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Hepatoblastoma is a malignant embryonal liver tumor that occurs almost exclusively in infants and very young children. Previous cytogenetic studies of hepatoblastoma have investigated small series or individual cases. This report is on the cytogenetics of a large series of 111 hepatoblastoma specimens, with cytogenetic results consecutively karyotyped over a 12-year period. Abnormal karyotypes were observed in 55 cases (∼50% of the total). Numerical aberrations were observed in 41 cases (36% of the total), particularly trisomies of chromosomes 2, 8, and 20. Chromosome losses were less common than chromosome gains. Structural abnormalities were observed in 43 cases (39% of the total). Unbalanced translocations resulting in trisomy 1q and involving breakpoints at 1q12–21 were the most common structural abnormality, observed in 20 tumors (18% of total cases); the corresponding translocated chromosome was highly varied. The previously reported t(1;4) was observed in seven cases. Most tumors with translocations involving 1q12–21 also displayed numerical chromosome aberrations, the most common of which were chromosomal trisomies, whereas tumors with other structural rearrangements had fewer numerical abnormalities. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html. © 2005 Wiley-Liss, Inc.

BACKGROUND Nasopharyngeal carcinoma (NPC) is rare in children, accounting for < 1% of all cases. Treatment most commonly includes radiotherapy but long-term side effects of such treatment can produce devastating cosmetic and functional sequelae in children. Chemotherapy may help to decrease the radiotherapy dose and limit the side effects of local therapies. However, little is known regarding the chemosensitivity of NPC tumors in pediatric patients. METHODS Patients with American Joint Committee on Cancer (AJCC) Stage I/II disease (Stratum 01) received irradiation only. Patients with AJCC Stage III/IV disease (Stratum 02) received 4 courses of preradiation chemotherapy comprising methotrexate (120 mg/m2) on Day 1, with cisplatin (100 mg/m2) 24 hours later, 5-fluorouracil 1000 mg/m2 per day as a continuous infusion for 3 days, and leucovorin 25 mg/m2 every 6 hours for 6 doses. Irradiation was given after chemotherapy and consisted of 50.4 gray (Gy) to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy. RESULTS One patient was enrolled in Stratum 01 and 16 evaluable patients were enrolled in Stratum 02. The median age of the patients was 13 years and 65% of the patients were black. All patients tested had evidence of Epstein–Barr virus infection. Two-thirds of the patients developed Grade 3–4 mucositis during chemotherapy. The overall response rate to induction chemotherapy was 93.7%. The overall 4-year event-free and overall survival rates (± the standard error) were 77% ± 12% and 75% ± 12%, respectively. CONCLUSIONS The current study demonstrated that childhood NPC was sensitive to chemotherapy and that chemotherapy before irradiation was feasible. Future trials should investigate equivalent efficacy with a reduced radiotherapy dose. Cancer 2005. © 2005 American Cancer Society.

Cyclin D1, encoded by the gene CCND1, is a major regulator of the cell cycle transition from G1 phase to S phase. A CCND1 polymorphism (G to A) at codon 242, the boundary of exon 4 and intron 4, affects splicing such that exon 5 is not expressed in the A allele. Since exon 5 is involved in rapid turnover, the variant cyclin D1 corresponding to the A allele may have a longer half-life. A previous study demonstrated that in families with hereditary nonpolyposis colorectal cancer, the age of onset of colorectal cancer varied according to variation at this polymorphic site. We examined this CCND1polymorphism in a series hepatoblastoma, a childhood liver cancer that shares other molecular features with colon cancer. We determined in an analysis of 84 children with hepatoblastoma that the G/A exon 4 polymorphism in CCND1 is correlated with the age of onset of hepatoblastomas. The A/A genotype is associated with an earlier age of onset compared to the G/A or G/G genotype. The median age of patients with the G/G genotype was 22 months, compared to 17 months in patients with the G/A genotype and 11 months for the A/A genotype. These findings suggest that the CCND1 A polymorphism may contribute to tumor development in children with hepatoblastoma.

PURPOSE: To determine surgical resectability, event-free survival (EFS), and toxicity in children with hepatocellular carcinoma (HCC) randomized to treatment with either cisplatin (CDDP), vincristine, and fluorouracil (regimen A) or CDDP and continuous-infusion doxorubicin (regimen B). PATIENTS AND METHODS: Forty-six patients were enrolled onto Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group (POG) 8945/Children’s Cancer Group (CCG) 8881). After initial surgery or biopsy, children with stage I (n = 8), stage III (n = 25), and stage IV (n = 13) HCC were randomly assigned to receive regimen A (n = 20) or regimen B (n = 26). RESULTS: For the entire cohort, the 5-year EFS estimate was 19% (SD = 6%). Patients with stage I, III, and IV had 5-year EFS estimates of 88% (SD = 12%), 8% (SD = 5%), and 0%, respectively. Five-year EFS estimates were 20% (SD = 9%) and 19% (SD = 8%) for patients on regimens A and B, respectively (P = .78), with a relative risk of 1.2 (95% confidence interval, 0.60 to 2.3) for regimen B when compared with regimen A. Outcome was similar for either regimen within disease stages. Events occurred before postinduction surgery I in 18 (47%) of 38 patients with stage III or IV disease, and tumor resection was possible in two (10%) of the remaining 20 children with advanced-stage disease after chemotherapy. CONCLUSION: Children with initially resectable HCC have a good prognosis and may benefit from the use of adjuvant chemotherapy. Outcome was uniformly poor for children with advanced-stage disease treated with either regimen. New therapeutic strategies are needed for the treatment of advanced-stage pediatric HCC.

PURPOSE: Previous studies demonstrated that chemotherapy with either cisplatin, vincristine, and fluorouracil (regimen A) or cisplatin and continuous infusion doxorubicin (regimen B) improved survival in children with hepatoblastoma. The current trial is a randomized comparison of these two regimens. PATIENTS AND METHODS: Patients (N = 182) were enrolled onto study between August 1989 and December 1992. After initial surgery, patients with stage I–unfavorable histology (UH; n = 43), stage II (n = 7), stage III (n = 83), and stage IV (n = 40) hepatoblastoma were randomized to receive regimen A (n = 92) or regimen B (n = 81). Patients with stage I–favorable histology (FH; n = 9) were treated with four cycles of doxorubicin alone. RESULTS: There were no events among patients with stage I-FH disease. Five-year event-free survival (EFS) estimates were 57% (SD = 5%) and 69% (SD = 5%) for patients on regimens A and B, respectively (P = .09) with a relative risk of 1.54 (95% confidence interval, 0.93 to 2.5) for regimen A versus B. Toxicities were more frequent on regimen B. Patients with stage I-UH, stage II, stage III, or stage IV disease had 5-year EFS estimates of 91% (SD = 4%), 100%, 64% (SD = 5%), and 25% (SD = 7%), respectively. Outcome was similar for either regimen within disease stages. At postinduction surgery I, patients with stage III or IV disease who were found to be tumor-free had no events; those who had complete resections achieved a 5-year EFS of 83% (SD = 6%); other patients with stage III or IV disease had worse outcome. CONCLUSION: Treatment outcome was not significantly different between regimen A and regimen B. Excellent outcome was achieved for patients with stage I-UH and stage II hepatoblastoma and for subsets of patients with stage III disease. New treatment strategies are needed for the majority of patients with advanced-stage hepatoblastoma.

