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Disseminated necrotizing leukoencephalopathy.

A 30-year-old male with chronic myelogenous leukemia was treated by intrathecal instillation of methotrexate and cytosine arabinoside because of meningeal infiltration of leukemic cells. He developed neurlogical signs of bilateral cerebral dysfunction with progressive deterioration and died. The neuropathological changes consisted of multiple small areas of demyelination and coagulative necrosis that were randomly disseminated in the cerebral white matter. There was a remarkable decrease of glial nuclei and occasional deposits of mineral salts. Numerous axonal swellings were observed within and around the necrotizing foci. A moderate astrocytosis and mild status spongiosus were found in the surrounding white matter. The etiological relationship of these changes to intrathecal methotrexate is discussed.

Adult↗

A clinicopathological review of 12 autopsied cases of adult T-cell leukemia.

Twelve autopsied cases with adult T-cell leukemia (ATL) were reviewed clinicopathologically. The prognosis of three cases who had suffered from severe cutaneous lesions was much better than that of the other nine cases with no or negligible cutaneous lesions. The surface marker of leukemic cells from six cases was ordinary inducer/helper phenotype (OKT4+ and 8-), but in one case leukemic cells showed OKT4+ and 8+. In another case, a significant amount of leukemic cell infiltration was found in the thymic cortex. Calcium content in the bone of ATL cases was lower than that of the patients without ATL (control group), and six cases with ATL (50%) were complicated by severe hypercalcemia. Neither adenoma nor hyperplasia of the parathyroid glands was found in any case. In most severely hypercalcemic patients, bone trabeculae were actively absorbed by numerous osteoclasts and partly replaced by fibrous tissues. In two normocalcemic patients, skeletal calcium content was also markedly reduced by osteoporosis, but the activation of osteoclasts was inconspicuous. It was speculated that the manner of bone resorption in ATL cases was diverse and there were some clinicopathological subtypes in ATL from the viewpoints of cutaneous lesions, hypercalcemia, and bone lesions.

Adult↗

Early metastatic stage of 2,7-FAA-induced leukemia in rats.

The development from primary focus to metastasis was histologically investigated in 2,7-FAA-induced leukemia in rats. The Wistar and Sprague-Dawley strains were used, and the results were similar in both strains. The spread of lesions was classified as solitary, scattered or diffuse. Scattered leukemia lesions were divided into two groups: A and B: (A) consisted of one or a few conspicuously large foci and many small foci, and (B) had no such large foci. The interval from the first appearance of orthochromatic erythroblasts to autopsy was short in animals with solitary lesions, slightly longer in those with scattered lesions in group (A), and still longer in group (B). Conspicuously large foci were predominantly localized in the bone marrow, while small foci were scattered in the bone marrow, spleen and liver. The (A) scattered lesions were considered to represent the early metastatic stage, since they consisted of the combination of large and small foci, and the time interval from the first appearance of erythroblasts to autopsy was between that of solitary lesions and (B) scattered lesions. The leukemia induced in rats by 2,7-FAA occurred predominantly in the bone marrow, which was the primary site. It was thought that this leukemia spread rapidly to other regions of the bone marrow, and to the spleen and liver, by hematogenous metastasis.

2-Acetylaminofluorene↗

Hepatosplenic gammadelta T-cell lymphoma following seven malaria infections.

Hepatosplenic gammadelta T-cell lymphoma (HSTL) is a clinicopathological entity associated with an immunocompromised status in approximately 25% of patients. Herein is described a case of HSTL in a 53-year-old Brazilian man with seven previous malaria infections, initially misdiagnosed as a hyperreactive splenomegaly due to chronic malaria. A characteristic lymphoid infiltrate was observed in spleen, liver and bone marrow sinusoids/sinuses. Neoplastic cells had a CD45RO+, CD2+, CD7+, CD3+, CD5-, CD8+, CD56+, perforin+, FasL-negative, T-cell receptor (TCR)alphabeta-negative, TCRgammadelta+ profile. Analyses of gamma and delta TCR rearrangements confirmed diagnosis of gammadelta T-cell lymphoma by detecting VgammaI/Vdelta1-Jdelta1 clonal rearrangements. Sensitive polymerase chain reaction (PCR) for Plasmodium falciparum, Epstein-Barr virus and herpesvirus-8 failed to demonstrate infection. The disease progressed to a fatal outcome following cutaneous infiltration and leukemic proliferation. The authors also comment on the association of lymphoma and infection, focusing on PCR diagnosis of TCRgamma and delta clonal rearrangements and the presumed pathogenic events leading to HSTL in the context of chronic malaria infection. Initial lymphomagenic stages might not be direct consequences of antigenic stimulation of Vdelta1 T-cells, but might depend on interactions between gammadelta T and B cells during cooperative or regulatory responses to Plasmodium sp.

DNA, Neoplasm↗

Testicular morphological changes in children with acute lymphoblastic leukemia following chemotherapy.

