Detection of N-myc oncogene expression in human neuroblastoma by in situ hybridization and blot analysis: relationship to clinical outcome.

We studied N-myc oncogene expression in 13 human neuroectodermal tumors and one teratoma by in situ hybridization. In four of six neuroblastomas, there was increased N-myc expression (15 to 49% of the cells). Many of the primitive neuroblastic cells had an increase of N-myc RNA not observed in the larger, more differentiated cells. Two neuroblastomas matured to ganglioneuromas; no biopsies performed during this progression expressed increased N-myc RNA. Three ganglioneuroblastomas, two tumors presenting as ganglioneuromas, a cerebral neuroectodermal tumor, a neurofibrosarcoma, and the teratoma did not have increased N-myc expression. The data obtained by in situ hybridization correlated well with data obtained by blot analysis. Neuroblastomas/ganglioneuroblastomas with a favorable course did not have appreciable elevation of N-myc expression over 10 to 77 mo of follow-up; thus N-myc may not be involved in the maintenance of the neoplastic state. However, such tumors with a fatal outcome 2 to 14 mo after diagnosis usually had elevated N-myc expression. These findings suggest a relationship between elevated levels of N-myc RNA and poor prognosis.

Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco.

PURPOSE: The purpose of our investigation was to correlate the extent and degree of organ involvement at presentation of Langerhans' cell histiocytosis (LCH) with subsequent disease course, survival, and late sequelae. MATERIALS AND METHODS: The medical records of 71 patients with a pathologic diagnosis of LCH, age 0 to 21 years, who presented between January 1, 1969 and June 30, 1994, were reviewed for organ involvement at diagnosis, treatment, disease course, and late sequelae. Supplementary data were obtained by mailed questionnaire. RESULTS: The median follow-up time from diagnosis for all patients was 8.1 years. Involvement at diagnosis included nine patients with skin-only disease, 22 with monostotic disease, 12 with polyostotic disease, and 28 with multisystem presentation. Treatment was surgery only in 17 and chemotherapy and/or radiotherapy in 54 patients. Recurrences were seen in 35 patients, with the highest rate in the polyostotic group. Ten patients died: seven with the multisystem presentation, two with monostotic disease, and one with skin-only disease. Causes included progressive LCH (n = 6) and late sequelae of either treatment (n = 3) or disease (n = 1). Late sequelae were seen in 64% of 51 patients with more than 3 years of follow-up data. The most common were skeletal defects in 42%, dental problems in 30%, diabetes insipidus in 25%, growth failure in 20%, sex hormone deficiency in 16%, hypothyroidism in 14%, hearing loss in 16%, and other CNS dysfunction in 14%. The overall estimated survival rates at 5, 15, and 20 years are 88%, 88%, and 77%, with an estimated event-free survival rate of only 30% at 15 years. CONCLUSION: Despite the favorable survival, more than half of LCH patients will have further dissemination of disease or late sequelae, including even some patients with single-system disease at diagnosis. Future treatment needs to be designed to prevent disease progression and late sequelae.

Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma.

PURPOSE: The analogue 131I-metaiodobenzylguanidine (MIBG), which is specifically targeted to neuroblastoma cells, may provide more effective and less toxic treatment for neuroblastoma than conventional external-beam radiotherapy. We report a dose escalation study of 131I-MIBG to define dose-limiting toxicity without and with autologous bone marrow support. PATIENTS AND METHODS: Thirty patients with relapsed neuroblastoma were treated in groups of six with escalating doses of 3 to 18 mCi/kg of 131I-MIBG. After rapid escalation in the first three patients treated at 3 to 6 mCi/kg, treatment was escalated in 3-mCi/kg increments from 9 to 18 mCi/kg. Autologous tumor-free bone marrow was cryopreserved in all patients receiving 12 mCi/kg and more. Toxicity and response were assessed. RESULTS: Eighty percent of patients who received 12 mC/kg or more experienced grade 4 thrombocytopenia and/or neutropenia. Dose-limiting hematologic toxicity was reached at 15 mCi/kg, at which level two of five assessable patients required bone marrow reinfusion for absolute neutrophil count (ANC) of less than 200/microL for more than 2 weeks, and four of nine at the 18-mCi/kg level. Prolonged thrombocytopenia was common, with failure to become platelet-transfusion independent in nine patients. One patient with extensive prior treatment developed secondary leukemia and three became hypothyroid. Responses were seen in 37% of patients, with one complete response (CR), 10 partial response (PR), three mixed response, 10 stable disease, and six progressive disease. The minimum dose of 131I-MIBG for 10 of the 11 responders was 12 mCi/kg. CONCLUSION: Treatment with 131I-MIBG has mainly hematologic toxicity, which can be abrogated with bone marrow rescue. The high response rate in refractory disease suggests that this agent may be useful in combination with myeloablative chemotherapy and autologous stem-cell rescue to improve outcome in advanced neuroblastoma.

Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67% and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas.

Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) undertook a study (CCG-823F) to test the feasibility of administering continuous infusion doxorubicin (CI DOX) and cisplatin (CDDP) in patients with unresectable or incompletely resected hepatoblastoma (HB) or hepatocellular carcinoma (HCC). Chemotherapy consisted of CI DOX 20 mg/m2/d for days 1 to 4 and CDDP 100 mg/m2 on day 1 followed by a 21-day rest period. Second-look surgery was performed after the administration of four chemotherapy courses. Forty-seven (47) assessable patients were entered on study, 33 with HB and 14 with HCC; of these, 34 (26 HB and eight HCC) completed the initial four courses of chemotherapy. Of the 26 HB patients, 25 were evaluated as responding to chemotherapy before the scheduled second-look procedure and were considered surgically resectable at that time. Surgery was performed on 22 patients; three patients refused the second-look surgery. Nine patients had no evidence of residual malignant disease, seven underwent surgical resection of remaining tumor, four were left with microscopic residual disease, one had a partial resection with gross tumor left behind, and one remained unresectable. Nine HCC patients completed four chemotherapy courses. Eight patients achieved a partial remission and second-look surgery was attempted on seven. Only two had all malignant disease removed at the second procedure. Data from 225 courses of chemotherapy were evaluated for toxicity. Neutropenia (absolute granulocyte count less than 500/mL) was observed in 68 courses, and five of these episodes were associated with sepsis. Severe mucositis was documented in 21 courses, and hypomagnesemia (magnesium less than 1.2 mg) was noted in 30 patients. Two patients developed decreased left ventricular shortening fraction, which resolved when chemotherapy was discontinued. In summary, CI DOX plus CDDP is a well-tolerated and effective regimen in inducing surgical resectability in HB patients who are unresectable at diagnosis and significantly improves survival for this group of patients to 66.6%.

Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106.

PURPOSE: On past Childrens Cancer Group (CCG) trials, children with acute lymphoblastic leukemia and unfavorable presenting features had obtained an event-free survival (EFS) rate of no better than 50%. Following promising pilot experience, this study was conducted to determine the benefit and morbidity of two intensive experimental regimens, Reg A, based on the Berlin-Frankfurt-Münster (BFM) 1976 regimen, and Reg B, the New York regimen. PATIENTS AND METHODS: Between February 1983 and November 1984, 217 eligible children with acute lymphoblastic leukemia and unfavorable presenting features were entered and randomly assigned to receive Reg A, Reg B, or Reg C, the control regimen. Assignment to Reg C was halted in November 1984 after interim analyses showed an inferior outcome. Subsequently, between November 1984 and March 1987, an additional 328 patients were randomly allocated to receive Reg A or Reg B. RESULTS: The 7-year EFS rate was 63% (+/- 6%, 1 SD) for Reg A, 61% (+/- 6%) for Reg B, and 40% (+/- 6%) for Reg C (P < .006). The difference between Reg A or Reg B and Reg C remained greater than 20 percentage points for EFS at 7 years and 15 percentage points for survival. Relative to Reg C, patients on Reg A accrued 16.3 additional days of hospitalization on average and, on Reg B, 20.2 days. EFS and survival were similar on Reg A and Reg B, but Reg B required more days of parenteral therapy and greater exposure to anthracyclines and alkylating agents. CONCLUSION: Both Reg A and Reg B provided a better outcome than Reg C for children with acute lymphoblastic leukemia and unfavorable presenting features. Outcomes on Reg A and Reg B were similar. Use of the more effective but more toxic regimens resulted in 78 additional hospital days per relapse prevented on Reg A and 101 days on Reg B. The current CCG trial for this population builds on Reg A.

Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study.

PURPOSE: To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%. PATIENTS AND METHODS: Patients with immature teratomas treated at Pediatric Oncology Group or Children's Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death. RESULTS: Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. CONCLUSION: Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.

Prophylactic cranial irradiation dose effects on late cognitive function in children treated for acute lymphoblastic leukemia.

Prophylactic central nervous system treatment has dramatically improved the disease-free survival of children with acute lymphoblastic leukemia (ALL). Long-term neuropsychological sequelae are documented in children who received 2400 cGy prophylactic cranial irradiation. The dose was reduced to 1800 cGy. Available reports on developmental consequences, with short follow-up, have yielded inconsistent results. This study assesses radiation dose effects on cognitive function in children with leukemia who received central nervous system prophylaxis with 2400 cGy versus 1800 cGy whole brain radiotherapy. All leukemic children also received intrathecal methotrexate. A control group of children (treated for Wilms' tumor) received no central nervous system therapy. Nineteen children were treated with 2400 cGy, 16 children with 1800 cGy. The 12 control children received no irradiation. All patients were off therapy for at least 70 months. The 1800 cGy and 2400 cGy patient groups were off therapy for equivalent periods of time (range 70-123 mo) at follow-up testing. Mean age at diagnosis was 49 months, at testing: 142 months. The male to female ratio was 1/1. Standardized psychological tests were administered. Full-Scale, Verbal, and Performance IQ were measured with the Wechsler Intelligence Scale for Children-Revised. Wide Range Achievement Testing evaluated reading, spelling, and arithmetic abilities. Children treated with 1800 cGy performed significantly better than those who received 2400 cGy, and at the same level as controls. There were statistically significant differences between the 1800 cGy and 2400 cGy subjects in all measures. 2400 cGy patients had deficiencies in IQ and academic performance. 1800 cGy patients scored approximately 12 points higher than 2400 cGy children. Eleven children, two in the control group, two in the 1800 cGy, and seven in the 2400 cGy group had IQ scores of less than 90. Eight of the nine irradiated children with deficits had radiotherapy before age 5. These results indicate a mild, but diffuse information processing deficit in children who received 2400 cGy, but not in children who received 1800 cGy. These findings with a minimum of 6 years of follow-up provide new information on late effects of CNS prophylaxis in ALL. Reducing the cranial RT dose from 2400 cGy to 1800 cGy reduced neurotoxicity to acceptable levels.

Functional and clinical outcomes of limb-sparing therapy for pediatric extremity sarcomas.

PURPOSE: To determine the clinical and functional outcomes of children undergoing limb-sparing therapy for extremity sarcomas. METHODS AND MATERIALS: We retrospectively reviewed 30 patients, age < or = 21 years, who were treated between l979 and l998 with external beam radiotherapy as a component of limb-sparing therapy for primary sarcomas of the extremity at UCSF. Included were patients for whom complete follow-up and functional outcome assessments were available. We assessed the patterns of failure, overall survival, disease-free survival, local control, and limb function. RESULTS: At a median follow-up of 3 years, 12 of the 30 patients recurred: 3 locally, 8 distantly, and 1 with synchronous local and distant disease as site of first progression. Eighteen patients were alive with no evidence of disease. The median overall survival was 10 years, with a median disease-free survival of 8 years. Functional outcome assessment revealed 15 patients retained excellent, 12 good, 1 fair, and 2 poor limb function. CONCLUSION: In pediatric patients receiving limb-sparing therapy, 90% maintained excellent or good limb function without compromising survival, demonstrating the validity of limb preservation in children with extremity sarcomas.

Measles pneumonia in childhood leukemia.

Fatal measles pneumonia developed in a 7-year-old boy who was in complete remission from acute lymphoblastic leukemia. There was no detectable antibody titer in two specimens taken eight days apart. Measles virus was grown from a lung biopsy taken shortely after hospital admission. Classical measles had been diagnosed in the patient and his siblings nine months previously. Immunosuppressed children who do not develop an antibody rise after a measles infection are at risk of later development of measles giant cell pneumonia. Suggestions are offered for the prevention of this often fatal complication.

Total body irradiation and bone marrow transplantation for immunodeficiency disorders in young children.

Congenital immunodeficiency disorders such as severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, and Chediak-Hegashi syndrome are almost uniformly fatal with most children dying before age one. Allogeneic bone marrow transplant (BMT) is the treatment of choice. Few of these children have matched donors. We use bone marrow processing techniques that allow us to utilize marrow from the parents. Children who lack HLA-identical donors are offered haploidentical, T-cell depleted parental BMTs. Some of these children do not have an immune deficiency severe enough to allow durable engraftment of processed mismatched bone marrow. Successful engraftment may necessitate the use of immunosuppression. Total body irradiation (TBI) is part of our intensive conditioning regimen for children with Wiskott-Aldrich and Chediak-Hegashi syndrome and most children with SCID who have undergone an unsuccessful prior mismatched, T-cell depleted BMT, or who have a high likelihood of donor marrow rejection based on pre-transplant immune function testing. TBI is considered extremely toxic therapy in infancy, with little information available on the acute and chronic effects. The 10 children presented in this report are among the youngest to have received TBI. Five patients were 2 to 6 months of age when they received TBI. The conditioning regimen for all patients was; antithymocyte globulin (25 mg/kg/day, x 3 days), cyclophosphamide (60 mg/kg/day, x 2 days), and TBI. 7.0 Gy TBI was given as a single dose AP-PA at approximately 15 cGy/min. Half value blocks shielded the brain, eyes and lungs. Six of 10 children were alive from 7 to 72 months post transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Orbital melanocytic hamartoma.

A male Chinese neonate had a melanocytic hamartoma that involved the entire orbit and the eye, but did not involve the orbital bones or eyelid skin. Although usually benign, these hamartomas may be locally invasive, and rare cases of malignant transformation have occurred.

Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy.

IQ decrements following cranial radiation therapy (CRT) for acute lymphoblastic leukemia (ALL) are most apparent years after treatment. The authors examined a developmental model for delayed deficits by evaluating the relationship between processing speed, working memory, and IQ in long-term survivors of childhood ALL (n = 27) compared with demographically matched controls (n = 27). The ALL group treated with CRT showed deficits in IQ, working memory, and processing speed relative to controls. Differences in IQ between the CRT group and controls were mediated by differences in working memory. Processing speed did not fully account for the working memory deficit in the CRT group. Participants with ALL treated only with chemotherapy showed similar working memory and processing speed as matched controls. Data suggest that deficits in processing speed and working memory following CRT may underlie declines in IQ.

Postirradiation cerebellar glioma. Case report.

A 13-year-old girl developed an anaplastic astrocytoma of the cerebellum 7 years after irradiation of the central nervous system and prophylactic chemotherapy for acute lymphocytic leukemia. The fact that the astrocytoma was anaplastic and infiltrative was unusual for astroglial tumors at this site. It is proposed that this is a radiation-induced glioma.

The surgical management of children with incompletely resected hepatic cancer is facilitated by intensive chemotherapy.

