Search

Das Osteosarkom (OS) ist der haufigste maligne primare Knochentumor. Er tritt v. a. an den Extremitaten junger Menschen auf, kann jedoch auch kraniofazial entstehen, mit entscheidenden epidemiologischen, therapeutischen und prognostischen Besonderheiten. Die Therapie des kraniofazialen Osteosarkoms (CFOS) wird masgeblich von der Operation gepragt, die im Gesunden erfolgen muss, um eine realistische Heilungschance zu gewahren. Andere lokaltherapeutische Verfahren wie innovative Strahlentherapien sind zwar beim CFOS haufig erforderlich, aber deutlich nachrangig. Adjuvante chemotherapeutische Verfahren konnen auch beim CFOS zum Einsatz kommen und werden von europaischen Leitlinien empfohlen. Nach der Therapie bedurfen Betroffene einer lebenslangen, risikoadaptierten Nachsorge.

Autoimmune pancreatitis is a rare, distinct and increasingly recognized form of chronic inflammatory pancreatic disease secondary to an underlying autoimmune mechanism. We report on a 14-year-old boy who developed autoimmune pancreatitis, while he was under treatment with eltrombopag for chronic immune thrombocytopenia. Therapy with corticosteroids resulted in complete remission of both. This is the first report on the co-occurrence of autoimmune pancreatitis and chronic immune thrombocytopenia in childhood, and clinicians should be aware of this rare association, because early diagnosis and therapy of autoimmune pancreatitis may prevent severe complications.

PURPOSE Rhabdoid tumor of the kidney (RTK) is one of the most aggressive childhood renal tumors. Overall survival ranges from 22% to 47%. The indication for radiation therapy (RT) in usually very young patients is an ongoing discussion. Recent protocols recommend RT independent of local stage, the latter being a good discriminator in other childhood kidney tumors. In this study, we analyze the evidence for RT in regard to risk factors, including tumor stage. METHODS AND MATERIALS This study analyzed 58 patients with RTK from Austria, Switzerland, and Germany treated in the framework of 4 consecutive, prospective renal/rhabdoid tumor studies from 1991 to 2014. All treatment protocols included multimodality treatment, including high-intensity chemotherapy, surgery, and RT. RESULTS Local stage distribution was not applicable, I, II, and III in 1, 6, 11, and 40, respectively. Twenty-nine (50%) patients had stage IV disease at diagnosis. Thirty-seven patients (64%) achieved complete remission, and 49% (18/37) relapsed. Thirty-four patients (60%) patients had progressive disease and died, 17 had local disease, 10 had combined disease, and 7 had distant disease; 2 treatment-related deaths were reported (3%). Twenty-one patients received RT during first-line treatment, 18 of them to all involved sites. Eight of the 34 cases of progressive disease occurred in irradiated patients. The local failure rate of treated patients with local stage II or III disease was 29% (6/18) in patients irradiated to all sites compared with 68% (15/22) in nonirradiated patients. One of 6 stage I patients received RT, and 1 patient experienced distant relapse (2-year progression-free and overall survival both 83% ± 15%). Progression-free survival for local stage II and III disease treated with RT, adjusted for early relapse or treatment abandonment, was 67% ± 11%, compared with 15% ± 7% without RT (P < .0001). CONCLUSION The 68% local failure rate in nonirradiated patients underlines the importance of local treatment. Our experience supports the use of RT for local control in higher stage disease. In contrast, no local relapse in 6 local stage I patients, including 5 nonirradiated patients, suggests omission of RT in this favorable subset of usually infant patients with RTK.

PURPOSE The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities. METHODS We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients. RESULTS A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively ( P = .007), and 5-year event-free survival (EFS) was 51% versus 58% ( P = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% ( P < .001), and 5-year EFS was 36% versus 56% ( P < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS ( P = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS ( P = .263; HR, 1.312). CONCLUSION In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.