Morphological changes in the testis induced by chemotherapy given according to the Tokyo Children's Cancer Study Group (TCCSG) regimens were studied in children with acute lymphoblastic leukemia (ALL). After informed consent, testicular biopsies were performed 14 times in 12 patients at the end of treatment. The testicular morphology in all cases had sustained a degree of damage. The tubular fertility index (TFI), calculated as the percentage of seminiferous tubules containing identifiable spermatogonia, was from 0 to 42.8% (mean 33.4%) below the normal value. Infiltration of leukemic cells was the most significant factor contributing to the decrease in TFI. There were no differences in the TFI among the TCCSG protocols. Formation of sperm was recognized in six cases, whose ages were 7, 8, 9, 10, 15 and 19 years. In two children, testicular biopsy was performed twice. In the second biopsy, TFI was elevated and sperm formation with the maturation of Leydig cells was observed. A number of other pathological changes were observed: modification of spermatogonia, Sertoli cells and inclusion bodies in spermatogonia, abnormal maturation of Leydig cells, evidence of interstitial fibrosis and thickening of the basement membrane. These results suggest that recent strong chemotherapy for the treatment of ALL might cause severe but not fatal damage to children's testicular tissue. As chemotherapy escalates, more investigation of testicular function will be necessary.

Antineoplastic Combined Chemotherapy Protocols↗

Granulocytic sarcoma of uterine cervix as presentation of acute myeloid leukemia: a case report and review of literature.

Localized extramedullary collection of leukemic cells is termed as granulocytic sarcoma. Incidences of 2-8% in acute myeloid leukemia have been reported in various autopsy studies. In female it usually involves ovary. Since most of such tumors are asymptomatic, they are detected only at autopsy. We report here a case who manifested as abnormal vaginal bleeding, large cervical mass, renal failure, and aspergillous fungaemia. The patient died before she could be treated. From the present report it would appear that granulocytic sarcoma at times may precede other manifestations of leukemia.

Adult↗

Humoral CSF parameters in the differential diagnosis of hematologic CNS neoplasia.

Cerebrospinal fluid (CSF) and serum samples of 20 patients with central nervous system manifestations of hematological malignancies including primary cerebral lymphoma (n = 5) and disseminated non-Hodgkin lymphoma (n = 7) were examined for albumin, IgG, IgM, fibronectin, beta 2-microglobulin, interleukin-6, soluble interleukin-2 receptor, tumor necrosis factor alpha, and oligoclonal immunoglobulin bands. Although a broad range of abnormalities were detected, no reliable CSF parameter for the diagnosis of leptomeningeal spread from hematological neoplasias could be identified. An analysis of 61 repeat lumbar punctures added little to the findings of the first CSF examinations. Currently, immunochemical studies of CSF cell surface markers and early biopsy have probably more clinical value than the determination of the humoral CSF parameters included in this study. However, analysis of cytokine synthesis by single CSF cells using molecular biology techniques may improve the differential diagnosis of hematological neoplasia of the brain and spinal cord in the future.

Biomarkers, Tumor↗

Plasminogen activation in human leukemia and in normal hematopoietic cells.

The active process of pericellular proteolysis is central in tumor invasion, and in particular the essential role of the urokinase-type plasminogen activator (uPA) is well established. uPA-mediated plasminogen activation facilitates cell migration and invasion through extracellular matrices by dissolving connective tissue components. uPA, its receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) are enriched in several types of tumors. The importance of proteolysis and especially plasminogen activation is less clear in hematopoietic malignancies than in solid tumors. However, patients with leukemia have an increased tendency to bleeding, not always attributable to thrombocytopenia, and tissue infiltration by leukemic cells, processes in which plasminogen activation may be involved. Several studies have indicated that plasminogen activators (PAs) are highly expressed by cultured leukemia cells. Furthermore, differing from adherent tumor cells, leukemic cells have an enhanced capacity to activate pro-uPA and mainly the active form of uPA is released to culture medium. Ex vivo studies have shown that uPAR, uPA and its inhibitors can be found on the surface of normal blood cells and on the blast cell surfaces from patients with acute leukemia as well as from plasma samples. Elevated levels of PAs and their inhibitors have been detected in leukemic cell lysates. Few studies have tried to demonstrate a correlation between prognosis of leukemia and levels of plasminogen activators. More in vivo studies are needed to show, if any of the factors of the plasminogen activation process can be used as tools in subclassification or as markers for prognosis in leukemia. This review article will focus on the in vivo studies of plasminogen activation in leukemia and will present several in vitro findings on PAs in normal leukocytes and leukemic cell lines.

Blood Cells↗

Myc-induced T cell leukemia in transgenic zebrafish.

The zebrafish is an attractive model organism for studying cancer development because of its genetic accessibility. Here we describe the induction of clonally derived T cell acute lymphoblastic leukemia in transgenic zebrafish expressing mouse c-myc under control of the zebrafish Rag2 promoter. Visualization of leukemic cells expressing a chimeric transgene encoding Myc fused to green fluorescent protein (GFP) revealed that leukemias arose in the thymus, spread locally into gill arches and retro-orbital soft tissue, and then disseminated into skeletal muscle and abdominal organs. Leukemic cells homed back to the thymus in irradiated fish transplanted with GFP-labeled leukemic lymphoblasts. This transgenic model provides a platform for drug screens and for genetic screens aimed at identifying mutations that suppress or enhance c-myc- induced carcinogenesis.

