Chromosome 1 abnormalities: a common feature of pediatric solid tumors.

Abnormalities of chromosome 1 were found in 32 of 46 pediatric solid tumors including Ewing's sarcoma, Wilms' tumor, rhabdomyosarcoma, primitive neuroectodermal tumor, and hepatoblastoma. Trisomy of 1q was the most common abnormality, and breakpoints were most frequent in the region 1cen to 1p22. Abnormalities of chromosome 1 are not specific to any type of tumor. However, their frequent occurrence indicates that they may endow a clonal advantage in the development of cancer.

Significance of pulmonary computed tomography at diagnosis in Wilms' tumor.

Pulmonary lesions were found by computed tomography (CT) despite normal chest roentgenograms (CXR) at diagnosis in 11 of 124 patients with Wilms' tumor. All patients were entered on a treatment protocol at St Jude Children's Research Hospital from 1978 to 1986. The 11 patients all had favorable histology Wilms' tumor. Staging and therapy were based on interpretation of the CXR and abdominal findings. Excluding CT findings, one patient had stage I disease, two stage II, seven stage III, and one stage IV on the basis of multiple liver metastases. Four patients have relapsed: one with stage II and three with stage III. All relapses have been pulmonary. Overall, 4/11 (36%) relapsed. This relapse rate is considerably greater than the 20% overall relapse rate of patients treated according to this protocol though not statistically significant. These relapses suggest that such patients may be at increased risk for pulmonary recurrence. The results also indicate that small lesions initially noted only on CT scans of the chest in children with Wilms' tumor frequently represent metastatic tumor. Further studies of larger numbers of patients will be necessary to confirm these findings.

Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease.

PURPOSE: We assessed the cumulative risk of malignancies following treatment for Hodgkin's disease in childhood and adolescence and investigated related patient and treatment characteristics. PATIENTS AND METHODS: Medical records of 499 Hodgkin's disease patients treated between 1962 and 1993 were reviewed. There were 385 adolescents (> or = 10 years of age at diagnosis) and 114 preadolescents (< 10 years). Most patients (n = 346) were treated with radiation plus multiagent chemotherapy, while 30 received only chemotherapy and 123 only radiation therapy. Radiation doses ranged from 20 to 42 Gy. RESULTS: At a median follow-up duration of 9 years (range, 0.1 to 27.4), 25 patients have had second malignancies: 19 solid tumors, four acute nonlymphoblastic leukemias (ANLLs), 1 non-Hodgkin's lymphoma (NHL), and one chronic myeloid leukemia (CML). Three patients have had a third malignancy. The estimated cumulative risk of second malignancies increased from 1.5% at 5 years to 7.7% at 15 years. All but two of the patients with second malignancies were > or = 10 years of age at initial diagnosis, which reflects the higher risk among patients treated for Hodgkin's disease as adolescents (P = .01). Second malignancies were more common among female patients (P = .0002), even when those breast cancer were excluded (P = .007), and in those treated for recurrent Hodgkin's disease (P = .02). Patients with ANLL/NHL were older at diagnosis of Hodgkin's disease than those with solid tumors, (median age, 18.3 v 13.8 years; P = .04). There was no difference between groups treated with radiation therapy alone, chemotherapy alone, or radiation plus multiagent chemotherapy. CONCLUSION: Adolescents treated for Hodgkin's disease are at greater at risk of second malignancies than younger patients. Overall, adolescent females treated for recurrent Hodgkin's disease appear to be at greatest risk, while preadolescents appear to be protected from this late complication.

Reduced therapy for Wilms' tumor: analysis of treatment results from a single institution.

From 1968 to 1986, 192 patients from 0 to 17 years of age were enrolled in three consecutive protocol-controlled studies of Wilms' tumor at St Jude Children's Research Hospital. Tumors were completely excised at the time of diagnosis whenever possible, and patients were subsequently treated with chemotherapy and radiotherapy according to the initial extent of disease. All patients received dactinomycin and vincristine, with doxorubicin added to the regimens in studies 2 and 3. Chemotherapy was extended to 18 months in study 2 (n = 53), but was limited to 12 months for most patients in study 3 (n = 107). In the third study, radiation was eliminated altogether for patients with stage I or II tumors and was reduced to 12 Gy for those with more advanced disease. Intensification of chemotherapy in study 2 improved the 5-year relapse-free survival rate over that in study 1 (82% v 52%), but the accompanying increase in toxicity was considered unacceptable. Comparison of 2-year relapse-free survival rates in studies 2 and 3 indicated that the reduction of therapy in the latter trial did not jeopardize disease control: 88% v 86% for patients with stage II or III disease, favorable histology; 75% v 57% for the same stages, unfavorable histology; and 57% v 61% for stage IV patients. At least 80% of all patients enrolled in study 3 will be long-term survivors. We conclude that rescheduling of effective antitumor drugs and eliminating or reducing radiotherapy are feasible alternatives in the treatment of Wilms' tumor with favorable histologic features.

Hyperdiploidy and chromosomal rearrangements define the anaplastic variant of Wilms' tumor.

Flow cytometric measurement of the DNA content of Wilms' tumor cells revealed a striking correspondence with the histologic subtype and treatment outcome. In the 48 cases studied, a hyperdiploid DNA content ranging from 1.7 to 3.2 times the result for normal diploid cells distinguished all but one of the ten anaplastic tumors. Lower values, from 1.0 to 1.4 times the diploid DNA content, characterized the nonanaplastic specimens. By Kaplan-Meier analysis, the probability of achieving 3 years of relapse-free survival was significantly lower in the group with higher DNA content (0.42 v 0.87, P less than .01). Analysis of banded chromosomes for a subset of 22 patients contributed important information beyond the flow cytometric study. Cases of anaplasia associated with poorer responses to therapy showed numerous complex translocations, whereas all others lacked such changes. By combining flow cytometric techniques and conventional methods of chromosome analysis, it should be possible to identify those patients with Wilms' tumor who are most likely to fail therapy. The biologic implication of these findings is that the development of clinical drug resistance in Wilms' tumor is a result of the genetic instability of the malignant clone.

Use of chest computed tomography in the staging of pediatric Wilms' tumor: interobserver variability and prognostic significance.

PURPOSE: To determine the specificity and prognostic significance of computed tomography (CT) of the chest in pediatric Wilms' tumor. PATIENTS AND METHODS: Patients treated for newly diagnosed Wilms' tumor at St Jude Children's Research Hospital between December 1978 and July 1995 were included in the study if an initial chest radiograph and CT were available and if pulmonary involvement (determined by chest radiographs) was absent. For the 202 patients studied, radiographs and CT scans were reviewed blindly and independently by three experienced radiologists for the presence of pulmonary nodules. Outcome variables consisted of intraobserver variability (in a subsample of 40 cases) and concordance between ratings on radiographs and CT scans (both by McNemar's test), interrater variability (by logistic regression), and the cumulative incidence of pulmonary relapse for patients with and without positive CT scans, by reviewer. RESULTS: As expected, ratings of pulmonary involvement on radiographs were discordant with CT ratings. There was marked variability among reviewers in CT ratings (P = .0001). Of 202 CT scans, 78 were read as positive by at least one reviewer, 41 were rated positive by only one reviewer, 18 by two reviewers, and 19 by all three. Intrarater variability on repeat reviews was not significant. Patients with nodules identified on CT had a significantly higher pulmonary relapse rate when analyzed separately by reviewer. However, for the 14 patients who had pulmonary relapse, CT scans were rated positive by all three reviewers in only five cases and as negative by all three in another five cases. CONCLUSION: The variability in interpretation of chest CT scans in patients with Wilms' tumor limits the predictive utility of these studies. Optimal, standardized techniques and central review are essential if chest CT is to be used for staging in cooperative studies.

Increased mortality after successful treatment for Hodgkin's disease.

PURPOSE: To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkin's disease. PATIENTS AND METHODS: We studied late events in 387 patients treated for pediatric Hodgkin's disease on four consecutive clinical trials at St Jude Children's Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated. RESULTS: As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkin's disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkin's disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38). CONCLUSION: Compared with age- and sex-matched control populations, survivors of pediatric Hodgkin's disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.

Glucose intolerance and insulin resistance in aplastic anemia treated with oxymetholone.

