This prospective, randomised pilot study was designed to evaluate safety, feasibility and efficacy of recombinant human erythropoietin (rhEPO) in the prevention and treatment of chemotherapy-induced anaemia in children with solid tumours. 20 children (age 4–18 years) undergoing cyclic combination chemotherapy were randomised either to a control group or to receive rhEPO at a dose of 150 U/kg/dose subcutaneously three times/week for a minimum of 12 weeks or three chemotherapy cycles. Of 15 evaluable patients, 8 were randomised to the rhEPO group and 7 to the control group. RhEPO-treated patients showed an increase in the haematocrit over the first 8 weeks of therapy, with a significantly higher mean haematocrit at week 8 (33.2 ± 2.1% versus 39.3 ± 4.2% in the control and rhEPO groups, respectively, P < 0.05). Similarly, significantly higher haemoglobin concentrations could be demonstrated in the rhEPO group by week 8 (11.06 ± 1.35 g/dl versus 13.11 ± 1.13 g/dl in the control and rhEPO groups, respectively, P < 0.05), with higher precycle haemoglobin before chemotherapy cycles 3 and 4 and higher midcycle haemoglobin between cycles 3 and 4. There was a trend towards a reduction of transfusion requirements during the 3rd month of therapy in rhEPO patients. The results of this pilot study indicate a significant benefit of rhEPO in children treated with intensive combination chemotherapy regimens. Further studies should target issues such as appropriate dosing, timing and duration of rhEPO therapy in children with cancer.

PURPOSE AND METHODS Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.

High dose (5 g/m2/24 h) methotrexate therapy was combined two times with etoposide (100 mg/m2/1h) infusions as a part of the Medulloblastoma protocol developed in our Department Vepesid therapy was administered in two different schedules. The first group of the patients have received etoposide immediately before and at the end (24th h) of methotrexate treatment. The second group was treated with etoposide at 24 h and at 48 hour after starting methotrexate infusion. In this latter group treatment related grade 3-4 toxicity developed more frequently than in the first group (58.6% vs 33.3%). The authors observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum methotrexate levels (determined by high performance liquid chromatography) were elevated by 53.14-109.19%, and 25.86-64.95%, respectively by the third hour after completion of Vepesid infusion. This effect was detectable for 6 hours. All the liver and kidney functions of the patients were in the normal range. These results suggest the possibility of partial recirculation of extra/intracellular methotrexate into the blood after etoposide administration. Based on these results the therapeutic protocol has been modified and Vepesid is given prior to and at the end (24 h) of high dose methotrexate treatment. Under these conditions only a slight decrease of methotrexate elimination has been detected between the 25-28th h. These results emphasize the role of possible schedule dependent interactions of cytostatic drugs.

Annals of the New York Academy of SciencesVolume 824, Issue 1 p. 232-233 Pediatric Oncology Outreach to Hungary: A Registry of Childhood Malignanciesa ENIKÖ APJOK, ENIKÖ APJOK Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorJOSEPH D. BORSI, JOSEPH D. BORSI Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorROZÁLIA KOÓS, ROZÁLIA KOÓS Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorDEZSÖ SCHULER, DEZSÖ SCHULER Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorROBERT E. BOLINGER, ROBERT E. BOLINGER The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this authorCATHY D. BOYSEN, CATHY D. BOYSEN The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this authorARIEL B. BAKER, ARIEL B. BAKER The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this authorFREDERICK F. HOLMES, FREDERICK F. HOLMES The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this author ENIKÖ APJOK, ENIKÖ APJOK Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorJOSEPH D. BORSI, JOSEPH D. BORSI Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorROZÁLIA KOÓS, ROZÁLIA KOÓS Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorDEZSÖ SCHULER, DEZSÖ SCHULER Second Department of Pediatrics Semmelweis University Medical School Tuzolto u 7–9 1095 Budapest, HungarySearch for more papers by this authorROBERT E. BOLINGER, ROBERT E. BOLINGER The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this authorCATHY D. BOYSEN, CATHY D. BOYSEN The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this authorARIEL B. BAKER, ARIEL B. BAKER The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this authorFREDERICK F. HOLMES, FREDERICK F. HOLMES The University of Kansas Medical Center 39th and Rainbow Boulevard Kansas City, Kansas 66160Search for more papers by this author First published: 17 December 2006 https://doi.org/10.1111/j.1749-6632.1997.tb46227.xCitations: 1 a This work was jointly sponsored by the Pediatric Oncology Outreach to Hungary project of the University of Kansas Medical Center, Kansas City, Kansas; the Second Department of Pediatrics of the Semmelweis University Medical School, Budapest, Hungary; and the National Institute of Neurosurgery, Budapest, Hungary, through a grant from the U.S. Agency for International Development. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume824, Issue1Challenges and Opportunities in Pediatric OncologySeptember 1997Pages 232-233 RelatedInformation

A two-year-old girl presented with clitoromegaly and an abdominal mass. Diagnostic procedures including sonography, computerized tomography, scintigraphy and measurement of catecholamines in urine excluded neuroblastoma, but suspected Wilms-tumor. Before completing the steroid measurements therapy was initiated according to Wilms-tumor (preoperative cytostatic therapy followed by surgical removal of the tumor). Morphology of the tumor, the serum and urinary steroid profile proved a benign adrenocortical adenoma producing mainly delta 5-steroids including the weak androgen, dehydroepiandrosterone.

