Guidelines for a therapeutic alliance between families and staff: a report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

This, the fifth official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, develops another important topic: the Therapeutic Alliance between families and staff. This is addressed to the Pediatric Oncology Community as Guidelines that could be followed. Every parent, medical staff member, and psychosocial professional involved in the care of the child should be responsible for cooperating in the child's best interest. Everyone must work together toward the common goal of curing the cancer and minimizing its medical and psychosocial side-effects.

SIOP Working Committee on psychosocial issues in pediatric oncology: guidelines for communication of the diagnosis.

This is the fourth official document of the SIOP Working Committee on psychosocial issues in pediatric oncology constituted in 1991. This document develops another topic discussed and approved by the SIOP Committee: "communication of the diagnosis" is addressed to the pediatric oncology community as guidelines that could be followed. The highly stressful nature of the diagnostic period must be acknowledged, and communication involving the staff and all family members should cover both medical and psychosocial issues. A well-planned and extensive initial session should be followed by continuing discussions. The goal is a knowledgeable family that can talk openly with its members and with the staff.

Characterization of cellular lipids in doxorubicin-sensitive and -resistant P388 mouse leukemia cells.

The purpose of this study was to determine whether changes in cellular lipid composition accompanied the selection of cells that are resistant to the anthracycline doxorubicin. Total cellular lipid extracts from doxorubicin-sensitive and doxorubicin-resistant P388 murine leukemia cells were prepared and separated into neutral glycosphingolipids, gangliosides, phospholipids, and neutral lipid families. No significant quantitative differences in total cholesterol, lipid-bound sialic acid, neutral hexose, and lipid-bound phosphate were found between the two cell lines. Gas-liquid chromatographic analysis of the fatty acids derived from each lipid class demonstrated that sensitive and resistant cells had essentially identical fatty acid compositions. Qualitative evaluation of the four lipid classes by high-performance thin-layer chromatography revealed only minor differences in lipid composition between the resistant and the sensitive cells. Results from this study indicate that although minor differences between the two cell lines are present, no major cellular lipid differences are evident to account for the marked differences in the cellular pharmacokinetics and cytotoxic effects of doxorubicin between doxorubicin-sensitive and doxorubicin-resistant P388 murine leukemia a cells.

Neuro-ocular damage in pediatric oncology patients: predictor of long-term visual disability or tool for limiting toxicity?

We present a group of eight pediatric cancer patients with a spectrum of visual afferent pathway abnormalities. Changes include decreased visual acuity, visual field alterations, abnormal visual evoked potentials, changes in the optic disc and nerve fiber layer of the retina, radiation retinopathy, and CNS injury. These changes occur in long term survivors of pediatric malignancy (especially those with prolonged, multimodal, and multicourse therapy), but they may be minimally symptomatic. The changes appear to be analogous to the CNS changes (leukoencephalopathy) described in patients with leukemia and attributed to multimodal therapy. By taking advantage of opportunities to detect adverse effects earlier in the treatment course, the present excellent cure rate may be improved by refinements in therapy that also improve the quality of survival.

Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma.

Ultrafiltrate and total plasma and cerebrospinal fluid (CSF) platinum concentrations were examined in a patient with neuroblastoma following a 2-hour infusion of 120 mg/m2 of cisplatin. Total plasma platinum was 93.4% bound, while the ultrafiltrate of plasma accounted for the remaining 6.6%. The CSF ultrafiltrate resulted in equivalent concentrations of platinum to total CSF platinum. CSF concentrations were 2.9% of the total plasma platinum and 43.5% of the ultrafiltrate plasma platinum 2 hours after the end of the infusion.

Empiric amphotericin B therapy in patients with acute leukemia.

Invasive fungal infections remain a considerable problem in the management of patients with acute leukemia. This review discusses and provides guidelines for empiric treatment in such circumstances, with emphasis on the use of amphotericin B. The topics covered include the risk factors associated with the development of fungal infections; the difficulties of diagnosing a fungal infection; the empiric use of amphotericin B (with a review of clinical trials and dosing guidelines); and the role of other therapeutic measures in oral prophylaxis and treatment. Although other organisms have been shown to cause fungal infections in patients with acute leukemia, only Candida and Aspergillus species are discussed formally in terms of diagnosis and therapy.

Endomyocardial biopsy to monitor anthracycline therapy in children.

