National estimates of the use of hematopoietic stem-cell transplantation in children with cancer in the United States.

National utilization data for hematopoietic stem-cell transplantation (HSCT) for childhood cancers in the United States have not been reported. We identified cancer encounters for children aged 18 years and younger from 1997 to 2001 in US nonfederal, acute care hospitals. We compared patient, hospital, and resource use characteristics and in-patient mortality associated with HSCT and non-HSCT encounters, estimated the number of HSCT encounters by stem-cell source and cancer type, and examined resource use and mortality in each category. We identified 461,175 cancer encounters, of which 6380 (1.4%) were HSCT encounters. There was wide variation in resource use and mortality by stem-cell source and cancer type. Of note, 17% of HSCT encounters were for patients with acute lymphoblastic leukemia without remission or sarcoma, conditions for which there is little evidence of benefit from HSCT in children. These encounters were associated with high in-patient mortality and long lengths of stay. Also, we observed an increasing use of cord blood over the study period. Future research should examine potentially important sociodemographic differences in patients undergoing HSCT compared to those who do not. Additional analyses incorporating disease stage and severity are needed.

Accurate case finding using linked electronic clinical and administrative data at a children's hospital.

To link hospital administrative data and an electronic medical record at a children's hospital in order to identify children with cancer admitted for fever and neutropenia. Hospital administrative data concerning 13,374 inpatient and outpatient encounters were validated against and linked to clinical data stored in an electronic medical record. Queries of the linked databases identified children with fever and neutropenia. Sensitivity and specificity of the experimental case-finding strategy were determined and compared to a control case-finding strategy utilizing administrative data alone. Linking of the clinical record to the administrative record was achieved in 233 (99%) of the 235 records. Of 1680 data elements reviewed from the administrative data that were also potentially available in the clinical data system, 1679 (99.9%) were verified in the electronic medical record. The experimental strategy for case finding had a sensitivity of 73.1% (95% CI: 58.1, 88.3), specificity 99.6% (95% CI: 99.1, 100). If only administrative data such as diagnosis-related group and hospital service were used for case finding, both the sensitivity (P < 0.01) and specificity (P < 0.01) were significantly lower. Linking a children's hospital administrative data system with clinical data is feasible and can be utilized for specific case finding for a common and costly condition in children.

Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma.

PURPOSE: This review summarizes the published data on the use of high-dose chemotherapy and hematopoietic stem cell rescue (HSCR) in the treatment of recurrent or metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Three hundred eighty-nine patients were identified from 22 articles selected by computer generated searching of MEDLINE (1979-present). One hundred seventy-seven patients had stage 4 disease and were treated during first complete remission (CRI). The remaining patients were treated during CR1/first partial remission (PR1) (110 patients), CR2/PR2 (53 patients), CR2 (12 patients), CR3 (1 patient), or treated with disease (36 patients). RESULTS: Patients treated during CR1 or CR1/PR1 had event-free survival (EFS) rates ranging from 24% to 29% at 3 to 6 years from diagnosis and overall survival (OS) rates ranging from 20% to 40% at 2 to 6 years after diagnosis according to data provided as Kaplan-Meier estimates. Studies without Kaplan-Meier estimates (n = 32) indicate that 12 patients (38%) with stage IV RMS treated during CR1 or CR1/PR1 were surviving 7 to 60 months from diagnosis, similar to patients with stage IV RMS treated on Intergroup Rhabdomyosarcoma Studies II or III. Patients treated during CR2, CR3, or with evidence of disease had a worse outcome with an estimated 3 years OS of 12% (n = 51). Studies without Kaplan-Meier estimates (n = 27) indicate that four patients (15%) treated during CR2, CR3, or with disease were surviving 17 to 33 months after transplant. CONCLUSIONS: Based on these data, there does not appear to be a significant advantage to undergoing high-dose chemotherapy with HSCR for patients with relapsed or refractory high-risk RMS. Clearly, there is a need for incorporating new treatment strategies for patients with high-risk RMS.

Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group.

PURPOSE: This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. PATIENTS AND METHODS: One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. RESULTS: Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012). CONCLUSIONS: Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Pediatric germ cell tumors.

