Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia.

The purpose of this study was to determine the induction rate, duration of response and toxicity of cytosine arabinoside (1.0 gm/m2 i.v. over 2 h q 12 h x 8 doses days 1 through 4) and mitoxantrone (12 mg/m2 over 1 h daily x 4 doses days 3 through 6) in pediatric patients with acute myeloid leukemia (AML). Patients achieving a complete remission received either bone marrow transplantation or further chemotherapy. Twenty-seven of 37 evaluable patients (73% (95% confidence interval 59-87%)) achieved a complete remission. For all responding patients, the projected median time to relapse is 12 months. The projected 1 and 2 year disease-free survival is 47% (28-66) and 41% (21-61) with a range of follow-up of 0 to 48+ months. The major toxicity was bone marrow suppression and infection. This therapy is very active in pediatric AML and has acceptable toxicity. Some patients treated achieve prolonged survival.

Improved relapse-free survival in medulloblastoma utilizing modern techniques.

Between 1969 and 1979, 22 patients with medulloblastoma were treated by the same surgical group and radiation therapy group. The patients were divided into two groups because of the clinical availability in December 1974 of the computed tomographic (CT) scanner and of the operating microscope used in the initial surgical procedure. There were 11 patients in each group. The percentage of patients with a relapse-free survival in the group treated between 1969 and 1974 (Group 1) was 38% at 4 years. The survival in the 11 patients treated between 1974 and 1979 (Group 2) was 84% at 4 years. This improvement is statistically significant (P less than or equal to 0.001). All patients received the same dose of radiation. Efforts to minimize the tumor burden by total surgical resection did not increase postoperative morbidity or mortality. These results are discussed, along with the relative impact of the CT scan, total resection at operation, and increased focus for radiation therapy on the improved outcome.

Osteoporosis as the presenting sign of leukemic relapse in an adolescent: case report and literature review.

Osteoporosis in adolescence is rare and usually secondary to an underlying disease process whose diagnosis may be difficult to detect. Osteoporotic vertebral collapse is an uncommon presenting sign of acute lymphoblastic leukemia (ALL). We describe a 13-year-old boy with osteoporotic vertebral collapse secondary to relapse of ALL whose blood count and blood morphology were normal but whose 1,25 = (OH2) = vitamin D level was deficient. A combination of chemotherapy, calcitriol and calcitonin therapy was successful in reversing the process. His case is presented to describe the diagnostic and therapeutic issues involved.

Late effects of treatment of cancer in children.

Advances in surgical techniques, in chemotherapy, and in radiation therapy have led to improved survival in children treated for cancer. Children cured of cancer will soon form a significant fraction of our adult population. As we follow such survivors, we have become more aware of long-term side effects of treatment. This is not a reason to withhold therapy. Instead, careful followup of oncology patients is needed to document the late effects, to identify the etiologic agents, and to alter treatment to give the least toxic therapy without sacrificing quality or duration of survival.

Proceedings of the tumor board of the Children's Hospital of Philadelphia. Testicular leukemia: incidence and management results.

The patient was an eight-year-old black male who presented to the Children's Hospital of Philadelphia (CHP) in June 1977 with foot pain. Abnormal findings on physical examination were diffuse shotty lymphadenopathy without hepatosplenomegaly. Examination of the extremities was normal. There was no evidence of increased bruising or bleeding. Laboratory data revealed a hemoglobin of 11.2 gm/dl, white blood cell count of 26,200/cu mm, and platelet count of 21,000/cu mm. Serum uric acid level was 4.2 mg/dl. The remainder of the laboratory findings were within normal limits. Bone marrow examination revealed a hypercellular marrow replaced with lymphoblasts. Immunologic evaluation showed these cells to have no surface immunoglobin and no rosette formation with sheep red blood cells. The patient received vincristine 1.5 mg/M2 daily, oral prednisone at 40 mg/M2 daily, L-asparaginase 6,000 IU/M2 for nine intramuscular doses, and methotrexate 12 mg intrathecally. After 28 days, bone marrow aspiration showed that the leukemia was in remission. He then received 2,400 rad cranial irradiation over three weeks, along with four more doses of intrathecal methotrexate, given once weekly. Maintenance consisted of monthly pulses of vincristine (1.5 mg/M2), prednisone (40 mg/M2 for five days), daily oral 6-mercaptopurine (75 mg/M2), and weekly oral methotrexate (20 mg/M2). After six months of maintenance, the patient was given a scheduled course of reinduction therapy with vincristine, prednisone, and L-asparaginase. Eleven months after diagnosis both testes were noted to be enlarged on physical examination. Wedge biopsy of both testes revealed leukemic infiltration. Examination of the bone marrow and cerebrospinal fluid (CSF) at that time were unremarkable. The patient was treated with vincristine, prednisone, and L-asparaginase again for four weeks and received intrathecal methotrexate as central-nervous-system (CNS) prophylaxis. Twenty-four hundred rad were given to both testes at 200 rad/day with decrease in testicular size. Maintenance consisted of monthly pulses of vincristine and prednisone with oral methotrexate and 6-mercaptopurine. Seven months after his testicular relapse the patient had a bone marrow relapse. He expired eight months later with disseminated leukemia.