This prospective study was undertaken to evaluate the efficacy of continuous-infusion doxorubicin and cisplatin (CI-DOX/CPPD) for the treatment of children with incompletely resected hepatic cancer. Of the 46 evaluable patients, 32 had hepatoblastoma (70%) and 14 had hepatocellular carcinoma. Ten children had stage II tumors (microscopic residual), 25 were defined as stage III (gross residual), and 11 had distant metastasis (stage IV). Twelve patients underwent initial incomplete resection of their hepatic lesions and in the 34 others tumor biopsy specimens were obtained. Chemotherapy was administered and the majority of the children (70%) had an excellent clinical response with a decrease in both alpha-fetoprotein levels and measured tumor dimensions. The combination of CI-DOX/CPDD clearly facilitated surgical management, allowing for delayed hepatic resections in 20 of the 34 patients (59%) whose tumors were initially biopsied and considered to be unresectable. Overall survival in this study demonstrates a significant improvement in comparison to the historical controls. Twenty-one patients (46%) remain in complete clinical remission an average of 30 months following diagnosis (range, 17 to 40 months). The outcome of the children with hepatoblastoma was much better than those with hepatocellular carcinoma (63% v 17% survival). Survival of the 20 children who underwent delayed hepatic resections was not statistically different from the 12 patients whose hepatic tumors were removed at the initial laparotomy (41% v 58% survival). Although no obvious survival advantage was observed in those patients who underwent initial hepatic resections, there did appear to be an increased risk of postoperative complications in children whose tumors were resected following chemotherapy (8% v 25%).

The CCSG prospective study of venous access devices: an analysis of insertions and causes for removal.

This is an interval analysis of the 2-year prospective multicenter Childrens Cancer Study Group study of 1,141 chronic venous access devices in 1,019 children with cancer. Device type was external catheter (EC) 72%, totally implantable (TID) 28%, and did not differ for diagnosis or age except more double-lumen devices in bone marrow transplant protocols (77%) and more TIDs in children less than 1 year old (17.7%). Insertion characteristics evaluated in 1,078 (95%) were: operating room placement 99%; general anesthesia 98%; cutdown 67%; percutaneous 33%; atrial position 50%, caval position 50%; and perioperative antibiotics 48%. Vein entry was the external jugular 33%, internal jugular 22%, subclavian 35%, cephalic 7%, and saphenous 3%. Insertion was difficult or very difficult in only 10% and operative complications occurred in only 0.7%. Degree of difficulty bore no relationship to device type or patient age. The reasons for removal in 736 devices (67%) were due to complications in 39%, of which infections were the most frequent. There was some variance between centers ranging from 8.5% to 31% for infection; 2.8% to 24% for dislodgment; and 0% to 13% for occlusion. ECs had a higher risk of dislodgment; elective removals were more frequent in TIDs; there was no difference in infection as a cause for removal between ECs and TIDs. Dislodgment was associated with the shortest distance of the cuff to the skin exit (mean, 4 cm): less than or equal to 2 cm, 49%; greater than 2 cm, 28% (P = .009) and occurred most frequently in the younger patient (18.9%, 0 to 1 years; 0.5%, greater than 8 years.

Bilateral testicular neuroblastoma. Scintigraphic depiction and therapy with I-131 MIBG.

The authors describe a 29-year-old man who had a 16-year history of neuroblastoma and uncommon manifestations. At age 13, he was diagnosed with stage III retroperitoneal ganglioneuroblastoma that was resected. Ten years later, bilateral testicular enlargement and a pelvic mass from infiltration of the neuroblastoma became palpable. Metastatic involvement was depicted with MIBG, a radiotracer that concentrates in tissues of the sympathetic nervous system. Using I-131 MIBG, the tumors were treated with therapeutic doses of radiation and a partial response was obtained. This case is unique because of the massive degree of bilateral testicular infiltration and its occurrence as a late manifestation of neuroblastoma in early adulthood.