Purpose: In June 1992, POG began accrual to a phase III study, POG-9239, designed to compare the time to disease progression, overall survival, and toxicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m 2 of infusional cisplatin and randomized to either conventional vs. hyperfractionated radiotherapy. Methods and Materials: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pons. Histologic confirmation of diagnosis was not mandatory, provided that the clinical and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiotherapy with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose escalation levels of POG-8495) (arm 2). Because of previously reported poor results with conventional radiotherapy alone, cisplatin was included as a potential radiosensitizer in an attempt to improve progression-free and ultimate survival rates. Based on results of the phase I cisplatin dose escalation trial, POG-9139, 100 mg/m 2 was chosen for this trial and was delivered by continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligible patients were treated on protocol, 66 on arm 1 and 64 on arm 2. Results: The results we report are from time of diagnosis through October 1997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2–15 months) and the median time to death 8.5 months (range 3–24 months); survival at 1 year was 30.9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1–12 months) and 8 months (range 1–23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluation of response by MRI at 4 or 8 wks post treatment was available in 108 patients and revealed a complete response in 1 patient of each Rx arm, a partial response (> 50% decrease in size) in 18 patients of arm 1 and 15 patients of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 patients of arm 2. The pattern of failure was local in all patients. Morbidity of treatment was similar in both Rx arms, with no significant toxicity (including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases. Conclusion: The major conclusion from this trial is that the hyperfractionated method of Rx 2 did not improve event-free survival ( p = 0.96) nor did it improve survival ( p = 0.65) over that of the conventional fractionation regimen of Rx 1, and that both treatments are associated with a poor disease-free and survival outcome.

We report four cases of hepatoblastoma with a derivative chromosome 4 from an unbalanced translocation between the long arms of chromosomes 1 and 4, an aberration reported only rarely in isolated cases of other types of neoplasms. The abnormality in three hepatoblastomas was der(4)t(1;4)(q12;q34), whereas the fourth case appeared to have a der(4)t(q25;q32). All had hyperdiploid tumor karyotypes; however, in the case with t(q25;q32), the der(4) was the only abnormality in the stemline. We speculate that the oncogenetic event in our cases may be the loss of a gene on distal 4q or their alteration by juxtaposition to 1q12 heterochromatin.

There is a clear association between multimodal therapy for bone tumors and the development of skeletal complications; however, this has not been addressed in children with soft tissue sarcomas. We reviewed records of the 70 children treated for soft tissue sarcoma of the lower extremity at St Jude Children's Research Hospital between 1962 and 1991. Of the 12 patients who received radiation after surgical excision of their tumors, three subsequently developed fractures. Two of the three had also received chemotherapy. Our findings indicate that, although the risk of fracture after therapy for soft tissue sarcoma may be multifactorial, radiation may play a significant role. Minimizing the size of surgical incisions, improving radiotherapy techniques, maximizing chemotherapy, and emphasizing physical therapy and appropriate follow up can all serve to decrease long-term toxicities. Such optimal use of therapy could subsequently reduce side effects, such as osteoporosis and muscle and bone atrophy, that predispose patients to fractures.

The der(16)t(1;16)(q21;q13) chromosomal abnormality has been reported rarely in Wilms' tumor. This abnormality has also been found in several other pediatric and adult neoplasms, and may imply a poor prognosis in at least some of these solid tumors. To investigate its clinical significance in Wilms' tumor, we examined the records of 65 consecutive children with Wilms' tumor whose tumor cells were successfully karyotyped. The t(1;16) was present in seven patients (10%) whose ages ranged from 2.5 to 4.7 years (median 3.5 years) at diagnosis. Six of the seven patients were female. All four stages of Wilms' tumor were represented (two patients had stage IV disease). No patient had bilateral disease. All tumors were of “favorable histology.” All seven patients are alive and off therapy with a median follow-up of 3.2 years (range, 2 to 8.5 years). One patient with this abnormality developed brain metastases within 4 months of completion of therapy. Comparison of these patients with the remaining 58 Wilms' tumor patients revealed no significant differences with regard to disease stage, histology, survival, or relapse-free survival. Cytogenetic evidence of der(16)t(1;16)(q21;q13) in Wilms' tumor does not appear to portend an adverse clinical outcome, although only a larger study that includes molecular detection methods can provide more conclusive evidence. © 1996 Wiley-Liss, Inc.

Background. Etoposide, ifosfamide, and cisplatin (VIP) are each active in treating pediatric solid tumors, and this combination has been shown to be effective in treating adult germ cell tumors. Etoposide, ifosfamide, and cisplatin therapy was used to treat 11 patients, with ages ranging from 14 months to 22 years, with relapsed sarcoma, Wilms' tumor, and hepatoblastoma. Methods. Etoposide, ifosfamide, and cisplatin therapy was administered daily for 3 days in doses of cisplatin 20 mg/m 2 with mannitol 10 g/m 2 for 1 hour, etoposide 100 mg/m 2 , and ifosfamide 1.5 g/m 2 with MESNA 360 mg/m 2 X 3 doses. A total of 65 courses (range, 3-10/patient) were administered, with 86% of the courses administered at full dose. Hematopoietic growth factors were not used. Results. All 10 evaluable patients responded. Six patients had a complete response (CR) by computed tomographic or magnetic resonance imaging scan after one to three courses. The remaining four patients had a partial response (PR) (>50% decrease in disease). One PR was converted to a CR by resection of the residual lesions. The major toxicity was myelosuppression. The median nadirs after full doses were as follows : leukocyte count of 900/mm 3 , absolute neutrophil count (ANC) of 156/mm 3 , platelet count of 61,000/mm 3 , and hemoglobin count of 8.6 g/dl; 75% of full dose courses led to an ANC of less than 500. Fever and neutropenia were observed after 8/55 (15%) full dose courses. Two episodes of bacteremia were noted, one with Staphylococcus epidermidis after full recovery of counts. The median time to hematologic recovery was 21 days (range, 14-29 days). No patient developed a decreased creatinine clearance level during therapy. Significant renal solute losses were observed in two patients, both of whom had been pretreated heavily with ifosfamide and had losses before VIP therapy. Conclusions. Etoposide, ifosfamide, and cisplatin appear to be active in treating childhood solid tumors. This therapy has predictable and tolerable myelotoxicity, and nephrotoxicity does not appear to be more severe than that observed after treatment with ifosfamide alone.