Results of immunotherapy in childhood solid cancer have been so far, with the exception of neuroblastoma, quite disappointing. Lack of knowledge of the immune contexture of these tumors may have contributed to the failure of immunotherapies so far. Here, we systematically reviewed the literature regarding the immunology of Wilms tumor (WT), one of the most frequent pediatric solid tumors of the abdomen. In Wilms tumor patients the high cure rate of >90%, achieved by the combination of surgery and radio-chemotherapy, is at the expense of a high early and late toxicity. Moreover, treatment-resistant entities, such as diffuse anaplastic tumors or recurrent disease, still pose unsolved clinical problems. Successful immunotherapy could represent a novel and possibly less-toxic treatment option. Employing the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) method of literature search, we analyzed the current knowledge of the immunological landscape of Wilms tumors in terms of tumor microenvironment, prognostic implications of single biomarkers, and immunotherapy response., Graphical abstract, The corresponding author and colleagues address the role of immunotherapy in Wilms tumor, in the attempt to evaluate the issues at the basis of the so-far disappointing results of immunomodulation in childhood solid cancer. On the basis of the current knowledge, novel reasonable areas of research are highlighted.

With ever increasing long-term, disease free survival rates, long-term toxicities of otherwise successful therapy have gained increasing importance. They can be grouped into potentially life-threatening, especially secondary malignancies and anthracycline cardiomyopathies, potentially disabling, particularly severe hearing loss and renal insufficiency, other, and rare events. Pathophysiology, frequency, and medical treatment approaches are discussed. Finally, fertility issues and quality of life issues are discussed, together with an outlook into the future. The challenge to cure as many patients as possible from osteosarcoma while enabling a life free of late effects will remain.

(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Anamien sind definiert als eine Verminderung der altersabhangigen Menge an zirkulierenden Erythrozyten. Weltweit gesehen sind Anamien eine wichtige Krankheits- und Todesursache und mehr als ein Drittel der Weltbevolkerung gilt als betroffen. Die wichtigsten Ursachen von Anamien sind Unter- und Fehlernahrung, Infektionen (z. B. Malaria) sowie chronische Erkrankungen wie Nierenerkrankungen, entzundliche Darmerkrankungen, Endokrinopathien (z. B. Hypothyreose) und Krebs. Auch die haufigsten monogenetischen Erkrankungen, die Hamoglobinopathien (z. B. Thalassamien und Sichelzellerkrankung) und der Glukose-6-Phosphat-Dehydrogenase(G6PDH)-Mangel sind phanotypisch Anamien. Etwa 400 Mio. Menschen haben einen G6PDH-Mangel und etwa 5 % der Weltbevolkerung sind Trager einer pathogenen Variante im Alpha-Thalassamie-Gen. In dieser kurzen Ubersicht werden Algorithmen, primar basierend auf der phanomenologischen Klassifikation (mikrozytare, normozytare und makrozytare Anamien), zur Differenzialdiagnose der Anamien prasentiert. Zudem werden ausgewahlte Erkrankungen anhand typischer Fallbeispiele dargestellt.

Extraosseous osteoblastoma of the breast, a rare disease, was diagnosed in a prepubertal girl. After tumor excision, the patient recovered well and an optimal cosmetic result was achieved. Interdisciplinary discussions about the case are essential.

Background: Bernard–Soulier Syndrome (BSS) is a rare autosomal recessive bleeding disorder with large platelets and thrombocytopenia. It is caused by homozygous or compound heterozygous mutations in the GP1BA, GP1BB, or GP9 genes, which together encode the platelet surface receptor glycoprotein complex GPIb-IX-V.Objectives: We report two novel heterozygous mutations in the GP1BA and the GP9 genes, respectively.Patients/Methods: We analyzed the platelet glycoprotein expression by flow cytometry and screened the relevant genes for responsible mutations in two unrelated families.Results: Flow cytometric analyses revealed the absence of CD42a (GPIX) and CD42b (GPIb) on the platelets in the two affected siblings of family 1 and a significantly reduced expression of CD42b (GPIb) in the patient of family 2. In the two siblings, we identified a known frameshift (c.1601_1602delAT) and a novel nonsense mutation (c.1036C>T) in the GP1BA gene that abrogated the production of GP1bα. In the other patient, we found a novel missense mutation (c.112T>C) that was co-inherited with a common one (c.182A>G) in the GP9 gene, respectively. All analyzed heterozygous carriers were asymptomatic and had a normal GPIb-IX-V expression.Conclusions: The two novel GP1BA and GP9 mutations reported herein increment the number of causative genetic defects in BSS.

