Genetic lesions associated with blastic transformation of polycythemia vera and essential thrombocythemia.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders that may progress to acute leukemia in a subset of patients. This study aimed at investigating the genetic lesions associated with the blastic transformation of PV and ET. A panel of PV and ET cases at different stages of disease was analyzed for the presence of genetic alterations of TP53, NRAS, KRAS, and MDM2 by a combination of mutational analysis and Southern blot hybridization. The occurrence of microsatellite instability (MSI) was also tasted in selected cases. Samples of PV and ET analyzed in chronic phase disease were consistently devoid of all genetic lesions tested, suggesting that alterations of TP53, NRAS, KRAS, and MDM2 do not contribute significantly to development of chronic phase PV and ET. Conversely, mutations of TP53 were detected in 7/15 (46.6%) blastic phase cases, including 3/5 PV and 4/10 ET. In blastic phase patients for whom the corresponding chronic phase DNA was also available, it could be documented that the genetic lesion had arisen at the time of blastic transformation. In addition to TP53 mutations, cases of blastic phase PV and ET occasionally harbored mutations of NRAS (one case of blastic phase ET) or displayed MSI (one case of blastic phase PV). These data indicate that inactivation of TP53 is a relatively frequent event associated with the blastic transformation of PV and ET and may be responsible for the tumor progression of these disorders.

Molecular events in chronic myeloid leukemia progression.

Chronic myelogenous leukemia presents two distinct clinical phases: the chronic phase is characterised by a marked expansion of the myeloid compartment which still retains a normal differentiative capacity, whereas a differentiation block is the clinical hallmark of the acute transformation. The molecular mechanism underlying the CML progression are still poorly understood. The occurrence of additional molecular lesions, involving the p53, the RAS and the p16 genes may complement and fulfil the BCR/ABL transforming potential, finally leading to an acute leukemic phenotype. However, several lines of evidence suggest that also quantitative changes of the BCR/ABL transcript amounts could explain the progression of the leukemic phenotype in the BCR/ABL-positive hematologic malignancies.

Serum erythropoietin and circulating transferrin receptor in thalassemia intermedia patients with heterogeneous genotypes.

BACKGROUND: Thalassemia intermedia patients usually do not require blood transfusions; however, all show variable degrees of erythropoietic marrow expansion to compensate for more or less marked anemia, and this represents the major cause of complications in untransfused individuals. MATERIALS AND METHODS: To assess the degree of erythropoietic expansion in thalassemia intermedia, serum erythropoietin (sEpo) and serum transferrin receptor (sTfr) were determined in thirty Italian patient's characterized by their beta-globin genotype. RESULTS: Six patients showed inappropriately low sEpo levels (O/P ratio < 0.85). Even excluding these cases, no clear relationship was observed between Hb levels and sEpo or sTfr. Two groups of patients were compared: the first with low HbF (< 40%) that included the majority of beta(+) genotypes, and the second with high HbF (> 40%) that contained a prevalence of beta(0) genotypes. Hb levels were similar in the two groups: 8.09 +/- 1.15 g/dL in low HbF and 8.82 +/- 1.28 g/dL in high HbF patients. Mean sEpo was 112 +/- 78.02 mU/mL (O/P ratio = 0.98 +/- 0.22) in the first and 246.62 +/- 184.30 mU/mL (O/P ratio = 1.25 +/- 0.30) in the second group, with a statistically significant difference, as expected, because of HbF oxygen hyperaffinity. No significant difference in sTfr levels was observed, indicating a comparable erythropoietic response in the two groups. CONCLUSIONS: The relationships between anemia, HbF and total erythropoiesis in thalassemia are more complex than expected. Further studies of subjects with high HbF and benign conditions, such as HPFH, could be of help in clarifying this point, to the aim of safely increasing HbF in thalassemia intermedia.

Interleukin 2 (IL2) in the management of acute myeloid leukemia: clinical and biological findings.

In this paper we review some of the preclinical findings which have led us to believe that immunotherapy with interleukin 2 (IL2)/lymphokine activated killer (LAK) cells may be a feasible approach in the management of acute myeloid leukemia. The main clinical and biological results so far obtained with IL2 treatment, and the currently ongoing protocols and strategies are discussed.

Immunoglobulin and T-cell receptor gene analysis in lymphoproliferative disorders.

The analysis of the configuration of the immunoglobulin (Ig) and T-cell receptor (TCR) gene regions has been of great relevance in defining conclusively the nature of several lymphoproliferative disorders in man. Furthermore, this technological tool has also helped to dissect between a monoclonal and polyclonal pattern of proliferation. The major results obtained, the potential use of molecular studies for the detection of minimal residual disease and the relevance of these techniques in the understanding of the processes of leukemogenesis and lymphomagenesis are discussed.

Cytokines in B-Cell Chronic Lymphocytic Leukemia.

The pleomorphic action of different cytokines in regulating the growth and proliferation of normal B- and T-lymphocyte populations is becoming progressively more apparent. Thus, the possibility that some cytokines, either alone or in variable combination, may play a role in different lymphoproliferative disorders has been increasingly suggested and potential autocrine or paracrine loops hypothesized. Here, we shall discuss some of the known B-cell growth factors which have been postulated to be involved in the hematological progression, clinical course and complications in B-cell lymphocytic leukemia.

Use of the MTT Chemosensitivity Assay in B-Cell Chronic Lymphocytic Leukemia.

The possibility of evaluating the susceptibility of B-cell chronic lymphocytic leukemia (B-CLL) cells to chemotherapeutic agents pre-clinically, was assessed using the MTT colorimetric assay. The results so far obtained suggest that this rapid 3-4 days' test is accurate and reliable and may allow the physician to recognize individual B-CLL cases in which the neoplastic clone is resistant to Chlorambucil. Furthermore, the high efficacy of Fludarabine clearly emerges from these in vitro analyses. The possibility of employing Chlorambucil in combination with alpha Interferon is suggested and the relevance of using this simple test for better drug selection in B-CLL patients is discussed.

Hematoma of the inferior colliculus: uncommon cause of trochlear nerve deficit and contralateral sensory hemisyndrome.

A 57 year old man consulted us for sudden onset of acuphenes in the right ear, followed by diplopia on forward and downward gaze and paresthesias on the right side of the body. Examination of ocular movements revealed a deficit of the superior oblique muscle of the left eye. CT and MR brainscans imaged a punctate bleed of the left inferior colliculus. The patient was discharged after 16 days still complaining of diplopia on forward and downward gaze. There was no change in neurological status at follow-up. It is rare for an intracerebral hematoma to be located in the midbrain. The case we report is distinguished by the smallness of the lesion and the uncommon neurological deficit it caused.