Literatur

Zuletzt geändert: 04.11.2024 https://kinderkrebsinfo.de/doi/e8952

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Autor(en)	Titel	Quelle
Packer RJ, Sutton LN, Goldwein JW, Perilongo G, Bunin G, Ryan J, Cohen BH, D'Angio G, Kramer ED, Zimmerman RA, et al.	Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma.	J Neurosurg 1991, 74: 433
Between 1975 and 1989, 108 children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor (MB/PNET) of the posterior fossa were treated at the authors' institution. The patients were managed uniformly, and treatment included aggressive surgical resections, postoperative staging evaluations for extent of disease, and craniospinal radiation therapy with a local boost. Beginning in 1983, children with MB/PNET were prospectively assigned to risk groups; those with "standard-risk" MB/PNET were treated with radiation therapy alone, while those in the "poor-risk" group received similar radiation therapy plus adjuvant chemotherapy with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), vincristine, and cisplatin. The 5-year actuarial disease-free survival rate for all patients treated between 1975 and 1982 was 68%, and 73% when patients who died within 2 weeks after operation were excluded. This survival rate was statistically better for patients treated after 1982 (82%) compared to those treated between 1975 and 1982 (49%) (p less than 0.004). There was no difference in disease-free survival rates over time for children with standard-risk factors; however, there was a significant difference in the 5-year survival rate for poor-risk patients treated prior to 1982 (35%) compared to those treated later (87%) (p less than 0.001). For the group as a whole, a younger age at diagnosis correlated with a poorer survival rate; however, this relationship between age and outcome was significant only for children treated before 1983 (p less than 0.001). These results demonstrated an encouraging survival rate for children with MB/PNET, especially those treated with aggressive surgical resection followed by both radiation therapy and chemotherapy. The results strongly suggest that chemotherapy has a role for some, and possibly all, children with MB/PNET.
Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, Mulne L, Boyett J, D'Angio G, Wechsler-Jentzsch K, et al.	Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy.	J Neurosurg 1994, 81: 690
It has previously been reported in a single-institution trial that progression-free survival of children with medulloblastoma treated with radiotherapy and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cisplatin, and vincristine chemotherapy during and after radiotherapy was better than the outcome in children treated with radiotherapy alone. To better characterize long-term outcome and duration of disease control, this treatment approach was used for 10 years and expanded to three institutions. Sixty-three children with posterior fossa medulloblastomas were treated with craniospinal local-boost radiotherapy and adjuvant chemotherapy with vincristine weekly during radiotherapy followed by eight 6-week cycles of cisplatin, CCNU, and vincristine. To be eligible for study entry, patients had to be older than 18 months of age at diagnosis and have a subtotal resection, evidence of metastatic disease, and/or brainstem involvement. Patients younger than 5 years of age and without these poor risk factors who received reduced-dose craniospinal radiotherapy (2400 cGy) were also eligible for entry into the study. Sixty-three of 66 eligible patients (95%) were entered and placed on this treatment regimen. Forty-two patients had brainstem involvement, 15 had metastatic disease at the time of diagnosis, and 19 had received a subtotal resection. Progression-free survival for the entire group at 5 years is 85% +/- 6%. Three children have succumbed to a second malignancy, and overall 5-year event-free survival is 83% +/- 6%. Progression-free survival was not adversely affected by younger age at diagnosis, brainstem involvement, or subtotal resection. Five-year actuarial progression-free survival for patients who received reduced-dose radiotherapy was similar to that for patients receiving conventional-dose radiotherapy. Patients with metastatic disease at the time of diagnosis had a 5-year progression-free survival rate of 67% +/- 15%, as compared to 90% +/- 6% for those patients with localized disease at the time of diagnosis (p = 0.037). The authors conclude that overall progression-free survival remains excellent for children with posterior fossa medulloblastomas treated with this drug regimen. Chemotherapy has a definite role in the management of children with medulloblastoma. Further studies are indicated to define which subpopulations of children with medulloblastoma benefit from chemotherapy and what regimens are optimum in increasing disease control and, possibly, in reducing the amount of radiotherapy required.
Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, Boyett JM	Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study.	J Clin Oncol 1999, 17: 2127
PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% +/- 4% at 3 years and 79% +/- 7% at 5 years. Sites of relapse for the 14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.
Packer RJ, Gurney JG, Punyko JA, Donaldson SS, Inskip PD, Stovall M, Yasui Y, Mertens AC, Sklar CA, Nicholson HS, Zeltzer LK, Neglia JP, Robison LL	Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003 Sep 1; 21: 3255
To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits.
Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R	Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma.	J Clin Oncol 2006, 24: 4202
PURPOSE: To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. METHODS: Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. CONCLUSION: This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.
Pachlopnik Schmid, J	Hämophagozytose-Syndrome.	PAEDIATRICA 2011, Vol. 22 Nr. 4, S.13
Packer RJ, Zhou T, Holmes E, Vezina G, Gajjar A	Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961.	Neuro-oncology 2013, 15: 97
The purpose of the trial was to determine the survival and incidence of secondary tumors in children with medulloblastoma receiving radiotherapy plus chemotherapy. Three hundred seventy-nine eligible patients with nondisseminated medulloblastoma between the ages of 3 and 21 years were treated with 2340 cGy of craniospinal and 5580 cGy of posterior fossa irradiation. Patients were randomized between postradiation cisplatin and vincristine plus either CCNU or cyclophosphamide. Survival, pattern of relapse, and occurrence of secondary tumors were assessed. Five- and 10-year event-free survivals were 81 Â± 2% and 75.8 Â± 2.3%; overall survivals were 87 Â± 1.8% and 81.3 Â± 2.1%. Event-free survival was not impacted by chemotherapeutic regimen, sex, race, age at diagnosis, or gender. Seven patients had disease relapse beyond 5 years after diagnosis; relapse was local in 4 patients, local plus supratentorial in 2, and supratentorial alone in 1. Fifteen patients experienced secondary tumors as a first event at a median time of 5.8 years after diagnosis (11 >5 y postdiagnosis). All non-CNS solid secondary tumors (4) occurred in regions that had received radiation. Of the 6 high-grade gliomas, 5 occurred >5 years postdiagnosis. The estimated cumulative 10-year incidence rate of secondary malignancies was 4.2% (1.9%-6.5%). Few patients with medulloblastoma will relapse â¥ 5 years postdiagnosis; relapse will occur predominantly at the primary tumor site. Patients are at risk for development of secondary tumors, many of which are malignant gliomas. This may become an increasing issue as more children survive.
Packer RJ, Pfister S, Bouffet E, Avery R, Bandopadhayay P, Bornhorst M, Bowers DC, Ellison D, Fangusaro J, Foreman N, Fouladi M, Gajjar A, Haas-Kogan D, Hawkins C, Ho CY, Hwang E, Jabado N, Kilburn LB, Lassaletta A, Ligon KL, Massimino M, Meeteren SV, Mueller S, Nicolaides T, Perilongo G, Tabori U, Vezina G, Warren K, Witt O, Zhu Y, Jones DT, Kieran M	Pediatric low-grade gliomas: implications of the biologic era.	Neuro-oncology 2017, 19: 750
For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras-mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.
Pagel J, Beutel K, Lehmberg K, Koch F, Maul-Pavicic A, Rohlfs AK, Al-Jefri A, Beier R, Bomme Ousager L, Ehlert K, Gross-Wieltsch U, Jorch N, Kremens B, Pekrun A, Sparber-Sauer M, Mejstrikova E, Wawer A, Ehl S, zur Stadt U, Janka G	Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).	Blood 2012, 119: 6016
Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.
Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, Wani K, Tatevossian R, Punchihewa C, Johann P, Reimand J, Warnatz HJ, Ryzhova M, Mack S, Ramaswamy V, Capper D, Schweizer L, Sieber L, Wittmann A, Huang Z, van Sluis P, Volckmann R, Koster J, Versteeg R, Fults D, Toledano H, Avigad S, Hoffman LM, Donson AM, Foreman N, Hewer E, Zitterbart K, Gilbert M, Armstrong TS, Gupta N, Allen JC, Karajannis MA, Zagzag D, Hasselblatt M, Kulozik AE, Witt O, Collins VP, von Hoff K, Rutkowski S, Pietsch T, Bader G, Yaspo ML, von Deimling A, Lichter P, Taylor MD, Gilbertson R, Ellison DW, Aldape K, Korshunov A, Kool M, Pfister SM	Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups.	Cancer cell 2015, 27: 728
Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
Pajtler KW, Tippelt S, Siegler N, Reichling S, Zimmermann M, Mikasch R, Bode U, Gnekow A, Pietsch T, Benesch M, Rutkowski S, Fleischhack G	Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors.	Journal of neuro-oncology 2016, 128: 463
Palagyi A, Neveling K, Plinninger U, Ziesch A, Targosz BS, Denk GU, Ochs S, Rizzani A, Meier D, Thasler WE, Hanenberg H, De Toni EN, Bassermann F, Schäfer C, Göke B, Schindler D, Gallmeier E	Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents.	Molecular cancer 2010, 9: 127
BACKGROUND: Inactivation of the Fanconi anemia (FA) pathway through defects in one of 13 FA genes occurs at low frequency in various solid cancer entities among the general population. As FA pathway inactivation confers a distinct hypersensitivity towards DNA interstrand-crosslinking (ICL)-agents, FA defects represent rational targets for individualized therapeutic strategies. Except for pancreatic cancer, however, the prevalence of FA defects in gastrointestinal (GI) tumors has not yet been systematically explored. RESULTS: A panel of GI cancer cell lines was screened for FA pathway inactivation applying FANCD2 monoubiquitination and FANCD2/RAD51 nuclear focus formation and a newly identified FA pathway-deficient cell line was functionally characterized. The hepatocellular carcinoma (HCC) line HuH-7 was defective in FANCD2 monoubiquitination and FANCD2 nuclear focus formation but proficient in RAD51 focus formation. Gene complementation studies revealed that this proximal FA pathway inactivation was attributable to defective FANCC function in HuH-7 cells. Accordingly, a homozygous inactivating FANCC nonsense mutation (c.553C > T, p.R185X) was identified in HuH-7, resulting in partial transcriptional skipping of exon 6 and leading to the classic cellular FA hypersensitivity phenotype; HuH-7 cells exhibited a strongly reduced proliferation rate and a pronounced G2 cell cycle arrest at distinctly lower concentrations of ICL-agents than a panel of non-isogenic, FA pathway-proficient HCC cell lines. Upon retroviral transduction of HuH-7 cells with FANCC cDNA, FA pathway functions were restored and ICL-hypersensitivity abrogated. Analyses of 18 surgical HCC specimens yielded no further examples for genetic or epigenetic inactivation of FANCC, FANCF, or FANCG in HCC, suggesting a low prevalence of proximal FA pathway inactivation in this tumor type. CONCLUSIONS: As the majority of HCC are chemoresistant, assessment of FA pathway function in HCC could identify small subpopulations of patients expected to predictably benefit from individualized treatment protocols using ICL-agents.
Palmi C, Bresolin S, Junk S, Fazio G, Silvestri D, Zaliova M, Oikonomou A, Scharov K, Stanulla M, Moericke A, Zimmermann M, Schrappe M, Buldini B, Bhatia S, Borkhardt A, Saitta C, Galbiati M, Bardini M, Lo Nigro L, Conter V, Valsecchi MG, Biondi A, Te Kronnie G, Cario G, Cazzaniga G	Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia.	HemaSphere 2023, 7:e892
Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, overexpression and deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by (n = 33) and (n = 16) alterations; only 2 cases were positive for -class or -fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; = 0.007, respectively), which further worsens when deletion was co-occurring with , qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies.
Pane F, Intrieri M, Quintarelli C, Izzo B, Muccioli GC, Salvatore F	BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical correlations.	Oncogene 2002, 21: 8652
Pan Y, Ren Z, Gao S, Shen J, Wang L, Xu Z, Yu Y, Bachina P, Zhang H, Fan X, Laganowsky A, Yan N, Zhou M	Structural basis of ion transport and inhibition in ferroportin.	Nature communications 2020, 11: 5686
Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H/Fe antiporter so that transport of each Fe is coupled to transport of two H in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H and Fe. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases.
Pape H, Laws H, Burdach S, van Kaick B, Glag M, Gripp S, Wittkamp M, Jürgens H, Göbel U, Schmitt G	Radiotherapy and high-dose chemotherapy in advanced Ewing's tumors.	Strahlenther Onkol 1999, 175: 484
Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dubé MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP	Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.	Nature genetics 2004, 36: 77
Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.