Introduction The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. Materials and methods The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. Results Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42–65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22–25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. Conclusions Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Introduction Clear cell sarcoma of the kidney (CCSK) is a rare malignant childhood renal tumour. Recently, the central nervous system (CNS) was found to be the most frequent site of relapse associated with a poor outcome. Optimal treatment strategies are scarce. Patients and methods Retrospective data analysis of all Austrian children with CCSK. They were enrolled in the Austrian-Hungarian Wilms Tumour Study (AHWTS) 1989, the SIOP93-01 or the SIOP2001 study between 1990 and 2019. Demographic, diagnostic, treatment-related variables and survival data were analysed. Results We identified 12 children with CCSK (M = 7, F = 5; median age 1.6 years). All had localised disease (stage I: 2; stage II: 2; stage III: 8) at diagnosis, and a first complete remission (CR1) was achieved in 12/12. Six patients are in an ongoing CR1 (median follow-up 10 years). Six other patients had a relapse (local 1; brain 5) a median time of 2.4 years from diagnosis. Two patients died of the disease 4 months and 2.8 years after first relapse. Four of five patients with CNS relapse are in CR2 with a median follow-up time of 9.3 years after relapse diagnosis. Relapse treatment included a combination of chemotherapy, radiation and surgery. Two children received high-dose chemotherapy followed by autologous stem cell rescue, and one child received intrathecal mafosphamide. Long-term side effects after treatment were impaired tubular renal function (n = 4), cardiomyopathy (n = 1) and growth disorders (n = 1). Conclusions In this series, the brain was the most common site of relapse. Long-term survival after recurrence was achievable with intensive multimodal therapy.

Osteosarcoma is the most common type of bone cancer in children and young adults with a peak incidence in adolescents. It has a propensity for lung metastases and is a prime example of a cancer where cure will only be achieved if many specialities closely cooperate within a dedicated multidisciplinary environment. Neither surgery nor chemotherapy alone will cure many patients, but their combination can lead to long-term, disease-free survival in 60–70%.

Background: Low survival rates in metastatic high-grade osteosarcoma (HGOS) have remained stagnant for the last three decades. This study aims to investigate the role of aminopeptidase N (ANPEP) in HGOS progression and its targeting with a novel lipophilic peptidase-enhanced cytotoxic compound melphalan flufenamide (melflufen) in HGOS. Methods: Meta-analysis of publicly available gene expression datasets was performed to determine the impact of ANPEP gene expression on metastasis-free survival of HGOS patients. The efficacy of standard-of-care anti-neoplastic drugs and a lipophilic peptidase-enhanced cytotoxic conjugate melflufen was investigated in patient-derived HGOS ex vivo models and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigated in vivo. Results: Elevated ANPEP expression in diagnostic biopsies of HGOS patients was found to significantly reduce metastasis-free survival. In drug sensitivity assays, melflufen has shown an anti-proliferative effect in HGOS ex vivo samples and cell lines, including those resistant to methotrexate, etoposide, doxorubicin, and PARP inhibitors. Further, HGOS cells treated with melflufen displayed a rapid induction of apoptosis and this sensitivity correlated with high expression of ANPEP. In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effects in vivo. Conclusion: This study may pave the way for use of melflufen as an adjuvant to doxorubicin in improving the therapeutic efficacy for the treatment of metastatic HGOS.

