Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors.

OBJECTIVE: A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40-45 mg/m(2)/dose) was conducted for the treatment of refractory pediatric solid tumors. The pharmacokinetics of CPT-11 and its metabolites were characterized using both traditional noncompartmental analysis and population pharmacokinetics using NONMEM VI; pharmacokinetic pharmacodynamic relationships of SN-38 with indices of toxicity were also evaluated. METHOD: 11 patients between 3 and 18 years were enrolled. Pharmacokinetic parameters and consideration of relevant covariates (performance status (PS), BSA, corrected body weight (CBW), exponent of 3/4 on weight, etc.) were evaluated. Relationships between pharmacokinetic parameters of SN-38 and percentage change from baseline in patient biochemical response data were investigated via regression analysis. RESULT: CPT-11 exhibited a mean clearance (CL) of 15.31 +/- 5.95 (l/h) (13.06 +/- 3.58 (l/hr/m(2))) and AUC(0-inf) of 3547.0 +/- 1406.5 (ng x h/ml); the AUC ratio of parent CPT-11 to SN-38 was 5.0%. Based on the population pharmacokinetic analysis, decreasing PS was significantly dependent on reduction in CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 x CBW(0.75) (omegaCL = 21.7%), Vss (l) = 2.66 x CBW (omegaVss = 21.2%), Vc (l) = 1.13 x CBW, inter-compartment CL (l/h) = 0.257 x CBW(0.75). Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with Cmax of SN-38 (r = 0.78 and r = 0.74) and AUC0-2 of SN-38 (r = 0.73 and r = 0.73). CONCLUSION: Pharmacokinetic parameters were similar to results published in several past reports. An allometric scaling of CBW(0.75) would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients.

Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony-stimulating factor in pediatric donors.

The advantages/disadvantages of the use of peripheral blood stem cells (PBSCs) for allogeneic transplantation still need to be clarified, particularly in children. We compared the kinetics, efficacy, and safety of PBSC mobilization by granulocyte colony-stimulating factor (G-CSF) and collection by apheresis between healthy pediatric and adult donors. A total of 19 pediatric (median age, 6 years) and 25 adult healthy donors (median age, 37 years) were given 10 micro/kg/day of G-CSF for 5 consecutive days for PBSC mobilization, which were harvested by apheresis on days 5 and/or 6. All of the donors tolerated the whole procedures. Serum trough levels of G-CSF determined by ELISA were significantly lower in the 16 pediatric donors evaluated than in adults (n = 16) on days 3 and 4 (P < 0.05). Although the WBC counts on days 4 and 5 were significantly higher in adults than in children (P = 0.006 and 0.004, respectively), the numbers of circulating CD34+ cells/unit of blood were identical. The number of blood CD34+ cells collected per unit of blood processed was identical in both donor populations. We propose that PBSCs could be effectively mobilized and collected in small children so that they could be donors for adult patients.

A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement.

The prognosis of patients with metastatic retinoblastoma is poor with conventional chemotherapy and radiation. Since retinoblastoma is highly chemosensitive, dose-escalation of chemotherapeutic agents with stem cell support should be promising. We report our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) in patients with metastatic retinoblastoma. Five patients with metastatic retinoblastoma underwent HDC with autologous SCT following conventional chemotherapy and local radiation therapy. Stem cells (bone marrow in four and peripheral blood stem cells in one) were collected after marrow involvement was cleared. Melphalan was a key drug in all patients, and was administered in combination with other agents such as cisplatin, cyclophosphamide, carboplatin or thiotepa. Three patients are currently alive disease-free at 113, 107 and 38 months, respectively, from the time of SCT. They had no central nervous system (CNS) involvement. The two patients who died of disease had CNS involvement. No long-term sequelae of HDC have been noted. Our treatment strategy using HDC appears to be effective for treating metastatic retinoblastoma without CNS involvement.

Transduction of retrovirus-mediated NeoR gene into CD34+ cells purified from granulocyte colony-stimulating factor (G-CSF)-mobilized infant and cord blood.