Nonocclusive ischemic colitis secondary to hemorrhagic shock.

A young male with a penetrating chest wound suffered modest and transitory hemorrhagic shock. Nonocclusive right-sided ischemic colonic necrosis developed secondarily. This became obvious on serial follow-up examinations, prompting exploration and curative surgical resection. This case represents ischemic colitis secondary to hemorrhagic shock following trauma. Upon review of the literature, only five other such cases have been reported. Although shock-associated ischemic colitis is well documented, it is extremely uncommon to see gangrenous changes of the bowel in young, otherwise healthy, trauma victims. Mesenteric vasospasm is believed to be the causative factor in these cases. For unknown reasons, the right colon seems to be the favored site of ischemic damage. Nonocclusive intestinal ischemia should be considered in patients who have abdominal pain after a hypotensive episode.

Reliability of colonoscopy.

In an effort to determine the reliability of colonoscopy the authors retrospectively reviewed preoperative colonoscopic findings and compared them with the postoperative pathologic specimen reports. Only lesions greater than 0.5 cm were included in the comparison. Over a 13-year period, 429 patients with colorectal cancer underwent preoperative colonoscopy. Four hundred thirteen (97 percent) of the colonoscopic examinations correlated with the pathologic specimen, but, in 16 cases (3 percent), lesions were missed. In total, 17 adenomatous polyps and 3 cancers were found in the surgical specimens that were not documented at colonoscopy. Eighteen patients had total preoperative colonoscopy and total abdominal colectomy, which makes for a reliable model to judge the accuracy of colonoscopy. In these 18 patients, 17 of the pathologic specimens correlated with the endoscopic findings, which yields an accuracy rate of 94 percent. Blind areas in the colon, plus misjudgment that the scope had reached the cecum, are responsible for the majority of colonoscopic errors.

Transient cortical blindness secondary to vincristine therapy in childhood malignancies.

Three children with malignancies developed severe neurotoxicity, including transient cortical blindness, following chemotherapy regimens. The only drug in common was vincristine sulfate. The clinical courses of these patient are described. All have completely recovered, although one child who was rechallenged with vincristine had a cardiorespiratory arrest, increasing neurotoxicity, and recurrence of blindness. Transient cortical blindness has not previously been attributed to vincristine sulfate therapy, but must be considered as a possible complication of treatment with this agent.

Adult Wilms tumor: effect of combined therapy on survival.

Thirty-one adults with Wilms tumor were reported to the National Wilms Tumor Study from 1968 to 1979. Treatment and survival data for these patients were analyzed and compared to similar information derived from children enrolled in the first National Wilms Tumor Study. The ages of the 31 adults ranged from 17 to 63 years (mean 29 years). All but 3 patients had surgical resection or excision of tumor, 7 did not receive postoperative irradiation and all but 1 had chemotherapy. Actinomycin D and vincristine were the drugs used most commonly, 26 of the 31 patients receiving both agents. Advanced disease at diagnosis (6 stage III and 9 stage IV versus 9 stage I and 5 stage II--in 2 cases stage was not known) was found more often than in children in whom stages III and IV disease made up 27 per cent of the first National Wilms Tumor Study population. The 3-year actuarial survival rate for the 31 adults was 24 per cent: 48 per cent for stages I and II disease and 11 per cent for Stage IV disease. Comparable data for children in the first National Wilms Tumor Study, adjusted for stage, were 74, 87 and 53 per cent, respectively. It is concluded that adults with Wilms tumor treated as were these have a worse prognosis than children managed according to the first National Wilms Tumor Study regimen. However, those adults in this series who were treated aggressively, that is surgical excision, postoperative irradiation and multi-agent chemotherapy, appeared to have fared better than adults treated in the pre-chemotherapy era. It is concluded that aggressive therapy should be given to all adults with Wilms tumor irrespective of stage.

Nuclear receptor co-repressor gene localizes to 17p11.2, a frequently deleted band in malignant disorders.