In the original article [1] there was a mistake in Table 2 as published. Table 2 contains wrong percentages in lines Bilateral disease and Patients with CPS or GU. For this reason the table should be replaced with the correct one as shown below.

Primary bone tumours are rare, accounting for < 0.2% of malignant neoplasms registered in the EUROCARE (European Cancer Registry based study on survival and care of cancer patients) database. Different bone tumour subtypes have distinct patterns of incidence, and each has no more than 0.3 incident cases per 100 000 per year. Osteosarcoma (OS) and Ewing sarcoma (ES) have a relatively high incidence in the second decade of life, whereas chondrosarcoma (CS) is more common in older age.

Purpose NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID). Methods and Results We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity. Conclusions Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease. Electronic supplementary material The online version of this article (doi:10.1007/s10875-016-0306-1) contains supplementary material, which is available to authorized users.

Although the fate of nephrogenic rests varies, they are known to be precursors of Wilms tumour. Thus, nephrogenic rests require adequate treatment to prevent malignant transformation. We added 13-cis retinoic acid to the standard chemotherapy with vincristine and actinomycin-D in two patients with bilateral nephrogenic rests/nephroblastomatosis. Patient 1 also had a history of Wilms tumour. 46 (patient 1) and 81 (patient 2) months after end of treatment, both patients show stable conditions with no signs of relapse or progressive disease. Our observation supports further investigation of retinoic acid in patients with nephrogenic rests and nephroblastomatosis.

Background High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor. In metastatic patients, survival rates are poor and remained virtually unchanged over the past 30 years. Furthermore, recent randomized trials failed to improve the efficacy of current chemotherapy. Here we tested the anti-neoplastic activity of a novel peptide-conjugated alkylator melflufen in preclinical osteosarcoma setting. Due to its high lipophilicity melflufen rapidly enters tumor cells where it is immediately cleaved by peptidases leading to entrapment and enrichment of alkylating payload. Overexpression of peptidases is often seen in tumor cells and can thus lead to increased melfufen sensitivity. In osteosarcoma, over-expression of aminopeptidase N (ANPEP/CD13) has been associated with poor survival and metastasis suggesting that melflufen may represent a valid new therapeutic option. Methods Gene expression of ANPEP/CD13 in patient samples from GEO datasets was analyzed using standard tools. Anti-neoplastic activity of melflufen and was evaluated in a panel of 11 osteosarcoma cell lines including early passage patient-derived primary lines. In vitro anti-neoplastic activity was examined using survival and apoptosis assays. In vivo activity of melflufen was tested in a chicken embryo xenograft model. Results Melflufen has demonstrated superior anti-neoplastic activity in comparison to other alkylating agents including melphalan, cyclophosphamide, ifosfamide, busulfan, and bendamustine. Melflufen was active in all osteosarcoma cell lines including the cells resistant to methotrexate, etoposide, and talazoparib. Anti-neoplastic activity of melflufen could be hindered by ANPEP inhibitor bestatin. Furthermore, in vivo administration of melflufen reduced tumor growth and metastasis of highly aggressive 143B osteosarcoma cells in a xenograft model. Conclusions Melflufen has demonstrated promising results in preclinical osteosarcoma model showing anti-neoplastic activity superior to other alkylating agents and PARP inhibitor talazoparib. Melflufen’s favorable toxicity profile suggests that it might represent a novel valid therapeutic approach for osteosarcoma patients with poor response to chemotherapy and metastasis. Legal entity responsible for the study The authors. Funding Oncopeptides AB. Disclosure A. Slipicevic: Full / Part-time employment: Oncopeptides AB. K. Byrgazov: Research grant / Funding (self): Oncopeptides AB. F. Lehmann: Full / Part-time employment: Oncopeptides AB; Leadership role: EpiEndo Pharmaceuticals. T. Lion: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Incyte. All other authors have declared no conflicts of interest.

Summary Establishing a precise diagnosis is essential in inborn haematological cytopenias to enable appropriate treatment decisions and avoid secondary organ damage. However, both diversity and phenotypic overlap of distinct disease entities may make the identification of underlying genetic aetiologies by classical Sanger sequencing challenging. Instead of exome sequencing, we established a systematic next generation sequencing‐based panel targeting 292 candidate genes and screened 38 consecutive patients for disease‐associated mutations. Efficient identification of the underlying genetic cause in 17 patients (44·7%), including 13 novel mutations, demonstrates that this approach is time‐ and cost‐efficient, enabling optimal management and genetic counselling.

Osteosarcoma of the foot is a very rare presentation of a rare tumor entity. In a retrospective analysis, we investigated tumor- and treatment-related variables and outcome of patients registered in the Cooperative Osteosarcoma Study Group (COSS) database between January 1980 and April 2016 who suffered from primary high-grade osteosarcoma of the foot. Among the 23 eligible patients, median age was 32 years (range: 6–58 years), 10 were female, and 13 were male. The tarsus was the most commonly affected site (n=16). Three patients had primary metastases. All patients were operated: 5 underwent primary surgery and 18 received surgery following preoperative chemotherapy. In 21 of the 23 patients, complete surgical remission was achieved. In 4 of 17 patients, a poor response to neoadjuvant chemotherapy was observed in the resected primary tumors. Median follow-up was 4.2 years (range: 0.4–18.5). At the last follow-up, 15 of the 23 patients were alive and 8 had died. Five-year overall and event-free survival estimates were 64% (standard error (SE) 12%) and 54% (SE 13%), which is similar to that observed for osteosarcoma in general. Event-free and overall survival correlated with primary metastatic status and completeness of surgery. Our findings show that high-grade osteosarcoma in the foot has a similar outcome as osteosarcoma of other sites.

Current standard treatment of patients with high-grade osteosarcoma (HGOS) includes complete surgical resection of the tumor and chemotherapy, most often with high-dose methotrexate, doxorubicin and cisplatin. With this approach > 60% of patients can be cured. However, conventional anticancer drugs have a narrow therapeutic index, and efficacy and toxicity vary considerably among patients. Pharmacogenomics aim to identify key genomic factors for drug effects (either desired or adverse) in normal host cells (germ-line variants) and cancer cells (somatic variants), and if an association between a genotype and a drug phenotype has been identified, validated and demonstrated to have a large effect size, these genotypes may be used to tailor therapy. In addition, pharmacogenomic models can be used to identify novel therapeutic targets. For example, germ-line variants in genes which potentially influence the disposition of methotrexate and cardiotoxicity of doxorubicin have recently been identified. Moreover, next-generation sequencing combined with several analytical methods has identified the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a potential therapeutic target in HGOS. Herein, we discuss whether and how these novel pharmacogenomic insights may help to improve future therapy in HGOS.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation.METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants.FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification.FUNDING: See Acknowledgments for funders.

Background Giant cell tumor of bone (GCT) is a rare primary bone tumor, which can metastasize and undergo malignant transformation. The standard treatment of GCT is surgery. In patients with unresectable or metastatic disease, additional therapeutic options are available. These include blocking of the receptor activator of NF-kappa B ligand (RANKL) signaling pathway, which plays a role in the pathogenesis of GCT of bone, via the anti-RANKL monoclonal antibody denosumab. Case Presentation Herein we report on a female teenager who presented in a very poor clinical condition (cachexia, diplopia, strabismus, dysphonia with palsy of cranial nerves V, VI, VIII, IX, X, XI and XII) due to progressive disease, after incomplete resection and adjuvant radiotherapy, of a GCT which affected the cervical spine (C1 and C2) as well as the skull base; and who had an impressive clinical response to denosumab therapy. To the best of our knowledge, this is the youngest patient ever reported with a skull base tumor treated with denosumab. Conclusion In situations when surgery can be postponed and local aggressiveness of the tumor does not urge for acute surgical intervention, upfront use of denosumab in order to reduce the tumor size might be considered. Principally, the goal of denosumab therapy is to reduce tumor size as much as possible, with the ultimate goal to make local surgery (or as in our case re-surgery) amenable. However, improvement in quality of life, as demonstrated in our patient, is also an important aspect of such targeted therapies. Electronic supplementary material The online version of this article (doi:10.1186/s13052-017-0353-0) contains supplementary material, which is available to authorized users.

While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.

Treatment of stage V nephroblastoma is less established and more complex than in unilateral nephroblastoma.Retrospective analysis of 121 consecutive patients with stage V nephroblastoma registered from January 1989 to May 2005. Registration, prospective data collection and treatment were carried out within the framework of 3 consecutive SIOP/GPOH-nephroblastoma-trials.19 patients had metastasis and 29 syndromes at diagnosis. 13 patients had been pretreated for bilateral nephroblastomatosis. 1 patient was not treated and 17 patients had upfront surgery. Preoperative treatment duration ranged from 1-12 weeks (n=103). 1-3 preoperative treatment-cycles resulted in average tumor-volume-reduction of 45%. 1 patient underwent bilateral nephrectomy. 52% of the patients had 2 functioning kidneys after the end of treatment. 20 patients had died after mean follow-up of 8.6 years. 5y-Progression-Free (PFS) and Overall-Survival (OS) were excellent for patients having a localized disease without pretreatment for nephroblastomatosis (5yPFS/OS: 80±4%/93±3%). Metastasis at diagnosis (51±12%/56±12%; p=0.003) and pretreatment for nephroblastomatosis (37±14%/67±13%; p0.001) were associated with significantly poorer outcome. Cox-regression analysis revealed an independent influence of pretreatment for nephroblastomatosis, metastasis and syndromes on PFS. The latter 2 as well as anaplasia and age (2 years or3 years) had an independent influence on OS.Pretreatment for nephroblastomatosis, metastasis and syndromes are independent risk factors. 1-3 preoperative treatment-cycles are sufficient to achieve save nephron-sparing-surgery in most patients.

Osteosarcoma, a bone cancer most commonly seen in adolescents and young adults, is usually a high-grade malignancy characterized by a very high risk for the development of pulmonary metastases. High-grade osteosarcomas are usually treated by preoperative and postoperative chemotherapy and surgery, with a very limited number of active agents available. Rarer lower-grade variants such as parosteal and periosteal osteosarcoma or low-grade central osteosarcoma are treated by surgery only. Imaging to search for possible metastases focuses on the lung. Computed tomography is the most sensitive method but cannot reliably distinguish small metastases from benign lesions. Advances of local imaging and surgical reconstruction now allow the use of limb-salvage in an ever-increasing proportion of patients. While still troubled by complications, non-invasive endoprosthesis-lengthening mechanisms have led to an increased uptake of limb-salvage, even for young, skeletally immature patients. Radiotherapy is employed when osteosarcomas cannot be removed with clear margins, but very high doses are required, and both proton and carbon-ion radiotherapy are under investigation. Unfortunately, the past 30 years have witnessed few, if any, survival improvements. Novel agents have not led to universally accepted changes of treatment standards. In patients with operable high-grade osteosarcomas, the extent of histological response to preoperative chemotherapy is a significant predictive factor for both local and systemic control. Attempts to improve prognosis by adapting postoperative treatment to response, recently tested in a randomized, prospective setting by the European and American Osteosarcoma Study Group, have not been proven to be beneficial. Many agree that only increased knowledge about osteosarcoma biology will lead to novel, effective treatment approaches and will be able to move the field forward.

The overall outcome for children with nephroblastomas is excellent when treated according to protocols that include surgery, chemotherapy, and, in selected cases, radiotherapy. This study was conducted to provide population-based data on Austrian children who had been treated in neoadjuvant nephroblastoma trials between October 1988 and July 2001. One hundred and forty-eight children with newly diagnosed untreated renal tumors were registered in the Austrian–Hungarian Wilms Tumor Study (AHWTS) 1989 (N = 63) and the SIOP 93-01/GPOH Study (N = 85). After a median follow-up of 11.8 years from diagnosis, 130 patients have been reported to be alive; 18 patients have died. Three patients had carcinoma and three had nephroblastomatosis; the 5-year event-free survival (EFS) and overall survival (OS) rates for the remaining 142 patients were 83 ± 3 % and 91 ± 2 %, respectively (SIOP 93-01/GPOH trial, 5-year EFS 85 ± 4 %, OS 95 ± 2 %; AHWTS 1989 trial, 5-year EFS 79 ± 5 %, OS 86 ± 5 %). Outcome was better for low-risk pathology (N = 14; 5-year EFS 92 ± 8 %, OS 100 %) than for intermediate-risk (N = 106; 5-year EFS 89 ± 3 %, OS 94 ± 2 %) and high-risk pathology (N = 22; 5-year EFS 50 ± 11 %, OS 68 ± 10 %; P

Benigne Neubildungen des Knochens und des Gelenkknorpels, welche in der Regel nicht aggressiv wachsen und nicht metastasieren, sind meist asymptomatisch und werden demnach meistens zufallig entdeckt. Schmerzen konnen auftreten, wenn eine Irritation der anliegenden Strukturen (zum Beispiel Sehnen oder Nerven) vorliegt oder wenn durch die Schwachung der Knochen eine pathologische Fraktur auftritt. Man unterscheidet Tumoren, die von Knochen- oder Knorpelgewebe ausgehen, sowie fibrose und zystische Lasionen und die Langerhanszell-Histiozytose. Von den nicht neoplastischen Erkrankungen ist vor allem die Osteomyelitis in differentialdiagnostische Uberlegungen einzubeziehen.

High-grade osteosarcomas are the most common primary malignant tumors of bone. With complete surgical resection and multi-agent chemotherapy up to 70% of patients with high-grade osteosarcomas and localized extremity tumors can become long-term survivors. The prognosis, however, is poor for patients with nonresectable, primary metastatic or relapsed disease. Outcome is essentially unchanged for three decades. Herein, we describe selected novel insights into the genomics, biology and immunology of the disease and discuss selected strategies, which hold promise to overcome the current stagnation in the therapeutic success in childhood osteosarcoma.

Chronic immune thrombocytopenia (cITP) is often associated with an underlying predisposition towards autoimmunity, recognition of which is relevant to guide treatment. International recommendations on diagnostic steps and therapeutic measures of cITP in childhood exist. However, due to the low prevalence (1-2/100,000) and a variation of availability of immunological and hematological tests and treatments across pediatric units, we postulated that these guidelines are not uniformly adhered to and that immune dysregulation syndromes remained undiscovered. To delineate the current management of children and adolescents with cITP in Austria, we performed a nationwide cross-sectional study. Between 2011 and 2014, 81 children with cITP were seen at seven centers (median age 8.75 years; range 1-17; female:male ratio 47:34) at 641 visits during 180 patient years after diagnosis of cITP (>12 months ITP duration). Additional diagnoses were noted, most frequently immune or autoimmune disorders, hematologic diseases, or infections (in 37.3%, including Evans syndrome, autoimmune lymphoproliferative syndrome, systemic lupus erythematosus, and Fanconi anemia), or other symptoms like bi- or pancytopenia (n=9), lymphoproliferation or granulomatous inflammation (n = 3). Both decision to treat as well as choice of treatment varied: smaller centers tended to observe more frequently, larger centers applied a pattern of treatment modalities that appeared to depend less on bleeding tendency than on center policy. More than 50% of therapeutic interventions occurred in bleedings scores ≤2 (of 5), suggesting a strong psychosocial intention to treat. Platelet increment upon 479 therapeutic interventions of eight types was evaluated, with multiple treatment approaches being pursued sequentially in refractory patients. These data confirm the hypothesis of heterogeneous diagnostic and therapeutic management of cITP in Austrian children and corroborate the need for (1) a precise panel of parameters to exclude underlying disorders and (2) for biomarkers to predict treatment response.

