Hemopoietic stem cells from human fetal liver were transplanted in utero into preimmune fetal sheep (48-54 days of gestation). The fate ofdonor cells was followed using karyotype analysis, by immunofluorescence labelingwith anti-CD antibodies, and by fluorescent in situ hybridization using human-specific DNA probes. Engrftment occurred in 13 of 33 recipients. Of five live born sheep that exhibited chimerism, all expressed human cells in the marrow, whereas three expressed them in blood as well.Engraftment was multilineage (erythroid, myeloid, and lymphoid) and human hemopoietic progenitors (multipotent colony-forming units, colony-forming units-granulocyte, macrophage, and erythroid burst-forming units) capable of forming colonies in vitro were detected in all five lambs for > 2 yr. These progenitors responded to human-specific growth-factors both in vitro and in vivo. Thus the administration of recombinanthumanIL-3andgranulocytemacrophage-colony-stimulating factor to chimeric sheep resulted in a 2.1-3.4-fold increase in the relative expression of donor (human) cells. These results demonstrate that the permissive environment ofthe preimmune fetal sheep provides suitable conditions for the engraftment and long-term multilineage expression of human hemopoietic stem cells in a large animal model. In this model, donor human cells appear to retain certain phenotypic and functional characteristics that can be used to manipulate the size of donor cell pool.

Palonosetron is an effective and well-tolerated agent for the prevention of CINV following highly emetogenic chemotherapy, with 3 and 10 microg/kg identified as the lowest effective palonosetron doses.

Records of 105 patients with central nervous system (CNS) lymphoma were analyzed in order to better define the incidence, setting, and management of CNS lymphoma and the role for CNS prophylaxis. Survival was best for patient under 30 years of age treated with whole-brain irradiation and intrathecal (IT) chemotherapy whose CNS involvement was an isolated event (median survival time, 1.8 years). Survival was worst for patients over 30 years of age whose CNS invasion occurred at a time of progressive systemic lymphoma (median time ten weeks if treated with whole-brain irradiation with or without IT chemotherapy). The risk of CNS invasion was greatest for those with lymphoblastic lymphoma. Among patients with Stage IIE, III, or IV histiocytic lymphoma, the risk of CNS involvement was greatest for those with progressive or relapsing disease or involvement of the testes, peripheral blood, or epidural space of the spinal cord.

The clinical courses of 54 consecutive adult patients with acute myelogenous leukemia (AML) who underwent 67 courses of intensive remission induction therapy were analyzed to assess factors associated with development of serious fungal and bacterial infections. Fever developed in 65 of 67 remission induction attempts and was due to bacterial, bacterial‐fungal, and fungal etiologies in 49%, 14%, and 9% of cases, respectively. No etiology of fever was found in 28% of cases. Bacteremia occurred in 54% of remission induction attempts. Invasive fungal disease (IFD) occurred in 22% of cases with an overall mortality of 60%, including 45% of the patients who died during treatment. Using multivariate logistic regression analysis, a mathematical model was constructed which correlated with the risk of IFD. Major factors associated with patients who ultimately develop IFD included the duration of chemotherapy, the number of sites colonized with fungi and the number of fungal species isolated on certain surveillance cultures, particularly Aspergillus species. These studies define characteristics of patients at high risk for development of IFD for whom early initiation of empiric antifungal therapy is strongly recommended.

Hematopoietic stem cell (HSC) transplantation in children and adults with congenital lymphohematopoietic disorders is limited by donor availability, graft failure, graft-versus-host disease (GVHD) and delayed immunological reconstitution. These problems may be circumvented by transplanting the patient before birth. Prenatal cellular therapy for the treatment of congenital diseases has tremendous theoretical appeal. Potential advantages of prenatal transplantation include: A) fetal immunologic immaturity and the potential for induction of donorspecific tolerance; B) available space in the developing bone marrow for engraftment of donor cells; C) the sterile, protective, fetal environment which provides isolation from environmental pathogens, and D) prevention of clinical manifestations of the disease. Normal hematopoietic and immunologic development during ontogeny creates a "window of opportunity" during which events favor the engraftment of transplanted allogeneic (and xenogeneic) HSC and their proliferation. This is a period in which the fetus is immunologically naive and thus incapable of rejecting the foreign HSC, and the expanding bone marrow spaces allow homing and engraftment of HSC without the need for myeloablation. Experiments in sheep have established the optimal age of the recipient, route of donor cell administration, sources of HSC, and other parameters necessary for the successful engraftment and long-term expression of donor HSC. In preclinical studies, transplantation of CD34-enriched or highly purified populations of human adult bone marrow cells in utero resulted in the long-term engraftment and expression of donor HSC without graft failure and GVHD. The strategies developed in allogeneic and xenogeneic fetal sheep models were used to successfully treat human fetuses with X-linked recessive severe combined immunodeficiency. Stem Cells 1997;15(suppl1):79-93The engraftment and proliferation of a relatively small number of normal hematopoietic stem cells (HSC) can sustain hematopoiesis for a lifetime. This observation provides the compelling rationale for HSC transplantation (HSC-T) and is now supported by thousands of long-term survivors of HSC-T who would otherwise have succumbed to lethal disease. However, the realization of the full potential of HSC-T continues to be limited by a critical shortage of immunologically compatible donors, the inability to specifically control the recipient or donor immune response and the requirement for recipient myeloablation to achieve engraftment [ 1-41, The combination of graft failure, delayed immunologic reconstitution, graft-versus-host-disease (GVHD), and the relatively high morbidity and mortality associated with allogeneic HSC-T present prohibitive problems for the majority of patients who might benefit from this procedure. Fortunately, a number of innovative approaches offer hope for the future. These include Hematopoietic Stem Cells. STEM CELLS 1997;15(suppl 1):79-93 0 1997 AlphaMed Press. All rights reserved. 80In Utero HSC Transplantatio...