Evaluation of the ultrastructure of material obtained by endomyocardial biopsy has been proposed as a means to evaluate patients for impending anthracycline cardiotoxicity. Eighteen biopsies obtained from 13 patients (age, 3-18 years) are reported. Twelve biopsy procedures were done to evaluate the cardiac status on reaching a cumulative dose of 400 mg/m2 and three patients had six subsequent biopsies after having received significantly more drug or receiving radiation therapy to the lungs or mediastinum. Scores were assigned to the tissue obtained and used to guide the decision to continue or stop anthracycline therapy. Three patients with abnormal cardiac studies at low cumulative doses, five of whom had received greater than 400 mg/m2 and three of whom had received considerably higher doses and thoracic irradiation were given more drug without incident. Two specimens were interpreted to indicate avoidance of further anthracycline and two patients were cautiously given more despite evidence of mild myocardial damage. These results indicate that endomyocardial biopsies can be performed on a pediatric population with a reasonable complication rate. Further studies should be undertaken to evaluate its usefulness as a means to predict and avoid anthracycline cardiomyopathy.

Acute nonlymphocytic leukemia developing during the course of Ewing's sarcoma.

Two children with Ewing's sarcoma developed acute nonlymphocytic leukemia (ANLL) during the course of their illness. One patient developed ANLL after apparently successful treatment of his primary malignancy with radiation therapy and multiagent chemotherapy. In the second patient, acute leukemia developed before the administration of radiotherapy or systemic chemotherapy. The development of secondary ANLL after Ewing's sarcoma has been reported only twice previously, most likely representing a therapy-induced complication. The occurrence of ANLL in Patient 2 prior to therapy suggests that these two disorders may have a more than treatment-related association. Close follow-up of long-term survivors of Ewing's sarcoma with surveillance for secondary acute leukemia is advised.

Uptake, metabolism, and cytotoxicity of doxorubicin in human Ewing's sarcoma and rhabdomyosarcoma cells.

Uptake, metabolism, and cytotoxicity of doxorubicin (DOX) in human Ewing's sarcoma (ES) and rhabdomyosarcoma (RS) cells were examined. Cellular uptake of DOX was determined by liquid scintillation spectrometry, and intracellular metabolism was examined by high performance liquid chromatography. The cytotoxicity of DOX was assessed by two different methods: an extracellular matrix detachment assay (ECM-D) and 3H-thymidine incorporation. The uptake of DOX by ES cells was 1.5-3.0 times greater than RS cells, even though both cell types achieved intracellular steady-state though both cell types achieved intracellular steady-state concentrations between 6-8 h. No significant intracellular metabolism ( less than 5%) was seen after 8-h incubations with the drug. The cytotoxic effects of DOX in both cell lines were concentration-dependent, with the RS cells being more sensitive. Measurement of 14C-DOX appears to be a reliable method for quantitating intracellular DOX. In addition, the ECM-D and 3H-thymidine assays used for assessing cytotoxicity produced similar results, showing that the ECM-D can be reliable and easily performed test of cell death.

Kinetics and sensitivity of daunorubicin in patients with acute leukemia.

Leukemia cells isolated from eight patients with acute leukemia before treatment were examined for in vitro uptake of daunorubicin (DNR) and inhibition of DNA synthesis. In addition, plasma and cellular levels of DNR and daunorubicinol (DOL) were examined in six of the eight patients. Inhibition of DNA synthesis was determined with a 3H-thymidine incorporation assay. In vitro cellular 14C-DNR was quantified by means of liquid scintillation spectrometry, whereas in vivo DNR and DOL concentrations were determined by high-performance liquid chromatography. In vitro intracellular plateau concentrations of DNR were achieved within 1-2 h after continuous exposure to 0.01, 0.1, and 1.0 microgram/ml in the majority of cases. Based on our in vitro studies, a dose-response curve was found between increasing intracellular DNR and incorporation of 3H-thymidine. Peak intracellular levels of DNR after treatment occurred immediately after administration of the drug, whereas intracellular DOL levels accumulated over several hours. Plasma concentrations of DNR and DOL were not useful in estimating target tissue concentrations or inhibition of 3H-thymidine incorporation. Extrapolation of in vivo cellular DNR concentrations to the in vitro dose-response curve allows an estimate of DNR sensitivity.

Lymphoblastic lymphoma: late relapse in childhood.

This report describes two children with lymphoblastic lymphoma who relapsed more than 2 1/2 years from diagnosis. Relapses occurred at seven and 20 months after completion of treatment. Their therapy consisted of an intensive pulse chemotherapy program combined with radiation therapy. Initial relapse after two years' treatment has been extremely rare in patients receiving contemporary chemotherapy programs, and two-year survival without disease has been considered a cure. These cases illustrate that late relapses can occur after intensive chemotherapy and that two-year disease-free survival must not be interpreted as a complete cure.

Cellular and plasma kinetics of daunorubicin given by two methods of administration in a patient with acute leukemia.