The t(8;21) between the AML1 and ETO genes is a commonly seen genetic alteration in acute myeloid leukemia. Recently, we reported that the fusion partner ETO binds to the human nuclear receptor co-repressor (NCOR), a member of the NCOR/SIN3/histone deacetylase complex. This complex mediates transcriptional repression as a result of chromatin remodeling. Here, we used a combination of fluorescence in situ hybridization and hybrid panels to localize the human NCOR gene (NCOR) to chromosome band 17p11.2. The position of human NCOR on 17p11 raises the possibility of deranged transcriptional regulation in malignant disorders associated with deletions of 17p.

Scrotal recurrence of paratesticular rhabdomyosarcoma in a previously undescended testicle 5 years after orchiectomy.

A case of scrotal recurrence of a paratesticular rhabdomyosarcoma 5 years after orchiectomy and chemotherapy is described. To our knowledge local recurrences have been reported previously only in the inguinal region. The patient had a history of orchiopexy, which may have contributed to the scrotal recurrence.

A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia.

BACKGROUND: Juvenile chronic myelogenous leukemia (CML) is a rare myeloproliferative disease of infants and young children for which there is no effective therapy other than allogeneic bone marrow transplantation. In vitro, isotretinoin (13-cis-retinoic acid) attenuates both the spontaneous proliferation of leukemic peripheral-blood progenitor cells (granulocyte-macrophage colony-forming units) and their selective hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). We conducted a pilot study to evaluate the clinical efficacy of isotretinoin in juvenile CML. METHODS: To be eligible the patients had to have newly diagnosed untreated disease, leukocytosis with monocytosis, marrow with less than 25 percent blasts, hepatosplenomegaly, no chromosomal abnormalities, and negative viral cultures and antibody titers. Isotretinoin was administered orally in single daily doses of 100 mg per square meter of body-surface area. When possible, patients subsequently underwent bone marrow transplantation. RESULTS: Ten children (median age, 10 months) were enrolled in the study. In all 10 there was spontaneous colony formation of leukemic progenitor cells in vitro. In the eight patients tested there was hypersensitivity to GM-CSF. The only toxic effect of isotretinoin therapy was cheilitis in two patients. Four children had disease progression. Two children had complete responses to isotretinoin (normalization of the white-cell count and disappearance of organomegaly), three had partial responses (more than a 50 percent reduction in the white-cell count and degree of organomegaly), and one had a minimal response (more than a 50 percent reduction in the white-cell count, but a 26 to 50 percent reduction in the degree of organomegaly). The median duration of response was 37 months (range, 6 to 83). Three of the four children who had a complete or partial response and who did not undergo bone marrow transplantation were alive 36 to 83 months after the diagnosis of juvenile CML. The spontaneous colony formation in vitro was reduced in samples from the five patients in whom this factor was reassessed during treatment. There was also a reduction in the hypersensitivity of leukemic progenitor cells to GM-CSF in the two patients retested. CONCLUSIONS: Isotretinoin can induce durable clinical and laboratory responses in patients with juvenile CML.

Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment.

The possibility that umbilical cord and placental blood from an HLA-identical sibling might produce stable donor-derived lymphohematopoietic engraftment was tested in a patient with juvenile chronic myelogenous leukemia (JCML). After conditioning with high-dose busulfan and cyclophosphamide, cryopreserved umbilical cord blood, containing 0.5 x 10(8) nucleated cells/kg and 2.7 x 10(4) colony forming units-granulocyte, macrophage (CFU-GM)/kg, was infused. A leukocyte count greater than 1,000/microL, absolute neutrophil count (ANC) greater than 500/microL, and platelet count greater than 20,000/microL (untransfused) were observed on days 39, 39, and 47 after transplantation, respectively. Donor cell engraftment was documented in the peripheral blood and bone marrow by cytogenetic analysis, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) as early as day 21. Furthermore, the donor origin of each lymphohematopoietic lineage (ie, CD5+ T cells, CD19/20+ B cells, CFU-GM, and burst-forming unit-erythrocyte [BFU-E]) was confirmed. On day 200, assays of the peripheral blood and bone marrow showed an abnormal proliferation of CFU-GM at low seeding densities in the absence of exogenous growth factors, as well as a hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), both pathophysiologic characteristics of JCML. Recurrent disease was confirmed histologically on day 225. Together, these results demonstrate that umbilical cord blood contains sufficient numbers of hematopoietic stem cells necessary for the engraftment of leukemia patients treated with myeloablative therapy and that the detection of "spontaneous" CFU-GM and hypersensitivity to GM-CSF after treatment is a marker of residual or recurrent disease in patients with JCML.

Pleuropulmonary blastoma: a marker for familial disease.

OBJECTIVE: To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS: Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS: In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS: The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases.