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Opportunistic fungal infections in children with cancer
PEDIATRIC L A B O R A T O R Y MEDICINE CONGRESS
reported to have specific effect on megakaryocytopoiesis and enhance platelet recovery post chemotherapy. A mixture of growth factors are being evaluated for the ex vivo of periphera! progenitor cells to further reduce the period of marrow aplasia post therapy. Recombinant proteins are also helpful to enhance immune functions of compromised patients. Interferon gamma (IFN--),), a T-cell derived lymphokine, possesses broad macrophage-monocyte activating effects. It has been used in combination of conventional antimicrobials in the treatment of refractory, opportunistic non-viral infections (such as atypical mycobacterium, fungal and parasitic infections) in patients with AIDS and cancer. IFN-3, may be combined with other cytokines (e.g., G-CSF) to treat children with resistant fungal infection. The use of G-CSF with antifungal agents was also suggested. Vaccines may be produced by recombinant technology to provide active immunization for selective groups of immunocompromised children. The immune system can also be promoted to express antitumor effects, IFN-a was given after BMT for hematologic malignancies and was shown to prolong the duration of tumor response. IL2 was similarly tested in children with Ewing's sarcoma, neuroblastoma and acute myeloid leukemia. Combined cytokine therapy may be active in the treatment of some chemoresistant maligancies.
30 Opportunistic Fungal Infections in Children with Cancer Philip A. Pizzo Pediatric Branch, National Cancer.Institute, National Institutes of Health, Bethesda, Maryland, USA During the last two decades, considerable progress has been made in the diagnosis and management of infectious complications in children with cancer. The early initiation of empirical antibiotic therapy when a neutropenic child becomes febrile has reduced the early morbidity and mortality of infection. However, the majority of children who develop fever and neutropenia do not have a specific source of infection identified. When the duration of neutropenia is short (<7-10 days) patients can be categorized as "low risk" and almost always recover without sequelae. However, when the duration of neutropenia is prolonged beyond 10 days, the risk for secondary infection in these "high risk" patients increases considerably, mandating vigilant surveillance and appropriate additions or modifications of the initial antimicrobial regimen. Among the most serious of the secondary infections that occur in these patients are the invasive mycoses, especially Candida and Aspergillus as well as Mucor, Cryptocoecus and an emerging array of less common fungal pathogens. These infections are characterized by tissue invasiveness and dissemination and, untreated, are a major source of morbidity and mortality. Unfortunately, these invasive mycoses can be difficult to diagnose and treatment options remain limited~ The spectrum of disease caused by opportunistic pathogens, including the methods for diagnosis as well as their treatment and prevention will be reviewed, highlighting recent development which might improve the outcome of patients in the future.
RECONSTITUTION OF HEMATOPOIETIC STEM CELL FUNCTION IN CHILDREN 31 Cord Blood and Peripheral Blood as a Source of Hematopoietic Stem Cells for Pediatric Patients Dr. Ka Wah Chan
354
Division of Pediatrics, M.D. Anderson Cancer Center, Houston, TX, U.S.A. The peripheral blood contains progenitor and stem cells that can restore long term, stable hematopoiesis after high dose cytotoxic therapy. Advantages of using peripheral blood stem cells (PBSC) for autotransplantation include: 1) Collection without the need of general anesthesia, 2) rapid hematologic recovery post cytotoxie therapy, 3) less likely contaminated by micrometastatic tumor cells. Recently PBSC have been applied in a number of investigative areas: 1) Support of multiple cycles of high dose therapy, 2) positive selection of CD34 hematopoietic progenitor ceils, 3) ex vivo expansion of progenitor cells and 4) insertion of multi-drug resistant genes into progenitors to allow post transplant chemotherapy. PBSC from normal donors have been used as the source of stem cells for allogeneic transplantation. Early results suggest good tolerance with no increase in incidence of acute graftvs-host disease (GVHD).