(1997). Safety of Dexrazoxane in Children with All Undergoing Anthracycline Therapy: Preliminary Results of a Prospective Pilot Study. Pediatric Hematology and Oncology: Vol. 14, No. 1, pp. 93-94.

A population-based cancer registry for childhood leukemia was started in Hungary in 1971. Data processing and analysis have been done at the Second Department of Pediatrics, Semmelweis University Medical School in Budapest, which is the main center for the treatment of childhood malignancies in Hungary. In 1992 a new computerized database structure was created in collaboration with Kansas University Medical Center, Kansas City, Kansas, United States. This work presents childhood leukemia frequency distribution and treatment results between 1988 and 1992 in Hungary. The number of patients diagnosed with leukemia under 18 years of age fluctuates between 69 and 82 cases per year. We present the main causes of death and outline our future objectives to improve the survival rate and quality of life.

The first report on the administration of the chemoprotective agent Ethyol (amifostine) in conjunction with high dose carboplatin to a patient in the pediatric/adolescent age group is presented. A 17 year old teenager with recurrent cerebellar medulloblastoma received a total of five courses of high dose carboplatin 2 x 600 mg/m2 (1200 mg/m2 total) in each cycle. A complete response has been observed following the third treatment cycle. However, cumulative grade IV hematological toxicity developed following each of the first four treatments. Therefore, the fifth treatment was administered in conjunction with amifostine, at a dose of 2 x 740 mg/m2. Time to complete hematological recovery (Hb > 100 g/l, granulocytes > 2.0 G/l, platelets > 100 G/l) was 52, 58, 72, 78 and 50 days, respectively, following treatments nos 1, 2,,3, 4 and 5. The duration of grade III-IV neutropenia (< 1.0 G/l) was 3, 7, 8, 10 and 5 days, respectively. The duration of grade II-IV thrombocytopenia (platelets < 75 G/l) was 10, 25, 35, 40 and 32 days, respectively. Grade IV thrombocytopenia (platelets < 25 G/l) lasted for 5, 10, 12, 18 and 3 days, respectively, after each consecutive treatment. The total number of platelet transfusions was 1, 2, 2, 3 and 1, with the transfusion of 6, 9, 11, 11 and 5 units of platelets. The administration of amifostine has not been accompanied by any serious side effect. A short decrease in body temperature and a transient drop of blood pressure have been observed. Although hematological toxicity of high dose carboplatin has not been eliminated by amifostine, we conclude that significant protection was achieved in this situation of progressive bone marrow exhaustion.

The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to abrogate chemotherapy-induced neutropenia has become a routine part of many cancer treatment regimes. However, there are still very few data available about possible complications related to repeated or prolonged use of these agents in patients with malignant solid tumors. The authors report a child with brainstem glioma who received repeated cycles of multiagent chemotherapy with G- or GM-CSF support. During this period of 10 months, no clinical side effects were observed that could have been attributed to growth factor administration. However, postmortem histological examination revealed the presence of diffuse plasmacytosis, a rare hematological disorder in childhood. Undifferentiated plasma cells of nonmonoclonal origin could be demonstrated infiltrating bone marrow, lungs, and lymph nodes of the patient. Based on previously published in vitro and in vivo evidence on the interleukin-6 (IL-6)-mediated stimulatory effect of G- and GM-CSF on myeloma cell proliferation, the authors suggest a possible link between extensive growth factor support and the development of plasmacytosis in this patient.

This paper reports preliminary experiences with human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in children with malignant diseases administered for three indications: (1) chemotherapy-induced neutropenia and sepsis, (2) prolonged neutropenia decreasing dose intensity, and (3) prevention of neutropenia after sublethal doses of chemotherapy. It was concluded that in the daily dose of 5 micrograms/kg subcutaneously, GM-CSF is capable of reducing the duration of chemotherapy-induced neutropenia and may be an effective tool in maintaining dose intensity and achieving dose escalation.