Leukemic cell and plasma concentrations of daunorubicin were examined serially in a patient with acute lymphoblastic leukemia following administration of the drug by two different regimens: regimen A-an iv bolus dose of 50 mg/m2, and regimen B-a loading dose of 15 mg/m2 followed by 35 mg/m2 infused over 4 hours. Peak plasma levels were four times higher after regimen A the B, whereas leukemic cell concentrations were not significantly different. No difference in acute toxicity or therapeutic efficacy was seen after either method of administration. However, we have demonstrated that peak plasma levels of daunorubicin can be reduced by continuous infusion without significantly altering target tissue concentrations.

Uptake and metabolism of daunorubicin by human leukemia cells.

Radiolabeled daunorubicin was used to study in vitro uptake of daunorubicin (DNR) by the human promyelocytic leukemia cell line HL-60 and by leukemic cells from five previously untreated patients with acute nonlymphocytic leukemia (ANLL). Uptake of the metabolite daunorubicinol (DOL) and the metabolism of DNR were examined using high-performance liquid chromatography (HPLC). Uptake of DNR and DOL by HL-60 and ANLL cells exhibited a similar kinetic pattern. The uptake of DOL was 35%-50% of the uptake of DNR at the same test concentration in both HL-60 and ANLL cells. Approximately 5%-10% of intracellular DNR was metabolized to DOL by HL-60 and ANLL cells after 24 h of drug exposure. Measurements of DNR or DOL derived from liquid scintillation spectrometry and HPLC permit a sensitive and accurate assessment of the pharmacokinetics of these drugs in human leukemia cells. In addition, the HL-60 cell line can be used as a model for studying in vitro pharmacokinetics of the anthracyclines.

Endodermal sinus tumor: the Stanford experience and the first reported case arising in the vulva.

A review of the histology, clinical findings and results of therapy in 9 females with endodermal sinus tumor (EST) is presented. Five patients had histologically pure EST; 4 had EST mixed with other germ cell components. The site of primary tumor was the ovary in 8 of the 9 females; the remaining patient with an extraovarian primary represents the first reported case of EST arising in the vulva. The addition of combination chemotherapy has prolonged survival over historical controls treated with surgery or surgery plus irradiation. Adjuvant chemotherapy appears warranted as treatment for occult metastatic disease; postoperative radiation therapy appears useful in providing local control of primary disease. There is a suggestion of increased sensitivity of EST to combination chemotherapy as compared to other germ cell histologies with which it is commonly admixed.

Adjuvant chemotherapy for osteogenic sarcoma.

Twenty-nine evaluable patients with nonmetastatic osteosarcoma were given sequential combination chemotherapy utilizing high-dose methotrexate with citrovorum factor rescue, vincristine, adriamycin, and cyclophosphamide. Fourteen (48%) of 29 patients are currently disease-free for 8--48 months from initiation of chemotherapy with a median disease-free survival of 21 months. The projected 4-year disease-free survival is 13%. At 4 years the projected overall survival is 57%. In this particular study, adjuvant chemotherapy does not appear to significantly prevent the development of overt metastases. In four patients, delayed onset of metastasis was observed at 18--43 months from initiation of treatment.

[Delayed hypersensitivity in pediatric patients with cancer]. / Fenómeno de hipersensibilidad retardada en pacientes pediátricos con cáncer.

Possible relationship between childhood cancer and host immunity was studied by assessment of delayed hypersensitivity assayed by skin testing. Reactivity to a battery of potential secondary skin test antigens and a primary antigen, dinitrochlorobenzene (DNCB) was determined in 46 children with various malignancies and 28 healthy controls. Rechallenge to DNCB 50 and 100 mcg was tested in 26 children an in the controls. Secondary antigenic patterns showed little difference from controls or between surviving or living patients. Anery to DNCG rechallenge was a prominent finding in children dying with cancer. Immune altertion of some non tumor specific factors therefore seems to be associated with prognosis in some childhood cancers.

Combined radiosensitizer infusion and irradiation of osteogenic sarcomas.

Three children with osteogenic sarcomas which were either unresectable or whose parents refused permission to amputate were treated with combined intra-arterial 5'bromodeoxyuridine (BUdR) infusion and high-dose-per-fraction megavoltage irradiation to the primary site. Pulsed, 48-hour BUdR infusions were performed prior to each 600-rad radiation therapy fraction, with a total radiation dose to the primary site of 4,200-4,800 rads in five weeks. Local control was obtained in all 3 children. One child is alive two years after treatment, another died with metastatic disease and the third patient who received radiotherapy to the lungs for pulmonary metastases is without evidence of disease one year later.