To help establish an effective gene therapy protocol for patients with congenital metabolic diseases, we evaluated retrovirus-mediated transduction and long-term (LT) expression of the NeoR gene in cryopreserved and thawed CD34+ cells purified from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) of infant and cord blood (CB). The results were compared with those in bone marrow (BM) CD34+ cells. The final purity of the CD34+-enriched fraction from PB, CB, and BM, based on FACS analysis, was 88 +/- 14%, 73 +/- 13%, and 68 +/- 19% (mean +/- SEM), respectively. Cells were then cultured for 96 hours with supernatant containing the vector in the presence of interleukin (IL)-3, IL-6, and stem cell factor (SCF). The average efficiency of gene transfer into mobilized PB (n = 5) or CB CD34+ cells (n = 6) was significantly higher than that into BM CD34+ cells, as measured by G418-resistant colony-forming units for granulocyte/macrophage (CFU-GM; 59% or 58% vs. 39%; p < 0.05) and PCR-positive CFU-GM (83% or 79% vs. 53%; p < 0.05). When the evaluation was made in an LT culture system with irradiated allogeneic marrow stroma, these efficiencies were, respectively, 74% or 61% vs. 34% (p < 0.005 or < 0.02) for G418-resistant CFU-GM at week 5 of long-term culture, and 88% or 83% vs. 63% (p < 0.05) for PCR-positive CFU-GM. Fluorometric examination was performed for cell-cycle analysis before and after culture, and the results showed that the fraction of cycling cells was largest in freshly prepared BM (18%), whereas only a small portion of PB (4.6%) and CB (2%) was cycling. However, this value was 17% in BM, 22% in PB, and 13% in CB after culture. These results suggest that mobilized PB from small children and CB cells are suitable and realistic targets for clinical gene therapy and that tandem transduction procedures can be achieved by combining CB and PB.

Engraftment potential of peripheral and cord blood stem cells evaluated by a long-term culture system.

The experiment was performed in an attempt to seek a suitable indicator of allogeneic transplantation using cord blood cells. The number of colony-forming cells (CFC) recovered after 5 weeks of culture represents that of primitive progenitors present in the initiating cell population. In this study of nine children who underwent autologous peripheral blood stem cell transplantation (PBSCT), we measured the amount of colony-forming units-granulocyte/macrophage (CFU-GM) and total CFC output after 5 weeks in long-term culture (LTC-CFC) contained in the infused grafts and compared them to the speed of hematopoietic recovery after marrow ablation. In this patient population, we found a significant negative correlation between the number of infused CFU-GM/kg body weight and the time to achieve an absolute granulocyte count (AGC) of 0.5 x 10(9)/L (r = -0.867, p < 0.01), but not with the time to achieve a platelet count of 50 x 10(9)/L (r = -0.700, p = 0.05). Although the number of infused LTC-CFC/kg did not correlate with the early phase of granulocyte recovery, a significant correlation was observed with platelet recovery speed (r = -0.930, p < 0.01) and with the time to regain an absolute granulocyte count of 2 x 10(9)/L after the nadir of the transient decrease in the number of AGC, which occurred 3 to 7 weeks following PBSCT (r = 0.967, p < 0.01). On the other hand, CFU-GM/kg showed no significant correlation with this late engraftment speed. Thus, LTC assay may reflect the kinetics of immature progenitor cells which are capable of reconstituting stable hematopoiesis after marrow ablative therapy. The data were then used in a comparative analysis of the transplantation potential of peripheral vs. cord blood stem cells. The numbers of LTC-CFC and CFU-GM per mononuclear cell (MNC) from cord blood were 2.5-fold and two-fold greater than those from peripheral blood cells, respectively. These results suggest the advantage of cord blood as an additional stem cell source in transplantation.

Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria.

OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder that manifests as hemolytic anemia, venous thrombosis, and deficient hematopoiesis. Although allogeneic hematopoietic stem cell transplantation is considered the only curative therapeutic measure, transplant-related mortality is not negligible. Several studies supported the use of nonmyeloablative stem cell transplantation (NST) for patients of advanced age or with organ dysfunction. Hence, we used NST in a PNH patient who suffered from acute renal failure due to repeated episodes of hemolysis. MATERIALS AND METHODS: We performed NST using a conditioning regimen consisting of cladribine 0.11 mg/kg x 6, busulfan 4 mg/kg x 2, and rabbit anti-thymocyte globulin 2.5 mg/kg x 2. He received peripheral blood stem cells from his human leukocyte antigen-matched brother. Prophylaxis against graft-vs-host disease was performed with cyclosporine A alone. Chimerism of peripheral blood mononuclear cells was evaluated serially using short tandem repeat analysis and flow cytometry. RESULTS: No meaningful regimen-related toxicities were documented. Donor chimerism of 90 to 100% was achieved on day 14 and thereafter. The patient is doing well, without any recurrence of hemolysis 6 months after transplant. Follow-up chimerism studies confirmed stable and functioning donor-type hematopoiesis. CONCLUSIONS: NST may become a safe and curative approach in patients with PNH. Further studies are needed to establish the role of NST for treatment of PNH.

Comparative analysis of engraftment after cryopreservation of peripheral blood stem cell autografts by controlled- versus uncontrolled-rate methods.

Peripheral blood stem/progenitor cells (PBSC) were cryopreserved by different methods and their clonogenic viabilities were compared. The traditional cryopreservation method involves controlled-rate freezing with 10% dimethyl sulfoxide (DMSO) and a programmed freezer (PF). The alternative method incorporates 6% hydroxyethyl starch and 5% DMSO without PF. In this non-randomized study, we analyzed the data of 24 patients (aged 1-17 years) who were in their first complete remission and who had undergone PBSC autograft (PBSCT) for high-risk acute lymphoblastic leukemia, to determine the effects of these two different methods of cryopreservation on time to engraftment and transfusion requirements after PBSCT. In all patients, PBSC were collected within 5 months of diagnosis and all had been conditioned with the high-dose MCVAC regimen (MCNU, cytosine arabinoside, etoposide and cyclophosphamide) without total body irradiation. Twelve patients received PBSC that had been cryopreserved by the uncontrolled method without PF and the data were compared by actuarial analysis to those of 12 historical controls whose cells had been frozen by PF. No difference was observed in the time to engraftment of granulocytes and platelets or the transfusion requirements between the two groups. Our results indicate that, in terms of preserving engraftment potential, the simplified uncontrolled-rate cryopreservation method is at least as effective as the traditional controlled-rate freezing procedure with PF.

Regeneration of immunity and varicella-zoster virus infection after high-dose chemotherapy and peripheral blood stem cell autografts in children.

We assessed recovery of the immune system in 41 children who underwent high-dose chemotherapy (without total body irradiation) and autologous peripheral blood stem cell transplantation (PBSCT) for acute leukemias or non-Hodgkin's lymphoma. The analysis was in two parts. Firstly, we performed serial monitoring of regenerating subsets and blastogenesis of lymphocytes. We then reviewed the incidence of varicella-zoster virus (VZV) infection, based on the belief that this served as a clinical indication of immunological recovery. The CD4/CD8 ratio markedly decreased in all patients, with a nadir at 3 months, due to both abnormally low levels of CD4+ cells and sustained higher levels of CD8+ cells. These abnormalities were sustained for > 12 months post-graft. Within 6 months after PBSCT, all patients showed a decreased in vitro response to mitogens including PHA, Con A and PWM but these responses gradually recovered during the subsequent 6 months. All patients had a previous history of chicken pox. The actuarial incidence of VZV was 45% at 6 months and 67% at 12 months. All patients were treated with intravenous acyclovir with relief of pain and cutaneous healing within 10 days. No patient developed visceral dissemination. These findings suggest that at least in children, no major difference is apparent between immunological reconstitution in bone marrow transplantation and PBSCT. The development of minor and reversible VZV is a common event in this group of patients.

Successful treatment of meningoencephalitis caused by methicillin-resistant Staphylococcus aureus with intrathecal vancomycin in an allogeneic peripheral blood stem cell transplant recipient.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common infectious pathogen during stem cell trans-plantation. We report a case of meningoencephalitis with multiple abscess formation caused by MRSA, which occurred in a 4-year-old boy soon after allogeneic peripheral blood stem cell transplantation. We successfully cured the infection with a combination of intravenous and intrathecal vancomycin.

Suspected delayed immune recovery against cytomegalovirus after reduced-intensity stem cell transplantation using anti-thymocyte globulin.