Animals↗

Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix.

BCL-2 family proteins constitute a critical control point for the regulation of apoptosis. Protein interaction between BCL-2 members is a prominent mechanism of control and is mediated through the amphipathic alpha-helical BH3 segment, an essential death domain. We used a chemical strategy, termed hydrocarbon stapling, to generate BH3 peptides with improved pharmacologic properties. The stapled peptides, called "stabilized alpha-helix of BCL-2 domains" (SAHBs), proved to be helical, protease-resistant, and cell-permeable molecules that bound with increased affinity to multidomain BCL-2 member pockets. A SAHB of the BH3 domain from the BID protein specifically activated the apoptotic pathway to kill leukemia cells. In addition, SAHB effectively inhibited the growth of human leukemia xenografts in vivo. Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.

Alkenes↗

Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases.

B-cell precursor (BCP) leukemia is the most common form of childhood cancer and the second most common form of acute leukemia in adults. Human BCP leukemia was treated in a severe combined immunodeficient mouse model by targeting of the tyrosine kinase inhibitor Genistein (Gen) to the B cell-specific receptor CD19 with the monoclonal antibody B43. The B43-Gen immunoconjugate bound with high affinity to BCP leukemia cells, selectively inhibited CD19-associated tyrosine kinases, and triggered rapid apoptotic cell death. At less than one-tenth the maximum tolerated dose more than 99.999 percent of human BCP leukemia cells were killed, which led to 100 percent long-term event-free survival from an otherwise invariably fatal leukemia. The B43-Gen immuno-conjugate might be useful in eliminating leukemia cells in patients who have failed conventional therapy.

Animals↗

Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.

Fourteen children who relapsed after initial remission of leukaemia were studied. Six received a second course of cranial radiotherapy, while the remaining eight children were given total body irradiation before bone marrow transplantation. The postirradiation somnolence syndrome was common after cranial radiotherapy. All children had mild/soft neurological signs, mostly of coordination. None had a major motor disability. All but the youngest child had cataracts; two children required an operation for these. All children were growth hormone deficient. Verbal IQ, attention, and concentration were selectively reduced (with respect to normative levels). The time between the two treatments, age at relapse, and higher doses of radiotherapy all correlated with cognitive outcome, with girls showing greater impairments than boys. Only two children were performing at age appropriate levels on measures of academic achievement. It is concluded that neurological and neuropsychological morbidity is significantly increased by the current treatments prescribed after the relapse of leukaemia.

Age Factors↗

Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex.

Cognitive outcome, as measured by verbal and performance IQs, was compared in 35 girls and 47 boys who were in first remission for acute lymphoblastic leukaemia. All children had received presymptomatic cranial radiotherapy and intrathecal methotrexate. The mean age at diagnosis was 4.2 years and the mean elapsed time from initial diagnosis to intellectual assessment was 7.1 years. Results showed that children irradiated before the age of 4 years were impaired in certain aspects of non-verbal ability, as well as in measures of short term memory and attention, calculated by factor scores derived from selected subtests of the IQ test. Subtests requiring verbal and non-verbal reasoning showed the greatest impairment after early diagnosis and treatment. In addition girls were selectively impaired in verbal IQ and other aspects of verbal ability, with the degree of impairment exacerbated by early treatment. No relationship was found between degree of impairment and either time since treatment or number of methotrexate injections. It is concluded that early age at irradiation increases the risk of impaired intellectual outcome, particularly in girls.

Adolescent↗

Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia.

Survival and endocrine status in a cohort of boys with acute lymphoblastic leukaemia (ALL) who started treatment between 1972 and 1987 and subsequently developed a testicular relapse were analysed. During this period there was a significant improvement in the overall event free survival for boys, but no significant decrease in the testicular relapse rate. Thirty three boys had an apparently isolated testicular relapse, whereas 21 boys had a combined relapse. The event free survival for boys with an isolated testicular relapse was 59% at six years (95% confidence interval (CI) 42 to 74%). The event free survival for the 16 patients with a combined relapse who received a second course of treatment was 32% (95% CI 17 to 60%). Those patients receiving adequate second line treatment for an isolated testicular relapse whose first remission was longer than or equal to two years had an event free survival of 82% (95% CI 63 to 93%) at six years. No boy relapsing within two years from diagnosis has survived. Endocrine late effects are significant, with 82% of the boys requiring hormonal treatment at some stage for induction of puberty or continuing pubertal maturation, or both. It is concluded that, despite the increasing intensity of initial treatment for ALL, isolated testicular relapse is treatable by conventional means in most patients. Careful endocrine follow up of these patients is essential as most will require hormone replacement treatment.

Adolescent↗