Blood recovered from the placenta and umbilical cord of newborn infants contains stem cells in concentrations equal to or greater than those in adult bone marrow, despite an average volume of 100 mL. More than 50 children worldwide have undergone umbilical cord blood (UCB) transplantation. All recipients weighed less than 50 kg. Engraftment of donor cells occurred in over 90% although hematologic recovery was slower than that of allogeneic bone marrow transplant. There seemed to be a lower incidence of severe GVHD despite using HLA disparate UCB for transplants. A number of cord blood banks have been established in different countries to provide a source of hematopoietic stem ceils to patients when no donor could be found in bone marrow registries.
32 The Biology of Purified Stem Cells P.M. Lansdorp Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, B.C., Canada Some of the most interesting questions in stem cell biology relate to the self-renewal properties of stem cells. Do the most primitive hematopoietic cells have unlimited proliferation potential or is this potential restricted? Two observations suggest that there are limits to the proliferative potential of stem cells and these observations will be discussed in some detail. In the first set of experiments we studied the behavior of highly purified stem cell "candidates" from different tissues in cytokine supplemented serum-free cultures ~. Primitive CD34+CD45RAt°CD71 ~ hematopoietic cells from adult bone marrow, umbilical cord blood and fetal liver showed striking differences in their ability to produce CD34 ÷ cells in cultures containing IL-6, IL-3, Steel factor and erythropoietin. Both the fraction of responding ceils and their proliferative potential decreased markedly with the age of the cell donor. These results suggested to us that the actual production of very primitive hematopoietic cells could be restricted to early stages of development. Similar findings have been obtained in a murine model2. The second set of observations which is indicative of restrictions in the proliferative and self-renewal capacity of stem cells is derived from analysis of telomeres in purified and cultured hematopoietic cells3. Loss of telomeric DNA at chromosome ends upon cell division has been linked to cellular senescence and aging and is thought to normally limit the proliferative potential of somatic cells. In collaborative studies with Cal Harley at Geron, we have found a striking decrease in the average telomere length of hematopoietic cells from adult bone marrow compared to those from fetal liver and cord blood3. These observations strongly suggest that telomere loss occurs during hematopoiesis in vivo. We CLINICAL BIOCHEMISTRY, VOLUME 28, JUNE 1995
reported to have specific effect on megakaryocytopoiesis and enhance platelet recovery post chemotherapy. A mixture of growth factors are being evaluated for the ex vivo of periphera! progenitor cells to further reduce the period of marrow aplasia post therapy. Recombinant proteins are also helpful to enhance immune functions of compromised patients. Interferon gamma (IFN--),), a T-cell derived lymphokine, possesses broad macrophage-monocyte activating effects. It has been used in combination of conventional antimicrobials in the treatment of refractory, opportunistic non-viral infections (such as atypical mycobacterium, fungal and parasitic infections) in patients with AIDS and cancer. IFN-3, may be combined with other cytokines (e.g., G-CSF) to treat children with resistant fungal infection. The use of G-CSF with antifungal agents was also suggested. Vaccines may be produced by recombinant technology to provide active immunization for selective groups of immunocompromised children. The immune system can also be promoted to express antitumor effects, IFN-a was given after BMT for hematologic malignancies and was shown to prolong the duration of tumor response. IL2 was similarly tested in children with Ewing's sarcoma, neuroblastoma and acute myeloid leukemia. Combined cytokine therapy may be active in the treatment of some chemoresistant maligancies.
30 Opportunistic Fungal Infections in Children with Cancer Philip A. Pizzo Pediatric Branch, National Cancer.Institute, National Institutes of Health, Bethesda, Maryland, USA During the last two decades, considerable progress has been made in the diagnosis and management of infectious complications in children with cancer. The early initiation of empirical antibiotic therapy when a neutropenic child becomes febrile has reduced the early morbidity and mortality of infection. However, the majority of children who develop fever and neutropenia do not have a specific source of infection identified. When the duration of neutropenia is short (<7-10 days) patients can be categorized as "low risk" and almost always recover without sequelae. However, when the duration of neutropenia is prolonged beyond 10 days, the risk for secondary infection in these "high risk" patients increases considerably, mandating vigilant surveillance and appropriate additions or modifications of the initial antimicrobial regimen. Among the most serious of the secondary infections that occur in these patients are the invasive mycoses, especially Candida and Aspergillus as well as Mucor, Cryptocoecus and an emerging array of less common fungal pathogens. These infections are characterized by tissue invasiveness and dissemination and, untreated, are a major source of morbidity and mortality. Unfortunately, these invasive mycoses can be difficult to diagnose and treatment options remain limited~ The spectrum of disease caused by opportunistic pathogens, including the methods for diagnosis as well as their treatment and prevention will be reviewed, highlighting recent development which might improve the outcome of patients in the future.
RECONSTITUTION OF HEMATOPOIETIC STEM CELL FUNCTION IN CHILDREN 31 Cord Blood and Peripheral Blood as a Source of Hematopoietic Stem Cells for Pediatric Patients Dr. Ka Wah Chan
354
Division of Pediatrics, M.D. Anderson Cancer Center, Houston, TX, U.S.A. The peripheral blood contains progenitor and stem cells that can restore long term, stable hematopoiesis after high dose cytotoxic therapy. Advantages of using peripheral blood stem cells (PBSC) for autotransplantation include: 1) Collection without the need of general anesthesia, 2) rapid hematologic recovery post cytotoxie therapy, 3) less likely contaminated by micrometastatic tumor cells. Recently PBSC have been applied in a number of investigative areas: 1) Support of multiple cycles of high dose therapy, 2) positive selection of CD34 hematopoietic progenitor ceils, 3) ex vivo expansion of progenitor cells and 4) insertion of multi-drug resistant genes into progenitors to allow post transplant chemotherapy. PBSC from normal donors have been used as the source of stem cells for allogeneic transplantation. Early results suggest good tolerance with no increase in incidence of acute graftvs-host disease (GVHD).
Blood recovered from the placenta and umbilical cord of newborn infants contains stem cells in concentrations equal to or greater than those in adult bone marrow, despite an average volume of 100 mL. More than 50 children worldwide have undergone umbilical cord blood (UCB) transplantation. All recipients weighed less than 50 kg. Engraftment of donor cells occurred in over 90% although hematologic recovery was slower than that of allogeneic bone marrow transplant. There seemed to be a lower incidence of severe GVHD despite using HLA disparate UCB for transplants. A number of cord blood banks have been established in different countries to provide a source of hematopoietic stem ceils to patients when no donor could be found in bone marrow registries.
32 The Biology of Purified Stem Cells P.M. Lansdorp Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, B.C., Canada Some of the most interesting questions in stem cell biology relate to the self-renewal properties of stem cells. Do the most primitive hematopoietic cells have unlimited proliferation potential or is this potential restricted? Two observations suggest that there are limits to the proliferative potential of stem cells and these observations will be discussed in some detail. In the first set of experiments we studied the behavior of highly purified stem cell "candidates" from different tissues in cytokine supplemented serum-free cultures ~. Primitive CD34+CD45RAt°CD71 ~ hematopoietic cells from adult bone marrow, umbilical cord blood and fetal liver showed striking differences in their ability to produce CD34 ÷ cells in cultures containing IL-6, IL-3, Steel factor and erythropoietin. Both the fraction of responding ceils and their proliferative potential decreased markedly with the age of the cell donor. These results suggested to us that the actual production of very primitive hematopoietic cells could be restricted to early stages of development. Similar findings have been obtained in a murine model2. The second set of observations which is indicative of restrictions in the proliferative and self-renewal capacity of stem cells is derived from analysis of telomeres in purified and cultured hematopoietic cells3. Loss of telomeric DNA at chromosome ends upon cell division has been linked to cellular senescence and aging and is thought to normally limit the proliferative potential of somatic cells. In collaborative studies with Cal Harley at Geron, we have found a striking decrease in the average telomere length of hematopoietic cells from adult bone marrow compared to those from fetal liver and cord blood3. These observations strongly suggest that telomere loss occurs during hematopoiesis in vivo. We CLINICAL BIOCHEMISTRY, VOLUME 28, JUNE 1995