Contains fulltext : 167540.pdf (Publisher’s version ) (Open Access) This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

With current therapy more than 80% of children with acute lymphoblastic leukaemia (ALL) can be cured in industrialized countries. However, ALL is still amongst the leading causes of death from disease in children aged 1–15 years. Of note, antileukaemic medications can cause significant adverse drug reactions; and some patients have leukaemia cell clones that are resistant to current antileukaemic treatment. Therefore, further improvement of childhood ALL therapy is urgently needed. Pharmacogenomics aims to elucidate functionally relevant genomic determinants for drug disposition and response to improve drug therapy based on a patient’s genomic profile. Results from recent pharmacogenomic investigations including large-scale genome-wide analyses hold promise to improve ALL therapy in the near future.

Progress in the treatment of acute leukemia in children has been remarkable, from a disease being lethal four decades ago to current cure rates exceeding 80%. This exemplary progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. However, despite these high cure rates, the annual number of children whose leukemia relapses after their initial therapy remains greater than that of new cases of most types of childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of human genome variability and its influence on drug response. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute lymphoblastic leukemia. These studies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm.

Purpose of review The cure rate in children with acute lymphoblastic leukemia now exceeds almost 80% in most treatment protocols in industrialized countries. This has mainly been achieved empirically through carefully controlled, randomized clinical trials. Due to relative nonspecific action and narrow therapeutic indices of antileukemic medications, however, current therapy can be associated with significant short and long-term adverse effects, and around 20% of patients will not be cured despite intensified treatment. Pharmacogenomics, which studies the role of inheritance in individual variation in drug disposition and response, could be a useful tool to further improve outcome in this heterogeneous disease by individualization of therapy based on information gained from the genetic ‘make-up’ of normal host cells and lymphoblastic leukemia cells. Recent findings The focus of this review is on recent progress in the field by discussing the results of selected studies in which information from functional genomics, high-throughput molecular analyses, and pharmacodynamics has been integrated to establish pharmacogenomic models. These models may be used to both maximize efficacy and minimize toxicity of existing antileukemic medications, or to identify novel therapeutic targets in lymphoblasts that are resistant to conventional antileukemic drugs. Summary The findings from recent pharmacogenomic studies can be integrated into decision-making in future clinical trials. Thus there is great promise for advancing event-free survival in childhood leukemia in the future.

Purpose: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. Patients and Methods: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. Results: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. Conclusion: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.

Background Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high-dose chemotherapy with autologous stem-cell transplantation (HDSCT) in an intensive first-line treatment offers additional benefit is an ongoing discussion. Methods A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93-01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014. Results Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III—1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty-seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment-related complication. Mean time to the first event was 3.5 months. Two-year EFS/OS (where EFS is event-free survival) for the whole group was 37 ± 6%/38 ± 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2-year OS in this group was 60 ± 15% compared to 34 ± 8% in the non-HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem-cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (

We describe the second patient with anionic exchanger 1/band 3 null phenotype (band 3 nullVIENNA ), which was caused by a novel nonsense mutation c.1430C>A (p.Ser477X) in exon 12 of SLC4A1. We also update on the previous band 3 nullCOIMBRA patient, thereby elucidating the physiological implications of total loss of AE1/band 3. Besides transfusion-dependent severe hemolytic anemia and complete distal renal tubular acidosis, dyserythropoiesis was identified in the band 3 nullVIENNA patient, suggesting a role for band 3 in erythropoiesis. Moreover, we also, for the first time, report that long-term survival is possible in band 3 null patients.

The prognosis after relapse of high-grade osteosarcoma is poor and complete resection of all tumors is essential for survival. A 6-year old was diagnosed with high-grade osteosarcoma and treated according to the COSS-96 protocol. Within 5 years from initial diagnosis, five osteosarcoma relapses occurred and every time it was possible to achieve complete surgical remission. Additional treatments included chemotherapy and dendritic cell-based cancer immune therapy. