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1. Thiopurine Methyl Transferase: Activity and Genotyping in Patients with Acute Lymphoblastic Leukemia

Author

Brouwer, C., Keizer-Garritsen, J. J., Lambooy, L. H. J., Ament, K., Ter Riet, P. G. J. H., De Abreu, R. A., Bökkerink, J. P. M., Van Wering, E. R., Van Der Does-Van Den Berg, A., Veerman, A. J. P., Trijbels, J. P. M. F., Back, Nathan, editor, Cohen, Irun R., editor, Kritchevsky, David, editor, Lajtha, Abel, editor, Paoletti, Rodolfo, editor, Zoref-Shani, Esther, editor, and Sperling, Oded, editor

Published
2002
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8. Landelijke richtlijnen voor follow-up van overlevenden van kinderkanker

Author

Kremer, L. C. M., Jaspers, M. W. M., van Leeuwen, F. E., Versluys, A. B., Bresters, D., Bökkerink, J. P. M., Hakvoort-Cammel, F. G. A. J., Postma, A., Schouten-van Meeteren, A. Y. N., van Dulmen-den Broeder, E., van der Pal, H. J. H., Hazelhoff, J., Ronckers, C. M., van Dam, E. W. C. M., Braam, K. I., van der Linden, G. H. M, Blaauwbroek, R., de Ridder-Sluiter, J. G., and van den Bos, C.

Published
2006
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9. Gezondheidsproblemen na de behandeling van kinderkanker

Author

Postma, A., Schouten-van Meeteren, A. Y. N., Hakvoort-Cammel, F. G. A. J., Bresters, D., Versluys, A. B., Bökkerink, J. P. M., van Dulmen-den Broeder, E., van der Pal, H. J. H., van Dam, E. W. C. M., van der Linden, G. H. M., Blaauwbroek, R., van Leeuwen, F. E., Jaspers, M. W. M., Kremer, L. C. M., and van den Bos, C.

Published
2006
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12. Abstracts of papers Pharmacological Meeting

Author

Bax, W. A., Saxena, P. R., Biewenga, Gerreke Ph., de Jong, Jan, Bast, Aalt, Bloemen, Pauline G. M., van den Tweel, Maria C., Henricks, Paul A. J., Engels, Ferdi, Nijkamp, Frans P., Molewijk, H. E., van der Poel, A. M., Olivier, B., Briejer, M. R., Schuurkes, J. A. J., Akkermans, L. M. A., Bruning, T. A., Hendriks, M. G. C., Chang, P. C., Kuypers, E. A. P., van Zwieten, P. A., Cappendijk, S. L. T., de Vries, R., Dzoljic, M. R., Bouwknecht, J. A., Crijns, F. R. L., Huijberts, M. S. P., Boudier, H. A. J. Struijker, Kruzeman, A. C. Nieuwenhuijzen, Wolffenbuttel, B. H. R., de Lannov, L. M., Danser, A. H. J., Schoemakef, R. G., Schalekamp, M. A. D. H., Du, Xiao Y., Schoemaker, Regien G., Saxena, Pramod R., Dubois, E. A., Batink, H. D., Pfaffendorf, M., van Roven, E. A., Garrelds, I. M., de Graaf-in 't Veld, C., Ziilstra, F. J., Jansen, A. P. H., van Wijk, R. Gerth, Gho, B. C. G., Schoemaker, R. G., Lee, C. v. d., Sharma, H. S., Verdouw, P. D., Groenink, L., van der Gugten, J., Zethof, T. J. J., Hasselaar, P., Jansen, J. W. C. M., van Giezen, J. J. J., Dreteler, G. H., Hulkenberq, A., Reinders, J. H., Toorop, G. P., Herremans, A. H. J., Hijzen, T. H., Slangen, J. L., Hessel, E. M., Van Oosterhout, A. J. M., Hofstra, C., Garssen, J., van Loveren, H., Savelkoul, H. F. J., Nijkamp, F. P., Hol, Thorwald, Van Ree, Jan M., Spruijt, Berry M., Hüsken, B. C. P., van Zwieren, P. A., Kalkman, E. A. J., Kam, K. L., Keuzenkamp-Jansen, C. W., De Abreu, R. A., Bökkerink, J. P. M., vd Heijden, M. A. H., Trijbels, J. M. F., Kraneveld, A. D., Buckley, T. L., van Schaik, Y., Koster, A. Sj., Mathôt R. A. A., Van den Aarsen B. C. F. M., Langemeijer M. W. E., Ijzerman A. P., Danhof M., Mohede, Inqe C. M., van Oosterhout, Antoon J. M., Monshouwer, M., Witkamp, R. F., Nijmeijer, S. M., Van Miert, A. S. J. P. A. M., Oosting, J., Janssen, B. J. A., Pijl, A. J., van der Wal, A. C., Mathy, M. -J., Pruimboom, W. M., van Dijk, A. P. M., Tak, C. J. A. M., Bonta, I. L., Wilson, J. H. P., Bac, D. J., Zijlstra, F. J., Hashjin, G. Sadeghi, Folkerts, G., Henricks, P. A. J., Santing, R. E., Pasman, Y., Olymulder, C. G., Roffel, A. F., Zaaqsma, J., Meurs, H., Scheerens, Heleen, Buckley, Theresa L., Van Loveren, Henk, Sipma, H., Duin, M., den Hertog, A., Nelemans, A., Smit, J., Coppes, R. P., Geurtsen, A., Zaagsma, J., Smit, M. J., Leurs, R., Bast, A., Timmerman, H., Stassen, F. R. M., De Mey, J. G. R., ten Berge, R. E. J., Tjon, Guno H. K., De Vries, Taco J., Ronken, Eric, Hogenboom, François, Warden, George, Mulder, Arie H., Schoffelmeer, Anton N. M., Van Bergen, P., Kleline, J. A., Janssen, P. M. L., Van Der Vaart, J. G. M., Kasbergen, C. M., Versteeg, D. H. G., De Wildt, D. J., van de Velde, M. J., Engels, F., van den Berg, C., Vleeming, W., van Amsterdam, J. G. C., Werner, J., van der Zee, L., den Hertoe, A., van Gelderen, E. Marcel, Agteresch, Hendrik J., De Bruijne, Emile L. E., Saxena, Pramod R., van Kats, J. P., Sassen, L. M. A., Admiraal, P. J. J., Verdouw, P. P., van Muiswinkel, F. L., Steinhusch, H. W. M., Drukarch, B., Sloof, J. C., de Vente, J., Vanderschuren, L. J. M. J., Van Ree, J. M., Verkade P., Verkleij A. J., Gispen W. H., Oestreicher A. B., Vermeulen, R. J., Goosen, C., Wolters, E. Ch., Stoof, J. C., Vincent, V. A. M., Schoffelmeer, A. N. M., Steinbush, H. W. M., Berlcenbosch, F., Voss, Hans-Peter, Donnell, David, Wesselman, J. P. M., VanBavel, E., Spaan, J. A. E., Zeilmaker, W. M., van 't Klooster, G. A. E., Horbach, G. J. M. J., Zhang, J., Zhang, J. S., and van Meet, J. C. A.

