Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma.

Recent improvements in survival of patients with Ewing's sarcoma have been made since the addition of cyclophosphamide-based adjuvant chemotherapy to primary surgery and radiation. A potential limitation to cyclophosphamide use is its urotoxicity, primarily in the form of hemorrhagic cystitis. The incidence of this adverse effect in patients treated for Ewing's sarcoma has not been established. In a Mayo Clinic series of 116 patients with Ewing's sarcoma treated with cyclophosphamide, 17 (15%) developed hemorrhagic cystitis diagnosed on the basis of gross hematuria or cystoscopic findings (or both). Microscopic hematuria also occurred in 53% of patients (56 of 105 examined). The dose and duration of therapy appeared to be unrelated to the development of urotoxicity. Most patients recovered uneventfully with or without discontinuation of cyclophosphamide therapy, but a significant loss of blood occurred in three patients, and one patient required a cystectomy because of bladder fibrosis. Long-term follow-up is mandatory in these patients because of late recurrences of hemorrhagic cystitis or the possibility of bladder carcinoma. New therapies, directed at protecting the bladder from urotoxicity during cyclophosphamide treatment, are available.

Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas.

Between June 1975 and April 1981, 61 of the 177 eligible patients whose nonosseous sarcomas of extremity or trunk origin had been completely excised primarily or after local recurrences agreed to participate in a randomized study of adjuvant chemotherapy. Dermatofibrosarcoma, lymphomas, myeloma, Kaposi's sarcoma, and embryonal rhabdomyosarcoma were excluded as were patients with significant second primary cancers and those who received either preoperative or postoperative radiation therapy. After stratification by anatomic status of disease, site of origin, and histologic grade, a random one half of the 61 participants began alternating courses of vincristine/cyclophosphamide/dactinomycin, and vincristine/doxorubicin/dacarbazine at six-week intervals for one year. The control group was evaluated at six-week intervals without adjuvant chemotherapy, but these patients were offered this chemotherapy later if they had progressive disease excised. Although 30% of the 61 patients experienced local recurrence of disease within the first five years after randomization, and only 54% were continuously disease free for five or more years, 82% were surviving at five years (Kaplan-Meier calculations) with a median follow-up of 64.3 months. Partial suppression of distant metastasis by adjuvant chemotherapy was apparent in the overall study, in the extremity tumor category, and in the subgroup of patients who had received limb-sparing surgery; however, no survival advantage for chemotherapy-treated patients was demonstrated. The 30 adjuvant chemotherapy-treated patients received a total of three thoracotomies as compared with 17 salvage thoracotomies for the 31 control patients; however, salvage surgery for local recurrences has been similar in the two groups. Recent improvement in the survival of patients with soft-tissue sarcomas is not necessarily a result of adjuvant chemotherapy or radiation therapy.

Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study.

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II.

Two hundred fourteen eligible patients with previously untreated, localized Ewing's sarcoma of bone were randomized on IESS-II to receive Adriamycin (ADR; doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, vincristine, and dactinomycin by either a high-dose intermittent method (treatment [trt] 1) or a moderate-dose continuous method (trt 2) similar to the four-drug arm of IESS-I. Patient characteristics (sex, primary site, type of surgery) were stratified at the time of registration; these and other patient characteristics (age, time from symptoms to diagnosis, race) were distributed similarly between treatments. Surgical resection was encouraged, but not mandatory. Local radiation therapy was the same as for IESS-I. The median follow-up time is 5.6 years. The overall outcome was significantly better on trt 1 than on trt 2. At 5 years, the estimated percentages of patients who were disease-free, relapse-free, and surviving were 68%, 73%, and 77% for trt 1 and 48%, 56%, and 63% for trt 2 (P = .02, .03, and .05, respectively). The major reason for treatment failure for both treatment groups was the development of metastatic disease. The lung was the most common site of metastases followed by bone sites. The combined incidence of severe or worse toxicity (67%) was comparable between the treatments; however, severe or worse cardiovascular toxicity was significantly greater on trt 1. Tne only treatment-associated deaths (N = 3) were on trt 1 and were cardiac-related.

Sequential half-body irradiation (SHBI) and combination chemotherapy as salvage treatment for failed Ewing's sarcoma--a pilot study.