Malignant germ cell tumors are relatively uncommon, accounting for approximately 3% of all childhood malignancies. Occurring with an incidence of approximately 4 per million among children less than 15 years of age, they account for approximately 225 new cases per year in the United States. Germ cell tumors occur in both gonadal and extragonadal sites, with extragonadal and testicular tumors predominating in children less than 3 years of age and with the gonads being the main location of tumors during and after puberty. They occur more frequently in girls than boys. Germ cell tumors are interesting for several reasons: (1) abnormal migration of primordial germ cells account for many of the childhood germ cell tumors; (2) markers exist to allow evaluation of the extent of resection and the development of recurrence for many of the tumors; and (3) the introduction of platinum-based chemotherapy has markedly improved the survival rate for germ cell tumors, as well as the salvage rate for recurrent or metastatic disease.

Pilot study of a point-of-use decision support tool for cancer clinical trials eligibility.

Many adults with cancer are not enrolled in clinical trials because caregivers do not have the time to match the patient's clinical findings with varying eligibility criteria associated with multiple trials for which the patient might be eligible. The authors developed a point-of-use portable decision support tool (DS-TRIEL) to automate this matching process. The support tool consists of a hand-held computer with a programmable relational database. A two-level hierarchic decision framework was used for the identification of eligible subjects for two open breast cancer clinical trials. The hand-held computer also provides protocol consent forms and schemas to further help the busy oncologist. This decision support tool and the decision framework on which it is based could be used for multiple trials and different cancer sites.

Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: Despite advances in therapy, nearly 30% of children with rhabdomyosarcoma experience progressive or relapsed disease, which is often fatal. PATIENTS AND METHODS: To facilitate the development of a retrieval therapy protocol, we studied potential risk factors that were predictive of survival after first relapse in 605 children who were enrolled onto three consecutive Intergroup Rhabdomyosarcoma Study Group protocols. RESULTS: The median survival time from first recurrence was 0.8 years; the estimated percentage of patients who survived 5 years from first recurrence was 17% +/- 2% (mean +/- SD). Univariate analysis showed that tumor histology was an important predictor of 5-year survival (P <.001): the 5-year survival rate was 64% for patients with botryoid tumors (n = 19), 26% for patients with embryonal tumors (n = 313), and 5% for patients with alveolar or undifferentiated sarcoma (n = 273). Further analysis identified prognostic factors within histologic subtypes (P <.001). For patients with embryonal tumors, the estimated 5-year survival rate was 52% for patients who initially presented with stage 1 or group I disease, 20% for those with stage 2/3 or group II/III disease, and 12% for those with group IV disease. For patients with stage 1/group I disease, estimated 5-year survival rates were higher for patients with local (72%) or regional (50%) recurrence than for those with distant (30%) recurrence. Among patients with alveolar or undifferentiated sarcoma, only the disease group predicted outcome: the 5-year survival estimate was 40% for group I versus 3% for groups II through IV. We identified a "favorable risk" group (approximately 20% of patients) whose 5-year estimated survival rate was near 50%; for all other patients, the estimated survival was near 10%. CONCLUSION: This analysis demonstrates that the probability of 5-year survival after relapse for rhabdomyosarcoma is dependent on several factors at the time of initial diagnosis, including histologic subtype, disease group, and stage. These findings will form the basis of a multi-institutional risk-adapted relapse protocol for childhood rhabdomyosarcoma.

A case controlled comparison of open and laparoscopic splenectomy in children.

BACKGROUND: This case controlled study compares the efficacy, safety, and cost of laparoscopic splenectomy (LS) and open splenectomy (OS) for hematologic disorders in children. METHODS: The records of 82 consecutive children and adolescents undergoing splenectomy for hematologic disorders between August 1994 and September 1997 were reviewed retrospectively. RESULTS: Fifty patients underwent LS by a lateral approach and 32 underwent OS through a left subcostal incision. Mean age was 7.76 years for LS and 6.9 years for OS. Patient weights were similar: (LS, mean 30.5 kg; OS, mean 27.6 kg). Hematologic indications included hereditary spherocytosis in 43 children (LS 26, OS 17), sickle cell anemia with sequestration in 13 (LS 7, OS 6), immune thrombocytopenic purpura in 14 (LS 8, OS 6), and 12 with other disorders (LS 9, OS 3). Concomitant cholecystectomy was performed in 10 of 50 LS and 6 of 32 OS cases. Accessory spleens were identified in 8 of 32 (25%) OS and 9 of 50 (18%) LS cases (P = .578). No LS procedures required conversion to OS. The mean estimated blood loss was 54.4 mL for LS and 49.0 mL for OS (P = .233). LS required a longer operative time (115 vs 83 minutes, P = .002), less need for postoperative intravenous narcotic (51% vs 100%, P < .0001), lower total narcotic doses (0.239 vs 0.480 mg/kg morphine, P = .006), shorter length of hospital stay (1.4 +/- 0.97 vs 2.5 +/- 1.43 days, P = .0001), and lower average total hospital charges ($5713 vs $6564) than OS. There were no deaths or major complications in either group. CONCLUSIONS: Laparoscopic splenectomy is a safe and effective procedure in children with hematologic disorders resulting in longer operative times, less narcotic administration, shorter length of stay, and lower total hospital charge.

High dose cyclophosphamide with carboplatin: a tolerable regimen suitable for dose intensification in children with solid tumors.

PURPOSE: To determine the hematopoietic and nonhematopoietic toxicity of a novel dose-intensive chemotherapy regimen for the treatment of children with relapsed solid tumors. PATIENTS AND METHODS: The time to hematopoietic recovery and toxicity experienced during 46 courses of high-dose cyclophosphamide (4.0 g/m2), MESNA, and carboplatin (400 mg/m2) with granulocyte colony stimulating factor (G-CSF) support in 14 children with recurrent solid tumors was reviewed. RESULTS: All patients developed grade 4 neutropenia and thrombocytopenia. Recovery to an absolute neutrophil count (ANC) of 500/microliter and platelet count of 50,000/microliter occurred at a median of 15 days and 23 days respectively. Median time to ANC > 1,000/microliter and platelets > 100,000/microliter was 27 days. Hospitalization for fever and neutropenia occurred during 35 of 46 courses, with documented bacteremia in six courses. There was no grade II or greater nonhematopoietic organ toxicity. Responses (CR + PR) were observed in 6 of 11 evaluable patients. CONCLUSIONS: These data suggest that this regimen is tolerable in heavily pretreated children with solid tumors with myelosuppression as the primary toxicity. Due to the lack of significant nonhematopoietic toxicity, this is a good candidate regimen for dose escalation using peripheral blood progenitor cell infusions and deserves further evaluation for efficacy in children with both recurrent and newly diagnosed high-risk solid tumors.

Dicentric (9;20)(p11;q11) identified by fluorescence in situ hybridization in four pediatric acute lymphoblastic leukemia patients.

Four children with acute lymphocytic leukemia (ALL) and a dic(9;20) are described. All four patients were diagnosed with pre-B-cell All, and the three for whom information was available were CD10+. Age at diagnosis ranged from 23 months to 12 years. All patients achieved remission, with two in continuous remission for 2 years 6 months and 3 years, one patient relapsed, dying 3 years 2 months after diagnosis, and one patient was lost to follow-up. These four patients were initially diagnosed as having a deletion of 9p and loss of one chromosome 20. Re-examination of the karyotypes indicated a possible dic(9;20). The dicentric chromosome was verified using dual-color fluorescence in situ hybridization (FISH) with centromeric probes for chromosomes 9 and 20 on interphase nuclei. Three of the four patients had multiple chromosomal abnormalities in addition to the translocation; one was hypodiploid, one was pseudodiploid, and two were hyperdiploid. This dicentric chromosome was recently described in four adult and nine pediatric patients with ALL [8, 9]. All reported patients had CD10+ pre-B-cell All, and achieved remission, as was the case for our four pediatric dic(9;20) patients. Two of our three patients for whom follow-up is available are in continuous remission as were two adults and five pediatric patients in the previous reports. These studies confirm the dic(9;20) as a recurring abnormality in ALL. Due to the subtle nature of the translocation, FISH is very useful in confirming the chromosomal abnormality.

Transjugular intrahepatic portosystemic shunting (TIPS) for treatment of severe hepatic veno-occlusive disease.

Severe veno-occlusive disease (VOD) of the liver is a frequent cause of morbidity and mortality in patients undergoing transplantation. While surgical portosystemic shunts have been reported to be useful in the treatment of severe hepatic VOD with intractable ascites, few of these patients are surgical candidates. We report a case of severe VOD after autologous peripheral blood progenitor cell transplantation treated with transjugular intrahepatic portosystemic shunting (TIPS). This procedure resulted in marked improvement in the patient's ascites, coagulation status and urinary output. The safety and efficacy of this non-surgical approach for the treatment of patients with severe VOD requires prospective studies.

Functional hyposplenism due to a primary epithelioid hemangioendothelioma of the spleen.

We present a unique case of functional hyposplenism due to massive involvement of the spleen by a rare tumor, an epithelioid hemangioendothelioma, in a 9-year-old girl. To our knowledge, three previous cases of this disorder involving the spleen have been reported, but this is the first associated with functional hyposplenism.

Favorable outcome in children with Beckwith-Wiedemann syndrome and intraabdominal malignant tumors.

Children with Beckwith-Wiedemann syndrome (BWS) have an increased risk of developing Wilms' tumors, hepatoblastomas, and adrenal tumors. This study evaluates disease-free survival in children with BWS and intraabdominal tumors. Sixteen tumors occurred in 13 children with BWS (8 boys, 5 girls). Diagnoses included Wilms' tumor (10) (2 bilateral, 20%), hepatoblastoma (2), bladder rhabdomyosarcoma (1), and adrenal cortical tumor (1). In the 10 children with Wilms' tumor, the average age at diagnosis was 3.5 years (range, 7 months to 5 years). Nine of 10 had initial tumor resection, chemotherapy, and radiation therapy (when indicated). One child with bilateral disease had tumor biopsy, chemotherapy, and partial nephrectomy. Tumors were classified as stage I (5), stage II (2), stage IV (1) and stage V (2), all with favorable histology. Disease-free survival rate was 100% with median follow-up of 9 years (range, 4 to 22 years). One patient had a left adrenal tumor detected during screening sonography 11 years after Wilms' tumor resection. Two infants with advanced-stage hepatoblastoma responded to chemotherapy, allowing subsequent complete hepatic resection. Both tumors had unfavorable histology. Both completed postoperative chemotherapy and have no evidence of disease (NED) with normal alpha-fetoprotein levels at 21 and 12 months, respectively, after tumor detection. One patient with stage III (group 3) bladder rhabdomyosarcoma underwent partial cystectomy following chemoradiation and is alive (NED) after 20 months. Children with BWS should be screened at regular intervals (every 3 to 6 months) for renal, adrenal, and hepatic tumors. The exact duration of screening is not yet determined.(ABSTRACT TRUNCATED AT 250 WORDS)

A case-control retrospective study of the efficacy of granulocyte-colony-stimulating factor in children with neuroblastoma.

PURPOSE: We conducted a retrospective case-control study to examine the effect of granulocyte-colony-stimulating factor (G-CSF) on the duration of the neutrophil nadir and other clinical parameters in children with neuroblastoma. PATIENTS AND METHODS: We retrospectively reviewed 85 courses of the same chemotherapy in 16 consecutive neuroblastoma patients. The first nine patients received no growth factor and the following seven patients received G-CSF. Data obtained included days of neutropenia, fever rate and duration, hospitalization rate and duration, antibiotic duration, and infection rate. RESULTS: Patients who received G-CSF had a significant decrease in the period of neutropenia (mean 5.4 +/- 2.6 days per course vs. 11.4 +/- 4.1 days per course in the control group; p < 0.001). There were no statistically significant differences in episodes of fever per course, rate of hospitalization per course, duration of hospitalization, or duration of antibiotic therapy. Control patients had documented infections during 16% (nine of 56) of their chemotherapy courses, whereas the patients receiving G-CSF had infections during 7% (two of 29) of their courses, but this difference was not statistically significant (p = 0.318). We calculated that a study of 220 courses in each group would be needed to have adequate power to confirm that this difference is statistically significant. CONCLUSIONS: The administration of G-CSF in this patient population did result in fewer days of neutropenia, a finding that has been reported previously in several adult studies. However, we conclude that the clinical benefit of more rapid hematologic recovery in children remains uncertain and deserves further investigation in a large, prospective multicenter trial.

Murine yolk sac endoderm- and mesoderm-derived cell lines support in vitro growth and differentiation of hematopoietic cells.

The mechanisms involved in the induction of yolk sac mesoderm into blood islands and the role of visceral endoderm and mesoderm cells in regulating the restricted differentiation and proliferation of hematopoietic cells in the yolk sac remain largely unexplored. To better define the role of murine yolk sac microenvironment cells in supporting hematopoiesis, we established cell lines from day-9.5 gestation murine yolk sac visceral endoderm and mesoderm layers using a recombinant retrovirus vector containing Simian virus 40 large T-antigen cDNA. Obtained immortalized cell lines expressed morphologic and biosynthetic features characteristic of endoderm and mesoderm cells from freshly isolated yolk sacs. Similar to the differentiation of blood island hematopoietic cells in situ, differentiation of hematopoietic progenitor cells in vitro into neutrophils was restricted and macrophage production increased when bone marrow (BM) progenitor cells were cultured in direct contact with immortalized yolk sac cell lines as compared with culture on adult BM stromal cell lines. Yolk sac-derived cell lines also significantly stimulated the proliferation of hematopoietic progenitor cells compared with the adult BM stromal cell lines. Thus, yolk sac endoderm- and mesoderm-derived cells, expressing many features of normal yolk sac cells, alter the growth and differentiation of hematopoietic progenitor cells. These cells will prove useful in examining the cellular interactions between yolk sac endoderm and mesoderm involved in early hematopoietic stem cell proliferation and differentiation.

Melanotic neuroectodermal tumor of infancy: an important mimicker of paratesticular rhabdomyosarcoma.

We report a case of a paratesticular tumor in a 6-month-old infant. This tumor was originally believed to represent a poorly differentiated sarcoma of the cord but upon further pathological consultation it was recognized as a rare melanotic neuroectodermal tumor of infancy involving the epididymis. Since the former is a highly aggressive lesion and the latter an indolent tumor, treatment of these 2 entities differs markedly. Therefore, although the histological distinction between these lesions is often difficult, it is of critical importance.

Effect of nocodazole on vesicular traffic to the apical and basolateral surfaces of polarized MDCK cells.

A polarized cell, to maintain distinct basolateral and apical membrane domains, must tightly regulate vesicular traffic terminating at either membrane domain. In this study we have examined the extent to which microtubules regulate such traffic in polarized cells. Using the polymeric immunoglobulin receptor expressed in polarized MDCK cells, we have examined the effects of nocodazole, a microtubule-disrupting agent, on three pathways that deliver proteins to the apical surface and two pathways that deliver proteins to the basolateral surface. The biosynthetic and transcytotic pathways to the apical surface are dramatically altered by nocodazole in that a portion of the protein traffic on each of these two pathways is misdirected to the basolateral surface. The apical recycling pathway is slowed in the presence of nocodazole but targeting is not disrupted. In contrast, the biosynthetic and recycling pathways to the basolateral surface are less affected by nocodazole and therefore appear to be more resistant to microtubule disruption.

Deletions in the cytoplasmic domain of the polymeric immunoglobulin receptor differentially affect endocytotic rate and postendocytotic traffic.

We have examined the function of the cytoplasmic domain of the polymeric immunoglobulin receptor (pIg-R) by producing two separate deletions in the cytoplasmic domain of the pIg-R, expressing the mutant receptors in polarized MDCK cells, and analyzing each for their effects on receptor and ligand traffic. Deletion of the C-terminal 30 amino acids (726-755) reduces the rate of internalization of receptor-bound ligand from the basolateral surface. However, this mutation has no effect on delivery of receptor from the Golgi to the basolateral surface or the post-endocytotic traffic of receptor and ligand. Mutation of a tyrosine at position 734 to serine produces a receptor with a similar phenotype. If residues 670-707 are deleted from the middle of the cytoplasmic domain, both basolateral delivery and internalization are unaffected. However, unlike wild type, after endocytosis from the basolateral surface, both receptor and ligand are largely degraded. We reported previously that deletion of the entire cytoplasmic domain prevents the basolateral delivery of newly synthesized receptor (Mostov, K.E., de Bruyn Kops, A., and Deitcher, D.L. (1986) Cell 47, 359-364). In contrast, the mutants reported here are delivered to the basolateral surface, suggesting that only residues 653-669 and/or 708-725 are necessary for basolateral delivery. Thus, different deletions in the cytoplasmic domain of the pIg-R can produce mutant receptors which alter different aspects of receptor traffic.

Phosphorylation of the polymeric immunoglobulin receptor required for its efficient transcytosis.

The endosomal compartment of polarized epithelial cells is a major crossroads for membrane traffic. Proteins entering this compartment from the cell surface are sorted for transport to one of several destinations: recycling to the original cell surface, targeting to lysosomes for degradation, or transcytosis to the opposite surface. The polymeric immunoglobulin receptor (pIgR), which is normally transcytosed from the basolateral to the apical surface, was used as a model to dissect the signals that mediate this sorting event. When exogenous receptor was expressed in Madin-Darby Canine Kidney (MDCK) cells, it was shown that phosphorylation of pIgR at the serine residue at position 664 is required for efficient transcytosis. Replacement of this serine with alanine generated a receptor that is transcytosed only slowly, and appears to be recycled. Conversely, substitution with aspartic acid (which mimics the negative charge of the phosphate group) results in rapid transcytosis. It was concluded that phosphorylation is the signal that directs the pIgR from the endosome into the transcytotic pathway.