Autologous bone marrow transplantation in adult patients with acute lymphoblastic leukemia

Autologous bone marrow transplantation (ABMT) was introduced as a treatment for terminal leukemic relapse more than 40 years ago. For childhood acute lymphoblastic leukemia (ALL) the role of ABMT is well defined. Some studies suggest that it is also beneficial for adult patients with high-risk factors or with relapse. However, these inferences are based on a relatively small number of patients with short follow-up. Nevertheless patients with high-risk ALL are candidates for ABMT if no histocompatible sibling is available. Similarly patients in second or later complete remission (CR) in the absence of a histocompatible donor may derive benefit from ABMT. The different conditioning regimens used by the treatment centers are associated with different toxicities but none has been proven to be superior than others. In the majority of studies the marrow has been purged of leukemic cells, but this maneuver has never been evaluated in a randomized comparative trial. Transplant related mortality rate of ABMT is low compared to allogeneic transplantation. The GvL effect, which is important to eliminate malignant cells in acute and chronic myelocytic leukemia, has not been definitively demonstrated in ALL. The tyrosine-kinase inhibitor STI 571 offers new perspectives for patients with the Phl/bcr/abl translocation. It may be especially useful for treating minimal residual disease (MRD) before and/or after ABMT.     

Dendritic cells cross-presenting viral antigens derived from autologous cells as a sensitive tool for visualization of human cytomegalovirus-reactive CD8+ T cells

BACKGROUND: CD8+ T lymphocytes are essential to contain viral infections, such as human cytomegalovirus (HCMV). To visualize these clinically important effector cells, we used dendritic cells (DC), which efficiently present exogenous antigens by MHC class I molecules (cross-presentation). METHODS AND RESULTS: Immature DC were fed with apoptotic debris derived from autologous HCMV-infected macrophages. After maturation, the antigen-loaded DC were used to stimulate lymphocytes from the same donor. We could detect high numbers of interferon-gamma producing CD8+ T cells in HCMV-seropositive but not in HCMV-seronegative healthy individuals and in only one of five HCMV-seropositive immunosuppressed patients. In contrast, autologous DC infected with live HCMV virions stimulated antiviral CD8+ T lymphocytes to a lesser extent. CONCLUSION: We suggest that DC cross-presenting HCMV antigens derived from autologous macrophages could serve as a valuable tool to monitor and possibly enhance the antiviral T-cell response in patients after transplantation.     

The immunophenotype of 325 adult acute leukemias: relationship to morphologic and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination

Bone marrow cells of 325 adults with acute leukemia were immunophenotyped using a panel of monoclonal antibodies proposed by the European Group for the Immunological Characterization of Leukemias (EGIL). Of these, 97.2% could be assigned clearly to myeloid or lymphoid lineage (254 acute myeloid leukemias [AMLs], 48 B-cell lineage acute lymphoblastic leukemias [ALLs], 14 T-cell lineage ALLs), 1.8% as biphenotypic, and less than 1% as undifferentiated. Immunologic subtyping of ALLs revealed an association between early precursor phenotypes and coexpression of myeloid antigens, particularly CD15/CD65s coexpression and pre-pre-B cell-specific phenotypes and genotypes. The common ALL phenotype was associated with BCR-ABL translocation. Among AMLs, CD2 coexpression was almost exclusively restricted to French-American-British subtypes M3 variant and M4Eo and related molecular aberrations. The most valuable markers to differentiate between myeloperoxidase-negative AML subtypes M0 and ALLs were CD13, CD33, and CD117, typical of M0, and intracytoplasmic CD79a, intracytoplasmic CD3, CD10, and CD2, typical of B cell- or T cell-lineage ALL. Our results confirm excellent practicability of the EGIL proposalfor immunologic classification of acute leukemias. For myeloperoxidase-negative AMLs, we suggest a scoring system based on markers most valuable to distinguish between AML-M0 and ALLs.     

Dietary restriction alters fine motor function in rats

A number of standard behavioral tasks in animal research utilize food rewards for positive reinforcement. In order to enhance the motivation to participate in these tasks, animals are usually placed on a restricted diet. While dietary restriction (DR) has been shown to have beneficial effects on recovery after brain injury, life span and aging processes, it might also represent a stressor. Since stress can influence a broad range of behaviors, the purpose of this study was to assess whether DR may have similar effects on skilled movement. Adult male Long-Evans rats were trained and tested in a skilled reaching task both prior to and during a mild food restriction regimen that maintained their body weights at 90-95% of baseline weight for eight days. The observations revealed that DR decreased reaching success and increased the number of attempts to grasp a single food pellet. The animals appeared to be more frantic when attempting to reach for food pellets, and the time taken to reach for 20 pellets decreased following the onset of DR. A second experiment investigating behaviors that do not require food rewards, including a ladder rung walking task and an open field test, confirmed that rats on DR display deficits in skilled movements and are hyperactive. These findings suggest that results obtained in motor tasks using food rewards need to be interpreted with caution. The findings are discussed with respect to stress associated with DR.     

Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy.

PURPOSE: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. PATIENTS AND METHODS: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. RESULTS: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). CONCLUSION: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.     

Preserved ipsilateral-to-lesion motor map organization in the unilateral 6-OHDA-treated rat model of Parkinson's disease

The classic view of dopamine (DA) loss in Parkinson's disease is that it produces a functional deafferentation in striatal-cortical circuitry that, in turn, contributes to sensorimotor deficits. The present study examines this view in the rat by assessing how DA-depletion affects the intracortical microstimulation (ICMS) topographic representation of movement in the rostral and caudal motor areas of the motor cortex. The ICMS map is used as an index of motor cortex function because it has been shown to reflect motor function and experience. Groups of rats received no training or skilled reach training and were then given unilateral 6-hydroxydopamine (6-OHDA) or sham lesions of the nigrostriatal bundle to deplete nigrostriatal DA. Lesion success was confirmed by abnormalities in skilled reaching, by apomorphine-induced rotation, and by loss of DA neurons in the substantia nigra. The size and threshold of the motor map in naive and skilled reach trained DA-depleted rats were preserved. In addition, there was an increase in distal limb representation in the caudal forelimb area (CFA) in the DA-depleted rats suggesting a possible plastic response to the behavioral effects of DA-depletion. The presence of preserved size and modified map organization in DA-depleted rats is discussed in relation to the hypothesis that preserved motor cortex functionality despite DA loss underlies the spared motor abilities of DA-depleted rats.