Because of a suspected association between the drug oxymetholone and abnormal glucose metabolism, we determined immunoreactive insulin (IRI) and plasma glucose during oral glucose tolerance testing in seven patients with aplastic anemia, six of whom received oxymetholone therapy. All patients receiving oxymetholone therapy had abnormal glucose and/or IRI values. This finding was independent of GH, cortisol, and glucagon. In one patient, glucose and IRI levels were normal before oxymetholone but became abnormally elevated after the use of this drug. Furthermore, normal glucose and IRI values were present in the single patient not receiving oxymetholone. Thus, a positive relationship was demonstrated between oxymetholone administration and the presence of glucose intolerance and insulin resistance.

Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults.

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including thiopurine antimetabolites (i.e. mercaptopurine and thioguanine). The activity of TPMT in erythrocytes and other tissues exhibits genetic polymorphism, which is inherited as an autosomal codominant trait. Although inheritance is the principal determinant of TPMT activity, other factors (e.g. renal function, race and thiopurine therapy) have been shown to influence erythrocyte TPMT activity. Because the TPMT polymorphism has not been established in early erythrocyte populations, and the activity of many enzymes differs in neonates, we determined the activity of TPMT in erythrocytes obtained from 60 full-term newborns. Median peripheral blood TPMT activity was 25.3 U per ml pRBC (range 9-52.8 U per ml pRBC), which was > 50% higher than race matched healthy adults (p < 0.001). Western blot analysis demonstrated higher TPMT protein content in erythrocytes from newborns compared to adults, and revealed a significant correlation between TPMT protein and TPMT activity in erythrocytes (rs = 0.63, p = 0.03). Although erythrocyte TPMT activity was significantly higher in newborns, the distribution of activity in newborns was consistent with the genetic polymorphism previously observed in adults.

Clinical studies of ifosfamide/mesna at St Jude Children's Research Hospital, 1983-1988.

A phase-II study of ifosfamide with mesna, given intravenously daily for five days by bolus injection, has demonstrated the activity of ifosfamide against a spectrum of childhood malignant solid tumors. Ifosfamide presently is being investigated in alternative phase-I schedules, daily times three or every other day times three with the aim of delivering comparable amounts of ifosfamide without increasing toxicity--specifically, neurotoxicity. Additionally, response following ifosfamide treatment is being evaluated for previously untreated children with osteosarcoma and rhabdomyosarcoma after 6 weeks of treatment, and for previously untreated patients with Ewing's sarcoma after 9 weeks of treatment with ifosfamide/VP-16 (etoposide) given in combination.

Long-term follow-up of patients treated with primary radiotherapy for supradiaphragmatic Hodgkin's disease at St. Jude Children's Research Hospital.

OBJECTIVE: To assess disease control, patterns of relapse, factors predictive of relapse, and late effects of treatment, we reviewed all cases of supradiaphragmatic (SD) Hodgkin's disease (HD) treated with primary radiation therapy (RT) at our institution. METHODS: We retrospectively reviewed the disease characteristics, treatment history, and long-term outcome of the 106 patients with Stage I and II supradiaphragmatic HD who received definitive irradiation at St. Jude Children's Research Hospital between 1970 and 1995. As of the date of analysis, 95 patients are alive, with a median follow-up of 13.3 years (range, 1.9-24.2 years). RESULTS: The median age at diagnosis was 14.7 years (range, 3.7-22.7). Involved-field RT was given to 13 patients (12%), whereas 37 (35%) had mantle RT, 51 patients (48%) had subtotal nodal irradiation, and 5 (5%) had total nodal irradiation. Relapsed disease developed in 26 patients at a median of 1.8 years (range, 0.2-9.3 years). The 5- and 10-year estimated cumulative incidences of relapse were 20.9% +/- 4.0% and 25.1% +/- 4.3%, respectively. With a median dose of 36 Gy (range, 32-40), in-field failure rate was 6.2%, whereas subdiaphragmatic relapse in sites irradiated prophylactically was 1.5%. There was a trend toward an increased incidence of relapse with higher ESR (p = 0.088) and greater number of sites of disease (p = 0.087). Age, stage, histology, nodal disease > or = 6 cm, the presence of bulky mediastinal disease, and the method of staging did not affect the incidence of relapse. The pattern of failure could not be predicted based on the stage of disease, the extent of subdiaphragmatic staging, the extent of radiation therapy, or the sequence of RT fields-"ping pong" vs. sequential. Subset analysis of Stage II patients revealed significantly more relapses in clinically staged patients. Excluding Stage IA patients with high cervical disease or peripheral nodal disease, nodal extension failures were more common for patients undergoing limited-volume RT, whereas extranodal relapses were likely after STNI or TNI. The estimated 10- and 15-year cumulative incidences of second malignancies were 2.9% +/- 1.6% and 7.9% +/- 3.3%, respectively. Our patients are at increased risk of second malignancies (11-fold), and fatal cardiac (68-fold) and infectious (33-fold) complications. Overall survival at 10 years was 90.8% +/- 3.2%; event-free survival was 72.1% +/- 5.0%. CONCLUSIONS: The current analysis confirms the curative potential of RT for HD in children and adolescents. Despite successful salvage therapy, relapsed disease remained the principal cause of death in our cohort. Excess risk of septic death in asplenic patients, fatal heart disease, and second malignancies may further compromise the ultimate cure of HD in long-term survivors.

Abnormalities of chromosomes 1 and 11 in Wilms' tumor.

Cytogenetic studies were performed successfully on 14 cases of Wilms' tumor. Six cases had detectable rearrangements of 11p, and 7 cases had structural abnormalities of chromosome #1. Two cases with advanced stage disease showed multiple translocations, resulting in hypodiploidy with a normal DNA complement.

Ifosfamide in pediatric malignant solid tumors.

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.

Pediatric hematology-oncology outreach for developing countries.

Health care in some developing countries is now at a level that makes programs for care of children with cancer feasible. Examples of successful international programs in this field include twinning programs, nongovernmental assistance organizations, such as the National Children's Cancer Society, and committees of professional organizations, such as the International Society of Pediatric Oncology (SIOP). The international outreach program at St. Jude Children's Research Hospital includes training programs within the hospital, partner sites in 13 countries, a school for Latin American nurses, a distance learning website, and telecommunications programs, which are described in detail. Future programs should be designed to maximize and evaluate impact, report accomplishments and failures, and avoid duplication.

Relapsed Wilms' tumor. Factors affecting survival and cure.

To identify factors contributing to extended survival among patients with relapsed Wilms' tumor, we assessed 10 clinical and biologic variables thought to have predictive value. With a median follow-up of 6 years, 32 (20%) of 156 patients who achieved complete remission have relapsed. Twenty-four have died with recurrent tumor, and eight are surviving for 2 to 12 years from diagnosis. Only time to relapse, or length of initial complete remission, had a significant influence on survival. Of 11 patients with complete remissions lasting longer than 12 months, six have died--compared with seven of 10 having remissions of 6 to 12 months and 11 of 11 with shorter remissions (p = 0.014). Surgery alone was the curative therapy in three of the eight surviving patients. Until more effective chemotherapy regimens are developed, an aggressive surgical approach may be indicated in selected patients with relapsed Wilms' tumor.

Laparoscopic splenectomy in childhood.

The authors describe their technique for laparoscopic splenectomy in childhood. Five ports, including one 12-mm port for an endoscopic stapler, are placed. With the patient in the supine position, the short gastric vessels are divided between clips. The patient is then placed in the lateral decubitus position for mobilization of the splenic flexure of the colon, division of the posterolateral ligamentous attachments, and en masse transection of the splenic hilum using the EndoGIA stapler. The freed spleen is placed in a nylon reinforced Lap Sac, which is exteriorized at the neck. The spleen is morcellated and the sac removed. Concomitant cholecystectomy is performed in patients with hereditary spherocytosis who have cholelithiasis or sludge. The procedure has been performed without complication in six patients who had hematologic disorders. For another patient, the procedure was converted to an open splenectomy to achieve better hemostasis.

Laparoscopic splenectomy.

Splenectomy is easily amenable to laparoscopic technique. Compared with the open technique, its advantages include improved exposure, decreased pain, improved pulmonary function, shortened hospitalization, rapid return to unrestricted activities, and improved cosmetic appearance. These advantages are at the expense of prolonged operative time that, with experience and improved instruments, should diminish.