells to preferential sites has long been unclear. Recent reports indicate that the chemokine receptor CXCR4 is found on ALL cells and its ligand is highly expressed at sites associated with ALL-induced organ infiltration. This results in chemotaxis, or directed migration of leukemic cells from the bone marrow via the circulation to preferential sites of extramedullary organ infiltration. Because overexpression of CXCR4 on ALL cells is associated with high extramedullary organ infiltration and shorter disease-free survival, numerous pharmacological agents affecting CXCR4 have currently been investigated. The most promising data are available for histone deacetylase inhibitors (HDAIs), which have been shown to be safe and well tolerated in phase I clinical trials. In vitro, HDAIs extensively down-regulate CXCR4 protein and mRNA levels. As a result, the ability of CXCR4 ligand to induce cellular migration is impaired. Wider recognition of the role of CXCR4 in ALL and manipulation of this important mechanism may lead to novel approaches in the treatment and outcome of this disease.

Down-Regulation↗

Spinal fluid cytology during chemotherapy of leukemia of the central nervous system in children.

During a two-year period 170 children were treated for leukemia. Forty-seven per cent had clinical and cytologic evidence of central nervous system involvement. Of these, 38 patients had repeated cytologic examinations of the spinal fluid and were suitable for a study of changes that occurred during the course of their disease and treatment. A total of 112 cytologyc specimens from the 38 patients over a period of 8 to 60 months was reviewed. There was accurate correlation between cytologic evidence of leukemia in the spinal fluid, clinical signs and symptoms of central nervous system disease, and autopsy evidence of meningeal leukemia, though the number of cells present did not predict the severity of clinical disease or extent of meningeal infiltrate. Almost every patient with leukemic cells in the spinal fluid had a corresponding leukemia infiltrate in the bone marrow, but not in peripheral blood. The differential diagnosis of leukemia in spinal fluid cytology is discussed and the clinical response to intrathecal chemotherapy correlated with cytologic findings. Serial cytologic observations during treatment, and the phenomenon of autonomous CNS leukemia, are discussed in terms of cell cycle physiology and chemotherapy. The results stress the usefulness of spinal fluid cytology as a screening procedure in asymptomatic patients with leukemia and are of interest in regard to the pathophysiology of leukemia of the central nervous system.

Adolescent↗

S100-positive, T-cell chronic lymphoproliferative disease: an aggressive disorder of an uncommon T-cell subset.

S100-positive T lymphocytes account for less than 3% of peripheral blood T cells. Rare cases of S100-positive T-cell lymphoma have been previously described. We report four such cases of S100-positive T-cell chronic lymphoproliferative disease. In all cases, hepatosplenomegaly was observed, without prominent lymphadenopathy. Central nervous system (CNS) involvement by the leukemic cells was suggested in three cases by physical symptoms and confirmed in two cases by cerebrospinal fluid studies. Despite treatment, three patients died at 3, 6, and 8 months after diagnosis. Although there was a leukemic presentation, only minimal bone marrow infiltration was evident. Splenectomy showed red pulp infiltration. Liver and lymph node biopsies showed sinusoidal leukemic involvement. In all cases, the leukemic cells expressed mature T-cell- and natural killer cell-associated antigens. Cytoplasmic S100 was detected in the leukemic cells in the blood, spleen, liver, and lymph node. Southern blot studies in two cases showed T-beta, T-gamma, and T-delta gene rearrangements. RNA Northern blots showed T-alpha and T-beta chain transcripts with no T-gamma or T-delta RNA identified. Southern blot analysis showed no hybridization to probes specific for Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus-1, or human T-cell lymphotropic virus type-1. These findings show that S100-positive T-cell chronic lymphoproliferative disorder is an aggressive, extramedullary-based disease frequently associated with CNS involvement and characterized by short survivals.

Adult↗

Lymphomatous skin infiltration at the site of previous varicella zoster virus infection in a patient with T cell lymphoma.

Cutaneous infiltrations in hemopoietic neoplasias are not uncommon. They are generally localized on the legs, arms, back, anterior chest, scalp and face. In rare cases specific infiltration of neoplastic cells is localized in the site of herpes zoster and herpes simplex scars. In this report a case with T cell lymphoma in leukemic phase with skin infiltration in the previous Varicella Zoster Virus (VZV) site of infection is reported and literature is reviewed.

Adult↗

31P and 13C NMR studies of isolated perfused hematopoietic cells from leukemic mice.

The myeloproliferative leukemic virus (MPLV) induces within 2-3 weeks a massive infiltration of the adult mouse liver by hematopoietic leukemic cells. Since the metabolism of the infiltrated organ might be correlated with an interaction of two cell populations, it was decided to study the isolated hematopoietic cells separately. The metabolism of these cells embedded in an agarose gel and perfused with labeled substrates was investigated using 31P and 13C NMR. Using [1-13C]glucose as precursor, sequential 13C NMR spectra showed that the hematopoietic cells were able to store glucose as [1-13C]glycogen and to metabolize it through the glycolytic pathway to give [3-13C]lactate as sole end-product. The liver neoglucogenic substrates: [2-13C]pyruvate and [3-13C]alanine are not metabolized by these cells. This suggests that the tricarboxylic acid cycle was not efficient. To investigate further the glycolytic properties of the cells, 10 mM sodium azide was added to the medium containing [1-13C]glucose. When compared to the aerobic conditions, a 40% decrease of nucleotides (0.10 vs 0.17 mumole NTP/10(9) cells), a degradation of [1-13C]glycogen and an increase of ca 35% of the glycolytic rate were observed. The analysis of 13C NMR spectra of the perfusates at the end of the perfusion indicates a total conversion of [1-13C]glucose into [3-13C]lactate and [3-13C]pyruvate under anaerobic conditions. These results permit a better understanding of the metabolism of the perfused leukemic livers which are extensively infiltrated by these hematopoietic cells.

Animals↗

Characterization of a novel human natural killer-cell line (NK-YS) established from natural killer cell lymphoma/leukemia associated with Epstein-Barr virus infection.

A novel cell line was established from a patient with a leukemic-state nasal angiocentric natural killer (NK) cell lymphoma with systemic skin infiltration. The morphology of the leukemic cells was large-granular-lymphocyte (LGL), and their immunophenotype was CD2+, CD3-, CD5+, CD7+, CD16-, CD56+, and CD57-. The presence of Epstein-Barr viral (EBV) genome was shown in specimens from the patient's nose, skin, and peripheral blood by in situ hybridization using an EBV-encoded small RNA-1 probe or by Southern blotting using a terminal-repeat probe of the EBV genome. Leukemic cells were cocultured with a mouse stromal cell line (SPY3-2) in the presence of 100 U/mL recombinant human interleukin-2 and a novel stromal cell-independent cell line, NK-YS, was established. The NK-YS cells showed LGL morphology and expressed surface CD2, CD5, CD7, CD25, CD56, and CD95. The NK-YS cells retained cytotoxicity against K562 and Jurkat cells. A Southern blotting using a terminal-repeat probe of EBV showed that NK-YS and fresh leukemic cells had a clonal EBV genome, whereas the T-cell receptor beta and gamma chain genes of NK-YS were not rearranged. In an immunocytochemical analysis, the NK-YS cells showed a type-II latent infection of EBV. The NK-YS cells preserved the original characteristics of NK cell lymphoma/leukemia and will be a useful tool for the study of biological characteristics of EBV-associated nasal angiocentric NK cell lymphoma/leukemia.

Adult↗

Prognostic relevance of histological findings on bone marrow biopsy in myelodysplastic syndromes.

Bone marrow biopsy (BMB) has aroused growing interest as a possible aid in the diagnostic and prognostic evaluation of myelodysplastic syndromes (MDS). Previous reports have pointed out that MDS patients with blastic aggregates or severe bone marrow (BM) fibrosis are characterized by a worse clinical outcome. BMBs of 106 MDS patients were retrospectively reviewed, and relationships among the different histological parameters as well as clinicopathological correlations were looked for. Three patterns of BM blastic infiltration ("diffuse," "cluster," and "large") were recognized. Overt leukemic transformation and overall survival were selected as prognostic end points. BM infiltration was "diffuse" in 18, "cluster" in 48, and "large" in 40 cases. RAEB-t patients accounted for about half of the "large" cases, and none had a "diffuse" pattern (p < 0.01). Nineteen patients showed extensive BM fibrosis; most of them were characterized by "cluster" blastic infiltration and megakaryocyte hyperplasia. Leukemic transformation occurred in 67% of "large" cases (p< 0.001) and in none of the "cluster" cases with severe BM fibrosis (p < 0.01); however, survival was equally poor in these two groups because of early leukemic transformation (large cases) and BM failure (cluster cases). The FAB classification did not significantly correlate with prognosis. Patients with "cluster" BM infiltration and severe fibrosis can be regarded as a true separate MDS subset characterized by unique clinicopathological and prognostic features. Because of the subacute clinical behavior of most cases, and the poor performance status of many elderly patients, there is still controversy as to the best therapeutic approach in MDS. Histological analysis allowed two groups of MDS patients to be identified, both characterized by poor life expectancy, who could benefit from early aggressive chemotherapy.