This study was undertaken to evaluate the toxicity of sequential half-body irradiation (SHBI) and combination chemotherapy (5-FU, VM-26 and BCNU) in patients who had failed primary aggressive therapy for their Ewing's sarcoma. A secondary goal was to evaluate the response of these previously treated patients to the combination of systemic radiation and multi-agent chemotherapy. The first patient in the study was treated with SHBI only and died 139 days following retreatment. Four subsequent patients successfully received the first cycle of combination chemotherapy. However, only one completed both upper and lower half-body irradiation while the remaining three patients, because of rapid progression of their disease, completed either the upper or the lower portion of their half-body irradiation (HBI). The time from retreatment to disease progression in these four patients ranged from 45 to 97 days (mean 79 days) and the time from retreatment to death ranged from 72 to 193 days (mean 126 days). The combination chemotherapy was tolerated well by all the patients, and the SHBI was accompanied by mild nausea and some vomiting within the first few hours following treatment. Failure to give the second half of the half-body irradiation and to complete further chemotherapy in three of the patients was a result of the progressive nature of the patients' disease and not to any limitations imposed by poor blood counts. Half-body irradiation provided good pain relief within 24 hours for all of the patients. Systemic radiation contributes to the palliative treatment of patients with failed Ewing's sarcoma, but appears to be relatively ineffective when the tumor burden is high.

Hypothalamic syndrome in children with acute lymphocytic leukemia.

Five children had six episodes of central nervous system leukemia which were characterized by features suggestive of hypothalamic infiltration. All five patients had been in prolonged bone marrow remission and had no other evidence of active leukemia when the hypothalamic syndrome was diagnosed. Five of the six episodes responded promptly to intrathecally administered methotrexate and cranial irradiation, but bone marrow relapse, which was resistant to further therapy, developed within 4 months in three patients and after 18 months in the fourth. Only one patient remains in bone marrow remission without recurrence of hypothalamic symptoms 10 months later.

Cardiopulmonary function in long-term survivors of childhood Hodgkin's lymphoma: a pilot study.

Twelve patients who had received mantle radiotherapy for Hodgkin's lymphoma during childhood underwent cardiopulmonary testing 7 years or more after the initial diagnosis and treatment. All but one patient had been asymptomatic. Results of echocardiography, pulmonary function tests, or exercise studies were abnormal in 9 of the 12 patients. Long-term follow-up of cardiopulmonary function will be important to determine the ultimate significance of these abnormalities. These potential complications must be considered in planning prospective therapeutic studies in children with Hodgkin's disease.

Extreme leukemic leukocytosis (blast crisis) in childhood.

Children with leukemia who have extremely high leukocyte counts (more than 100,000/mm3) when seen initially are at high risk of early sudden death, usually from massive intracerebral hemorrhage. Nine such patients were seen during a 39-month period. Eight had pronounced adenopathy and hepatosplenomegaly without severe anemia or thrombocytopenia. The first six patients died suddenly. Cerebral perivascular infiltration and increased blood viscosity are the probable pathophysiologic mechanisms. A treatment program was developed, the goal being the early elimination of blast cells. Three consecutive patients patients presenting with leukocyte counts greater than 100,000/mm3 were treated with emergency cranial irradiation, and all three survived to receive systemic chemotherapy.

Testicular relapse in childhood leukemia.

Five patients in bone marrow remission from childhood leukemia who subsequently had relapse in the testicle are reviewed. Clinically, recurrence of disease is often limited to this site. In spite of satisfactory local control with radiotherapy, further systemic progression generally occurs within 1 year. Previous studies suggest that patients who are in clinical remission harbor tumor in multiple occult "sanctuaries." Testicular leukemia reflects this uncontrolled extramedullary disease, and studies in optimal management of the generalized process are needed.

Hypertrophic osteoarthropathy in association with pulmonary metastasis from osteogenic sacroma.

Hypertrophic osteoarthropathy in children is rare, especially when it is associated with lung metastsis. The patient reported herein had metastic osteogenic sarcoma and failed to respond to chemotherapy or thoractomy. There are several theories as to the pathogenesis of osteoarthropathy, but none is totally convincing. Vagotomy or transection of intercostal nerves has been advocated to relieve the symptoms of osteoarthropathy.

Acute myelomonocytic leukemia after irradiation and chemotherapy for Ewing's sarcoma.

A case is presented in which the diagnosis of acute myelomonocytic leukemia was made 16 months after the start of irradiation and chemotherapy for Ewing's sarcoma. The association of these two diseases is rare. The etiologic role of therapy in the development of leukemia is speculative in this case. However, there is need for surveillance for secondary neoplasms of all types so that the benefits of therapy may be properly weighed against the risks.

Intra-abdominal, angiofollicular lymph node hyperplasia (plasma-cell variant) with an antierythropoietic factor.