Malignant pediatric tumors of the central nervous system (CNS) have a poor prognosis, with local failure rates as high as 50%. In an attempt to improve local tumor control, we used stereotactic interstitial therapy with 125I implants in patients with recurrent/secondary or newly diagnosed CNS malignancies. Catheters were placed using computed tomography (CT) guidance; computerized dosimetry was completed with the aid of orthogonal films. Implants delivered 1,000 cGy/day to the tumor periphery (0.5 cm beyond the boundary of enhancement on CT scans), to a total dose of 60 Gy. Hyperfractionated external beam irradiation (HEBI), started 2-4 weeks after removal of implants, delivered total doses of 66-70.4 Gy in 110-cGy fractions twice daily to a 3-cm margin around the implant volume. Eight of the 11 patients with newly diagnosed tumors also received 48.4 Gy HEBI to the craniospinal axis. Tumor regression was noted at 2 months after implantation in the 4 patients treated for recurrent/secondary tumors; local progression was subsequently documented in 2 cases at 6 and 20 months after implantation, while a third patient died 6 months after implantation with no evidence of local recurrence. The remaining recurrent/secondary tumor patient has no evidence of active recurrence 15 months after implantation. Local control was maintained in 9 of the 11 patients treated for primary tumors for a median of 27 months (range 15 to 48+ months). The two local failures occurred at 5 and 7 months after implantation. Six patients are alive without evidence of progressive disease (median = 23 months after implantation). There were no severe acute toxicities, but 7 patients later developed histologically confirmed tumor necrosis. Quality of life assessment (QLA) following initial primary therapy with implantation was evaluated utilizing an established criteria and found to be excellent with only one child showing marked QLA score decrease which was related to neurosurgical intervention for radiation-induced necrosis and dysfunctional family social situation. This small series suggests that stereotactic 125I implantation followed by HEBI merits further evaluation in selected children with supratentorial malignant lesions.

Myeloperoxidase (MPO) is a major enzyme found in neutrophils. Oxidation by MPO produces free radicals that demonstrate genotoxic properties. A polymorphism (G to A) within the promotor region of the MPO gene reduces transcription and expression. This polymorphism is associated with a protective effect against some cancers in adults including lung cancer. The objective of our study was to investigate the effect of this MPO polymorphism on the risk of hepatoblastoma, the most common cancer of the liver in childhood. By using PCR-SSCP, we determined the genotype at this polymorphism in 48 cases of Caucasian children with hepatoblastoma and 180 normal controls. Genotypes were confirmed by a second method using Aci I restriction enzyme restriction. We found that A allele was associated with reduced risk of hepatoblastoma of 50% (OR, 0.51; 95%CI, 0.27-0.93) and G/A or A/A genotype reduced the risk by 56% (OR, 0.44; 95%CI, 0.21-0.90). Our data suggest that A allele is a protective factor with regard to the risk of hepatoblastoma, perhaps by altering genotoxic properties of xenobiotic substances which may act as carcinogens.

BACKGROUND 5-Fluorouracil (5-FU) activity for various carcinomas of adults has been enhanced through the synergistic effect of leucovorin. Few pediatric studies of 5-FU in pediatric patients have been previously reported. METHODS Fifty-eight patients were treated with a 4-hour infusion of leucovorin, 400 mg/m2, administered daily for 5 days every 3-4 weeks. 5-Fluorouracil was administered by bolus injection 1 hour into each leucovorin infusion. Eleven adolescent patients with colorectal carcinoma, Stage 3 or 4, were treated with therapeutic intent, and other patients with a variety of drug-resistant pediatric solid neoplasms received similar treatment. RESULTS Patients with measurable disease of colorectal carcinoma responded favorably to 5-FU/leucovorin. Stable disease activity was seen with other tumor types. Specifically, there were no objective responses in 12 patients with Ewing's Sarcoma or 11 with osteosarcoma. There were 4 deaths in this study from causes related to toxicity. Nonfatal grade 3/4 toxicities included mucositis, rash, myelosuppression, nausea, vomiting, diarrhea, and infection. CONCLUSION The authors do not plan further evaluation of 5-FU/leucovorin in additional pediatric patients with colon cancer or other heavily pretreated malignant solid tumors and are presently treating their patients with colon carcinoma with 5-FU/leucovorin/interferon-alpha 2a.

PURPOSE To evaluate survival and neurodevelopmental outcomes following radiation therapy in infants and young children with residual or progressive medulloblastoma after primary chemotherapy. PATIENTS AND METHODS Thirteen young patients (< or = 36 months old) with medulloblastoma were treated with preirradiation multiagent chemotherapy and maximal surgical resection. Patients were scheduled to receive radiation therapy at the time of documented disease progression or upon completion of chemotherapy with residual disease. All patients underwent neurodevelopmental evaluation at the time of diagnosis, before receiving radiation therapy, and at yearly intervals posttreatment. RESULTS Two patients completed the scheduled chemotherapy with residual disease and received delayed radiation therapy. The remaining 11 patients had either local or leptomeningeal progression during chemotherapy (median time to progression, 5 months). Six patients had a complete response (CR) to radiation therapy, and three of these children are alive 48 to 104 months postdiagnosis. Of the five patients who had progressive disease (PD) during radiation therapy or residual imaging abnormalities after treatment, only one is alive (with stable enhancing leptomeningeal abnormalities) 48 months postirradiation. Two additional survivors were rendered disease-free by surgical resection before radiation therapy and are without evidence of disease at 91 and 107 months after diagnosis. Thus, six of 13 patients are alive at 48 to 107 months postdiagnosis. Neurodevelopmental scores tended to be below age norms at diagnosis; scores improved during chemotherapy, but then decreased during posttreatment follow-up evaluation. CONCLUSION Radiation therapy appears to produce long-term disease-free survival in a proportion of very young patients who have progressive or residual medulloblastoma during or after primary chemotherapy. However, neurodevelopmental deficits are frequent among long-term survivors.

Two patients having rhabdomyosarcomas with the recently described "solid variant" pattern of alveolar rhabdomyosarcoma are reported. Both tumors had aggressive cytologic features with monotonous sheets of round nuclei, but without fibrous septa, and both had been initially classified as embryonal rhabdomyosarcomas. Cytogenetic analyses of tumor explants from both cases revealed the t(2;13) chromosomal aberration typical of alveolar rhabdomyosarcoma. Both patients died of metastases, despite aggressive surgical and adjuvant therapy. This report represents the first karyotypic analyses of solid alveolar rhabdomyosarcomas and supports the inclusion of these tumors in the alveolar category despite the lack of fibrous septa.

We report a new translocation t(8;22)(q22;q11) in a single case of epithelioid sarcoma. The band involved in chromosome 22 is the same found in 70-80% of the case of Ewing's sarcoma/peripheral neuroepithelioma (PNET) with cytogenetic characterization. The histologic characteristics of this tumor were typical for epithelioid sarcoma. Immunohistochemical stains were also entirely consistent with this diagnosis, including non-reactivity with P30/32MIC2, a specific marker for Ewing's sarcoma/primitive neuroepithelioma.

Ifosfamide, carboplatin, and etoposide (ICE) chemotherapy has promising activity against various solid tumors but produces significant myelotoxicity that might be ameliorated by hematopoietic growth factors. Twelve patients with relapsed solid tumors were treated with ICE chemotherapy. Carboplatin was given on day 1 at a targeted area under the concentration-time curve (AUC) of 8 mg/mL × min (adjusted for each patient's glomerular filtration rate), followed by ifosfamide 2 g/m2 and etoposide 100 mg/m2 on days 2 through 4. Granulocyte-macrophage colony-stimulating factor (GM-CSF), 1,000 μg/m2/day, was started 24 hours after each course and given for 17 days or until the absolute neutrophil count (ANC) reached 10 × 109/L. Myelotoxicity and responses in these patients were compared to those of eight patients who received the same therapy without GM-CSF. Patients received a median of three courses (range, 1–8). All 20 patients developed grade 4 neutropenia and grade 3 or 4 thrombocytopenia. The median duration of neutropenia was significantly shorter in patients who received GM-CSF (16.75 vs. 10 days, P = 0.005). However, the two groups did not differ in the proportion of courses associated with hospitalization for febrile neutropenia, the duration of hospitalization, or the median duration of thrombocytopenia. There were two complete, four partial, and three objective responses in the 12 patients treated with ICE plus GM-CSF, and two partial and three objective responses in the 8 patients treated with ICE only. GM-CSF did not reduce the occurrence of febrile neutropenia or the duration of thrombocytopenia associated with ICE chemotherapy. Studies of other hematopoietic growth factors in conjunction with this promising combination are merited. © 1994 Wiley-Liss, Inc.

PURPOSE To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. PATIENTS AND METHODS Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. RESULTS Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. CONCLUSION This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

Background. Patients with bilateral Wilms tumor have an increased incidence of associated abnormalities and nephrogenic rests and require individualized multi-modality therapy for cure. The authors reported the associated abnormalities, outcome, complications, and late effects of treatment in a group of children with bilateral Wilms tumor treated at St. Jude Children's Research Hospital, Memphis, Tennessee, over a 28-year period. Methods. The records of 36 consecutive pediatric patients diagnosed with bilateral Wilms tumor between 1962–1990 were analyzed. Biopsy material was also reviewed, with particular emphasis on characterization of nephrogenic rests and histology. Results. Twenty-nine patients had synchronous tumors and 7 had metachronous lesions. Associated physical abnormalities were present in 12 patients and involved the genitourinary, cardiovascular, integumentary, and musculoskeletal systems. The overall survival for patients with metachronous tumors (71%) was similar to that for those with synchronous tumors (70%). There was no effect of age or the presence of nephroblastomatosis. Two patients with synchronous tumors initially treated with nephrectomy eventually required bilateral nephrectomies for contralateral recurrence after chemotherapy and radiation therapy. Nephrogenic rests were present in 22 of 30 evaluable patients. Two of three patients with metachronous tumors had intralobar nephrogenic rests. Bilateral renal salvage procedures were demonstrated to be technically feasible and effective in controlling disease without compromising renal function or survival. Late effects included scoliosis in three patients treated before 1970, cardiomyopathy in one patient who received 300 mg/m2 doxorubicin and 12 Gy pulmonary irradiation, and benign tumors in two patients, one of whom also had a bowel obstruction. Serum creatinine, urea nitrogen, and blood pressure were normal in 23 of 26 survivors. Conclusions. The authors' experience supports a favorable outcome with minimal late effects for patients with bilateral Wilms tumor who receive individualized therapy at pediatric oncology centers.

PURPOSE Evaluation of high-dose chemotherapy with autologous bone marrow rescue (ABMR) in pediatric malignant gliomas. PATIENTS AND METHODS Newly diagnosed (n = 11) and recurrent (n = 2) malignant glioma patients received high-dose chemotherapy within 4 weeks of surgery; three had near total and 10 had subtotal resection/biopsy. High-dose thiotepa (300 mg/m2) and cyclophosphamide (2 g/m2) daily for 3 days were followed by ABMR; response was evaluated at day 30. At day 60, patients with at least stable disease received hyperfractionated (n = 9) or conventional external-beam radiotherapy (n = 2) preceded by local radioactive iodine 125 implantation (n = 2) or radiosurgery (n = 1). RESULTS Grade III and IV toxicities after ABMR consisted of mucositis (n = 12), cardiomyopathy (n = 1), acute abdomen (n = 1), pneumonitis (n = 2), and infection (n = 2). One complete and three partial responses were observed; the objective response rate was 31% (95% confidence interval, 9% to 61%). Seven had stable disease, one had disease progression, and one died of toxicity before response evaluation. The median overall and progression-free survival durations after combined modality therapy were 14 months (range, 4 to 30+) and 9 months (range, 0 to 30+), respectively. One patient remains progression-free at 30+ months. Radionecrosis and white matter changes occurred in three patients: one after hyperfractionated irradiation, and two after 125I implants. CONCLUSION For patients with bulky residual disease after surgery, survival with this aggressive chemotherapy and radiation regimen is not better than that reported for conventional treatment regimens.

Background. The authors conducted a Phase I dose escalation trial of ifosfamide given daily for 3 consecutive days to 29 children with malignant solid tumors. Twenty-eight of these children had received prior chemotherapy. Methods. Patients were assigned to dosage cohorts separately on the basis of prior exposure to the platinum alkylating agents cisplatin or carboplatin (n = 20) or the absence of such exposure (n = 9). At least three patients in each category were treated at a starting dosage of 2133 mg/m2/d for 3 days. This dosage represented 80% of the total dose delivered in the prior study of ifosfamide given daily over 5 days with dosage escalation of 20% in subsequent cohorts. Results. Myelosuppression was dose-limiting at the second dosage level (2560 mg/m2/d) for patients previously treated with platinum and at the third dosage level (3072 mg/m2/d) for those not previously treated with platinum. Dose-limiting neurotoxicity was seen at 2560 mg/m2/d for the former group, but was not encountered in the latter group. Conclusions. Delivery of ifosfamide daily for 3 days is feasible and safe at recommended dosages of 2133 mg/m2/d for children with prior exposure to platinum and 3000 mg/m2/d for those without prior exposure.

Background. Malignant rhabdoid tumor (MRT) is an aggressive, invariably lethal tumor that is resistant to multimodal therapy. Methods. The authors reviewed the clinicopathologic features, treatment, and outcome of 13 children (7 boys and 6 girls) with diagnoses of primary extracranial MRT at St. Jude Children's Research Hospital between 1981 and 1990. Results. The median age at diagnosis was 8 months (range, 10 weeks-18 years). Primary sites included the kidney (seven patients), liver (three patients), soft tissue of scapula, posterior mediastinum, and retroperitoneum. Seven patients had metastatic disease (lungs, six patients; cutaneous hemangioma, one patient). Ten patients had surgical resection of primary tumor (complete, nine patients; incomplete, one patient). Eleven patients had chemotherapy with multiple agents. Three of four chemotherapy responses observed were with regimens containing ifosfamide. Partial responses (PR, > 50% reduction in tumor size) were obtained in one patient who received single-agent ifosfamide during disease relapse (PR lasting 2 months), one patient who received a combination of ifosfamide, carboplatin, and etoposide at diagnosis (PR lasting 5 months), and one patient who was treated with bleomycin, cyclophosphamide, doxorubicin, and vincristine at diagnosis (PR lasting 5 months) and subsequently with ifosfamide in combination with carboplatin and etoposide during disease relapse (PR lasting 4 months). All patients died at a median period of 5 months (range, 0.5-30 months) after diagnosis. Conclusions. Based on this review, the authors recommend using ifosfamide alone or in combination with carboplatin and etoposide in front-line therapy for malignant rhabdoid tumor.

PURPOSE The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.

PURPOSE To estimate the disease-free survival rate in children with grossly resected hepatoblastoma treated with cisplatin, vincristine, and fluorouracil (CDDP/VCR/FU) and to assess the disease-response rate and disease-free survival (DFS) rate in children with unresectable or metastatic tumors treated with this combination. PATIENTS AND METHODS Sixty assessable patients with hepatoblastoma received therapy with five (stage I and II) to seven (stage III and IV) courses of CDDP (90 mg/m2), day 1, and VCR (1.5 mg/m2), and FU (600 mg/m2), day 3. RESULTS Nineteen of 21 patients with stage I or II disease survive free of disease (actuarial survival, 90% at 5 years). Twenty-four of 31 patients with stage III disease achieved a complete remission (CR) after chemotherapy and surgical excision; actuarial DFS at 4 years is 67%. Only one of eight patients with stage IV disease achieved a remission and survives. CONCLUSION Relatively brief exposure to chemotherapy with CDDP/VCR/FU provided excellent disease control to patients with grossly resected tumors. In patients with initially unresectable disease, this therapy provides a response rate and DFS rate comparable to regimens that contain doxorubicin (DOX).

Widely disseminated neuroblastoma in children older than infancy remains a very poor prognosis disease. Even the introduction of marrow ablative chemotherapy with autologous rescue has not significantly improved the outlook for these children, presumably because of a failure to eradicate minimal residual disease. One additional approach which may hold promise is the use of immunomodulation with cytokines such as IL2 in the setting of minimal residual disease (MDR), for example after intensive chemotherapy and ABMT. However, considerable variability in the susceptibility of neuroblastoma cells to natural killer (NK) and lymphokine-activated (LAK) killing has been observed, and it is presently unclear how NK and LAK cells recognise neuroblastoma cells. In this paper we examine expression of cell adhesion molecules on neuroblastoma to determine which of these modify interaction with NK and LAK cells. We find that LFA-3 (CD58), the ligand for CD2 is of predominant importance in predicting susceptibility of neuroblastoma to the cytotoxic actions of NK and LAK cells, while expression of ICAM-1 (CD54) may also modify susceptibility. These findings were confirmed by blocking experiments in which co-culture of target cells with ICAM-1 and LFA-3 reduced LAK and NK cytotoxicity. Study of the immunophenotypic features of each patient's neuroblastoma cells before induction of MRD may be valuable in determining the likely effect of IL2 in predicting disease reactivation.

Leiomyosarcomas (LMS) are extremely rare in children, accounting for only 2% of their soft-tissue sarcomas [11]. We report our experience with nine children treated for LMS between 1962 and 1990. Their ages at diagnosis ranged from 1 day to 17 years (median 5 years); six were female and eight were Caucasian. Five tumors were stromal sarcomas originating in the gut (ileum 2, stomach 1, jejunum, sigmoid 1). Three were intra-abdominal tumors that originated in the retroperitoneum (2) and abdominal wall (1). In one patient the tumor appeared in the subcutis of the thigh. Operations were uniformly performed, resulting in complete resection of the tumor in six of nine cases. Five patients received adjuvant chemotherapy and one received radiation therapy only. Five patients were alive 6–38 months (median 16 months) after diagnosis. The remaining four died of their disease 4–27 months after diagnosis, three of locally recurrent disease and one of hepatic metastasis. Four of the six patients with complete resection were alive 6–27 months after diagnosis. Both patients with low-grade (grade I) sarcomas had complete resections and were alive 33–38 months after diagnosis. Clinical outcome correlated roughly with the mitotic rate of the tumors, as all three patients with mitotic count >5/10 high power fields (HPF) died between 4 and 14 months after diagnosis. Immunohistochemical stains using the avidin-biotin-complex procedure on formalin-fixed tissue were performed for six tumors. Only muscle-specific actin (MSA) was uniformly positive (6/6). The other significant marker was desmin, which was positive in three tumors. Favorable outcome of LMS in children correlates best with low mitotic counts (

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal me-tastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression. Cancer 1992; 69:1061–1066.

Many fragile sites in the human genome occur at or near chromosomal breakpoints reportedly involved in translocations of DNA material in neoplastic cells. This fact has led some investigators to postulate that fragile sites have a pathogenic role in human neoplasia. To learn whether caffeine-induced fragile sites relate to breakpoints found in the neoplastic cells of an individual patient, we studied lymphocytes from the peripheral blood of 32 patients in remission from malignant disease. Lymphocytes were cultured in medium containing either 5-Fluoro-2'-deoxyuridine (FdU) or FdU plus caffeine, and G-banded metaphases were examined for nonrandom breaks. Analyses of completely G-banded malignant cell chromosomes from 31 of the 32 patients were available for comparison. In only once case, a 5-year-old child with acute lymphoblastic leukemia, did a caffeine-induced fragile site (1q44) coincide with a breakpoint in the neoplastic cells [dup(1)(q21--q44)]. Our findings suggest that chromosomal abnormalities in childhood malignancies cannot generally be explained by the presence of FdU- or FdU plus caffeine-induced fragile sites.

Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1,500 micrograms/m2 as 2-hour intravenous infusions, beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts, resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2), treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1,500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.

Fifty-two children with favorable histology Wilms' tumor who had residual abdominal disease (Surgical Stages III and IV) were treated from 1979 to 1988 on a protocol designed to assess the effectiveness of reduced radiation doses. All patients received three-agent chemotherapy, beginning within 1 week after surgery. To permit assessment of disease response to initial chemotherapy, radiation therapy was delayed for a median of 28 days after surgery (range, 14–71 days). Total doses of abdominal radiation were limited to 12 Gy, given as 150 cGy daily fractions; 18 patients with Stage IV disease received 12 Gy bilateral pulmonary irradiation. Two year disease-free survival was 85% and 71% for Stage III and IV, respectively ( p = .24). Abdominal relapses occurred in 3 cases (5.7%). The interval between surgery and initiation of irradiation was not related to disease-free survival. Of several patient and disease-related factors analyzed, only patient age was related to outcome. Disease-free survival was 100% at 3 years for children under the age of 3 versus 78% for children greater than age 3 ( p = .05). Reduced-dose abdominal radiotherapy in conjunction with multi-agent chemotherapy and surgery provided excellent disease control with minimal toxicity in advanced-stage, favorable histology Wilms' tumor.

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.

The ability of computed tomographic (CT) criteria to predict the potential for resection with renal salvage in unilateral Wilms' tumor was evaluated retrospectively in 10 children given preoperative treatment for initially inoperable disease. Criteria were (a) tumor involving only one pole and occupying less than one-third of the kidney, (b) functioning kidney, (c) no invasion of collecting system or renal vein, and (d) clear margins between tumor, kidney, and surrounding structures. Review of preoperative CT scans correctly predicted nonsalvageability (as assessed by surgicopathologic findings) in seven cases. Sufficient pathologic data were lacking to confirm positive CT predictors in one case. One patient was rated resectable with salvage on surgicopathologic review, but not by CT criteria, and in one case, a prediction could not be made. The potential for renal salvage may be greater in samples with smaller initial tumor size, and addition of other imaging modalities might enhance the accuracy of prediction. Further studies are needed to assess the feasibility of prospective trials evaluating the risks and benefits of partial nephrectomy in unilateral Wilms' tumor.

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for1% of all cases. Treatment most commonly includes radiotherapy but long-term side effects of such treatment can produce devastating cosmetic and functional sequelae in children. Chemotherapy may help to decrease the radiotherapy dose and limit the side effects of local therapies. However, little is known regarding the chemosensitivity of NPC tumors in pediatric patients.Patients with American Joint Committee on Cancer (AJCC) Stage I/II disease (Stratum 01) received irradiation only. Patients with AJCC Stage III/IV disease (Stratum 02) received 4 courses of preradiation chemotherapy comprising methotrexate (120 mg/m2) on Day 1, with cisplatin (100 mg/m2) 24 hours later, 5-fluorouracil 1000 mg/m2 per day as a continuous infusion for 3 days, and leucovorin 25 mg/m2 every 6 hours for 6 doses. Irradiation was given after chemotherapy and consisted of 50.4 gray (Gy) to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy.One patient was enrolled in Stratum 01 and 16 evaluable patients were enrolled in Stratum 02. The median age of the patients was 13 years and 65% of the patients were black. All patients tested had evidence of Epstein-Barr virus infection. Two-thirds of the patients developed Grade 3-4 mucositis during chemotherapy. The overall response rate to induction chemotherapy was 93.7%. The overall 4-year event-free and overall survival rates (+/- the standard error) were 77%+/-12% and 75%+/-12%, respectively.The current study demonstrated that childhood NPC was sensitive to chemotherapy and that chemotherapy before irradiation was feasible. Future trials should investigate equivalent efficacy with a reduced radiotherapy dose.

Purpose: To define the maximum-tolerated dose and dose-limiting toxicities (DLTs) of an oral formulation of ZD9331, a novel thymidylate synthase inhibitor that is not a substrate for folylpolyglutamate synthase. Patients and Methods: Patients had Cancer and Leukemia Group B performance status ≤ 2 and refractory solid tumors. Initially, patients received ZD9331 daily for 2 weeks, with the duration of treatment escalated to a maximum of 4 weeks, followed by a 2-week rest period. Once the maximum-tolerated duration of treatment was determined, the dose of ZD9331 was increased until DLT occurred. Results: Fifty-five patients were enrolled at eight dose levels. The DLTs were thrombocytopenia and neutropenia. At 3 mg/d, two of 19 patients developed DLT; one patient had grade 3 thrombocytopenia and grade 4 neutropenia, and the other patient had grade 3 thrombocytopenia only. Anemia was common, with a median hemoglobin nadir of 75% of baseline, before recovery or transfusion. The apparent oral clearance of ZD9931 was 11.6 ± 6.3 mL/min. Dose-limiting myelosuppression was associated with both an increased 24-hour ZD9931 concentration and blood urea nitrogen. Conclusion: The recommended phase II dose on this schedule is 3 mg/d for 4 weeks, followed by a 2-week rest period. ZD9331 seems to have a manageable toxicity profile, although it should be used with caution in patients with renal impairment.

BACKGROUND Children with hepatocellular carcinoma (HCC) were treated on a prospective, randomized trial and were then analyzed to determine whether children with the fibrolamellar (FL) histologic variant of HCC have a more favorable presentation, increased surgical resectability, greater response to therapy, and improved outcome compared with children who have typical HCC. METHODS Forty-six patients were enrolled on Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group Study 8945/Children's Cancer Group Study 8881) between August 1989 and December 1992. After undergoing initial surgery or biopsy, children with Stage I HCC (n = 8 patients), Stage III HCC (n = 25 patients), and Stage IV HCC (n = 13 patients) were assigned randomly, regardless of histology, to receive treatment either with cisplatin, vincristine, and fluorouracil (n = 20 patients) or with cisplatin and continuous-infusion doxorubicin (n = 26 patients). RESULTS Ten of 46 patients (22%) had the fibrolamellar variant of HCC (FL-HCC). For the entire cohort, the estimated 5-year event free survival (EFS) rate (± standard deviation) was 17% ± 6%. There was no difference in outcome among patients who were treated with either regimen. The 5-year EFS rate for patients with FL-HCC was no different the rate for patients with typical HCC (30% ± 15% vs. 14% ± 6%, respectively; P = 0.18), although the median survival was longer in patients with FL-HCC. There was no difference in the number of patients with advanced-stage disease, the incidence of surgical resectability at diagnosis, or the response to treatment between patients with FL-HCC and patients with typical HCC. CONCLUSIONS Children with FL-HCC do not have a favorable prognosis and do not respond any differently to current therapeutic regimens than patients with typical HCC. Children with initially resectable HCC have a good prognosis irrespective of histologic subtype, whereas outcomes are poor uniformly for children with advanced-stage disease. The use of novel chemotherapeutic agents and the incorporation of other treatment modalities are indicated to improve the dismal survival of pediatric patients with all histologic variants of advanced-stage HCC. Cancer 2003;97:2006–12. © 2003 American Cancer Society. DOI 10.1002/cncr.11292

PURPOSE: To estimate the disease-response rate, proportion of patients whose tumors can be made resectable, event-free survival (EFS), and toxicity in children with unresectable or metastatic hepatoblastoma (HB) after sequential treatment with the following: (1) carboplatin (CARBO); (2) CARBO, vincristine, and fluorouracil (CARBO-VCR-5-FU); and (3) high-dose cisplatin and etoposide (HDDP-ETOP). PATIENTS AND METHODS: Thirty-three assessable patients with stage III (n = 22) and stage IV (n = 11) HB were treated sequentially with one course of CARBO (700 mg/m2), followed by three courses of CARBO (700 mg/m2), day 0; 5-FU (1,000 mg/m2/d), by continuous infusion days 0 to 2; and VCR (1.5 mg/m2), days 0, 7, and 14. After that therapy, patients whose tumors were resectable underwent surgery and then received two additional courses of CARBO-VCR-5-FU. Children whose tumors remained unresectable after CARBO-VCR-5-FU or who demonstrated no response or progressive disease during this therapy received two courses of HDDP (40 mg/m2/d), days 1 to 5; and ETOP (100 mg/m2/d), days 2 to 4. RESULTS: Five-year EFS estimates were 59% ± 11% for stage III disease (n = 22) and 27% ± 16% for stage IV disease (n = 11), respectively (P = .037). Twenty-seven (82%) of 33 patients had at least a partial response to chemotherapy; 18 (55%) of 33 responded to CARBO; 24 (80%) of 30 responded to CARBO and CARBO-VCR-5-FU; and nine (75%) of 12 responded to HDDP-ETOP. Surgical resection was achieved in 19 (58%) of 33 patients, including 15 (68%) of 22 stage III patients and four (36%) of 11 stage IV patients. Five-year EFS for patients whose tumors were completely resected was 79% ± 10%. CONCLUSION: Patients treated sequentially with CARBO, CARBO-VCR-5-FU, and HDDP-ETOP had response rates and EFS comparable to other therapeutic regimens. This regimen is effective in treating localized, unresectable HB and potentially has less toxicity than other regimens. Novel approaches are needed for patients with metastatic disease.

Primary malignant liver tumors are uncommon in pediatric patients. Hepatoblastoma, hepatocellular carcinoma, and embryonal sarcoma are the primary entities that challenge the pediatric oncologist. Although these tumors are potentially curable, the efficacy of treatment is highly dependent on anatomic location and responsiveness to chemotherapy.

PURPOSE We evaluated the clinical efficacy of preirradiation carboplatin (CARBO) and etoposide (VP-16) in 25 patients with newly diagnosed embryonal CNS tumors. PATIENTS AND METHODS Sixteen patients with high-risk medulloblastoma and nine with other embryonal tumors were treated with two daily doses of CARBO 350 mg/m2 and VP-16 100 mg/m2 (CARBO/VP) every 21 days for four cycles before standard craniospinal irradiation. Patients with disease progression (PD) before radiation therapy were additionally treated with intensive postirradiation cyclophosphamide (CYCLO) and vincristine (VINC). RESULTS Among 23 assessable patients, 48% (95% confidence interval, 27% to 69%) had a complete response (CR) or partial response (PR) to CARBO/VP; eight had PD. Among the subgroup of 15 assessable patients with medulloblastoma, 53% had a CR or PR (95% confidence interval, 27% to 79%) and five PD. The toxicity of CARBO/VP was predominantly hematologic; although grade IV neutropenia was common, only five episodes of febrile neutropenia occurred. Only thrombocytopenia was a more common toxicity than in other reported chemotherapy regimens; ototoxicity was less common than in cisplatin (CDDP) regimens. CONCLUSION The responses and survival associated with neoadjuvant CARBO/VP are similar to those with CDDP-containing and other neoadjuvant drug regimens. Although the rate of progression with this regimen may be higher than with similar CDDP-containing regimens, the numbers of patients in other published studies of these agents are too small to detect meaningful statistical differences. Future studies must balance the apparently comparable efficacy of CARBO and CDDP with their differing toxicities.

Despite reported activity in many other solid tumors, high-dose ifosfamide produces few objective responses in recurrent pediatric brain tumors. Alkylating agents such as cyclophosphamide (CYCLO) possess good activity in many of solid tumors, including brain tumors. Although Ifosfamide (IFOS), a structural congener of CYCLO, has been suggested to have greater activity in several tumors, its activity in brain tumors is uncertain. We conducted a phase II trial of every-other day IFOS (3 gm/M2/qod × 3) in 87 recurrent pediatric brain tumors. Responses were evaluable in 71 patients. Partial responses occurred in 1/6 patients with low grade astrocytoma, 1/16 with malignant glioma, 1/16 with medulloblastoma, 1/3 with pineoblastoma and 1/12 patients with ependymoma. No responses occurred among 10 patients with brain stem gliomas or 8 patients with other brain tumors. Despite the poor objective response rate, 23/71 patients were clinically and imaging stable for periods of 8–62 weeks. There was no relationship between prior CYCLO treatment and subsequent response or failure with IFOS. The predominant toxicity was myelosuppression. Although generally reversible, prolonged suppression and sepsis were responsible for the deaths of 3 heavily pretreated patients. Renal toxicity was uncommon; 2 patients had grade III, and one grade IV renal tubular dysfunction. One patient had grade IV hematuria. Neurotoxicity was less common than in studies of daily ifosfamide; only 1 patient had grade IV neurotoxicity. Three patients had grade III or IV IFOS related hyponatremia. Despite the good stable disease rate, the poor rate of objective response suggests that IFOS monotherapy possesses little clinically meaningful activity in brain tumors.

We report the magnetic resonance imaging (MRI) and clinico-histologic characterization of dorsally exophytic brain stem gliomas (DEBSGs). Between 1983 and 1991, 12 of 51 patients evaluated for the diagnosis of brain stem glioma were found to have DEBSGs emanating from the pons, pontomedullary junction or medulla. Eleven of the 12 patients had classic juvenile pilocytic astrocytomas. Unlike most other brain stem tumors, these patients were young (median 38 months, range 17-75), had a relatively long duration of symptoms (median 7 months, range 2-24) and displayed signs of increased intracranial pressure with limited cranial nerve paresis, absence of pyramidal tract findings, and near normal brain stem auditory-evoked potentials. MRI characteristically showed sharply demarcated lesions with decreased signal intensity on T1, and increased intensity on T2 sequences. Except for cystic areas, these tumors showed bright, uniform enhancement after gadolinium-DTPA. In all patients, 50-100% of the tumor volume could be resected. Three of 10 patients who received no immediate postoperative treatment eventually demonstrated disease progression, and 2 patients with subtotal resections who were treated with radiation and/or chemotherapy postoperatively remain disease-free for extended periods of time. The only death occurred in the 1 patient treated with chemotherapy who died of secondary leukemia. The overall and progression-free survival of these patients at 2 years is 100 and 67% as compared to 18 and 21%, respectively, for other concomitantly treated nonexophytic brain stem gliomas.2+ the ability to achieve significant degrees of resection.

Peripheral neuroepithelioma (PN) can be difficult to distinguish from undifferentiated neuroblastoma (NBL) in the absence of molecular and cytogenetic studies. These primitive neural tumors of childhood are similar in morphology and immunocytochemistry, despite their distinct biochemical and behavioral characteristics. The recently developed monoclonal antibody HBA 71 is specific for the product MIC2, a marker of peripheral primitive neuroectodermal tumors. Because beta 2-microglobulin also is selectively expressed by most tumors in this subset, we examined whether a combination of the antibodies HBA 71 and anti-beta 2-microglobulin could facilitate the differentiation of the two malignancies. We histologically confirmed the diagnoses of 45 paraffin-embedded tumors of presumed neuroectodermal origin (19 PNs and 26 NBLs) from the pathology files of St Jude Children's Research Hospital. Samples were immunohistochemically stained using HBA 71 and anti-beta 2-microglobulin. Molecular and cytogenetic data were correlated with the results in a subset of eight patients. Sixteen (84%) of the 19 PNs reacted with HBA 71 and 13 (76%) of 17 PNs reacted with anti-beta 2-microglobulin. None of the NBLs reacted with either antibody. Three PNs were identified by HBA 71 alone and one was identified by anti-beta 2-microglobulin alone. Cellular genetic findings were consistent with the results. HBA 71 and anti-beta 2-microglobulin, when used in combination, can facilitate the differential diagnosis of PN and NBL.