Adult↗

Cutis verticis gyrata: unusual chloromatous disease in acute myelogenous leukemia.

Chloromas are an unusual finding in patients with acute or chronic granulocytic leukemia. The present report describes a man with acute myelogenous leukemia (AML) whose course was complicated by cutis verticis gyrata (CVG), a mediastinal mass, neuropathies, and hepatosplenomegaly as a result of visceral involvement. Leukemic tumors and organ infiltration developed independent of his hematologic status and resulted in significant morbidity and, eventually, mortality from gastrointestinal hemorrhage. Nevertheless, at least temporary control over these complications was achieved when they were managed as leukemic "sanctuaries" and treated with local irradiation.

Adenoma↗

Bullous pyoderma gangrenosum as a manifestation of leukemia cutis.

The authors present the case of a 67-year-old patient in whom bullous pyoderma gangrenosum was the first symptom of acute myeloid leukemia. Histologically leukemic cells were found in the skin infiltrate, on the basis of which this lesion satisfied the criteria of leukemia cutis. It was underlined that in the background of such atypical bullous cases there are often hemoblastoses or their malignant transformation. Finally the connection between bullous pyoderma gangrenosum and atypical vesiculous Sweet syndrome is discussed.

Acute Disease↗

Augmentation of human leukemic cell invasion by activation of a small GTP-binding protein Rho.

OBJECTIVE: The functions of a small GTP-binding protein, Rho, in human leukemic cell invasion was investigated in vivo and in vitro. MATERIALS AND METHODS: Human leukemic KM3 and Reh cells (derived from B-cell-type common acute lymphoid leukemias) were inoculated into severe combined immundeficiency (SCID) mice. Alteration of invasion in SCID mice inoculated with KM3 cells that were introduced with the expression vector for Rho Val14 (Rho V14), an activated mutant form of Rho, was observed. RESULTS: SCID mice inoculated with KM3 and Reh cells developed paraplegia 21 days after inoculation. All died by day 26-27. The leukemic cells were localized to bone marrow and around the spinal cord, with no infiltration into peripheral blood, spleen, liver, thymus, or lymph nodes. SCID mice inoculated with Rho V14-transfected KM3 cells showed a 5-day reduction in the time to paraplegia and death compared with SCID mice inoculated with hygromycin-resistance gene-transfected KM3 (hyg(r)) cells. In addition, the mice inoculated with Rho V14 cells showed leukemic cell infiltration, not only into bone marrow and around the spinal cord but also into peripheral blood, liver, and spleen. There were no in vitro or in vivo differences in growth rates of Rho V14 and hyg(r) cells. However, the Rho V14 cells showed markedly increased cell adhesion compared to the hyg(r) cells. CONCLUSION: Results suggest that Rho activation accelerates human leukemic cell invasion via augmentation of cell adhesion.

Animals↗

Follicular lymphoma of compartmentalized small cleaved center cells and mantle zone lymphocytes. Evidence for a common derivation.

The authors have observed a unique case of follicular lymphoma in which the central zones of neoplastic nodules were composed predominantly of small cleaved cells (SCC) that were surrounded by small lymphoid cells proliferating in wide mantles as in mantle zone (MZ) lymphoma. The central SCC component displayed a follicular SCC lymphoma-like phenotype (IgD-, CD10+, CD5-, CD68-), whereas the neoplastic cells of the peripheral zones had an MZ lymphoma-like phenotypic profile (IgD+, CD10-, CD5+, CD68+). In extranodal involved tissues, either follicular or diffuse (leukemic-like) patterns of lymphoma infiltration were noted. Flow cytometric analyses showed in the bone marrow or the peripheral blood two leukemic B cell populations, one mimicking the phenotypic profile (IgM+, IgD+, CD5+, CD10-, Leu8-) of small lymphoid cells with MZ-like features, and the other with phenotypic features (IgM+, IgD-, CD5+, CD10+, Leu8+) intermediate between those of MZ-like cells and those of the SCC component (follicular center-like) detected in the lymph node. Immunomagnetic sorting and gene rearrangement studies indicated that both CD10+ and CD10- B lymphocytes and lymph node neoplastic B cells shared the same clonal origin. This unusual follicular lymphoma can be viewed as the result of the proliferation of a single follicular progenitor capable of differentiating toward both a germinal center and an MZ phenotype. The simultaneous presence in the same patient of at least three neoplastic B-cell populations at different maturation stages, encompassing follicular center and MZ phenotypes, and showing the same clonal derivation, indicates a close lineage relationship between follicular SCC and MZ lymphomas.

Aged↗