An 11-year-old girl presented with a refractory hypochromic microcytic anemia, hypoferremia, normoblastic hyperplastic bone marrow, hypergammaglobulinemia, and growth retardation. Many varied treatments failed to produce any improvement. Ferrokinetic studies revealed rapid plasma clearance and increased plasma iron turnover, but impaired incorporation of 59Fe. Excretion of 57Co after an oral dose indicated an increased iron absorption. A (99M)Tc-sulfur colloid scintigram of the abdomen failed to demonstrate abnormal uptake. A nodal mass showing the plasma-cell variant of angiofollicular hyperplasia was removed from the gastrolienal ligament. Follow-up studies at 3 and 6 months revealed complete correction of the anemia, a 4.8-cm increase in height, and normal serum gamma-globulin levels. Serum obtained before operation inhibited the incorporation of 59Fe that was induced by a standard dose of erthyropoietin in the exhypoxic mouse system, and this inhibition persisted in serum obtained 3 days after surgery but disappeared by 6 days. The data suggest that the hyperplastic angiofollicular lymph node (plasma-cell variant) secreted a substance the inhibited erythropoiesis.

Acute megakaryocytic leukemia (M7) in children.

We analyzed the clinical and laboratory features of eight children (median age, 20 months; range, 13 months to 11 years) with acute megakaryocytic leukemia (M7) and compared the findings with those reported in the literature. The diagnosis was supported by ultrastructural examination for platelet peroxidase or immunophenotyping for glycoprotein IIb/IIIa or the von Willebrand factor protein. Two patients had Down's syndrome. Initial findings included anemia (in all patients), thrombocytopenia (in six), myelofibrosis (in three), lytic bone lesions (in two), and pronounced leukocytosis (in one). Stem cell culture studies of peripheral blood specimens revealed an aberrant phenotype of the megakaryocytes in one patient and reversal to a normal pattern after successful therapy. Remission was achieved in seven of the eight patients after aggressive chemotherapy, and four patients remained in remission 27 to 57 months after diagnosis. Three of these four patients underwent allogeneic bone marrow transplantation. M7 leukemia is not infrequent in children younger than 3 years of age, especially in those with Down's syndrome. The availability of monoclonal antibodies specific to restricted antigens of the megakaryocytic lineage has made the diagnosis of M7 leukemia both possible and practical.

Hereditary red cell disorders in Southeast Asian refugees and the effect on the prevalence of thalassemia disorders in the United States.

This investigation established the frequency and prevalence of hemoglobin E, alpha and beta thalassemia, and glucose-6-phosphate dehydrogenase deficiency in a group of Southeast Asian individuals and determined the impact upon the prevalence of thalassemia disorders in the United States. The resettlement program of Southeast Asian refugees has significantly increased the total number of serious thalassemic disorders in the United States. For several generations Southeast Asian children will be the principal thalassemic group.

Wilms' tumor in a 'lump' kidney associated with sacral agenesis.

Many cases of Wilms' tumor developing in a horseshoe kidney have been previously reported. We present a case of Wilms' tumor developing in a "lump" kidney, associated with sacral agenesis. We discuss the implications for staging and make recommendations for follow-up in these cancer-prone children.

Abdominal Burkitt's lymphoma: role of early aggressive surgery.

Current surgical teaching advocates debulking of the abdominal Burkitt's lymphoma to decrease tumor burden and improve survival. The records of 16 children who had Burkitt's lymphoma were reviewed. Eleven of these children presented with abdominal tumors. Five of these 11 patients are long-term survivors and six have died. Three of the tumors were primarily resected; two were in patients who became long-term survivors. One resection was complicated by acute renal failure, leading to the early demise of the patient. Four tumors were debulked; only one of these was in a long-term survivor. Acute renal failure also complicated the hospital course in one of these children. Finally, four patients underwent initial incisional biopsies and plans were made for subsequent resection of any residual tumor 6 weeks later. Two of these children survived and two have died. The results of this pilot study do not confirm that there is a clear advantage to aggressive operative cytoreduction. Although this approach decreases the total tumor burden, it may also impose severe metabolic complications and postpone the administration of chemotherapy. These results do suggest the need for a multi-institutional review of the surgical management of abdominal Burkitt's lymphoma.

Bilateral massive nephroblastomatosis in infancy.

This report describes an infant with bilateral diffuse nephroblastomatosis, illustrating the typical clinical and pathologic characteristics that allow it to be differentiated from true bilateral Wilms' tumor.

Intraoperative irradiation: a new technique in pediatric oncology.

Adverse effects on normal tissue are the principal limiting factor in the use of radiation therapy. Maturing tissues are most susceptible to these side effects, so high-dose applications can be a particularly difficult challenge in children. Intraoperative radiation therapy (IORT) enables the radiation oncologist to displace or shield dose-limiting organs or structures. These first two cases of children treated with IORT suggest that IORT, used alone or in conjunction with external beam irradiation, may be useful in the pediatric age group.