Pappo AS, Dirksen U	Rhabdomyosarcoma, Ewing Sarcoma, and Other Round Cell Sarcomas.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018 Jan 10; 36: 168
Several recent advances have been made in the diagnosis and therapy of malignant small round cell tumors that affect children, particularly in rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. These advances have provided new insights into the pathologic, histologic, and genomic characterization of specific tumor subtypes, which has led to the identification of novel therapeutic targets and improved stratification of risk. This has, in turn, led to improved efficacy in clinical trials of new drug combinations, thereby increasing the survival of patients with newly diagnosed and refractory or recurrent round cell sarcomas. Here, we review the progress that has been made using genomics to identify novel pathologic genomic rearrangements, as well as therapeutic targets. We also describe how clinical and molecular factors have helped refine risk stratification and therapies that have led to improved clinical outcomes in patients with round cell sarcomas.
Papadaki HA, Mavroudi I, Almeida A, Bux J, Cichy J, Dale DC, Donadieu J, Höglund P, Karanfilski O, Mecucci C, Palmblad J, Skokowa J, Stamatopoulos K, Touw I, Warren AJ, Welte K, Zeidler C, Dufour C	Congenital and Acquired Chronic Neutropenias: Challenges, Perspectives and Implementation of the EuNet-INNOCHRON Action.	HemaSphere 2020, 4:e406
No abstract available
Parlowsky T, Bucsky P, Hof M, Kaatsch P	Malignant endocrine tumours in childhood and adolescence--results of a retrospective analysis.	Klin Pädiatr 1996, 208: 205
Parlowsky T, Bucsky P	Aktueller Stand der interdisziplinären multizentrischen Therapiestudie "Maligne endokrine Tumoren im Kindes- und Jugendalter - GPOH-MET 97".	Monatsschr. Kinderheilkd 2000, 148: 971 Abstr.
Parlowsky T, Dralle H, Farahati J, Feyerabend T, Reiners C, Schmoll HJ, Bucsky P	Maligne endokrine Tumoren im Kinds- und Jugendalter GPOH-MET 97.	Deutsches Ärzteblatt 2001, 98:A 764-A 767
Park CH, Valore EV, Waring AJ, Ganz T	Hepcidin, a urinary antimicrobial peptide synthesized in the liver.	The Journal of biological chemistry 2001, 276: 7806
Cysteine-rich antimicrobial peptides are abundant in animal and plant tissues involved in host defense. In insects, most are synthesized in the fat body, an organ analogous to the liver of vertebrates. From human urine, we characterized a cysteine-rich peptide with three forms differing by amino-terminal truncation, and we named it hepcidin (Hepc) because of its origin in the liver and its antimicrobial properties. Two predominant forms, Hepc20 and Hepc25, contained 20 and 25 amino acid residues with all 8 cysteines connected by intramolecular disulfide bonds. Reverse translation and search of the data bases found homologous liver cDNAs in species from fish to human and a corresponding human genomic sequence on human chromosome 19. The full cDNA by 5' rapid amplification of cDNA ends was 0.4 kilobase pair, in agreement with hepcidin mRNA size on Northern blots. The liver was the predominant site of mRNA expression. The encoded prepropeptide contains 84 amino acids, but only the 20-25-amino acid processed forms were found in urine. Hepcidins exhibited antifungal activity against Candida albicans, Aspergillus fumigatus, and Aspergillus niger and antibacterial activity against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and group B Streptococcus. Hepcidin may be a vertebrate counterpart of cysteine-rich antimicrobial peptides produced in the fat body of insects.
Parulekar MV	Retinoblastoma - current treatment and future direction.	Early human development 2010, 86: 619
Retinoblastoma is the commonest primary ocular malignancy of childhood. There are two forms - heritable and non heritable. Heritable retinoblastoma is a cancer susceptibility syndrome. Presentation is in the first few years of life, sometimes in the neonatal period. Early detection and prompt treatment can give cure rates up to 95% for intraocular tumours, but extraocular disease carries a very high mortality. The diagnosis is essentially clinical and biopsy is contraindicated due to the risk of extraocular spread. Treatment requires significant multidisciplinary input, with local ophthalmic treatment, systemic chemotherapy and external beam or plaque radiotherapy, or surgery to remove the affected eye. Screening of family members is essential for early detection. Lifelong surveillance of mutation carriers is needed due to the risk of second cancers. Newer treatment modalities including intra-arterial chemotherapy have been added to the therapeutic armamentarium in recent years.
Parsons K, Bernhardt B, Strickland B	Targeted immunotherapy for high-risk neuroblastoma--the role of monoclonal antibodies.	The Annals of pharmacotherapy 2013, 47: 210
To systematically review clinical trials evaluating anti-disialoganglioside (GD2) antibodies in treating high-risk neuroblastoma in children.
Park JR, Villablanca JG, Hero B, Kushner BH, Wheatley K, Beiske KH, Ladenstein RL, Baruchel S, Macy ME, Moreno L, Seibel NL, Pearson AD, Matthay KK, Valteau-Couanet D	Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting.	Cancer 2022, 128: 3775
International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking.
Partanen M, Kang G, Wang WC, Krull K, King AA, Schreiber JE, Porter JS, Hodges J, Hankins JS, Jacola LM	Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease.	Br J Haematol 2020 Feb 26; ePup
Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16-17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ+ thalassaemia; n = 52 HbSS/HbSβ0 thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ+ thalassaemia; n = 8 HbSS/HbSβ0 thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ0 thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ0 thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ+ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ+ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ0 thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD
Pastor V, Hirabayashi S, Karow A, Wehrle J, Kozyra EJ, Nienhold R, Ruzaike G, Lebrecht D, Yoshimi A, Niewisch M, Ripperger T, Göhring G, Baumann I, Schwarz S, Strahm B, Flotho C, Skoda RC, Niemeyer CM, Wlodarski MW	Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants.	Leukemia 2016, epub ahead of print
Pastor V, Hirabayashi S, Karow A, Wehrle J, Kozyra EJ, Nienhold R, Ruzaike G, Lebrecht D, Yoshimi A, Niewisch M, Ripperger T, Göhring G, Baumann I, Schwarz S, Strahm B, Flotho C, Skoda RC, Niemeyer CM, Wlodarski MW	Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants.	Leukemia 2016, epub ahead of print
Pasqualini C, Furtwängler R, van Tinteren H, Teixeira RAP, Acha T, Howell L, Vujanic G, Godzinski J, Melchior P, Smets AM, Coulomb-L'Hermine A, Brisse H, Pritchard-Jones K, Bergeron C, de Camargo B, van den Heuvel-Eibrink MM, Graf N, Verschuur AC	Outcome of patients with stage IV high-risk Wilms tumour treated according to the SIOP2001 protocol: A report of the SIOP Renal Tumour Study Group.	European journal of cancer 2020, 128: 38
High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome.
Pathak R, Zin F, Thomas C, Bens S, Gayden T, Karamchandani J, Dudley RW, Nemes K, Johann PD, Oyen F, Kordes U, Jabado N, Siebert R, Paulus W, Kool M, Frühwald MC, Albrecht S, Kalpana GV, Hasselblatt M	Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.	Acta neuropathologica 2021, 142: 361
Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.
Paulussen M, Bielack S, Jürgens H, Jost L, ESMO Guidelines Working Group	Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up.	Annals of oncology 2008, 19 Suppl 2:ii97
Paulussen M, Ahrens S, Burdach S, Craft A, Dunst J, Fröhlich B, Winkelmann W, Zoubek A, Jürgens H	Primary metastatic (stage IV) Ewingtumor.	Ann Oncol 1998, 9: 275
Paulussen M, Ahrens S, Craft A, Dunst J, Fröhlich B, Jabar S, Winkelmann W, Wissing S, Zoubek A, Jürgens H	Ewing tumors with primary lung metastases.	J Clin Oncol 1998, 16: 3044
Paulussen M, Ahrens S, Braun-Munzinger G, Craft A, Dörffel W, Dunst J, Fröhlich B, Göbel U, Haussler M, Klingebiel T, Koscielniak E, Mittler U, Rübe C, Winkelmann W, Voute P, Zoubek A, Jürgens H	EICESS 92 (European Intergroup Cooperative Ewing's Sarcoma Study)-- preliminary results.	Klin Pädiatr 1999, 211: 276
Paulino AC	Trilateral retinoblastoma: is the location of the intracranial tumor important?	Cancer 1999, 86: 135
BACKGROUND: Trilateral retinoblastoma refers to bilateral retinoblastoma associated with an intracranial primitive neuroectodermal tumor in the pineal or suprasellar region. The purpose of this study was to review patient and tumor characteristics and treatment outcome in patients with trilateral retinoblastoma and to determine whether there is a difference in presentation or outcome according to the location of the intracranial tumor. METHODS: A MEDLINE search of all English language articles pertaining to trilateral retinoblastoma published between 1977-1997 was performed. A total of 94 different cases were identified and analyzed. RESULTS: The gender was male in 39 patients (41.5%), female in 50 patients (53.2%), and unknown in 5 patients (5.3%). Family history for retinoblastoma was positive in 44 patients (46.8%), negative in 39 patients (41.5%), and unknown in 11 patients (11.7%). The median age at the time of diagnosis of retinoblastoma was 6 months. The median time interval to the development of an intracranial tumor from the time of diagnosis of retinoblastoma was 21 months. In 78 patients (83.0%) the intracranial tumor was in the pineal region and in 16 patients (17.0%) it was in the suprasellar region. The median time interval from the time of diagnosis of retinoblastoma to the development of a pineal region tumor was 24 months whereas the median time interval for the development of a suprasellar region tumor was 1 month. At 6 months after the diagnosis of intraocular tumors, 6 of 61 children with pineal region tumors and 10 of 14 patients with suprasellar region tumors had developed intracranial disease (P = 0.005). Unilateral intraocular retinoblastoma associated with intracranial tumor was more likely to occur in patients with suprasellar region tumors than pineal region tumors (P < 0.015). The median survival after the diagnosis of an intracranial tumor was 6 months regardless of the location of the intracranial tumor. For patients who received no treatment for the intracranial tumor the median survival was 1 month whereas it was 8 months for those who received treatment. Children who were asymptomatic at the time of diagnosis of the intracranial tumor had a better overall survival than those who were symptomatic (P = 0.002). CONCLUSIONS: The prognosis of children who develop trilateral retinoblastoma is dismal with current treatment strategies. Tumors of the suprasellar region present earlier than tumors of the pineal region after the diagnosis of intraocular tumors. Because patients who were asymptomatic at the time of diagnosis of intracranial disease had a better overall survival than those who were symptomatic, screening for intracranial tumors may be a valuable strategy in the management of patients with bilateral and/or hereditary retinoblastoma. [See editorial on pages 3-5, this issue.]
Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner G, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Muller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voute P, Zoubek A, Gadner H, Jürgens H	Localized Ewing tumor of bone.	J Clin Oncol 2001, 19: 1818
Paulussen M, Ahrens S, Lehnert M, Taeger D, Hense H, Wagner A, Dunst J, Harms D, Reiter A, Henze G, Niemeyer C, Göbel U, Kremens B, Folsch U, Aulitzky W, Voute P, Zoubek A, Jürgens H	Second malignancies after ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study.	Ann Oncol 2001, 12: 1619
Paulussen M, Frohlich B, Jürgens H	Ewing tumour: Incidence, prognosis and treatment options.	Paediatr Drugs 2001, 3: 899
Ewing tumours, i.e. Ewing's sarcoma and malignant peripheral neuroectodermal tumours, are the second most common primary malignant tumours of bone in childhood and adolescence, with an annual incidence rate in Caucasians of 3 per 1 million children <15 years of age. Histopathologically small blue round cell tumours, Ewing tumours show a typical chromosomal rearrangement in >95% of cases linking the EWS gene on chromosome 22q12 to a member of the ETS transcription gene family, most commonly to Fli-1 on 11q24. This fusion contributes to the malignant potential of Ewing tumour cells, indeed antisense oligonucleotides may prevent tumour growth in vitro. After open biopsy, and histological and possibly molecular biological confirmation of the diagnosis, treatment consists of several months of multidrug cytostatic therapy and local therapy. Both surgery and radiotherapy may control local disease, but without consequent cytostatic chemotherapy all patients will eventually succumb to distant metastases. With the use of alkylating agents including doxorubicin, cyclophosphamide and/or ifosfamide, and other cytostatic drugs such as actinomycin D (dactinomycin), vincristine and etoposide, long-term survival can be achieved in >50% of patients with localised disease. Patients with clinically detectable metastases at diagnosis, patients not responding to therapy and patients with disease relapse have a significantly poorer prognosis. Maximum supportive care and local therapy managed by an experienced physician are required in all patients, and inclusion of high-risk patients in phase I and II studies is warranted. Hence, treatment of patients with Ewing tumours should be performed in experienced centres only and preferably within controlled clinical trials.
Paulussen M, Poremba C, Schuck A, Winkelmann W, Dunst J, Jürgens H	Behandlungskonzept des Ewing-Tumors.	Onkologe 2001, 7: 428
Paulussen M, Jürgens H	Ewing-Sarkom und PNET.	Buchbeitrag 2004
Paulides M, Stöhr W, Bielack S, Jürgens H, Treuner J, Schuck A, Willich N, Sauer R, Dörr, HG, Rascher W, Langer T, Beck, JD	Major sequelae of antineoplastic therapy prospectively evaluated in 162 relapse-free adult sarcoma patients.	Onkologie 2005, 28;S3; 56
Paulussen M, Kovar H, Jürgens H	Ewing sarcoma and peripheral PNET.	Buchbeitrag 2005, 5. Aufl.
Paulussen M, Jürgens H, Dunst J, Schmoll, HJ, Winkelmann W, Hoffmann, C	Ewing-Tumor (Ewing-Sarkom und maligner peripherer neuroektodermaler Tumor, PNET).	Book Chapter In "Kompendium Internistische Onkologie, Standards in Diagnostik und Therapie - Teil 2: Therapiekonzepte maligner Tumoren" (Ed. Schmoll,H.J.; Höffken,K.; Possinger,K.) 2005, 4th Ed.; 5292
Paulides M, Kremers A, Stohr W, Bielack S, Jürgens H, Treuner J, Beck JD, Langer T, German Late Effects Working Group in the Society of Pediatric Oncology and Haematology (GPOH)	Prospective longitudinal evaluation of doxorubicin-induced cardiomyopathy in sarcoma patients: a report of the late effects surveillance system (LESS).	Pediatric blood & cancer 2006, 46: 489
BACKGROUND: Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland. PROCEDURE: The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2). RESULTS: In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval. CONCLUSIONS: After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.
Paulides M, Stohr W, Bielack S, Jürgens H, Koscielniak E, Klingebiel T, Zimmermann R, Stachel D, Langer T, Beck JD	Prospective evaluation of hepatitis B, C and HIV infections as possible sequelae of antineoplastic treatment in paediatric sarcoma patients: a report from the Late Effects Surveillance System.	Oncology reports 2006, 15: 687
Cancer therapy and supportive measures entail the risk of infection with hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV). The objective of this analysis was to establish the incidence of infections with these viruses during antineoplastic treatment in our paediatric sarcoma patients, who are being followed-up within the Late Effects Surveillance System (LESS), which prospectively registers sequelae of therapy for Ewing's-, soft tissue- and osteosarcoma in patients treated in Germany, Austria and Switzerland within the trials EICESS-92/EURO-E.W.I.N.G.-99, CWS-96/CWS-2002P and COSS-96. We studied 264 eligible relapse-free paediatric patients [median age at diagnosis 14.3 (IQR 11.1-16.4) years], treated from January 7, 1998 until April 24, 2004. According to the LESS protocol, serological examinations for HBV, HCV and HIV were scheduled 4 weeks and 6 months after cessation of antineoplastic treatment. The median follow-up was 20.6 (IQR 12.4-26) months. None of the patients was reported to have acquired HBV, HCV or HIV during antineoplastic treatment. Blood donor screening and prophylactic measures employed in Germany, Austria and Switzerland to prevent infections of cancer patients with HBV, HCV and HIV seem to be very effective, having fully prevented new infections in this large cohort of paediatric sarcoma patients.
Paulides M, Dörr HG, Stöhr W, Bielack S, Koscielniak E, Klingebiel T, Jürgens H, Bölling T, Willich N, Sauer R, Langer T, Beck JD, Late Effects Surveillance System	Thyroid function in paediatric and young adult patients after sarcoma therapy: a report from the Late Effects Surveillance System.	Clinical endocrinology 2007, 66: 727
OBJECTIVE: The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients. DESIGN: Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998. PATIENTS: We studied 340 relapse-free paediatric patients (median age at diagnosis 12.2 [interquartile range (IQR) = 7.3-15.6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 +/- 9.7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24.6 (IQR = 11.9-44.9) months. MEASUREMENTS: We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations. RESULTS: The incidence of thyroid disorders was 37% (19/51, 95% CI 24-52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8-15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0.027) and trofosfamide (P = 0.016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0.008) or idarubicin (P = 0.037) (n = 250). CONCLUSIONS: The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.
Paulides M, Haupt R, Jankovic M, Möricke A, Langer T, Beck JD, ELTEC GroupELTEC members: E Frey, H Lackner, A Moser, Austria, R Maurus, J Otten, P Philippet, Belgium, JD Beck, G Calaminus, HG Dörr, T Langer, A Möricke, M Paulides, T Rau, Germany, MM Hawkins, A Taylor, Great Britain, E Magyarosy, Hungary, E Castagnola, A Colombini, F Fioredda, R Haupt (Chairman), M Jankovic, C Manganini (Secretary), C Micalizzi, P Reciputo, MG Valsecchi, Italy, JPM Bökkerink, W Tissing, The Netherlands, A Feldges, J Greiner, Swit	Over 15 years of ELTEC: A report of the international BFM study group.	Pediatric blood & cancer 2007, 49: 113-4; discussion 112
Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H, European Intergroup Cooperative Ewing's Sarcoma Study-92	Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients.	Journal of clinical oncology 2008, 26: 4385
PURPOSE: The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients. PATIENTS AND METHODS: SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume >or=100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS). RESULTS: A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, -35% to 5%; P = .12) and 15% reduction in dying (95% CI, -34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84). CONCLUSION: Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.
Paulussen M, Bielack S, Jürgens H, Casali PG, ESMO Guidelines Working Group	Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up.	Annals of oncology 2009, 20 Suppl 4: 140
Paulides M, Stöhr W, Laws HJ, Graf N, Lakomek M, Berthold F, Schmitt K, Niggli F, Jürgens H, Bielack S, Koscielniak E, Klingebiel T, Langer T	Immunity against tetanus and diphtheria after childhood sarcoma treatment.	Klinische Padiatrie 2010, 222: 196
Paulides M, Stöhr W, Laws HJ, Graf N, Lakomek M, Berthold F, Schmitt K, Niggli F, Jürgens H, Bielack S, Koscielniak E, Klingebiel T, Langer T	Antibody levels against tetanus and diphtheria after polychemotherapy for childhood sarcoma: a report from the Late Effects Surveillance System.	Vaccine 2011, 11; 29: 1565
BACKGROUND: It is known that antineoplastic treatment may induce secondary immunodeficiency, but studies after childhood sarcoma are rare. Since 1998, the Late Effects Surveillance System (LESS) of the German Society for Paediatric Oncology and Haematology (GPOH) prospectively registers late effects in soft tissue-, osteo- and Ewing's sarcoma patients treated within the therapy trials EICESS-92/EURO-E.W.I.N.G.-99, CWS-96/CWS-2002P, COSS-96 in Austria, Germany and Switzerland. PATIENTS AND METHODS: Antibody levels (AL) against diphtheria and tetanus were used as markers for immunity and classified according to established guidelines for protective AL values. There were 47 eligible relapse-free patients<21 years of age (31 males; 10 osteosarcoma, 12 Ewing's and 25 soft tissue sarcoma patients). Median age at diagnosis was 9.6 (interquartile range: 4.4-14.7) years. RESULTS: A median 7.2 (3.7-12.2) months after end of antineoplastic therapy, in 28% (13/47; 95% CI 16-43%) of patients there were no protective AL (<0.1 IU/ml) against diphtheria and/or tetanus. Diphtheria and tetanus AL were positively correlated (r=0.39; p=0.007). In multivariable analysis, the type of treatment had no effect on AL, similar to tumour type and time of examination after treatment end. Younger patients had significantly lower AL against tetanus (p=0.009) and girls had significantly lower AL against diphtheria than boys (p=0.015). CONCLUSION: Lack of protective AL against tetanus and/or diphtheria is frequent after childhood sarcoma treatment. Prospective surveillance of immunity and, if indicated, re-immunization is warranted in patients treated for childhood cancer.
Paustian L, Chao MM, Hanenberg H, Schindler D, Neitzel H, Kratz CP, Ebell W	Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany.	Pediatric hematology and oncology 2016, 33: 5
A substantial number of individuals with Fanconi anemia (FA) develop bone marrow failure and are treated with androgen therapy in order to increase blood counts. The authors retrospectively identified 70 patients who received androgen therapy any time between July 1976 and September 2014. Among these patients, 37 had medical records for analysis. Twenty-five of the 37 (68%) patients had response in hemoglobin level (n = 25), platelet count (n = 21), and/or absolute neutrophil count (n = 13). The median rise in hemoglobin was 6.5 mg/dL, platelet count 70,000/mm(3), and absolute neutrophil count (ANC) 1530/μL. The majority of patients (n = 22) had a response in 2 or more blood parameters. Reasons for discontinuation of therapy included development of cytogenetic aberrations (n = 9), lack of response (n = 7), hepatic adenoma (n = 6), progression to myelodysplastic syndrome/acute myeloid leukemia (n = 3), stabilization of blood parameters (n = 3), resolution of cytopenia secondary to mosaicism (n = 1), virilization (n = 1), development of anogenital carcinoma (n = 1), inaccessibility of medication (n = 1), and unknown (n = 1). Four patients at last follow-up remain on androgen therapy. These results highlight that androgen therapy can significantly improve blood counts for many FA patients, but progression of underlying bone marrow disease and development of liver adenomas requires careful monitoring.
Paul U, Richter J, Stuhlmann-Laiesz C, Kreuz M, Nagel I, Horn H, Staiger AM, Aukema SM, Hummel M, Ott G, Spang R, Rosenwald A, Feller AC, Cogliatti S, Stein H, Hansmann ML, Moller P, Szczepanowski M, Burkhardt B, Pfreundschuh M, Schmitz N, Loeffler M, Truemper L, Siebert R, Klapper W	Advanced patient age at diagnosis of diffuse large B-cell lymphoma is associated with molecular characteristics including ABC-subtype and high expression of MYC.	Leukemia & lymphoma 2018, 59: 1213
Pedersen-Bjeregaard J, Christiansen DH, Andersen MK, Skovby F	Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities.	Leukemia 2002, 16: 2177
Peeters J, Meitert J, Paulides M, Beck JD, Langer T	Late effects surveillance system after childhood cancer in Germany, austria and parts of Switzerland--update 2009.	Strahlentherapie und Onkologie 2009, 185 Suppl 2: 5
Peeters J, Meitert J, Paulides M, Wiener A, Beck JD, Calaminus G, Langer T	Health-related quality of life (HRQL) in all-patients treated with chemotherapy only: a report from the late effects surveillance system in Germany.	Klinische Padiatrie 2009, 221: 156
BACKGROUND: The study examines the HRQL in children suffering from ALL over time. PATIENTS: 96 patients (average age 7.1 years) were included, treated with chemotherapy in 15 German study centres between 1997 and 2003. METHODS:The HRQL was assessed based on both the parent report (POQOLS) and the patient self-report (KINDL) at 3 intervals: up to 2 weeks after diagnosis (T1), upon completion of the re-induction therapy (T2) and at the end of the maintenance therapy (T3). To analyse the changes of HRQL over time, the differences between the individual scores (T2-T1 and T3-T1) were calculated and statistically tested. The HRQL results from KINDL were also compared to a sample from the German general population. RESULTS: POQOLS (scale 0 (optimum) to 6): A decrease of HRQL was found in the domain
Peffault de Latour R, Peters C, Gibson B, Strahm B, Lankester A, de Heredia CD, Longoni D, Fioredda F, Locatelli F, Yaniv I, Wachowiak J, Donadieu J, Lawitschka A, Bierings M, Wlodarski M, Corbacioglu S, Bonanomi S, Samarasinghe S, Leblanc T, Dufour C, Dalle JH, Pediatric Working Party of the European Group for Blood and Marrow Transplantation,Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation	Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.	Bone marrow transplantation 2015, 50: 1168
Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, Krämer A, Roncaioli JL, Sand F, Heuckmann JM, Ikram F, Schmidt R, Ackermann S, Engesser A, Kahlert Y, Vogel W, Altmüller J, Nürnberg P, Thierry-Mieg J, Thierry-Mieg D, Mariappan A, Heynck S, Mariotti E, Henrich KO, Gloeckner C, Bosco G, Leuschner I, Schweiger MR, Savelyeva L, Watkins SC, Shao C, Bell E, Höfer T, Achter V, Lang U, Theissen J, Volland R, Saadati M, Eggert A, de Wilde B, Berthold F, Peng Z, Zhao C, Shi L, Ortmann M, Büttner R, Perner S, Hero B, Schramm A, Schulte JH, Herrmann C, O'Sullivan RJ, Westermann F, Thomas RK, Fischer M	Telomerase activation by genomic rearrangements in high-risk neuroblastoma.	Nature 2015 Oct 29; 526: 700
Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
Peinemann F, van Dalen EC, Enk H, Berthold F	Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.	The Cochrane database of systematic reviews 2017 Aug 25; 8:CD010685
Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review.
Peikert ML, Inhestern L, Krauth KA, Escherich G, Rutkowski S, Kandels D, Bergelt C	Returning to daily life: a qualitative interview study on parents of childhood cancer survivors in Germany.	BMJ open 2020 Mar 8; 10:e033730
To investigate experiences of parents of paediatric cancer survivors in cancer-related changes in the parents' daily life (work life, family life, partner relationship and social life) during and after intensive cancer treatment and to examine the reintegration process with its impeding and facilitating factors.
Pennesi E, Michels N, Brivio E, van der Velden VHJ, Jiang Y, Thano A, Ammerlaan AJC, Boer JM, Beverloo HB, Sleight B, Chen Y, Vormoor-Bürger B, Rives S, Bielorai B, Rössig C, Petit A, Rizzari C, Engstler G, Starý J, Bautista Sirvent FJ, Chen-Santel C, Bruno B, Bertrand Y, Rialland F, Plat G, Reinhardt D, Vinti L, Von Stackelberg A, Locatelli F, Zwaan CM	Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial.	Leukemia 2022, 36: 1516
Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1-18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9-93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49-20.07). One year Event Free Survival was 36.7% (95% CI: 22.2-60.4%), and Overall Survival was 55.1% (95% CI: 39.1-77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.
Perilongo G, Moras P, Carollo C, Battistella A, Clementi M, Laverda A, Murgia A	Spontaneous partial regression of low-grade glioma in children with neurofibromatosis-1: a real possibility.	J Child Neurol 1999, 14: 352. Review
Perilongo G, Walker D, Taylor R, Zanetti I, Gnekow A, Garree M, Kühl J, Robinson K	Vincristine (VCR) Carboplatin (BCDCA) in Hypothalamic-chiasmatic low grade glioma (HC-LGG). SIOP-LGG study report.	Medical & Pediatric Oncology 2000, 35: 1
Perrotta S, Gallagher PG, Mohandas N	Hereditary spherocytosis.	Lancet 2008, 372: 1411
Hereditary spherocytosis is a common inherited disorder that is characterised by anaemia, jaundice, and splenomegaly. It is reported worldwide and is the most common inherited anaemia in individuals of northern European ancestry. Clinical severity is variable with most patients having a well-compensated haemolytic anaemia. Some individuals are asymptomatic, whereas others have severe haemolytic anaemia requiring erythrocyte transfusion. The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2. Many isolated mutations have been identified in the genes encoding these membrane proteins; common hereditary spherocytosis-associated mutations have not been identified. Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder. Common complications are cholelithiasis, haemolytic episodes, and aplastic crises. Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits.
Perrotta S, Gallagher PG, Mohandas N	Hereditary spherocytosis.	Lancet 2008 Oct 18; 372: 1411
Hereditary spherocytosis is a common inherited disorder that is characterised by anaemia, jaundice, and splenomegaly. It is reported worldwide and is the most common inherited anaemia in individuals of northern European ancestry. Clinical severity is variable with most patients having a well-compensated haemolytic anaemia. Some individuals are asymptomatic, whereas others have severe haemolytic anaemia requiring erythrocyte transfusion. The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2. Many isolated mutations have been identified in the genes encoding these membrane proteins; common hereditary spherocytosis-associated mutations have not been identified. Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder. Common complications are cholelithiasis, haemolytic episodes, and aplastic crises. Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits.
Perrin GQ, Herzog RW, Markusic DM	Update on clinical gene therapy for hemophilia.	Blood 2019 Jan 31; 133: 407
Perwein T, Benesch M, Kandels D, Pietsch T, Schmidt R, Quehenberger F, Bison B, Warmuth-Metz M, Timmermann B, Krauss J, Thomale UW, Kortmann RD, Driever PH, Gnekow AK	High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group.	Neuro-oncology 2021, 23: 1148
Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce.
van der Perk MEM, Cost NG, Bos AME, Brannigan R, Chowdhury T, Davidoff AM, Daw NC, Dome JS, Ehrlich P, Graf N, Geller J, Kalapurakal J, Kieran K, Malek M, McAleer MF, Mullen E, Pater L, Polanco A, Romao R, Saltzman AF, Walz AL, Woods AD, van den Heuvel-Eibrink MM, Fernandez CV	White paper: Oncofertility in pediatric patients with Wilms tumor.	International journal of cancer 2022, 151: 843
The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.
Perotti D, Williams RD, Wegert J, Brzezinski J, Maschietto M, Ciceri S, Gisselsson D, Gadd S, Walz AL, Furtwaengler R, Drost J, Al-Saadi R, Evageliou N, Gooskens SL, Hong AL, Murphy AJ, Ortiz MV, O'Sullivan MJ, Mullen EA, van den Heuvel-Eibrink MM, Fernandez CV, Graf N, Grundy PE, Geller JI, Dome JS, Perlman EJ, Gessler M, Huff V, Pritchard-Jones K	Hallmark discoveries in the biology of Wilms tumour.	Nature reviews. Urology 2023 Oct 17;
The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.
Mañú Pereira MDM, Colombatti R, Alvarez F, Bartolucci P, Bento C, Brunetta AL, Cela E, Christou S, Collado A, de Montalembert M, Dedeken L, Fenaux P, Galacteros F, Glenthøj A, Gutiérrez Valle V, Kattamis A, Kunz J, Lobitz S, McMahon C, Pellegrini M, Reidel S, Russo G, Santos Freire M, van Beers E, Kountouris P, Gulbis B	Sickle cell disease landscape and challenges in the EU: the ERN-EuroBloodNet perspective.	The Lancet 2023, 10:e687-e694
Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted.
Peters O, Gnekow A, Rating D, Wolff J	Childhood Low-Grade Oligodendroglioma.	in press 2003
Peters U, Preisler-Adams S, Lanvers-Kaminsky C, Jürgens H, Lamprecht-Dinnesen A	Sequence variations of mitochondrial DNA and individual sensitivity to the ototoxic effect of cisplatin.	Anticancer Res 2003, 23: 1249
Peters O, Gnekow AK, Rating D, Wolff JE	Impact of location on outcome in children with low-grade oligodendroglioma.	Pediatric blood & cancer 2004, 43: 250
BACKGROUND: Childhood low-grade oligodendroglioma (WHO grade II) are rare. No controlled pediatric study has been published, to generate high level evidence for the best treatment. Therefore, we retrospectively analyzed data available from pediatric patients. PROCEDURE: We pooled data from two prospective German multicentre studies (HIT-DOK and HIT-LGG). Eligibility criteria were: (1) primary neoplasm, (2) histology of pure oligodendroglioma WHO grade II, (3) intracranial location, (4) age <18 years, (5) date of diagnosis: 1990-2002, (6) observation time >6 months. The outcome was analyzed by using the SPSS-software. RESULTS: Nineteen boys and 13 girls were eligible (median age 10.3 years). The tumor locations included: 26 peripheral tumors (23 cerebral hemisphere, 3 cerebellum), and 6 central tumors (4 thalamus, 1 frontal mesencephalon, 1 basal ganglia). Resections were classified as complete in 18 (14 cerebral hemispheres, 3 cerebellum, 1 thalamus) and less than complete in 14 patients (3 subtotal resections, 8 partial resections, 3 biopsy). The 5-year event-free survival (EFS) and overall survival (OS) rates of all patients were 81.3 and 84.4%, respectively (median observation time 3.8 years). All of the 26 children with peripheral tumors were alive with no tumor progression, but five of six patients with central tumors died of disease (median time to death 1.6 years). This survival difference was statistically significant for EFS (P < 0.0001) and OS (P < 0.0001). The difference between completely resected versus incompletely resected tumors was far less striking (P > 0.06). CONCLUSIONS: The outcome of children with centrally located low-grade oligodendroglioma is particularly poor, while tumors of the cerebral hemispheres and cerebellum carry an excellent prognosis, even with minor tumor resection.
Peters C, Schrauder A, Schrappe M, von Stackelberg A, Stary J, Yaniv I, Gadner H, Klingebiel T, BFM Study Group, the IBFM-Study Group and the Paediatric Disease Working Party of the EBMT	Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: the BFM/IBFM/EBMT concepts.	Bone marrow transplantation 2005, 35 Suppl 1:S9
Children with high risk or relapsed acute lymphoblastic leukaemia (ALL) can benefit from allogeneic haematopoietic stem cell transplantation (SCT). To reduce transplantation-associated complications, the BFM study group, the IBFM study group and the PD-WP-EBMT initiated a prospective cooperative multicentre trail for paediatric ALL patients with an indication for allogeneic stem cell transplantation. Four-digit high-resolution HLA typing for all nonsibling donors, standardised GvHD prophylaxis and therapy, uniform conditioning regimen and minimum standards for supportive care should reduce not only treatment-related mortality but also ameliorate late effects for young patients. Furthermore, the prospective evaluation aims to assess the role of haematopoietic SCT in comparison to chemotherapy to enable valuable treatment recommendations for further decisions.
Petersen I, Spix C, Kaatsch P, Graf N, Janka G, Kollek R	Parental informed consent in pediatric cancer trials: a population-based survey in Germany.	Pediatric blood & cancer 2013, 60: 446
Ensuring adequate parental consent is a key issue of ethical practice in pediatric oncology. In Germany, however, knowledge about parental comprehension and satisfaction with the informed consent procedure is limited, and representative data on parents' perspectives are still missing. Based on data collected by means of a population-based survey, we evaluated the parental recall of the informed consent process for pediatric clinical trials, and how they rated the consent process retrospectively.
Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T	Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial.	Journal of clinical oncology 2015, 33: 1265
Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia).
Peters C	CAR-T-Zellen: Eine komplett neue Therapieoption bei Kindern und Jugendlichen.	Spectrum Onkologie SO 06/2019
Derzeit ist Kymriah® das einzige für Kinder, Jugendliche und junge Erwachsene zugelassene CAR-T-Zell-Produkt zur Therapie der therapieresistenten akuten CD19-positiven B-ALL. Das initiale Ansprechen auf die Behandlung ist hoch, akute schwere Nebenwirkungen können durch erfahrene Teams in spezialisierten Einheiten meist beherrscht werden. Um in Zukunft Leukämierezidive effektiver verhindern zu können, werden derzeit zahlreiche Therapieverbesserungen untersucht, z. B. der Einsatz von kombinierten CAR-T-Zellen (CD19 + CD22), humanisierten CAR-T-Zellen, allogenen CAR-T-Zellen oder adaptiven Zellen. Die dezentrale Produktion von CAR-T-Zellen wird das Intervall zwischen Leukapherese und Infusion verkürzen. Darüber hinaus wird der Einsatz dieser Zellen in einem früheren Krankheitsstadium Hoffnung auf weitere Verbesserungen bringen. Um diese neuen Therapiemodalitäten effektiv zu untersuchen und zu nutzen, sind internationale Kooperationen im Rahmen von prospektiven Studien unerlässlich.
Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Güngör T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M, IBFM Study Group,, von Stackelberg A, IntReALL Study Group, Balduzzi A, I-BFM SCT Study Group, Corbacioglu S, EBMT Paediatric Diseases Working Party, Bader P	Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2021, 39: 295
Purpose: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. Patients and methods: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). Results: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. Conclusion: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Peters C, Balduzzi A, Bader P	Editorial: Allogeneic haematopoietic stem cell transplantation for children with acute lymphoblastic leukaemia in the era of immunotherapy.	Frontiers in pediatrics 2022, 10: 959471
Peterziel H, Jamaladdin N, ElHarouni D, Gerloff XF, Herter S, Fiesel P, Berker Y, Blattner-Johnson M, Schramm K, Jones BC, Reuss D, Turunen L, Friedenauer A, Holland-Letz T, Sill M, Weiser L, Previti C, Balasubramanian G, Gerber NU, Gojo J, Hutter C, Øra I, Lohi O, Kattamis A, de Wilde B, Westermann F, Tippelt S, Graf N, Nathrath M, Sparber-Sauer M, Sehested A, Kramm CM, Dirksen U, Kallioniemi O, Pfister SM, van Tilburg CM, Jones DTW, Saarela J, Pietiäinen V, Jäger N, Schlesner M, Kopp-Schneider A, Oppermann S, Milde T, Witt O, Oehme I	Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM.	NPJ precision oncology 2022, 6: 94
The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
Peters S, Merta J, Schmidt L, Jazmati D, Kramer PH, Blase C, Tippelt S, Fleischhack G, Stock A, Bison B, Rutkowski S, Pietsch T, Kortmann RD, Timmermann B	Evaluation of dose, volume, and outcome in children with localized, intracranial ependymoma treated with proton therapy within the prospective KiProReg Study.	Neuro-oncology 2022, 24: 1193
Radiotherapy (RT) of ependymoma in children is an important part of the interdisciplinary treatment concept. However, feasibility and dose concepts are still under investigation, particularly in very young children. The aim of this study was to evaluate the standard dose and volume of proton therapy (PT) in children with ependymoma.
Pettit C, Kanagaratnam R, Coughlan F, Graf N, Hahn D, Durkan A	Kidney biopsy adequacy and complications in children - does technique matter?	European journal of pediatrics 2022, 181: 2677
Kidney biopsy is part of the diagnostic workup of many children with renal disease. Traditionally, a perpendicular approach to the biopsy has been used, but more recently, some proceduralists have favoured a tangential approach. It is not clear if one technique is superior with regards to tissue adequacy or complication rates. In our centre, interventional radiologists (IR) use general anaesthetic and a tangential approach, whereas paediatric nephrologists (PN) use sedation and a perpendicular approach. We examined consecutive native kidney biopsies performed between January 2008 and December 2017 for adequacy (sufficient tissue for light and electron microscopy and immunofluorescence) and examined the electronic medical records for data regarding technique and complications. IR performed 72 (29%) of the 245 native kidney biopsies, obtaining more total glomeruli (median 39 vs 16, p < 0.001) and more glomeruli per tissue core (median 13 vs 8, p < 0.001) than PN. No differences in specimen adequacy were observed between the two groups (79% IR vs 81% PN, p = 0.75) and a diagnosis could be made in 99% and 94% respectively (p = 0.1). A statistically lower rate of peri-nephric haematoma (28% vs 42%, p = 0.04) was detected in the IR group, but there were no significant differences in other complications. One patient required a blood transfusion (PN) and another required surgical intervention for a perinephric haematoma (IR).
Pfaff E, El Damaty A, Balasubramanian GP, Blattner-Johnson M, Worst BC, Stark S, Witt H, Pajtler KW, van Tilburg CM, Witt R, Milde T, Jakobs M, Fiesel P, Frühwald MC, Hernáiz Driever P, Thomale UW, Schuhmann MU, Metzler M, Bochennek K, Simon T, Dürken M, Karremann M, Knirsch S, Ebinger M, von Bueren AO, Pietsch T, Herold-Mende C, Reuss DE, Kiening K, Lichter P, Eggert A, Kramm CM, Pfister SM, Jones DTW, Bächli H, Witt O	Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience.	European journal of cancer 2019, 114: 27
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome.
Pfaff E, Aichmüller C, Sill M, Stichel D, Snuderl M, Karajannis MA, Schuhmann MU, Schittenhelm J, Hasselblatt M, Thomas C, Korshunov A, Rhizova M, Wittmann A, Kaufhold A, Iskar M, Ketteler P, Lohmann D, Orr BA, Ellison DW, von Hoff K, Mynarek M, Rutkowski S, Sahm F, von Deimling A, Lichter P, Kool M, Zapatka M, Pfister SM, Jones DTW	Molecular subgrouping of primary pineal parenchymal tumors reveals distinct subtypes correlated with clinical parameters and genetic alterations.	Acta neuropathologica 2020, 139: 243
Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis.
Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P	BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.	The Journal of clinical investigation 2008, 118: 1739
The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.
Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A	Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci.	Journal of clinical oncology 2009, 27: 1627
PURPOSE: Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Novel tumor-derived biomarkers may improve the risk stratification of medulloblastoma patients. PATIENTS AND METHODS: A model for the molecular risk stratification was proposed from an array-based comparative genomic hybridization (array-CGH) screen (n = 80). Fluorescence in situ hybridization (FISH) analyses for chromosome arms 6q, 17p, and 17q and the MYC and MYCN loci were performed in an independent validation set (n = 260). Copy number aberrations were correlated with clinical, histologic, and survival data. RESULTS: Gain of 6q and 17q and genomic amplification of MYC or MYCN were each associated with poor outcome in the array-CGH study (n = 80). In contrast, all patients with 6q-deleted tumors survived. Given these findings, the following hierarchical molecular staging system was defined: (1) MYC/MYCN amplification, (2) 6q gain, (3) 17q gain, (4) 6q and 17q balanced, and (5) 6q deletion. The prognostic value of this staging system was investigated by FISH analysis (n = 260). The addition of molecular markers to clinical risk factors resulted in the identification of a large proportion of patients (72 of 260 patients; 30%) at high risk for relapse and death who would be considered standard risk by application of clinical variables alone. CONCLUSION: Genomic aberrations in medulloblastoma are powerful independent markers of disease progression and survival. By adding genomic markers to established clinical and histologic variables, outcome prediction can be substantially improved. Because the analyses can be conducted on routine paraffin-embedded material, it will be especially feasible to use this novel molecular staging system in large multicenter clinical trials.
Pfitzer C, Zynda A, Hohmann C, Keil T, Borgmann-Staudt A	Educational level of childhood brain tumor survivors: results from a German survey.	Klinische Padiatrie 2013, 225: 138
Among adult survivors of childhood brain tumors in Germany, we assessed their educational level and examined potentially influencing factors.
Pfitzer C, Chen CM, Wessel T, Keil T, Sörgel A, Langer T, Steinmann D, Borgmann-Staudt A	Dynamics of fertility impairment in childhood brain tumour survivors.	Journal of cancer research and clinical oncology 2014t; 140: 1759
Fertility impairment and recovery after chemo- and radiotherapy have been reported in both male and female childhood cancer survivors, but little is known about the dynamics. Our aim, therefore, was to describe the development of fertility impairment and possible recovery in childhood brain tumour survivors.
Pfitzer C, Orawa H, Balcerek M, Langer T, Dirksen U, Keslova P, Zubarovskaya N, Schuster FR, Jarisch A, Strauss G, Borgmann-Staudt A	Dynamics of fertility impairment and recovery after allogeneic haematopoietic stem cell transplantation in childhood and adolescence: results from a longitudinal study.	Journal of cancer research and clinical oncology 2015, 141: 135
Fertility impairment and recovery after haematopoietic stem cell transplantation (HSCT) have been reported in both sexes, but little is known about how they develop over time. Our aim was to describe the dynamics of fertility impairment and recovery after HSCT.
Philip T, Bergeron L	Le lymphome de Burkitt: un modèle pour la cancérologie pédiatrique.	Arch Pediatr 2000, 7: 924
Pichler H, Möricke A, Mann G, Teigler-Schlegel A, Niggli F, Nebral K, König M, Inthal A, Krehan D, Dworzak MN, Janousek D, Harbott J, Schrappe M, Gadner H, Strehl S, Haas OA, Panzer-Grümayer R, Attarbaschi A, Berlin-Frankfurt-Münster (BFM) Study Group	Prognostic relevance of dic(9;20)(p11;q13) in childhood B-cell precursor acute lymphoblastic leukaemia treated with Berlin-Frankfurt-Münster (BFM) protocols containing an intensive induction and post-induction consolidation therapy.	British journal of haematology 2010, 149: 93
The presence of a dicentric chromosome dic(9;20) has been reported to have an unfavourable prognosis in children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). As outcome may be influenced by type and composition of treatment, we analyzed 19 BCP-ALL patients with dic(9;20) who have been treated with ALL-BFM (Berlin-Frankfurt-Münster) protocols that included a 4-drug induction and subsequent consolidation therapy. All patients were good responders to prednisone and in complete remission after induction therapy. Eight patients had no molecular disease after induction and another eight patients had levels < or =10(-4) after consolidation therapy. After a median follow-up of 3.4 years, probabilities of 5-year event-free and overall survival were 75 +/- 11% and 94 +/- 6%, respectively. Of note, there was a tendency for extramedullary disease in case of relapse (two of three relapses with central nervous system involvement). In conclusion, in the context of ALL-BFM protocols dic(9;20)-positivity appeared to have a favourable prognosis, which could be due to a dose- and time-intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)-positive leukemic blasts to l-asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM-like induction and consolidation therapy, may have contributed to this good outcome.
Pieters R, Den Boer M, Durian M, Janka G, Schmiegelow K, Kaspers G, van Wering E, Veerman A	Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants.	Leukemia 1998, 12: 1344
Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, Hovi L, LeBlanc T, Szczepanski T, Ferster A, Janka G, Rubnitz J, Silverman L, Stary J, Campbell M, Li CK, Mann G, Suppiah R, Biondi A, Vora A, Valsecchi MG	A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.	Lancet 2007, 370: 240
BACKGROUND: Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. METHODS: Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487. FINDINGS: In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. INTERPRETATION: Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.
Pieper S, Ranft A, Braun-Munzinger G, Jürgens H, Paulussen M, Dirksen U	Ewing's tumors over the age of 40: a retrospective analysis of 47 patients treated according to the International Clinical Trials EICESS 92 and EURO-E. W.I. N.G. 99.	Onkologie 2008, 31: 657
BACKGROUND: Ewing's tumors (ET) are rare in patients over the age of 40 years. Published data on presentation, treatment, and clinical outcome are limited. PATIENTS AND METHODS: We present a retrospective analysis of data from 47 patients in this age group diagnosed with ET and enrolled in the 2 consecutive trials, EICESS 92 and EURO-E.W.I.N.G. 99. The median age at diagnosis was 47.7 years (range, 40-68.6 years). RESULTS: The median follow-up was 2.23 years from diagnosis (range, 0.35-12.92 years). 72.3% of patients were found to have localized disease, and 27.7% had primary metastases. Good clinical response to induction therapy was observed in 55%, and 73% of patients showed good histological response. The event-free survival was 0.77 at 1 year and 0.50 at 3 years (n = 44). CONCLUSION: ET are rare in patients over the age of 40 years. With adequate multimodal therapy, the results in terms of survival are comparable to those in adolescence. Specific age-adapted treatment regimens are not established. Patients should be enrolled in international trials, and if necessary treatment should be adjusted for lower tolerance and co-morbidity.
Pietrangelo A	Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.	Gastroenterology 2010, 139: 393-408, 408.e1
In the late 1800s, hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism that is common among white people: a 845G-->A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (Hjv) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin (Fpn) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.
Pietsch T, Schmidt R, Remke M, Korshunov A, Hovestadt V, Jones DT, Felsberg J, Kaulich K, Goschzik T, Kool M, Northcott PA, von Hoff K, von Bueren AO, Friedrich C, Mynarek M, Skladny H, Fleischhack G, Taylor MD, Cremer F, Lichter P, Faldum A, Reifenberger G, Rutkowski S, Pfister SM	Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort.	Acta neuropathologica 2014, 128: 137
This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a test (n = 57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n = 83). All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining
Piel FB, Steinberg MH, Rees DC	Sickle Cell Disease.	The New England journal of medicine 2017, 376: 1561
Pieters R, De Lorenzo P, Ancliffe P, Aversa LA, Brethon B, Biondi A, Campbell M, Escherich G, Ferster A, Gardner RA, Kotecha RS, Lausen B, Li CK, Locatelli F, Attarbaschi A, Peters C, Rubnitz JE, Silverman LB, Stary J, Szczepanski T, Vora A, Schrappe M, Valsecchi MG	Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study.	Journal of clinical oncology 2019, 37: 2246
Infant acute lymphoblastic leukemia (ALL) is characterized by () gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value.
Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM	Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with ß-thalassemia.	Blood 2019, 133: 1279
β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
Pilz T, Pilgrim T, Bisogno G, Knietig R, Koscielniak E, Carli M, Treuner J	Chemotherapy in fibromatoses of childhood and adolescence.	Klinische Pädiatrie 1999, 211: 291
Pinkwart C, Stiefel M, Mauz-Körholz C, Körholz D	[Akute Psychose bei einer jugendlichen Patientin während der Therapie eines nodulären lymphozytenprädominanten Hodgkin-Lymphoms (nLPHL) Stadium IIB].	Klinische Padiatrie 2011, 223: 370
Pirenne F	Prevention of delayed hemolytic transfusion reaction.	Transfus clin biol 2019, 26: 99
Post-transfusion hemolysis is the most frequent immune reaction to transfusion in sickle cell disease. Its frequency is underestimated due to its biological and clinical characteristics. It results principally from the high incidence of alloimmunization in these patients, but no antibodies are detectable in 30% of cases. Prevention is based on the prevention of alloimmunization through the use of matched RBCs for highly immunogenic blood groups, taking into account the patient's transfusion history, particularly in patients undergoing occasional transfusion, which is associated with a higher risk of DHTR development than chronic transfusion. In addition to the use of matched RBCs, the prevention of alloimmunization through immunotherapy should be considered.
Pitsika M, Tsitouras V	Cerebellar mutism.	Journal of neurosurgery. Pediatrics 2013, 12: 604
Mutism of cerebellar origin is a well-described clinical entity that complicates operations for posterior fossa tumors, especially in children. This review focuses on the current understanding of principal pathophysiological aspects and risk factors, epidemiology, clinical characteristics, treatment strategies, and outcome considerations. The PubMed database was searched using the term cerebellar mutism and relevant definitions to identify publications in the English-language literature. Pertinent publications were selected from the reference lists of the previously identified articles. Over the last few years an increasing number of prospective studies and reviews have provided valuable information regarding the cerebellar mutism syndrome. Importantly, the clarification of principal terminology that surrounds the wide clinical spectrum of the syndrome results in more focused research and more effective identification of this entity. In children who undergo surgery for medulloblastoma the incidence of cerebellar mutism syndrome was reported to be 24%, and significant risk factors so far are brainstem involvement and midline location of the tumor. The dentate-thalamo-cortical tracts and lesions that affect their integrity are considered significant pathophysiological issues, especially the tract that originates in the right cerebellar hemisphere. Moderate and severe forms of the cerebellar mutism syndrome are the most frequent types during the initial presentation, and the overall neurocognitive outcome is not as favorable as thought in the earlier publications. Advanced neuroimaging techniques could contribute to identification of high-risk patients preoperatively and allow for more effective surgical planning that should focus on maximal tumor resection with minimal risk to important neural structures. Properly designed multicenter trials are needed to provide stronger evidence regarding effective prevention of cerebellar mutism and the best therapeutic approaches for such patients with a combination of pharmacological agents and multidisciplinary speech and behavior augmentation.
Pizzo PA, Poplack DG (eds)	Principles and Practise of Pediatric Oncology.	Lippincott Williams & Wilkins Fifth edition 2006
Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F	Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017 Feb 20; 35: 605
Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
Poetschke-Langer, M	Krebsprävention und Gesundheitsförderung: Was Hänschen nicht lernt .. - Themen der Zeit: Berichte.	Deutsches Ärzteblatt 1998, 95: A-1364 / B-1160 / C
Pötzsch B, Madlener K (Hrsg)	Hämostaseologie.	Springer Verlag 2010
Pogozhykh D, Yilmaz Karapinar D, Klimiankou M, Gerschmann N, Ebetsberger-Dachs G, Palmblad J, Carlsson G, Masmas T, Kinsey S, Bartels M, Mellor-Heineke S, Welte K, Skokowa J, Zeidler C	HAX1-related congenital neutropenia: Long-term observation in paediatric and adult patients enrolled in the European branch of the Severe Chronic Neutropenia International Registry (SCNIR).	British journal of haematology 2023, 202: 393
HAX1-related congenital neutropenia (HAX1-CN) is a rare autosomal recessive disorder caused by pathogenic variants in the HAX1 gene. HAX1-CN patients suffer from bone marrow failure as assessed by a maturation arrest of the myelopoiesis revealing persistent severe neutropenia from birth. The disorder is strongly associated with severe bacterial infections and a high risk of developing myelodysplastic syndrome or acute myeloid leukaemia. This study aimed to describe the long-term course of the disease, the treatment, outcome and quality of life in patients with homozygous HAX1 mutations reported to the European branch of the Severe Chronic Neutropenia International Registry. We have analysed a total of 72 patients with different types of homozygous (n = 68), compound heterozygous (n = 3), and digenic (n = 1) HAX1 mutations. The cohort includes 56 paediatric (<18 years) and 16 adult patients. All patients were initially treated with G-CSF with a sufficient increase in absolute neutrophil counts. Twelve patients required haematopoietic stem cell transplantation for leukaemia (n = 8) and non-leukaemic indications (n = 4). While previous genotype-phenotype reports documented a striking correlation between two main transcript variants and clinical neurological phenotypes, our current analysis reveals novel mutation subtypes and clinical overlaps between all genotypes including severe secondary manifestations, e.g., high incidence of secondary ovarian insufficiency.
Pollack IF	Brain tumors in children.	N Engl J Med 1994, 331: 1500
Pollack IF, Claassen D, al-Shboul Q, Janosky JE, Deutsch M	Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases.	J Neurosurg 1995, 82: 536
Pollard JA, Furutani E, Liu S, Esrick E, Cohen LE, Bledsoe J, Liu CW, Lu K, de Haro MJR, Surrallés J, Malsch M, Kuniholm A, Galvin A, Armant M, Kim AS, Ballotti K, Moreau L, Zhou Y, Babushok D, Boulad F, Carroll C, Hartung H, Hont A, Nakano T, Olson T, Sze SG, Thompson AA, Wlodarski MW, Gu X, Libermann TA, D'Andrea A, Grompe M, Weller E, Shimamura A	Metformin for treatment of cytopenias in children and young adults with Fanconi anemia.	Blood advances 2022, 6: 3803
Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.
Politis G, Wagenpfeil S, Welter N, Mergen M, Furtwängler R, Graf N	An Observational Case-Control Study on Parental Age and Childhood Renal Tumors.	Cancers 2023, 15
Despite excellent outcomes, many open questions remain about Wilms tumor (WT). Influences and risk factors for tumorigenesis, as well as tumor aggressiveness and recurrence, are not fully understood. Parental age plays a role in various childhood diseases and is also discussed as a risk factor for childhood cancer. We analyzed both maternal and paternal age at birth as risk factors for the occurrence of Wilms and non-Wilms tumors in children and investigated whether older maternal or paternal age is associated with a higher tumor incidence. During 1990 and 2019 we collected data from 3991 patients from the multicenter studies SIOP9/GPO, SIOP 93-01/GPOH, and SIOP 2001/GPOH, of whom maternal and paternal age was available in 2277 cases. Data from the Federal Statistical Office containing live births in Germany from 1990-2019 served as a comparative database. For maternal age at birth, the control data yielded 22,451,412 cases and for paternal age yielded 19,046,314 cases. Comparing maternal and paternal ages of the study patients with those of the control data, we confirmed that higher parental age is not correlated with the incidence of renal tumors in childhood. Mean ages of fathers and mothers in patients and the control cohort increased between 1991 and 2019 (fathers: 30.28 vs. 34.04; mothers: 27.68 vs. 29.79 in the patient group and 31.29 vs. 34.23 and 28.88 vs. 32.67 in the control group, respectively) without higher numbers of patients with kidney cancer over time. No influence was found for the subtype of cancer nor for syndromes. In addition, overall survival of patients is independent of the year of diagnosis and the age of the parents but depends on histology type and stage in WT.
Pommerening K, Miller M, Schmidtmann I, Michaelis J	Pseudonyms for cancer registries.	Methods Inf Med 1996, 35: 112
Pommerening K, Debling D, Kaatsch P, Blettner M	[Registries for rare diseases. Compliance and data protection].	Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 2008, 51: 491
For rare diseases, clinical and epidemiological research suffers from very small numbers of cases. A comprehensive collection of data and information in registries is an essential precondition to improve this situation. To this end, a number of disease specific networks have started collecting data with support from the German Ministry of Research. The past experiences of the German Childhood Cancer Registry show that voluntary participation, based on informed consent, can result in a satisfactory completeness of data collection and, thus, enable successful medical research. There are several ways to build registries and research networks conforming to the data protection rules.
Poon MC, Di Minno G, d'Oiron R, Zotz R	New Insights Into the Treatment of Glanzmann Thrombasthenia.	Transfusion medicine reviews 2016, 30: 92
Poremba C, Willenbring H, Hero B, Christiansen H, Schafer K, Brinkschmidt C, Jürgens H, Bocker W, Dockhorn-Dworniczak B	Telomerase activity distinguishes between neuroblastomas with good and poor prognosis.	Ann Oncol 1999, 10: 715
Poremba C, Hero B, Heine B, Scheel C, Schaefer K, Christiansen H, Berthold F, Kneif S, Stein H, Jürgens H, Boecker W, Dockhorn-Dworniczak B	Telomerase is a strong indicator for assessing the proneness to progression in neuroblastomas.	Med Pediatr Oncol 2000, 35: 651
Poremba C, Scheel C, Hero B, Christiansen H, Schaefer K, Nakayama J, Berthold F, Jürgens H, Boecker W, Dockhorn-Dworniczak B	Telomerase activity and telomerase subunits gene expression patterns in neuroblastoma.	J Clin Oncol 2000, 18: 2582
Poremba C, Hero B, Goertz H, Scheel C, Wai D, Schaefer K, Christiansen H, Berthold F, Jürgens H, Boecker W, Dockhorn-Dworniczak B	Traditional and emerging molecular markers in neuroblastoma prognosis.	Klin Pädiatr 2001, 213: 186
Porcu P, Farag S, Marcucci G, Cataland SR, Kennedy MS, Bissell M	Leukocytoreduction for acute leukemia.	Therapeutic apheresis : official journal of the International Society for Apheresis and the Japanese Society for Apheresis 2002, 6: 15
Both in children and adults, acute leukemia may present with extremely high blast counts; a phenomenon known as hyperleukocytosis. Respiratory failure, intracranial bleeding, and severe metabolic abnormalities frequently occur in acute hyperleukocytic leukemias (AHLs) and are the primary determinants of the high early mortality (20% to 40%) observed. The process leading to these complications has long been known as leukostasis, but the biological mechanisms underlying its development and progression have remained unclear. Traditionally, leukostasis has been attributed to overcrowding of leukemic blasts in the microcirculation, and its treatment has focused on prompt leukocytoreduction. However, it is becoming increasingly evident that leukostasis results from the adhesive interactions between leukemic blasts and the endothelium; a mechanism that none of the current therapies directly addresses. The endothelial damage associated with leukostasis is likely to be mediated by cytokines released in situ and by subsequent migration of leukemic blasts in the perivascular space. The adhesion molecules displayed by the leukemic blasts and their chemotactic response to the cytokines in the vascular microenvironment are probably more important in causing leukostasis than the cell number. This may explain why leukostasis may develop in some patients with AHL and not in others, and why some patients with acute leukemia without hyperleukocytosis (<50,000 blasts/mm(3)) develop leukostasis and respond to leukocytoreduction. Leukapheresis effectively reduces the blast count in many patients with AHL and is routinely used for immediate leukocytoreduction. However, the most appropriate use of leukapheresis in acute leukemia remains unclear, and the procedure may not prevent early death more efficiently than fluid therapy, hydroxyurea, and prompt induction chemotherapy. The use of cranial irradiation remains very controversial and is not generally recommended. The identification of the adhesion molecules, soluble cytokines, and chemotactic ligand-receptor pairs mediating endothelial cell damage in AHL should become a priority if better outcomes are desired.
Porcu P, Farag S, Marcucci G, Cataland SR, Kennedy MS, Bissell M	Leukocytoreduction for acute leukemia.	Therapeutic apheresis : official journal of the International Society for Apheresis and the Japanese Society for Apheresis 2002, 6: 15
Both in children and adults, acute leukemia may present with extremely high blast counts; a phenomenon known as hyperleukocytosis. Respiratory failure, intracranial bleeding, and severe metabolic abnormalities frequently occur in acute hyperleukocytic leukemias (AHLs) and are the primary determinants of the high early mortality (20% to 40%) observed. The process leading to these complications has long been known as leukostasis, but the biological mechanisms underlying its development and progression have remained unclear. Traditionally, leukostasis has been attributed to overcrowding of leukemic blasts in the microcirculation, and its treatment has focused on prompt leukocytoreduction. However, it is becoming increasingly evident that leukostasis results from the adhesive interactions between leukemic blasts and the endothelium; a mechanism that none of the current therapies directly addresses. The endothelial damage associated with leukostasis is likely to be mediated by cytokines released in situ and by subsequent migration of leukemic blasts in the perivascular space. The adhesion molecules displayed by the leukemic blasts and their chemotactic response to the cytokines in the vascular microenvironment are probably more important in causing leukostasis than the cell number. This may explain why leukostasis may develop in some patients with AHL and not in others, and why some patients with acute leukemia without hyperleukocytosis (<50,000 blasts/mm(3)) develop leukostasis and respond to leukocytoreduction. Leukapheresis effectively reduces the blast count in many patients with AHL and is routinely used for immediate leukocytoreduction. However, the most appropriate use of leukapheresis in acute leukemia remains unclear, and the procedure may not prevent early death more efficiently than fluid therapy, hydroxyurea, and prompt induction chemotherapy. The use of cranial irradiation remains very controversial and is not generally recommended. The identification of the adhesion molecules, soluble cytokines, and chemotactic ligand-receptor pairs mediating endothelial cell damage in AHL should become a priority if better outcomes are desired.
Porter JB, Walter PB, Neumayr LD, Evans P, Bansal S, Garbowski M, Weyhmiller MG, Harmatz PR, Wood JC, Miller JL, Byrnes C, Weiss G, Seifert M, Grosse R, Grabowski D, Schmidt A, Fischer R, Nielsen P, Niemeyer C, Vichinsky E	Mechanisms of plasma non-transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients.	British journal of haematology 2014, 167: 692
In transfusional iron overload, extra-hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non-transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond-Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin-iron utilization (DBA).
Posl M, Amling M, Werner M, Basler I, Salzer-Kuntschik M, Winkler K, Delling G	Osteosarcoma-apoptosis and proliferation. Study of bcl-2 expression.	Pathologe 1994, 15: 337
Posl M, Grahl K, Amling M, Werner M, Ritzel H, Stenzel I, Hentz M, Winkler K, Delling G	P-glycoprotein expression in osteosarcoma.	Pathologe 1996, 17: 50
Potter R, Roes F, Schellong G, Bartenstein P, Bramswig J, Lengerke H, Rath B, Mohring R, Rossi R	Subclinical impairment of renal function after radiotherapy for Hodgkin's disease in children.	Recent Results Cancer Res 1993, 130: 259-67: 259
Pötter R, Knocke T, Kovacs G, Schmilowski G, Haverkamp U, Hawliczek R, Seitz W, Rube C, Wuisman P, Maragakis G	Brachytherapy in the combined modality treatment of pediatric malignancies. Principles and preliminary experience with treatment of soft tissue sarcoma (recurrence) and Ewing's sarcoma.	Klinische Pädiatrie 1995, 207: 164
Radiotherapy is an integral part in the treatment of soft tissue and Ewing's sarcoma in children. By brachytherapy a high dose can be delivered in a restricted volume with sparing of normal tissues surrounding the target. Taking into account this principle potential benefit brachytherapy may play some role in the local treatment especially in children. However, only limited experience with pediatric brachytherapy has been reported apart from a few centers, which have gained their experience with Low-Dose-Rate (LDR)-brachytherapy. Since 1991 - 12 patients with soft tissue sarcoma and 6 patients with Ewing's sarcoma were treated with High-Dose-Rate (HDR) and Pulse-Dose-Rate (PDR)-brachytherapy at the departments of radiotherapy in Münster, Kiel and Vienna. The combined modality treatment was performed according to the CWS-86/91, EICESS-92 and CESS/CWS-REZ-91 protocols. In 8 patients with soft tissue sarcoma brachytherapy was part of the recurrence treatment regime, in 4 patients brachytherapy was part of the primary treatment alone or in combination with external beam therapy. In HDR-treatment a dose of 15 to 43 Gy was delivered in 3 to 16 fractions, in PDR-treatment 13 to 36 Gy in fractions of 1 Gy/hour. Follow-up is 3-39 months (median 14 months). 7 patients show no evidence of disease, 9 patients are locally controlled and 3 patients progressed locoregionally. In 6 patients with Ewing's sarcoma brachytherapy was performed intraoperatively as a boost treatment after external beam therapy (50-55 Gy), if no wide resection could be achieved within first line-treatment. A dose of 10-12 Gy was applied in one fraction in a limited volume (20-50 ccm) at the time of surgery. Follow-up is 13-26 months (median 21 months). There is no evidence of disease in all patients, perioperative and subacute morbidity was not increased. These encouraging preliminary results with HDR/PDR-brachytherapy must be further evaluated prospectively and systematically within an interdisciplinary approach by some specialized collaborating centers, which not only have the equipment (HDR/PDR/(LDR)-brachytherapy) but also can meet the complex demands to accumulate the necessary experience.
Potratz J, Zoubek A, Bielack, S	Malignant bone tumors in children and adolescents.	Monatsschr Kinderheilkd 2006, 154; 10
With an approximate incidence of only 0.1% of all cancers, malignant primary bone tumors are rare. However, they are among the most frequent solid cancers in children and adolescents. Approximately 300-400 new cases are diagnosed in Germany each year; more than half of these are first encountered in the second decade of life, and boys are affected more often than girls. Histologically, malignant bone tumors are a diverse group, but in childhood and adolescence they can usually be assigned to the group of osteosarcomas or that of Ewing tumors. Current multimodal therapeutic strategies consist of neoadjuvant systemic polychemotherapy, followed by surgery - and in the case of Ewing tumors sometimes radiotherapy - and continuation of chemotherapy as an adjuvant therapy. Such intensive treatment makes it possible to achieve long-term disease-free survival in more than 60% of patients. Interdisciplinary treatment makes high demands on oncology, the surgical disciplines, and radiology and pathology and should therefore be performed in specialized centers and monitored in prospective trials
Potratz J, Bielack S	Osteosarkome bei Kindern und Jugendlichen - Verbesserte Prognose durch multimodale Therapiekonzepte.	pädiatrie hautnah 2; 2006, 66
Foulon S, Brennan B, Gaspar N, Dirksen U, Jeys L, Cassoni A, Claude L, Seddon B, Marec-Berard P, Whelan J, Paulussen M, Streitbuerger A, Oberlin O, Jürgens H, Grimer R, Le Deley MC	Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E. W.I. N.G group.	European journal of cancer 2016, 61: 128
The role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORTÂ on local control in patients with localised ES and good histological response to chemotherapy (<10% cells).
Poyer F, Füreder A, Holter W, Peters C, Boztug H, Dworzak M, Engstler G, Friesenbichler W, Köhrer S, Lüftinger R, Ronceray L, Witt V, Pichler H, Attarbaschi A	Relapsed acute lymphoblastic leukaemia after allogeneic stem cell transplantation: a therapeutic dilemma challenging the armamentarium of immunotherapies currently available (case reports).	Therapeutic advances in hematology 2022, 13: 20406207221099468
While survival rates in paediatric acute lymphoblastic leukaemia (ALL) nowadays exceed 90%, systemic ALL relapse, especially after haemopoietic stem cell transplantation (HSCT), is associated with a poor outcome. As there is currently no standardized treatment for this situation, individualized treatment is often pursued. Exemplified by two clinical scenarios, the aim of this article is to highlight the challenge for treating physicians to find a customized treatment strategy integrating the role of conventional chemotherapy, immunotherapeutic approaches and second allogeneic HSCT. Case 1 describes a 2-year-old girl with an early isolated bone marrow relapse of an infant -rearranged B-cell precursor ALL after allogeneic HSCT. After bridging chemotherapy and lymphodepleting chemotherapy, chimeric antigen receptor (CAR) T-cells (tisagenlecleucel) were administered for remission induction, followed by a second HSCT from the 9/10 human leukocyte antigen (HLA)-matched mother. Case 2 describes a 16-year-old girl with a late, isolated bone marrow relapse of B-cell precursor ALL after allogeneic HSCT who experienced severe treatment toxicities including stage IV renal insufficiency. After dose-reduced bridging chemotherapy, CAR T-cells (tisagenlecleucel) were administered for remission induction despite a CD19 clone without prior lymphodepletion due to enhanced persisting toxicity. This was followed by a second allogeneic HSCT from the haploidentical mother. While patient 2 relapsed around Day + 180 after the second HSCT, patient 1 is still in complete remission >360 days after the second HSCT. Both cases demonstrate the challenges associated with systemic ALL relapse after first allogeneic HSCT, including chemotherapy-resistant disease and persisting organ damage inflicted by previous therapy. Immunotherapeutic approaches, such as CAR T-cells, can induce remission and enable a second allogeneic HSCT. However, optimal therapy for systemic ALL relapse after first HSCT remains to be defined.
Prados MD, Edwards MS, Chang SM, Russo C, Davis R, Rabbitt J, Page M, Lamborn K, Wara WM	Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumors: results of a Phase II study.	International journal of radiation oncology, biology, physics 1999, 43: 279
PURPOSE: To report the results of a Phase II study of hyperfractionated craniospinal radiation therapy, with and without adjuvant chemotherapy for primitive neuroectodermal brain tumors (PNETs) and malignant ependymomas. METHODS AND MATERIALS: Newly diagnosed PNET or malignant ependymomas were treated with hyperfractionated craniospinal radiation therapy. The primary tumor site was treated to a dose of 72 Gy, with 30 Gy given to the rest of the craniospinal axis. The fraction size was 1.0 Gy, given twice a day. Patients with poor risk factors also received adjuvant chemotherapy with CCNU, cisplatin, and vincristine. Patients had follow-up for survival, time to tumor progression, and patterns of relapse. RESULTS: A total of 39 patients (21 males/18 females) were treated between March 12, 1990 and October 29, 1992. The median age was 16 years (range 3-59 years). Tumor types included 25 medulloblastomas, 5 pineoblastomas, 5 cerebral PNETs, 1 spinal cord PNET, and 3 malignant ependymomas. Twenty cases were staged as poor-risk and received adjuvant chemotherapy following radiation. Three-year progression-free survival (PFS) was 60% and 63% for poor-risk and good-risk patients, respectively. Overall 3-year survival for these groups was 70% and 79%, respectively. For the 25 patients with medulloblastoma, there were 16 good-risk and 9 poor-risk patients. Three-year PFSs were 63% and 56%, respectively. The 5-year survival for good-risk medulloblastoma was 69% with 43.7% of these patients having failures outside the primary site. CONCLUSIONS: Survival in patients with good-risk medulloblastoma was no better than that seen in previous studies with single-fraction radiation, and the rate of failure outside the primary site is excessive. Those with poor-risk features had comparable survival to that seen in patients with good risk factors, but these patients were treated with chemotherapy, and the role that hyperfractionated radiation played in their outcome is uncertain.
Prante O, Einsiedel J, Haubner R, Gmeiner P, Wester HJ, Kuwert T, Maschauer S	3,4,6-Tri-O-acetyl-2-deoxy-2-[(18)F]fluoroglucopyranosyl Phenylthiosulfonate: A Thiol-Reactive Agent for the Chemoselective (18)F-Glycosylation of Peptides.	Bioconjugate chemistry 2007, 18: 254
3,4,5-Tri-O-acetyl-2-[18F]fluoro-2-deoxy-d-glucopyranosyl 1-phenylthiosulfonate (Ac3-[18F]FGlc-PTS) was developed as a thiol-reactive labeling reagent for the site-specific 18F-glycosylation of peptides. Taking advantage of highly accessible 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[18F]fluoroglucopyranose, a three-step radiochemical pathway was investigated and optimized, providing Ac3-[18F]FGlc-PTS in a radiochemical yield of about 33% in 90 min (decay-corrected and based on starting [18F]fluoride). Ac3-[18F]FGlc-PTS was reacted with the model pentapeptide CAKAY, confirming chemoselectivity and excellent conjugation yields of >90% under mild reaction conditions. The optimized method was adopted to the 18F-glycosylation of the alphavbeta3-affine peptide c(RGDfC), achieving high conjugation yields (95%, decay-corrected). The alphavbeta3 binding affinity of the glycosylated c(RGDfC) remained uninfluenced as determined by competition binding studies versus 125I-echistatin using both isolated alphavbeta3 and human umbilical vein endothelial cells (Ki = 68 +/- 10 nM (alphavbeta3) versus Ki = 77 +/- 4 nM (HUVEC)). The whole radiosynthetic procedure, including the preparation of the 18F-glycosylating reagent Ac3-[18F]FGlc-PTS, peptide ligation, and final HPLC purification, provided a decay-uncorrected radiochemical yield of 13% after a total synthesis time of 130 min. Ac3-[18F]FGlc-PTS represents a novel 18F-labeling reagent for the mild chemoselective 18F-glycosylation of peptides indicating its potential for the design and development of 18F-labeled bioactive S-glycopeptides suitable to study their pharmacokinetics in vivo by positron emission tomography (PET).
Prante O, Einsiedel J, Haubner R, Gmeiner P, Wester HJ, Kuwert T, Maschauer S	3,4,6-Tri-O-acetyl-2-deoxy-2-[(18)F]fluoroglucopyranosyl Phenylthiosulfonate: A Thiol-Reactive Agent for the Chemoselective (18)F-Glycosylation of Peptides.	Bioconjugate chemistry 2007, 18: 254
3,4,5-Tri-O-acetyl-2-[18F]fluoro-2-deoxy-d-glucopyranosyl 1-phenylthiosulfonate (Ac3-[18F]FGlc-PTS) was developed as a thiol-reactive labeling reagent for the site-specific 18F-glycosylation of peptides. Taking advantage of highly accessible 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[18F]fluoroglucopyranose, a three-step radiochemical pathway was investigated and optimized, providing Ac3-[18F]FGlc-PTS in a radiochemical yield of about 33% in 90 min (decay-corrected and based on starting [18F]fluoride). Ac3-[18F]FGlc-PTS was reacted with the model pentapeptide CAKAY, confirming chemoselectivity and excellent conjugation yields of >90% under mild reaction conditions. The optimized method was adopted to the 18F-glycosylation of the alphavbeta3-affine peptide c(RGDfC), achieving high conjugation yields (95%, decay-corrected). The alphavbeta3 binding affinity of the glycosylated c(RGDfC) remained uninfluenced as determined by competition binding studies versus 125I-echistatin using both isolated alphavbeta3 and human umbilical vein endothelial cells (Ki = 68 +/- 10 nM (alphavbeta3) versus Ki = 77 +/- 4 nM (HUVEC)). The whole radiosynthetic procedure, including the preparation of the 18F-glycosylating reagent Ac3-[18F]FGlc-PTS, peptide ligation, and final HPLC purification, provided a decay-uncorrected radiochemical yield of 13% after a total synthesis time of 130 min. Ac3-[18F]FGlc-PTS represents a novel 18F-labeling reagent for the mild chemoselective 18F-glycosylation of peptides indicating its potential for the design and development of 18F-labeled bioactive S-glycopeptides suitable to study their pharmacokinetics in vivo by positron emission tomography (PET).
Prasad P, Vasquez H, Das CM, Gopalakrishnan V, Wolff JE	Histone acetylation resulting in resistance to methotrexate in choroid plexus cells.	J Neurooncol 2009, 91: 279
Choroid plexus carcinomas are rare tumors that typically occur in young children. Prognosis is poor, and very little information is available to optimize treatment protocols. We used a cell culture model to evaluate whether combining chemotherapeutic agents such as methotrexate with histone deacetylase inhibitors (HDACI) such as valproic acid and MS-275 could improve efficacy. Valproic acid increased the cytotoxicity of radiation and of all the chemotherapeutic agents in Z310 and SV11 mouse choroid plexus cell lines, with the exception of methotrexate. Both HDACIs made choroid plexus cells resistant to this folate antagonist. Searching for a molecular explanation, we found that thymidylate synthase was up regulated when the cells were incubated with HDACI. We also confirmed this finding in human choroid plexus carcinoma cells. Methotrexate should not be combined with HDACI in the treatment of choroid plexus carcinoma.
Prabu R, Thulkar S, Chand Sharma M, Mohanti BK, Dhawan D, Bakhshi S	PNET spine: morbid and mortal, but ignored till late.	Journal of pediatric hematology/oncology 2012, 34:e164
Spinal primitive neuroectodermal tumor (PNET) is rare. We present clinical, radiologic profile and treatment outcome of 15 spinal PNET patients from June 2003 to March 2010 treated with chemoradiotherapy. Median duration of backache was 6.5 months; all had features of myelopathy and/or radiculopathy; 5/15 (33.3%) patients were diagnosed initially as spinal tuberculosis. The event-free survival (EFS) was 24.73% at a median follow-up of 22 months. Complete functional recovery to treatment significantly predicted better EFS; 4 patients discontinued treatment because of poor functional recovery. It is important to recognize spinal PNET early to prevent permanent neurological damage, which in turn would improve compliance, quality of life, and perhaps EFS.
Preuner S, Peters C, Pötschger U, Daxberger H, Fritsch G, Geyeregger R, Schrauder A, von Stackelberg A, Schrappe M, Bader P, Ebell W, Eckert C, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Lawitschka A, Mann G, Panzer-Grümayer R, Güngör T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Lion T	Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia.	Haematologica 2016, 101: 741
Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.
Priolo T, Lamba LD, Giribaldi G, De Negri E, Grosso P, De Grandis E, Veneselli E, Buoncompagni A, Viola S, Alpigiani MG, Gandullia P, Calevo MG	Childhood thalidomide neuropathy: a clinical and neurophysiologic study.	Pediatric neurology 2008, 38: 196
Thalidomide was recently reintroduced to treat several immune-mediated pathologies. Peripheral neuropathy is a significant side effect limiting its clinical use. Our aims include: (1) describing and identifying the incidence of clinical or electrophysiologic peripheral neuropathy in children, (2) determining whether peripheral neuropathy correlates with cumulative dose of thalidomide and with age, and (3) defining its reversibility rate. We studied 13 children manifesting immune-mediated pathologies treated with thalidomide at doses ranging from 25-100 mg/day. Clinical and neurophysiologic evaluation was performed before and after starting treatment. Seven children (53.8%) showed neurophysiologic signs of sensory peripheral axonal polyneuropathy. Five presented associated clinical symptoms, while the other two only presented subclinical, neurophysiologic signs of peripheral neuropathy. We found a significant correlation between the incidence of peripheral neuropathy and thalidomide cumulative dose (P = 0.02). We observed a lower incidence of peripheral neuropathy at a cumulative dose <20 gm, and a correlation with age (P < 0.01). The clinical and electrophysiologic recovery rate was 40%, and clinical improvement alone was observed in another 40%. Thalidomide induces dose-dependent and age-dependent peripheral neuropathy at a significant frequency in childhood (53.8%). In our experience a cumulative dosage at >20 gm and long-term administration for >10 months seem to increase the risk of peripheral neuropathy. We propose clinical and neurophysiologic follow-up every 3 months to identify and monitor possible side effects.
Prokop A, Pichlmaier H, Berthold F	Peripheral neurogenic tumors--surgical therapy of neuroblastoma. Review and personal results.	Zentralbl Chir 1993, 118: 315
Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, Ludwig W, Henze G, Dorken B, Daniel P	Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo.	Leukemia 2000, 14: 1606
Prosch H, Grois N, Prayer D, Waldhauser F, Steiner M, Minkov M, Gadner H	Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis.	Pediatric blood & cancer 2004, 43: 594
BACKGROUND AND OBJECTIVES: Central diabetes insipidus (CDI) is a rare disorder associated with various underlying diseases. Among the systemic diseases that may cause CDI, Langerhans cell histiocytosis (LCH) is the most common. Therefore, in patients with endocrinologically proven CDI, a comprehensive diagnostic evaluation is crucial to identify possible extracranial sites of LCH. The goal of the diagnostic evaluation is to yield histopathological proof of the underlying disease. If possible, this histopathological proof should be provided by a biopsy of extracranial lesions to avoid a potentially hazardous biopsy of the pituitary stalk. STUDY DESIGN: In this retrospective study we included 54 patients registered at the LCH study reference center in whom the onset of CDI preceded the diagnosis of LCH, and we investigated their presentation and course to define a clinical pattern characteristic for LCH. RESULTS: In 49/54 patients (91%) the detection and biopsy of extracranial lesions led to the diagnosis of LCH. The most frequently involved organs were bones, skin, and lungs; 86% of the patients with bone lesions had skull lesions. In 18% of the patients extracranial lesions were already found at presentation of CDI, in another 51% of the patients extracranial lesions were found within 1 year from onset of CDI. CONCLUSIONS: These observations underline that a comprehensive search for extracranial lesions at presentation and during the first year thereafter may help to achieve a specific diagnosis without a pituitary stalk biopsy.
Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J, Kuter DJ	International consensus report on the investigation and management of primary immune thrombocytopenia.	Blood 2010, 115: 168
Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making.
Proschmann R, Baldow C, Rothe T, Suttorp M, Thiede C, Tauer JT, Müller MC, Hochhaus A, Roeder I, Glauche I	Response dynamics of pediatric patients with chronic myeloid leukemia on imatinib therapy.	Haematologica 2016,
Pruss A, Salama A, Ahrens N, Hansen A, Kiesewetter H, Koscielny J, Dörner T	Immune hemolysis-serological and clinical aspects.	Clinical and experimental medicine 2003, 3: 55
The differential diagnosis of anemia must consider immune hemolytic anemias as a frequent cause. Whereas detection of anti-red blood cell (RBC) alloantibodies frequently induced by immunogenic stimuli (transfusion, pregnancy) is performed by routine serology, diagnosing autoimmune hemolytic anemias or drug-induced hemolytic anemias remains a challenge, usually requiring close collaboration of a number of disciplines. Positive direct antiglobulin test (Coombs' test) represents a central criterion in diagnosing immune hemolytic anemias, leading to further detailed analyses. The most-severe type of immune-mediated hemolysis is acute intravascular hemolysis after ABO incompatible RBC transfusion. This review highlights underlying biochemical aspects, immunohematological diagnostics, and the clinical relevance of RBC allo- and autoantibodies, including paroxysmal nocturnal hemoglobinemia and drug-induced hemolysis. Finally, current and partly experimental therapeutic strategies of immune hemolytic anemias are summarized.
Berufsgruppe Kunst- und Musiktherapeuten in der PSAPOH	Berufsbild der Kunst- und Musiktherapeuten in der pädiatrischen Onkologie.	November 2004, 1. Aktualisierung: November 2016
Puhlmann U, Reinhardt D, Vorwerk H, Ziemann Ch	Association between COX-2 MDR1 expression and MDR1 mediated functional Rhodamine 123 efflux in AML blast.	Naunyn-Schmiedeberg's Archives of Pharmakology 2002, 365
Puhlmann U, Ziemann C, Ruedell G, Vorwerk H, Schaefer D, Langebrake C, Schuermann P, Creutzig U, Reinhardt D	Impact of the cyclooxygenase system on doxorubicin-induced functional multidrug resistance 1 overexpression and doxorubicin sensitivity in acute myeloid leukemic HL-60 cells.	The Journal of pharmacology and experimental therapeutics 2005, 312: 346
Multidrug resistance (MDR), a challenge in treating childhood acute myeloid leukemia (AML), is frequently associated with decreased drug accumulation caused by multidrug transporter MDR1. Doxorubicin, an important anti-AML drug, is a known MDR1 substrate and inducer. Its cytostatic efficacy is thus limited by MDR1 overexpression. A recent study demonstrated cyclooxygenase-2-dependent, prostaglandin E(2) (PGE(2))-mediated regulation of mdr1b expression in primary rat hepatocyte cultures. Cyclooxygenase-2 expression is increased in several malignancies and considered a negative prognostic factor. Our study focused on cyclooxygenase system's impact on drug-induced MDR1 overexpression in AML cells. As a prerequisite, coexpression of MDR1 and cyclooxygenase-2 mRNA in HL-60 cells and primary AML blasts was demonstrated by Northern blot. Interestingly, incubation of AML cells with doxorubicin not only induced functionally active MDR1 overexpression but also mediated increased cyclooxygenase-2 mRNA and protein expressions with subsequent PGE(2) release (determined by flow cytometry, rhodamine123 efflux assay, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay). After preincubation and subsequent parallel treatment with the cyclooxygenase-2-preferential inhibitor meloxicam, doxorubicin-induced MDR1 overexpression and function were reduced (maximally at 0.1-0.5 microM meloxicam), whereas cytostatic efficacy of doxorubicin in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays was significantly increased by up to 78 (HL-60) and 30% (AML blasts) after 72 h of doxorubicin treatment. In HL-60 cells, meloxicam-dependent effect on doxorubicin cytotoxicity was neutralized by PGE(2) preincubation. In conclusion, the cyclooxygenase system, especially the cyclooxygenase-2 isoform, might be involved in regulating doxorubicin-induced MDR1 overexpression in AML cells, with PGE(2) seeming to be a mediating factor. Cyclooxygenase inhibitors thus bear promise to overcome MDR in AML and improve therapy.
Pui CH, Boyett JM, Rivera GK, Hancock ML, Sandlund JT, Ribeiro RC, Rubnitz JE, Behm FG, Raimondi SC, Gajjar A, Razzouk B, Campana D, Kun LE, Relling MV, Evans WE	Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital.	Leukemia 2000, 14: 2286
Pui CH, Sallan S, Relling MV, Masera G, Evans WE	International Childhood Acute Lymphoblastic Leukemia Workshop: Sausalito, CA, 30 November-1 December 2000.	Leukemia 2001, 5: 707
Pui C, Gaynon P, Boyett J, Chessells J, Baruchel A, Kamps W, Silverman L, Biondi A, Harms D, Vilmer E, Schrappe M, Camitta B	Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.	Lancet 2002, 359: 1909
Pui C, Chessells J, Camitta B, Baruchel A, Biondi A, Boyett J, Carroll A, Eden O, Evans W, Gadner H, Harbott J, Harms D, Harrison C, Harrison P, Heerema N, Janka-Schaub G, Kamps W, Masera G, Pullen J, Raimondi S, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman L, Valsecchi M, Vilmer E, Zhou Y, Gaynon P, Schrappe M	Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.	Leukemia 2003, 17: 700
Pui CH	Treatment of Acute Leukemias. New Directions for Clinical Research.	Totowa, NJ: Humana Press Inc 2003
Pui C, Schrappe M, Masera G, Nachman J, Gadner H, Eden O, Evans W, Gaynon P	Ponte di Legno Working Group.	Leukemia 2004, 18: 1043
Pui CH	Recent advances in childhood acute lymphoblastic leukemia.	J Formos Med Assoc 2004, 103: 85
Pui CH, Relling MV, Downing JR	Acute lymphoblastic leukemia.	The New England journal of medicine 2004 Apr 8; 350: 1535
Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV	Treating childhood acute lymphoblastic leukemia without cranial irradiation.	The New England journal of medicine 2009 Jun 25; 360: 2730
Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.
Purz S, Mauz-Körholz C, Körholz D, Hasenclever D, Krausse A, Sorge I, Ruschke K, Stiefel M, Amthauer H, Schober O, Kranert WT, Weber WA, Haberkorn U, Hundsdörfer P, Ehlert K, Becker M, Rössler J, Kulozik AE, Sabri O, Kluge R	[18F]Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin's lymphoma.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011, 10; 29: 3523
Currently, a routine bone marrow biopsy (BMB) is performed to detect bone marrow (BM) involvement in pediatric Hodgkin's lymphoma (HL) stage greater than IIA. [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used for the initial staging of HL. The value of using FDG-PET to detect BM involvement has not been sufficiently defined. We compared the results of BMBs and FDG-PET for the diagnosis of BM involvement in a large pediatric group with HL.
Pötter R, Kuhnen C, Ritter J, Rath B, Wuismann P, von Eiff M, von Lengerke HJ, Brämswig J, Paulus S	Side-effects after combination therapy for Ewing's sarcoma.	Recent Results Cancer Res 1993, 130: 251
Pötter R, Roes F, Schellong G, Bartenstein P, Bramswig J, von Lengerke H, Rath B, Mohring R, Rossi R	Subclinical impairment of renal function after radiotherapy for Hodgkin's disease in children.	Recent Results Cancer Res 1993, 130: 259
Pötter R	Paediatric Hodgkin's disease.	Eur J Cancer 1999, 35: 1466
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