During the period 1979 to 1992 we treated 141 children for various malignant diseases with protocols including methotrexate (MTX) infusions in doses ranging from 0.5 to 33.6 g/m2 During a total of 922 courses, there were no fatal complications associated with MTX treatment. Serum MTX concentration and pharmacokinetic data were monitored continuously during the infusions. In this study, we evaluated the occurrence of serious untoward reactions to MTX infusions. Impaired renal function with delayed drug elimination was seen in seven patients, all boys, especially after short infusion times. All recovered completely without any serious clinical symptoms. In three leukemia patients who later died from resistant disease, we observed late neurological disturbances and computer tomography (CT) brain scan abnormalities. Pharmacokinetic data from the patients with complications are described and confirm that serial MTX concentration monitoring is the most important early indicator of renal toxicity.

Systemic pharmacokinetics of high-dose (500 mg/m2), orally administered dibromodulcitol (Elobromol) were studied in 16 chemotherapeutic courses administered to 5 patients. Cerebrospinal fluid dibromodulcitol levels were also analysed in two patients. Bromoepoxydulcitol, dianhydrodulcitol are cytotoxic, whereas bromoanhydrodulcitol, andhydroepoxydulcitol are inactive metabolites detectable during the biotransformation of dibromodulcitol. The HPLC method, developed by our team, is suitable for the determination of both dibromodulcitol and its main metabolites (dianhydrodulcitol and bromoanhydrodulcitol). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexite-derivatives in pediatric patients. With the exception of one patient, concentration-time curves were analysed by the one-compartment model. From the 30th minute following administration, dibromodulcitol was detectable in all plasma samples for at least 12 hours, its concentration however was usually undetectable by the 24th hour. Though highly variable in value, dianhydrodulcitol concentrations were detectable during all but one therapeutic courses. The following peak concentrations were observed: dibromodulcitol: 3.46-30.63 microM; dianhydroldulcitol: 1.70-6.17 microM; bromoanhydrodulcitol: 0-5.63 microM. The correlation of area under the curve for bromoanhydrodulcitol and dibromodulcitol was exponential up to 200 microMxh with no additional increase detectable above this limit; the distribution of dianhydrodulcitol values were described by a maximum-curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives were detectable in the cerebrospinal fluid even if the concentration of the individual metabolite remained undetectable in plasma. The cerebrospinal fluid concentrations of dibromodulcitol were almost constant in the period from 2.5 to 8 hours following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis (programmed cell death) is a physiologic phenomenon wherein the dying cell plays an active part in its own destruction. It has an important role in regulation of the balance of cell proliferation and cell death. The pharmacologic manipulation of apoptosis offers new possibilities for the prevention and treatment of cancer. One of the independent prognostic factors in the treatment of acute lymphoblastic leukemia is the sensitivity of the leukemic cells to corticosteroids. Apoptosis after glucocorticoid therapy is suggested as a prognostic factor in children with leukemia. Peripheral blood of children with acute leukemia was taken for morphologic and flow cytometric studies before and after the onset of prednisolone monotherapy. In most of the cases a positive correlation was observed between the decrease of blast numbers and the increase in apoptotic ratio in peripheral blood. In one case no response was observed either clinically or regarding apoptosis.

Systemic pharmacokinetics of high dose (500 mg/m2), orally administered Elobromol (dibromodulcitol, DBD) were studied in 16 chemotherapeutic courses administered to five patients. Cerebrospinal fluid (CSF) DBD levels were also analyzed in two patients. Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 min following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable in value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD = 3.46-30.63 microM, DAD = 1.70-6.17 microM and BAD = 0-5.63 microM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 microM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the individual metabolite remained undetectable in plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Medical and Pediatric OncologyVolume 22, Issue 2 p. 133-136 Article Wernicke-encephalopathy in children with cancer Rozalia Kálmánchey MD, Corresponding Author Rozalia Kálmánchey MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungaryDepartment of Radiation Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104Search for more papers by this authorRozalia Koós MD, Rozalia Koós MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungarySearch for more papers by this authorKatalin Majtényi MD, Katalin Majtényi MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungarySearch for more papers by this authorJozsef Borsi MD, Jozsef Borsi MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungarySearch for more papers by this author Rozalia Kálmánchey MD, Corresponding Author Rozalia Kálmánchey MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungaryDepartment of Radiation Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104Search for more papers by this authorRozalia Koós MD, Rozalia Koós MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungarySearch for more papers by this authorKatalin Majtényi MD, Katalin Majtényi MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungarySearch for more papers by this authorJozsef Borsi MD, Jozsef Borsi MD Department of Pediatrics, Semmelweis Medical University, Budapest, HungarySearch for more papers by this author First published: 1994 https://doi.org/10.1002/mpo.2950220214Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume22, Issue21994Pages 133-136 RelatedInformation