Thirteen patients with low grade astrocytomas were treated with alkylating agent or platinum-based chemotherapy regimens. Eleven of these patients received chemotherapy as their initial postoperative treatment modality, and 2 others as treatment for progessive disease postradiation therapy. Responses were objectively determined using CT or MRI. One patient had a complete response (CR), 6 had partial responses (PR), and 3 others had stable disease (SD) as their best response. Clinical responses paralleled those determined objectively. Chemotherapy was well tolerated with the exception of ototoxic-ity in 4 patients treated with cisplatin. Despite good initial responses, 5 of 6 patients who received no further treatment postchemotherapy (4 PR, 1 SD) developed progressive disease 5–13 months after completing chemotherapy. The remaining 4 patients with objective responses or stable disease (1 CR, 2 PR, 1 SD), all received further postchemotherapy treatment with radiation therapy or surgery, and have not demonstrated disease progression. Our experience suggests that alkylator or platinum-based chemotherapy can successfully delay the growth of these locally infiltrative neoplasms, and should be considered in their primary management. Despite the experience of others, further therapy appears necessary in patients with residual CT or MRI abnormalities postchemotherapy.

The surgical evaluation and management of children with hepatoblastoma has changed with recent advances in imaging modalities and preoperative chemotherapy. Pediatric Oncology Group (POG) Study no. 8697 has followed 63 patients with hepatoblastoma from 1986 to 1991. Twenty-six patients underwent primary tumor resection followed by chemotherapy consisting of cisplatin, vincristine, and 5-fluorouracil (group I). Thirty-seven patients with "unresectable" tumors received preoperative chemotherapy. Twenty-nine of these patients responded to chemotherapy and 26 underwent delayed surgical resection (group II). Eight patients had an inadequate response to chemotherapy; two have had successful liver transplantation and six are dead of disease progression. "Unresectable tumor" involved both liver lobes (25 patients), encased the inferior vena cava (2), involved adjacent tissues (1), involved the hepatic veins (2), or was deemed too large for safe resection (7). Two patients had distant metastases. The reason for an unresectable designation was not reported in five patients. The determination for an unresectable designation included exploratory laparotomy in 14 patients, angiogram in 7, computed tomography scan in 20, and magnetic resonance imaging in 3 patients. Operative times and transfusion requirements were similar in both groups. Perioperative complications were higher in patients in group II. There was no mortality and only minor morbidity associated with chemotherapy in each group. In both groups 77% of the patients are in complete remission after 13 to 54 months. Preoperative chemotherapy can allow successful resection of initially "unresectable" hepatoblastoma. Primary resection that may result in exsanguination should be postponed and chemotherapy given.

The murine Pax-2 gene contains a protein coding domain homologous to the Drosophila paired-box, first described in certain developmental control genes of the segmentation type. Polyclonal antibodies recognize two Pax-2 proteins that are encoded by differentially spliced mRNAs. The Pax-2 proteins can bind a DNA sequence known to interact with the paired domain of a Drosophila protein. By immunocytochemistry, expression of Pax-2 could be localized to the nuclei of condensing mesenchyme cells and their epithelial derivatives in the developing kidney. Expression is abruptly down-regulated as the tubular epithelium differentiates. High levels of Pax-2 expression could also be detected in the epithelial cells of human Wilms tumors. These data suggest that Pax-2 is a transcription factor active during the mesenchyme-to-epithelium transition in early kidney development and in Wilms tumor.

To evaluate the anticancer agent flavone acetic acid (FAA), we conducted a Phase I trial involving 17 pediatric patients with various malignant solid tumors. Dosages investigated included 5,120 and 6,144 mg/m2 given as 3-hour intravenous infusions; and 10,000, 12,500, 15,000, and 17,500 mg/m2 delivered in a 24-hour constant infusion with alkalinization. Grade 2 or worse toxicity was minimal, with 2 patients having nausea/vomiting, 2 having diarrhea, 1 becoming hypertensive, 1 becoming hypotensive, and 2 having myalgia. Three patients who received a 17,500 mg/m2 dose had no toxicity. Disease was stabilized for a brief period in 2 patients--1 with brain stem glioma and 1 with astrocytoma. The FAA pharmacokinetics varied with an average (SD) terminal half-life of 27.9 hr (18.7), clearance of 2.04 L/hr/m2 (0.37), and steady-state volume of 19.9 L/m2 (10.6). This study was discontinued because FAA caused no significant toxicity or therapeutic responses at doses 2.5 gm/m2 greater than had been tolerated by adults.

In three cases of alveolar rhabdomyosarcoma with variant translocations, two tumors contained an identical translocation, t(1;13)(p36.1;q14); the third tumor contained a t(8;13)(p21;q14). All three patients were 2 years old, markedly younger than the median age for patients with t(2; 13)-positive alveolar rhabdomyosarcoma. The alteration of genetic material on chromosome 13 may be of primary importance in the development of alveolar rhabdomyosarcoma.

We assessed tumor cell DNA content (ploidy) and N-myc gene copy number as predictors of long-term disease-free survival in 298 children with neuroblastoma. Diploid tumor stem lines were identified in 101 patients (34%), clonal hyperdiploid abnormalities in 194 (65%), and hypodiploid stem lines in three (1%). In children with widely disseminated tumors at diagnosis (stage D), ploidy had a highly age-dependent influence on prognosis. Among infants (less than 12 months) treated with cyclophosphamide-doxorubicin, hyperdiploidy was closely associated with long-term disease-free survival (greater than 90% of cases), while diploidy invariably predicted early treatment failure (P less than .001). Similarly, in children 12 to 24 months of age who were treated with cisplatin-teniposide and cyclophosphamide-doxorubicin, diploidy uniformly predicted early failure, whereas half of the children with hyperdiploidy achieved long-term disease-free survival (P less than .001). There was no relationship between ploidy and treatment outcome in children older than 24 months with stage D tumors who had a very low probability of long-term disease-free survival (less than 10%). N-myc gene amplification was detected in 37 (25%) of the 147 tumors tested, with the remainder showing single-copy levels of the gene. N-myc gene amplification was more frequent in diploid than in hyperdiploid tumors (23 of 57 v 14 of 87, P = .001) and predicted a high likelihood of early treatment failure. In children younger than 2 years with disseminated neuroblastoma, tumor cell ploidy and N-myc gene copy number provide complementary prognostic information that will distinguish patients who can be cured on current regimens from those who require new treatment strategies.

To assess the clonality of Wilms' tumor, glucose-6-phosphate dehydrogenase (G6PD) enzymes were studied in normal and tumor tissue from 11 black girls who were heterozygous for G6PD. Normal tissues expressed both A and B type G6PD, whereas only a single G6PD enzyme was found in all tumor specimens. These data support the clonal nature of Wilms' tumor. In the one patient with bilateral disease, type B G6PD was found in both a recurrence and a subsequent tumor in the contralateral kidney. This finding is consistent with either the chance occurrence of the same G6PD in independent tumors or persistence of the original malignant clone. Another patient, who presented with the nephroblastomatosis complex (a precursor of Wilms' tumor), also had only type B enzyme detected. Further studies in patients with bilateral disease or the nephroblastomatosis complex, including the use of molecular biologic probes, are needed to test the hypothesis that Wilms' tumor in these cases arises from a somatic mutation as a second event in persons with an underlying genetic alteration.