Published
1993
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13. Abstracts of oral presentations

Author

Boulieu, R., Lenoir, A., Mornex, J. F., Bohman, C., Balzarini, J., Wigerinck, P., Van Aerschot, A., Herdewijn, P., De Clercq, Erik, Brosh, S., Zoref-Shani, E., Sperling, O., Danziger, E., Sidi, Y., Bromberg, Y., Burgemeister, Renate, Rötzer, Elke, Gutensohn, Wolf, Connolly, G. P., Harrison, P. J., Diasio, R. B., Lu, Z., Zhang, R., Gresser, U., Gutensohn, W., Resta, R., Thompson, L. F., Javaux, F., Vincent, M. F., Van den Berghe, G., Kamilli, I., Rauch, R., Hahn, D., Keuzenkamp-Jansen, C. W., De Abreu, R. A., Bökkerink, J. P. M., vd Heijden, M. A. H., Löffler, M., Becker, C., Wegerie, E., Marcussen, M., Overgaard-Hansen, K., Klenow, H., Marinaki, A. M., Harley, E. H., McBride, M. B., Simmonds, H. A., Moro, F., Cameron, J. S., Ogg, C. S., Williams, D. G., Rigden, S., Haycock, G., Miranda, M. E., Puig, J. G., Mateos, F. A., Vázquez, J. O., van Haperen, V. W. T. Ruiz, Veerman, G., Vermorken, J. B., Peters, G. J., van der Wilt, C. L., Noordhuis, P., Smid, K., Pinedo, H. M., Salerno, C., Lomonte, A., Giardini, O., Crifo, C., Smolenski, R. T., Yacoub, M. H., Seymour, A. M. -L., Stegmann, A. P. A., Honders, M. W., Willemze, R., Landegent, J. E., Stet, E. H., Vogels-Mentink, G. M., Lambooy, L. H. J., Trijbels, J. M. F., Torres, R. J., Tozzi, M. G., Pesi, R., Turriani, M., Allegrini, S., Camici, M., Ipata, P. L., van den Berg, A. A., Meinsma, J. R., van Lenthe, H., van Gennip, A. H., van Kuilenburg, A. B. P., Abeling, N. G. G. M., Bakker, H. D., Slingerland, R. J., Van den Bergh, F., and Sabina, R. L.

Published
1993
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16. Preface

Author

Giacomello, Alessandro, Peters, G. J., Eriksson, Staffan, De Abreu, Ronney, Kristensen, T., Munch-Petersen, B., Vincenzetti, S., Cambi, A., Neuhard, J., Garattini, E., Vita, A., Oka, J., Matsumoto, A., Hosokawa, Y., Inoue, S., Allegrini, S., Johnson, R. B., Fiol, C. J., Eriksson, S., Fabianowska-Majewska, K., Wasiak, T., Duley, J., Simmonds, A., Bretner, M., Felczak, K., Poznański, J., Dzik, J. M., Golos, B., Jarmuła, A., Rode, W., Kulikowski, T., Codacci-Pisanelli, G., Pinedo, H. M., Noordhuis, P., van Groeningen, C. J., van der Wilt, C. L., Franchi, F., Hatse, S., Balzarini, J., De Clercq, E., Marinello, E., Rosi, F., Dispensa, E., Mangiavacchi, P., Riario-Sforza, G., Agostinho, A. B., Smolenski, R. T., Müller, Mathias M., Roch-Ramel, F., Guisan, B., Diezi, J., Tavenier, M., Skladanowski, A. C., de Abreu, R. A., de Jong, J. W., Åmellem, Øystein, Löffler, Monika, Pettersen, Erik O., Boulieu, R., Lenoir, A., Bertocchi, M., Mornex, J. F., Makarewicz, W., Spychala J., Mitchell B. S., Barankiewcz J., Góra-Tybor, Joanna, Robak, Tadeusz, Spasokukotskaja T., Sasvári-Székely M., Piróth Zs., Kazimierczuk Z., Staub M., Keuzenkamp-Jansen, C W, De Abreu, R A, Bökkerink, J P M, Trijbels, J M F, Eriksson S., Warzocha, K., Krykowski, E., Góra-Tybor, J., Fronczak, A., Robak, T., Minelli, A., Moroni, M., Monacelli, N., Mezzasoma, I., Amici, A., Emanuelli, M., Raffaelli, N., Ruggieri, S., Magni, G., Carta, M. C., Mattana, A., Poddie, F., Sgarrella, F., Tozzi, M. G., Veerman, G., Ruiz van Haperen, V. W. T., van Moorsel, C. J. A., Pesi, R., Baiocchi, C., Camici, M., Ipata, P. L., Kozłowska, M., Świerczyński, J., Smoleński, R. T., Jastorff, B., Messina, E., Savini, F., Procopio, A., Giacomello, A., Wielgus-Kutrowska, B., Kulikowska, E., Wierzchowski, J., Bzowska, A., Shugar, D., Fairbanks, Lynette D, Ruckemann, Katarzyna, Simmonds, H Anne, Kaletha, K., Szymańska, G., Thebault, M., Raffin, J. P., Le Gal, Y., Griesmacher, Andrea, De Abreu, Ronney A., Zych, M., Ruckemann, K., Jagodzinski, P., Kochan, Z., Stolk, J., Boerbooms, A., De Abreu, R., de Koning, D., van de Putte, L., Fiorini, M., Bazzichi, L., Bertolini, G., Martini, C., Ciompi, M. L., Lucacchini, A., Pizzichini, M., Terzuoli, L., Arezzini, L., Fe, L., Pagani, R., Miscetti, P., Allegrucci, C., Sebesta, I., Duley, J. A., Simmonds, H. A., Gross, M., Salerno, C., Stone, T. W., Van den Berghe, G., Valik, Dalibor, Jones, James D., Guerranti, R., Fè, L., Sforza, G. Riario, Knecht, Wolfgang, Grein, Klaus, Lodi, R., Iotti, S., Barbiroli, B., Bonin, B., Chantin, C., Bory, C., Micheli, V., Jacomelli, G., Morozzi, G., Fioravanti, A., Marcolongo, R., Pompucci, G., Peters G J, Noordhuis P, Komissarov A, Holwerda U, Kok R M, Van Laar J A M, Van der Wilt C L, Van Groeningen C J, Pinedo H M, Perrett, David, Jacobsson, Bengt, Sisto A., Iezzi A., Di Carlo M., Pizzigallo E., Akhondzadeh, S., MacGregor, D. G., Ogilvy, H. V., Zoref-Shani, E., Brosh, S., Sidi, Y., Bromberg, Y., Sperling, O., van Gennip, A. H., Abeling, N. G. G. M., Stroomer, A. E. M., van Lenthe, H., Bakker, H. D., van Kuilenburg, A. B. P., Connolly, G. P., Abbott, N. J., Lilling, G., Gozes, I., Vreken, P., Meinsma, R., de Ahreu, R. A., Diasio, R. B., Albin, N., Johnson, M. R., Shahinian, H., Wang, K., Gathof, B. S., Rocchigiani, M., Puig, J. G., Mateos, F., Sestini, S., Krijt, J., Shin, Y., Gresser, U., Costa, A., Maximova, N., Andolina, M., Paci, M., Carrozzi, M., Osbich, A., Durighello, M., Cavalli, F., Geatti, O., Zammarchi, E., Morgan, Gareth, Webster, A. D. B., Slavin, S., Naparstek, E., Nagler, A., Acker, M., Cividalli, G., Kapellushnik, Y., Varadi, G., Ben-Yoseph, R., Or, R., Parfenov, V. V., Ignatenko, M. A., Amchenkova, A. M., Narovlyansky, A. N., Spoto, G., Mastropasqua, L., Gizzi, F., Arduini, A., Del Gallo, P., Ciancaglini, M., Gallenga, P. E., Šebesta, I., Zeman, J., Crifò, C., Di Vito, M., Lomonte, A., Gerber, G., Carlucci, F., Tabucchi, A., Vannoni P., Di Pietro M. C., Vincent, M. F., Bontemps, F., Boer, P., Rötzer, E., Ehrmann, D., Empl, W., Bride, M. B. Mc, Ogg, C. S., Cameron, J. S., Moro, F., Rigden, S., Rees, L., Hoff, W. Van't, Raman, V., Palmieri, P., Mastropierro, G., Albertazzi, A., Rucci, C., Darlington, L. G., Cotton, S. R., de Gorter, J. J., Lawrence, E. S., Petrie, A., Sarsam, R. P., Semple, M. J., Warburton, E. A., Quaratino, C. P., Talone, L., Di Sciascio, N., Hrebíček, M. H., Poupětová, H., Ledvinová, J., Elleder, M., Vondrák, K., Rees, P. C., Wonke, B., Thein, S. L., Clegg, J. B., Marlewski, M., Pennelli, A., Di Marzio, M., Angelini, G., Sabatino, G., de Koning, P., Kerstens, P., de Graaf, R., Hayek, G., and Cardona, F.

Published
1995
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17. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: Results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988-1991)

Author

Kamps, W. A., Bökkerink, J. P. M., Hählen, K., Hermans, J., Riehm, H., Gadner, H., Schrappe, M., Slater, R., Den Berg-De Ruiter, E., Smets, L. A., Vaan, G. A. M., Weening, R. S., J. Fransje Weerden, van, Wering, E. R., Does-Van Den Berg, A., Faculteit Medische Wetenschappen/UMCG, Pediatrics, and Molecular Genetics

Subjects
RISK, PREDNISONE, LYMPHOCYTIC-LEUKEMIA, PROGNOSIS, Behandelingsresultaten bij kinderen met hematologische maligniteiten, LONG-TERM SURVIVORS, Treatment of children with hematologic malignancies, IN-VITRO, CHEMOTHERAPY, THERAPY, PREVENTION, CLASSIFICATION
Abstract

In The Netherlands from July 1988 to October 1991, children (0 to 16 years of age) with de novo acute lymphoblastic leukemia (ALL) were treated according to protocol ALL-7 of the Dutch Childhood Leukemia Study Group (DCLSG). In this protocol, chemotherapy and treatment stratification were identical to the ALL-BFM-86 protocol (Reiter et at, Blood 84:3122, 1994), but cranial irradiation was restricted to patients with initial central nervous system (CNS) involvement. Patients were stratified into 3 risk groups, based on leukemia cell mass and response to initial treatment: standard-risk group (SRG), risk group (RG), and experimental group (EG). As in ALL-BFM-86, a randomized study on late intensification (protocol S) was performed in RG patients, and during the study (since October 1990), early reinduction treatment (protocol II) was introduced for SRG patients. Treatment duration for all patients was 18 months. Two hundred eighteen children entered the study: 74 SRG, 127 RG, and 17 EG patients. The overall complete remission (CR) rate was 98%. The 5-year event-free survival (EFS) for all DCLSG ALL-7 patients was 65.3% (standard error [SE] 3.2%), which was significantly different from the 73% (SE 1%) 8-year EFS achieved in the ALL-BFM-86 study (P = .02, Z-test). However, restricting the analysis to SRG patients receiving protocol II with a total duration of treatment of 18 months, the 5-year EFS rates were 64.6% (SE 4.0%) and 67% (SE 4%), respectively, and no significant difference could be established (P = .67, Z-test). The 5-year EFS rates for SRG, RG, and EG patients were 63.5% (SE 5.6%), 66.6% (SE 4.2%), and 63.3% (SE 12.0%), respectively. SRG patients receiving protocol II fared better than patients not receiving protocol II (5-year EFS 76.7% [SE 7.7] and 54.5% [SE 7.5], respectively). No difference in 8-year EFS was observed in RG patients randomized to receive or not to receive late intensification with protocol S. The overall CNS relapse rate at 5 years was 5.5%. The incidence rate at 5 years was 11.4% in SRG patients not receiving protocol II, whereas no CNS relapses occurred in SRG patients receiving protocol II. Six children died in first complete remission and 2 children developed a second malignancy (thyroid carcinoma and acute nonlymphoblastic leukemia). Systemic high-dose methotrexate (MTX) and intrathecal chemotherapy is a safe and effective method of CNS prophylaxis in the context of BFM-oriented treatment for all children with ALL, regardless of the risk group (with the possible exception of T-ALL patients with high white blood cell counts). The results of the DCLSG ALL-7 study confirm those of the ALL-BFM-86 study showing that early reinduction with protocol II is essential in the treatment of SRG patients and that late intensification with protocol S does not improve the prognosis for RG patients. (C) 1999 by The American Society of Hematology.

Published
1999

20. Analysis of handwriting of children during treatment for acute lymphoblastic leukemia

Author

Reinders-Messelink, H, Schoemaker, M, Snijders, T, Göeken, L, Bökkerink, J, and Kamps, W

Abstract

BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) often complain about handwriting problems. PROCEDURE: Using a computerized writing task, we have prospectively studied the processes necessary for the production of handwriting movements in 11 children (5-12 years old) during treatment for ALL. Children were tested at time points closely related to the vincristine administration. RESULTS AND CONCLUSIONS: Children treated for ALL drew slower, with longer pause durations and increased drawing pressure. Children were able to overcome the problems, except for a consistently increased drawing pressure. This increased drawing pressure may be an attempt of the children to obtain sufficient kinesthetic information and thus can be seen as an adequate adaptation mechanism in case of peripheral neuropathy due to the neurotoxic effects of vincristine. However, neurotoxic effects of other cytostatic drugs cannot be excluded.

Published
2001

22. DNA methylation patterns in the calcitonin gene region at first diagnosis and at relapse of acute lymphoblastic leukemia (ALL).

Author

Leegwater, P A J, Lambooy, L H J, De Abreu, R A, Bökkerink, J P M, van den Heuvel, L P, Leegwater, P A, Lambooy, L H, and Bökkerink, J P

Subjects
DNA, METHYLATION, CALCITONIN, LEUKEMIA, COMPARATIVE studies, DOCUMENTATION, IMMUNOBLOTTING, LYMPHOBLASTIC leukemia, RESEARCH methodology, MEDICAL cooperation, NUCLEOTIDES, NUCLEOTIDE separation, RESEARCH, DISEASE relapse, EVALUATION research, DNA methylation
Abstract

Aberrant DNA methylation can occur early in neoplastic transformation and may lead to the development of cancer. We describe the alterations of methylation patterns at the DNA sequence level which occurred in the 5' region of the calcitonin gene in lymphoblasts from 14 pediatric patients with acute lymphoblastic leukemia (ALL). The DNA methylation status of 25 CpG sites was determined by sequence analysis after bisulfite treatment of the DNA. This method showed that 13 out of 14 patients had increased numbers of methylated CpG sites in the calcitonin gene region at initial diagnosis when compared to control DNA from healthy individuals. The 5' region of the calcitonin gene appears to be methylated to a significantly higher degree in T lineage ALL compared to B lineage ALL (P < 0.01). Each of six ALL patients who were investigated at initial diagnosis and at relapse showed alterations in DNA methylation between the two stages. These six cases were also investigated by Southern blot analysis with methylcytosine-sensitive restriction enzymes and this method showed an increase in DNA methylation in only four of the six cases. The DNA sequencing method thus appears to be better suited to assess alterations of DNA methylation than Southern blot analysis. There are marked regional differences in the frequency of methylation of individual CpG sites and in the frequency of alterations between the two stages. Our results show that alterations in DNA methylation continue to occur from the initial stage to the relapse stage of ALL, suggesting that aberrant DNA methylation may play a role in tumor progression. [ABSTRACT FROM AUTHOR]

Published
1997
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27. BEP/VIP bei Kindern und Jugendlichen mit malignen nichttestikulären Keimzelltumoren

Author

Göbel, U., primary, Calaminus, G., additional, Teske, C., additional, Bamberg, M., additional, Bökkerink, J., additional, Haas, R., additional, Holschneider, A., additional, Janka-Schaub, G., additional, Jürgens, H., additional, Mittler, U., additional, von der Ölsnitz, G., additional, Pelzer, V., additional, Urban, C., additional, Weißbach, G., additional, and Harms, D., additional

Published
1993
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30. Microdontia after chemotherapy in a child treated for neuroblastoma.

Author

Remmers, D., Bökkerink, J. P. M., and Katsaros, C.

Subjects
NEUROBLASTOMA, NERVOUS system tumors, DRUG therapy, THERAPEUTICS, SARCOMA
Abstract

Structured Abstract Authors – Remmers D, Bökkerink JPM, Katsaros C Objective – Chemotherapy used on paediatric oncology patients often causes disturbances in dental development. Aim of this case report is to present the late effects of chemotherapy on dental development in a patient treated for neuroblastoma at early age. Design – Case report. Results – This paper presents a female patient treated at early age with surgery and chemotherapy for a neuroblastoma (stage IVS) in the right thorax and massive liver metastases. The examination of the patient at age 11.7 years showed microdontia of six teeth. In three of them size and form of the crown were affected, while in the other three the size was reduced but the form was not affected. Conclusions – Chemotherapy on children treated for neuroblastoma can adversely influence tooth development. This has to be taken into consideration by the dentist when monitoring the development of the dentition and occlusion. [ABSTRACT FROM AUTHOR]

Published
2006
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32. Zur Bedeutung des Procarbazins in der Chemotherapie des Morbus Hodgkin - Ein Bericht der kooperativen Therapiestudie DAL-HD-85*

Author

Schellong, G., primary, Hörnig, Isabell, additional, Brämswig, J., additional, Bökkerink, J. P., additional, Steinhoff, A., additional, Ludwig, R., additional, Niethammer, D., additional, Reiter, A., additional, Lengerke, H. J., additional, Heinecke, H., additional, Schwarze, E., additional, Pötter, R., additional, Müller, R., additional, and Wannenmacher, M., additional

Published
1988
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33. Nichttestikuläre Keimzelltumoren: Analyse der Therapiestudie MAKEI 83/86 und Protokolländerungen für die Nachfolgestudie

Author

Göbel, U., primary, Bamberg, M., additional, Haas, R., additional, Bökkerink, J. P., additional, Brämswig, G., additional, Calaminus, G., additional, Engert, J., additional, Gadner, H., additional, Havers, W., additional, Janka-Schaub, G., additional, Jürgens, H., additional, Matthiesen, H., additional, Niethammer, D., additional, Sauer, D., additional, Spaar, H., additional, Sternschulte, W., additional, Weißbach, L., additional, and Harms, D., additional

Published
1989
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34. Simultane bilaterale Wilms-Tumoren

Author

van den Berg, F., primary, Hendriks, J., additional, Boetes, C., additional, Bökkerink, J., additional, van der Staak, F., additional, Holland, R., additional, and Rosenbusch, G., additional

Published
1983
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35. Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: final results of the multinational trial GPOH-HD95.

Author

Dörffel W, Rühl U, Lüders H, Claviez A, Albrecht M, Bökkerink J, Holte H, Karlen J, Mann G, Marciniak H, Niggli F, Schmiegelow K, Schwarze EW, Pötter R, Wickmann L, and Schellong G

Subjects
Adolescent, Child, Child, Preschool, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Etoposide administration & dosage, Female, Follow-Up Studies, Hodgkin Disease mortality, Hodgkin Disease radiotherapy, Humans, International Agencies, Male, Neoplasm Grading, Neoplasm Staging, Prednisone administration & dosage, Procarbazine administration & dosage, Prognosis, Remission Induction, Survival Rate, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemoradiotherapy, Hodgkin Disease drug therapy
Abstract

Unlabelled: PURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission., Patients and Methods: Between 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals., Results: Rates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate., Conclusion: RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy.

Published
2013
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36. Central diabetes insipidus: Is it Langerhans cell histiocytosis of the pituitary stalk? A diagnostic pitfall.

Author

Prosch H, Grois N, Bökkerink J, Prayer D, Leuschner I, Minkov M, and Gadner H

Subjects
Biopsy, Child, Diabetes Insipidus, Neurogenic complications, Female, Germinoma complications, Germinoma drug therapy, Histiocytosis, Langerhans-Cell complications, Histiocytosis, Langerhans-Cell drug therapy, Humans, Magnetic Resonance Imaging, Pituitary Neoplasms complications, Pituitary Neoplasms drug therapy, Diabetes Insipidus, Neurogenic pathology, Germinoma pathology, Histiocytosis, Langerhans-Cell pathology, Pituitary Gland pathology, Pituitary Neoplasms pathology
Abstract

Central diabetes insipidus (CDI) is a rare disorder that may be caused by a variety of diseases. In pediatric and adolescent patients the most common causes for CDI are Langerhans cell histiocytosis (LCH) and germinoma. To avoid a potentially hazardous biopsy of the hypothalamic pituitary region it is recommended to evaluate patients with CDI carefully to identify potential extracranial lesions. Since LCH is the most common systemic disease that may cause CDI, special focus is paid to the identification of LCH lesions. We report on a 9(1/2) year old girl who presented with central diabetes insipidus and a thickening of the pituitary stalk on magnetic resonance imaging. Diagnostic workup revealed a history of recurrent ear infections and a compressed 6th thoracic vertebral body on radiographs. Based on these findings LCH was anticipated. Upon growth of the pituitary stalk lesion the patient was treated with LCH standard chemotherapy. After an initial shrinkage of the lesion, a further growth of the pituitary stalk lesion was observed and the tumor was resected. Histopathology revealed germinoma. This case underscores the importance of a istopathologically proven diagnosis in patients with HPR tumors before the initiation of a specific therapy, even if the clinical findings are highly suggestive.

Published
2006
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37. Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89.

Author

Calaminus G, Schneider DT, Bökkerink JP, Gadner H, Harms D, Willers R, and Göbel U

Subjects
Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Neoplasms blood, Bone Neoplasms therapy, Child, Preschool, Combined Modality Therapy, Female, Humans, Infant, Male, Neoplasm Invasiveness, Neoplasm Staging, Neoplasms, Germ Cell and Embryonal blood, Neoplasms, Germ Cell and Embryonal therapy, Prognosis, Risk Factors, Testicular Neoplasms blood, Testicular Neoplasms therapy, Treatment Outcome, Biomarkers, Tumor blood, Bone Neoplasms secondary, Neoplasms, Germ Cell and Embryonal secondary, Sacrococcygeal Region pathology, Testicular Neoplasms pathology, alpha-Fetoproteins analysis
Abstract

Purpose: To evaluate the prognostic value of metastases, extension into bone, and alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ cell tumors (GCTs) prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (83/86 and 89)., Patients and Methods: Between October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1 and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients had metastases, and 35 children presented with extension into bone. At diagnosis, 22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values of greater than 100,000 ng/mL. Five patients died of complication during treatment and were excluded from further evaluation. Seventy-one patients could be analyzed., Results: The 5-year relapse-free survival rate (RFS, Kaplan-Meier) was 0.76 +/- 0.03 (54 of 71 patients; median observation time, 54 months after diagnosis). The RFS of patients with and without metastases was different, but not significantly so (0.71 v 0.82). The outcome of patients with extension into bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5 years). Above-normal AFP level had no prognostic significance (P =.52)., Conclusion: In children with malignant sacrococcygeal GCTs treated with an intensive, short-interval, platinum-based regimen, the stage, extent of metastases, extension into bone, and AFP level had no prognostic significance.

Published
2003
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38. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996).

Author

Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, and van der Does-van den Berg A

Subjects
Antineoplastic Combined Chemotherapy Protocols administration & dosage, Asparaginase administration & dosage, Brain radiation effects, Child, Child, Preschool, Disease-Free Survival, Female, Germany, Humans, Infant, Male, Mercaptopurine administration & dosage, Netherlands, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Survival Rate, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Abstract

Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of patients treatment still fails. The objectives of the DCLSG study ALL 8 were to decrease the toxicity and to increase the effectivity of BFM-oriented treatment. Decrease of toxicity was aimed at by confirmation of the results of the previous DCLSG study ALL-7, showing that the majority (94%) of children with ALL can successfully be treated with BFM-oriented therapy without cranial irradiation, and by reduction of treatment for standard risk (SRG) patients. To increase the cure rate in medium risk (MRG) patients the efficacy of high doses of intravenous 6-mercaptopurine (HD-6MP) during protocol M and in SRG patients the efficacy of high doses of L-asparaginase (HD-L-ASP) during maintenance treatment was studied in randomized studies. Patient stratification and treatment were identical to protocol ALL-BFM90, with the following differences: no prophylactic cranial irradiation, SRG patients received only phase 1 of protocol I. Four hundred and sixty-seven patients entered the protocol: 170 SRG, 241 MRG and 56 HRG patients. The 5 years event-free survival rate for all patients was 73% (s.e. 2%); for SRG, MRG and HRG patients 85% (s.e. 3%), 73% (s.e. 3%) and 39% (s.e. 7%), respectively. In patients >1 year of age at diagnosis unfavorable prognostic factors were male sex, >25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) >50 x 10(9)/l. The cumulative risk of CNS relapse rate was 5% (s.e. 1%) at 5 years. These results confirm that the omission of cranial irradiation in BFM-oriented treatment does not jeopardize the overall good treatment results, nor does early reduction of chemotherapy in SRG patients. No benefit was observed from treatment intensification with HD-L-ASP in SRG patients, nor from HD-6MP in MRG patients.

Published
2002
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39. SIOP treatment guidelines for renal tumours in small infants: fact or fantasy?

Author

Levie NS, de Kraker J, Bökkerink JP, Appel IM, and Aronson DC

Subjects
Combined Modality Therapy, Female, Humans, Infant, Infant, Newborn, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Male, Neoplasm Staging, Nephroma, Mesoblastic congenital, Nephroma, Mesoblastic drug therapy, Nephroma, Mesoblastic pathology, Practice Guidelines as Topic, Preoperative Care, Retrospective Studies, Wilms Tumor drug therapy, Wilms Tumor pathology, Guideline Adherence, Kidney Neoplasms surgery, Nephrectomy, Nephroma, Mesoblastic surgery, Wilms Tumor surgery
Abstract

Aims: Since as far back as 1980, SIOP (Société Internationale d>>Oncologie Pédiatrique) have advocated primary nephrectomy (PN) only for unilateral renal tumours in patients > tumour (WT). Fourteen of the 25 patients (56%) were treated with PN, including four patients with CMN. In group B there was one patient (2%) with CMN and 40 patients with WT. Thirteen of the patients (31%) were treated with PN. A total of 15 patients were treated before 1980 and 26 after 1980. Eight of 15 (53%) patients were treated with PN before 1980 and 21/26 (81%) were pre-treated after 1980, according to the protocol., Conclusion: Despite the SIOP recommendations, only 56% of patients

Published
2000
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40. Mild axonal neuropathy of children during treatment for acute lymphoblastic leukaemia.

Author

Reinders-Messelink HA, Van Weerden TW, Fock JM, Gidding CE, Vingerhoets HM, Schoemaker MM, Göeken LN, Bökkerink JP, and Kamps WA

Subjects
Achilles Tendon, Action Potentials drug effects, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Axons drug effects, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Humans, Male, Neural Conduction drug effects, Polyneuropathies physiopathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Prospective Studies, Reflex, Stretch drug effects, Regression Analysis, Sensory Thresholds drug effects, Vibration, Vincristine administration & dosage, Antineoplastic Agents, Phytogenic adverse effects, Polyneuropathies chemically induced, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma physiopathology, Vincristine adverse effects
Abstract

Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children.

Published
2000
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41. Motor performance of children during treatment for acute lymphoblastic leukemia.

Author

Reinders-Messelink H, Schoemaker M, Snijders T, Göeken L, van Den Briel M, Bökkerink J, and Kamps W

Subjects
Analysis of Variance, Child, Child, Preschool, Female, Humans, Male, Movement drug effects, Movement physiology, Postural Balance drug effects, Postural Balance physiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Prospective Studies, Psychomotor Performance drug effects, Sex Factors, Time Factors, Vincristine therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma physiopathology, Psychomotor Performance physiology
Abstract

Background: Daily life motor skills of children with acute lymphoblastic leukemia (ALL) were studied during treatment using the Movement Assessment Battery for Children (Movement ABC). In addition, the possible relation with vincristine treatment was investigated., Procedure: Seventeen children treated for ALL, aged 4-12 years, were compared to an age- and sex-matched control group., Results: The leukemia group performed more poorly than the control group on both fine and gross motor skills. In looking at the number of children with ALL who scored in the clinical range of the different subtests, problems in balance skills were found to be most pronounced at the end of induction therapy. Remarkably, half a year after reinduction therapy, problems with balance had decreased, whereas the number of children with fine motor problems had increased., Conclusions: A relation between the gross motor problems and vincristine neurotoxicity seems plausible based on a descriptive analysis of the data, but this was not supported statistically., (Copyright 1999 Wiley-Liss, Inc.)

Published
1999
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42. Osteosarcoma: oncologic and functional results. A single institutional report covering 22 years.

Author

Renard AJ, Veth RP, Schreuder HW, Pruszczynski M, Bökkerink JP, van Hoesel QG, and van Der Staak FJ

Subjects
Adolescent, Adult, Aged, Bone Neoplasms physiopathology, Bone Neoplasms therapy, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Osteosarcoma physiopathology, Osteosarcoma therapy, Bone Neoplasms mortality, Osteosarcoma mortality
Abstract

Background and Objectives: The oncologic and functional results in patients treated because of osteosarcoma (OS) were evaluated., Methods: Fifty-one patients with high-grade OS were treated between 1974 and 1996 at our hospital. All patient records were studied, and the surviving patients were evaluated according to the American Musculoskeletal Tumor Society functional rating system. The majority of patients received adjuvant chemotherapy (prior to 1983) or neoadjuvant chemotherapy (from 1983). Until 1987, all patients with extremity OS had ablative surgery; from 1987, the majority had limb-saving surgery. Lung metastases were resected in most cases., Results: Overall 2-year and 5-year disease-free survival (DFS) rates were 27 of 51 and 16 of 42, respectively. Patients with vertebral or pelvic OS or contaminated margins after resection had a very bad outcome. In all other subgroups, including patients with various types of chemotherapy, response to chemotherapy, diameter of tumor, presence or absence of metastatic spread, and location of tumor, a 5-year DFS of about 50% was found. Recurrent disease in patients who had achieved a 2-year disease-free interval was relatively low (4/23 patients)., Conclusions: Survival in our series was worse than in most other studies. A very bad outcome was found in patients with vertebral or pelvic OS or with contaminated margins after resection., (Copyright 1999 Wiley-Liss, Inc.)

Published
1999
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43. Teratomas in infancy and childhood.

Author

Göbel U, Calaminus G, Engert J, Kaatsch P, Gadner H, Bökkerink JP, Hass RJ, Waag K, Blohm ME, Dippert S, Teske C, and Harms D

Subjects
Adolescent, Bleomycin administration & dosage, Chemotherapy, Adjuvant, Child, Child, Preschool, Cisplatin administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Dactinomycin administration & dosage, Etoposide administration & dosage, Female, Humans, Infant, Infant, Newborn, Male, Prognosis, Radiotherapy Dosage, Recurrence, Retrospective Studies, Risk Factors, Survival Rate, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Teratoma drug therapy, Teratoma epidemiology, Teratoma surgery
Abstract

Background and Procedure: Outcomes in children with teratomas collected between October 1982 and December 1995 in cooperative protocols of the German Society of Pediatric Oncology and Hematology (GPOH) were analyzed. Teratomas were diagnosed in 329 (42%) of 780 registered patients with germ cell tumors. The annual incidence was 0.24/100,000. Main primary sites were coccygeal (n = 132, 2.2:1 female predominance), ovary (n = 81), testis (n = 40) and brain (n = 15, 2.8:1 male predominance)., Results: Two hundred seventy cases of extracranial non-testicular teratoma were evaluated: In mature teratomas (n = 154) the observed relapse rate was 10%. Incomplete resection was the main risk factor for relapse. After complete resection, the relapse-free survival (RFS, Kaplan-Meier-estimation) was 0.96 +/- 0.01 (n = 126, observation time 18-155 months) in comparison to an RFS of 0.56 +/- 0.09 in incompletely resected teratomas grade 0 (n = 28, observation time 28-94 months) (P < 0.01). Im-mature teratomas were treated by surgery alone in 76 cases and by surgery and adjuvant chemotherapy in 40 cases. The observed relapse risk was 18%. Main risk factors for relapse were incomplete tumor resection (n = 38) as well as immaturity in incompletely resected teratomas. Fifteen of 29 relapsing patients presented with malignant tissue in the recurrent tumor (mainly yolk sac tumor); in contrast, seven of 40 patients with immature teratoma relapsed despite adjuvant chemotherapy without showing malignant components (P = 0.014). Nine of 36 (25%) relapsing patients died of disease. Eleven of the 27 (41%) surviving children suffered from mutilation after repeated surgery., Comments: It is suggested that an international randomized trial for patients with incompletely resected high risk teratoma be initiated to evaluate the effect of adjuvant chemotherapy on specific end-points: 1) influence on relapse rate in general; 2) reduction of the proportion of malignant relapses; 3) avoidance of mutilating surgery.

Published
1998
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44. Inhibition of DNA methylation in malignant MOLT F4 lymphoblasts by 6-mercaptopurine.

Author

Lambooy LH, Leegwater PA, van den Heuvel LP, Bökkerink JP, and De Abreu RA

Subjects
Carbon Radioisotopes, Humans, Lymphocytes, Methionine metabolism, Radioisotope Dilution Technique, Thymidine metabolism, Tritium, Tumor Cells, Cultured, DNA Methylation drug effects, DNA, Neoplasm biosynthesis, Mercaptopurine pharmacology
Abstract

Treatment of MOLT F4 lymphoblasts with 6-mercaptopurine (6-MP) resulted in a decrease of ATP and a depletion of S-adenosylmethionine (AdoMet). To investigate whether this might affect the methylation of DNA, we treated MOLT F4 lymphoblasts with increasing concentrations of 6-MP, followed by labeling with [methyl-14C]methionine and [methyl-3H]thymidine. After DNA isolation, we measured the incorporated radioactivity and determined the 14C/3H ratio as a measure for the methylation of newly formed DNA. The 14C/3H ratio was decreased by 17% with 1 mumol/L 6-MP; treatment with increasing concentrations of 6-MP up to 10 mumol/L showed a further decrease to 70%, in comparison with untreated cells. To demonstrate that the methylation of deoxycytidine residues in DNA was reduced, we quantified hydrolyzed DNA by HPLC. The 14C/3H ratio showed a decrease with increasing 6-MP concentrations, indicating that treatment with 6-MP resulted in hypomethylation of DNA.

Published
1998

45. Wilms tumor with teratomatous cysts in a horseshoe kidney: a diagnostic pitfall.

Author

van der Poel HG, Feitz WF, Bökkerink J, Staak FV, and de Vries JD

Subjects
Diagnosis, Differential, Female, Humans, Infant, Teratoma complications, Wilms Tumor complications, Kidney abnormalities, Kidney Diseases, Cystic complications, Kidney Diseases, Cystic diagnosis, Kidney Neoplasms complications, Kidney Neoplasms diagnosis, Teratoma diagnosis, Wilms Tumor diagnosis
Published
1997
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46. Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia.

Author

Keuzenkamp-Jansen CW, De Abreu RA, Blom HJ, Bökkerink JP, and Trijbels JM

Subjects
Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Child, Erythrocytes metabolism, Homocysteine blood, Humans, Mercaptopurine administration & dosage, Mercaptopurine pharmacokinetics, Methionine blood, Methotrexate administration & dosage, Methotrexate pharmacokinetics, Methylation, Purine Nucleotides blood, S-Adenosylhomocysteine blood, S-Adenosylmethionine blood, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Abstract

6-mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleotides. Thiopurine methylation occurs to a large extent in vivo and in vitro. In this reaction, S-adenosyl-L-methionine (AdoMet), produced from methionine and ATP, is converted into S-adenosyl-L-homocysteine (AdoHcy) which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts, AdoMet: AdoHcy ratio and DNA methylation decrease after incubation with 6MP. The aim of the present study was to investigate the influence of high-dose 6MP on the methylation capacity in children with acute lymphoblastic leukemia. Five patients received 4 courses with high-dose intravenous MTX (5' g.m-2 in 24 hr) immediately followed by high-dose 6MP (1300 mg.m-2 in 24 hr). Five control patients received high-dose MTX and oral 6MP (25 mg.m -2 daily for 8 weeks). Leucovorin rescue was started at 36 hr in both groups. In the intravenous 6MP group, 6-methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were detectable in plasma in concentrations of 0.3-2.6 muM (6MP steady state levels: 11.6 muM). In red blood cells, mean methylthioinosine nucleotide levels were one third of those of ATP (13.1 nmol/10(8)). AdoHcy levels (10 pmol/10(8)) remained constant in both groups and AdoMet was not detectable ( < 20 pmol/10(8)). In both groups, plasma homocysteine increased and methionine decreased following administration of MTX. The delay in the recovery of methionine in the intravenous 6MP group after MTX infusion is probably the result of an increased demand on methyl groups during 6MP infusion.

Published
1996
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47. Metabolism of intravenously administered high-dose 6-mercaptopurine with and without allopurinol treatment in patients with non-Hodgkin lymphoma.

Author

Keuzenkamp-Jansen CW, DeAbreu RA, Bökkerink JP, Lambooy MA, and Trijbels JM

Subjects
Allopurinol blood, Antimetabolites, Antineoplastic blood, Antineoplastic Agents therapeutic use, Child, Child, Preschool, Dose-Response Relationship, Drug, Enzyme Inhibitors blood, Erythrocytes metabolism, Female, Humans, Hypoxanthine, Hypoxanthines blood, Individuality, Infusions, Intravenous, Male, Mercaptopurine therapeutic use, Methylthioinosine blood, Nucleotides blood, Xanthine, Xanthine Oxidase antagonists & inhibitors, Xanthines blood, Allopurinol therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Agents blood, Enzyme Inhibitors therapeutic use, Lymphoma, Non-Hodgkin blood, Lymphoma, Non-Hodgkin drug therapy, Mercaptopurine blood
Abstract

Purpose: We investigated the metabolism of high dose 6 mercaptopurine (HD-6MP) infusions and its influence on the metabolism by allopurinol, an inhibitor of xanthine oxidase, the enzyme that catabolizes 6MP into thioxanthine and thiouric acid., Patients and Methods: Nine patients (aged 2-11 years) with non-Hodgkin lymphoma (NHL) were treated with HD-6MP (1300 mg/m(2).24h) within a therapeutic window after diagnosis. Four patients received oral allopurinol (200 mg/m(2).day) to prevent urate nephropathy, and five did not. Plasma and RBC were isolated before and 4, 20, 24, 28, and 48h after the start of the infusion. All measurements were performed with HPLC., Results: Considerable variations were found in the plasma levels of 6MP, thioxanthine, and thiouric acid and of RBC-MeTIN levels. 6MP-riboside was not detectable, and MeMP and MeMPR levels were <1.3 muM in the plasma. In general, 6MP, thioxanthine, and MeMP levels in plasma were higher, and thiouric acid plasma levels and RBC-MeTIN levels were lower in the patients treated with allopurinol compared to those who did not receive allopurinol., Conclusions: 6MP is extensively metabolized in patients with NHL treated with HD-6MP. Thiopurine methylation, at the levels of nucleotide, nucleoside, and base, is an important metabolic pathway after HD-6MP. Co-administration of allopurinol can result in both a decreased catabolism and anabolism of 6MP compared to treatment with HD-6MP alone. This observation may have consequences for the therapeutic efficacy and toxic effects of 6MP in combination with allopurinol.

Published
1996
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48. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.

Author

Caron H, van Sluis P, de Kraker J, Bökkerink J, Egeler M, Laureys G, Slater R, Westerveld A, Voûte PA, and Versteeg R

Subjects
Blotting, Southern, Child, Preschool, Chromosome Aberrations, Chromosome Disorders, DNA, Neoplasm analysis, Disease-Free Survival, Gene Amplification, Genes, myc, Humans, Infant, Multivariate Analysis, Neoplasm Staging, Neuroblastoma pathology, Prognosis, Proportional Hazards Models, Chromosome Deletion, Chromosomes, Human, Pair 1, Neuroblastoma genetics
Abstract

Background: Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic abnormalities in neuroblastoma to determine their prognostic value., Methods: We used Southern blot analysis to study the allelic loss of chromosomes 1p, 4p, 11q, and 14q, the duplication of chromosome 17q, and the amplification of the N-myc oncogene in 89 neuroblastomas. We also determined the nuclear DNA content of the tumor cells., Results: Allelic loss of chromosome 1p, N-myc amplification, and extra copies of chromosome 17q were significantly associated with unfavorable outcome. In a multivariate analysis, loss of chromosome 1p was the most powerful prognostic factor. It provided strong prognostic information when it was included in multivariate models containing the prognostic factors of age and stage or serum ferritin level and stage. Among the patients with stage I, II, or IVS disease, the mean (+/- SD) three-year event-free survival was 100 percent in those without allelic loss of chromosome 1p and 34 +/- 15 percent in those with such loss; the rates of three-year event-free survival among the patients with stage III and stage IV disease were 53 +/- 10 percent and 0 percent, respectively., Conclusions: The loss of chromosome 1p is a strong prognostic factor in patients with neuroblastoma, independently of age and stage. It reliably identifies patients at high risk in stages I, II, and IVS, which are otherwise clinically favorable. More intensive therapy may be considered in these patients. Patients in stages III and IV with allelic loss of chromosome 1p have a very poor outlook, whereas those without such loss are at moderate risk.

Published
1996
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49. Ewing's sarcoma of bone: oncologic and functional results.

Author

Renard AJ, Veth RP, Pruszczynksi M, Hoogenhout J, Bökkerink J, van der Staak FJ, Wobbes T, Lemmens JA, van Hoesel R, and van Horn JR

Subjects
Adolescent, Adult, Bone Neoplasms physiopathology, Child, Child, Preschool, Combined Modality Therapy, Disease-Free Survival, Female, Humans, Male, Middle Aged, Radiotherapy adverse effects, Sarcoma, Ewing physiopathology, Bone Neoplasms therapy, Sarcoma, Ewing therapy
Abstract

This paper describes 29 patients with Ewing's sarcoma of bone treated between 1975 and 1990 at the University of Nijmegen Hospital, Nijmegen, The Netherlands. Osteomyelitis was the primary diagnosis in 24%. Treatment consisted of chemotherapy in combination with surgery and/or radiotherapy. Nine patients received radiotherapy only; five of them died of disease. Five patients underwent an intralesional excision; four of them died of disease. Twelve patients underwent a wide excision; there is no evidence of disease in any of them. Three patients underwent a radical disarticulation; all died of disease. The disease-free survival at 1.5 years was 66%. This figure at 5 years was 55%. After wide excision and reconstruction in tumors of expendable, femoral or radial bones good functional results were obtained in all cases.

Published
1995
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50. The art of limb salvage in musculoskeletal oncology.

Author

Veth RP, van Hoesel QG, Bökkerink JP, Hoogenhout J, and Pruszczynski M

Subjects
Amputation, Surgical psychology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms pathology, Bone Neoplasms radiotherapy, Bone Transplantation methods, Clinical Trials as Topic, Combined Modality Therapy, Cryosurgery methods, Extremities pathology, Humans, Multicenter Studies as Topic, Neoplasm Staging, Palliative Care, Postoperative Complications, Prostheses and Implants psychology, Quality of Life, Sarcoma drug therapy, Sarcoma pathology, Sarcoma radiotherapy, Sarcoma surgery, Treatment Outcome, Bone Neoplasms surgery, Extremities surgery
Published
1995
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