A reduced-intensity hematopoietic stem cell transplantation (RIST) regimen was developed to induce immunosuppression to facilitate the engraftment of donor cells. However, there have been concerns that the incidence of opportunistic infection may increase after this procedure. To address this problem, we retrospectively analyzed the medical records of 24 RIST recipients who were treated over a recent 16-month period for comparison with 31 recipients of conventional allogeneic transplantation (CST). The RIST regimen consisted of cladribine (0.66 mg/kg), busulfan (8 mg/kg), and rabbit anti-thymocyte globulin (ATG; 5-10 mg/kg). All of the patients received allogeneic peripheral blood stem cells from an HLA-identical or one-locus mismatched related donor. Although the incidence of positive CMV antigenemia was comparable between the two groups (58% vs 68%), RIST patients developed positive antigenemia significantly sooner than did CST patients (P = 0.01) and showed higher initial and maximum antigenemia values (P = 0.026 and P = 0.003, respectively). These findings may suggest that immune recovery against CMV was delayed after our RIST procedure, but this did not directly translate into an increase in clinically significant CMV disease. Early therapeutic intervention with ganciclovir might play a role in preventing the progression of early CMV infection to CMV disease.

Induction of graft-versus-autoimmune (GVA) disease effect against refractory psoriasis by complete donor-type chimerism and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

A 67-year-old man with AML, who had a 21-year history of psoriasis without remission, received a reduced-intensity transplantation from an HLA-identical sibling. The preparative regimen consisted of busulfan and fludarabine. Graft-versus-host-disease (GVHD) prophylaxis was cyclosporine and methotrexate. Psoriasis was completely resolved on day 18. The subsequent clinical course was uneventful until day 42, when psoriasis recurred at the same sites as before RIST. Peripheral blood examined on day 63 showed mixed chimerism with 54% recipient type. Cyclosporine was rapidly tapered off over the next 2 weeks. On day 90, 100% donor-type chimerism was confirmed. Subsequently, psoriasis improved simultaneously with the occurrence of mucositis and rash as a manifestation of GVHD. Scattered erythematous patches of psoriasis disappeared again by day 105. We initiated 0.5 mg/kg prednisolone on day 119, and resumed cyclosporine on day 133. At 7 months after RIST, he still suffers from chronic GVHD, but his psoriasis remains in remission for the first time in 21 years. The anti-psoriasis effect of the conditioning is mild and transient, while the graft-versus-autoimmunity effect, related to the induction of complete donor-type chimerism and GVHD, is more profound and persisting. A graft-versus-autoimmunity effect lies in the delicate balance between alloimmunity and immunosuppressant used for GVHD prophylaxis/treatment.

Clinically applicable bulk isolation of blood CD34+ cells for autografting in children.

CD34+ cells were purified in bulk from apheresis-collected cells of children with cancer using monoclonal antibody (MoAb) and magnetic beads (Baxter ISOLEX system). To improve the purity of the final product for possibly better tumor cell purging and to make the manufacturer's original procedure more cost-effective, we incubated the cells for 30 min with l-phenylalanine methylester hydrochloride (PME) to reduce the cell number by removing contaminating granulocytes and monocytes in the initial step before incubation with MoAb. Our modification prevented nonspecific interactions between MoAb and magnetic beads, and thereby saved expensive materials for purification. A total of 40 purifications were performed with samples containing a mean of 3.1 x 10(9) blood cells mobilized from 15 children by chemotherapy plus granulocyte colony-stimulating factor (G-CSF). The entire purification procedure, from the end of apheresis to storage, was completed within 5h. After incubation with PME and double-layered (40/60%) Percoll separation, the number of CD34+ cells was reduced to 48+/-29%, which suggests the possibility that half of the CD34+ cells in the inoculum were nonclonogenic in the hematopoietic progenitor assay. PME/Percoll-treated cells were then subjected to a final isolation procedure with MoAb according to the manufacturer's suggestions, and 52+/-42% and 32+/-22%, respectively, of the CFU-GM and CD34+ cells present in the initial bag inoculums were recovered. The recovery rates were, respectively, 54% and 67%, when the calculation was limited to the isolation procedure with MNoAb. The purity of isolated CD34+ cells and the plating efficiency in methylcellulose culture were, respectively, 77+/-24% and 33+/-13%. Fourteen children were subsequently autografted with purified CD34+ cells after marrow ablative chemotherapy. The median number of days to achieve an ANC of 0.5 x 10(9)/l was 12 and that to achieve a platelet count of 50 x 10(9)/l was 22.5, which were comparable to those in our historical group of 55 patients who underwent transplant with unmanipulated blood cells (13 and 16 days). These results suggest that our modified purification procedure with PME is useful for the initial reduction of cell numbers to save costly materials, and that cells isolated by this procedure can be directly used in clinical transplantation procedures.

Late hemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST).

We reviewed medical records of 256 patients to investigate the frequency and characteristics of hemorrhagic cystitis (HC) associated with reduced-intensity stem cell transplantation (RIST) as opposed to conventional stem cell transplantation (CST); 137 patients underwent CST and 119 RIST. Diagnosis of HC was made based on two or more episodes of sterile, macroscopic hematuria with normal coagulation profiles, without any evidence of renal stones or genitourinary malignancy. Actuarial frequency of HC development in RIST group was 7.6% (9/119), which gave a cumulative annual incidence of 11.7%. In CST group, 13 of 137 patients (9.5%) developed HC, giving an estimated annual incidence of 9.7%. The probability of developing HC was similar between the two groups (P=0.77). The viral etiologies of HC, adenovirus (n=12) and BK virus (n=2), were documented in eight patients after RIST and in six after CST. HC was milder and of a shorter duration, with less blood transfusion requirements, in RIST group than in CST group. A multivariate analysis revealed that HC was associated with antiadenovirus antibody positivity in the recipients, total dose of busulfan, and chronic GVHD. Although HC following RIST is less severe than that following CST, it is still a significant problem.

Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation.

To evaluate the efficacy of long-term administration of acyclovir as prophylaxis against varicella-zoster virus (VZV) reactivation, we analyzed the medical records of 86 consecutive adult patients who obtained engraftment after allogeneic hematopoietic stem cell transplantation from January 1996 to March 2000. We started long-term low-dose (400 mg/day) oral administration of acyclovir in June 1999, and this was continued until the end of immunosuppressive therapy after transplantation. There was no breakthrough reactivation of VZV in patients receiving acyclovir. Five patients who were receiving cyclosporine or prednisolone developed VZV reactivation after discontinuing acyclovir. With this prophylaxis, the cumulative incidence of VZV reactivation at 1 year after transplantation decreased from 33% to 10% (P = 0.025). On multivariate analysis, the use of long-term acyclovir was identified as a significant independent parameter for the development of VZV reactivation. These findings suggest the efficacy of long-term prophylaxis with low-dose acyclovir. Resumption of acyclovir upon restarting immunosuppressive therapy might be important for the further prevention of VZV reactivation. The benefit of long-term low-dose acyclovir should be confirmed prospectively.

New consecutive high-dose chemotherapy modality with fractionated blood stem cell support in the treatment of high-risk pediatric solid tumors: a feasibility study.

For the treatment of childhood solid tumors, we performed a pilot feasibility study of consecutive high-dose therapies, in which each course was followed by transplantation with granulocyte colony-stimulating factor-mobilized peripheral blood cells which had been separated into CD34-positive and -negative fractions by an Isolex system (Baxter). Positive selection of CD34+ cells has been associated with inevitable cell loss. To overcome this loss, CD34+ cells that had migrated into the negative fraction were saved and used for the first transplant, which was followed by a second transplant after a 3- to 5-month interval. In this phase I feasibility study, the results in six children were evaluated for safety and engraftment. Multi-drug cytoreductive regimens using ranimustine (MCNU), melphalan, thiotepa, carboplatin, cyclophosphamide or VP-16 were comparable between the two transplant procedures in terms of their intensity. The number of CD34+ cells in the 'CD34(+) fraction' was 3.31 x 10(6)/kg (0.63-4.3 x 10(6)/kg), while this number in the 'CD34(-) fraction' could not be evaluated correctly due their scarcity (<0.1%). The median numbers of infused MNC and CFU-GM were, respectively, 4.2 x 10(6)/kg and 1.75 x 10(5)/kg in the CD34(+) fraction, and 4.8 x 10(8)/kg and 3.35 x 10(5)/kg in the CD34(-) fraction. The number of days required to achieve an ANC >0.5 x 10(9)/l and a platelet count >20 x 10(9)/l and >50 x 10(9)/l were, respectively, 14.5, 15.0 and 19.5 in the first transplant with CD34- cells, and 13.5, 18.0 and 25.0 in the second transplant with CD34+ cells, with no essential difference between the two treatments. Although the small number of patients, the variation in clinical status and treatment, and the short follow-up invalidate any evaluation of the therapeutic benefit of this strategy, the encouraging results support the feasibility of this strategy, which enables an escalation of dose intensity with an improved cost/benefit ratio.

[A new exanthematous disease in newborn infants caused by exotoxins producing methicillin-resistant Staphylococcus aureus; pathology from viewpoints of local and systemic levels of exotoxin and cytokine].

Neonatal exanthematous diseases induced by toxic shock syndrome toxin-1 (TSST-1)-producing methicillin-resistant Staphyloccocus aureus (MRSA) is one of emerging infectious diseases in Japan. We experienced 36 patients with this disease in National Kagawa Children's Hospital and in 13 patients of them, investigated the role of both the toxin and cytokines in pathogenesis of it. The results are summarized as follows: 1. The TSST-1 level was high in the umbilical inflammatory exudate of cases induced by umbilical infection and in the gastric fluid of cases induced by respiratory infection. The blood TSST-1 level was below the detection limit in most of the exathematous++ cases examined, but it was detected in one of the nine cases induced by respiratory infection and a case secondary to severe MRSA infection (phlegmonous abscess in buttock). 2. Local cytokine levels were examined in the abscess pus obtained from a case of severe MRSA infection and in the gastric fluid from cases induced by respiratory infection. The local levels of TNF [alpha], IL-1 [beta], IL-6 and IL-8 were markedly high, but the local levels of IL-2 and IFN-[gamma] were similar to their blood levels. 3. The severity of hypercytokinemia (IL-1 [beta], IL-2, IL-6, IFN-[gamma]) was proportionate to the severity of exanthematous disease. Accompanied by increased levels of inhibitory factors sTNF-R, IL-1 ra, sIL-2R and IL-10, this hypercytokinemia normalized soon within four or five days. 4. As compared to cases induced by umbilical infection, cases induced by respiratory infection often had higher blood cytokine levels and some of them had cardiorespiratory disorders. Based on the results of this study, we consider that this disease is generally induced by toxemia with a small number of toxins without tissue destructive lesions by MRSA infection and that this is closely related to the course of the disease that shows a tendency to a spontaneous recovery.

New variant of congenital dyserythropoietic anemia with trilineage myelodysplasia.

We report the case of a male infant with a variant of congenital dyserythropoietic anemia (CDA), who developed severe hyperbilirubinemia on the day of birth, subsequent severe anemia, and hyperferritinemia. Bone marrow and laboratory examinations revealed features of CDA including trilineage myelodysplasia and erythroblasts with a binucleated nuclear morphology and ineffective erythropoiesis. The CDA in this patient was assumed to be a new variant type because of: the lack of internuclear chromatin bridges in the erythroblasts with abnormal nuclear morphology; a negative acid serum test; the presence of erythrocyte antigen I, and the effect of splenectomy. Trilineage myelodysplasia in CDA is not known. An abnormality in the stem cells was suggested to be the cause of CDA in this case.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in children undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

The incidence of SIADH (the syndrome of inappropriate antidiuretic hormone secretion) was analyzed retrospectively in 43 children who received marrow-ablative chemotherapy before autografts with peripheral blood stem cells for lymphoid malignancies. SIADH was documented in three children (ages 3, 13, and 13 years) who received chemotherapy, which included high-dose methyl 6-[3-(chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU) and cyclophosphamide, under a concomitant overhydration protocol. SIADH was manifested as frequent vomiting in two patients and as generalized seizure in one. Hyponatremia (< 125 mEq/L), hypo-osmolality (< 260 mOsm/kgH2O), and continued urinary excretion of sodium (> 30 mEq/L) were used to diagnose SIADH in these three patients. All signs and symptoms subsided within 24 hours either by fluid restriction alone (n = 1) or by supportive care including anticonvulsant and D-mannitol, or hyperhydration with saline plus 5% glucose and diuretic. None of the patients died. Careful monitoring of the serum sodium level, as well as the osmolality of plasma and urine, should be incorporated into the patient management protocol for this type of high-dose chemotherapy.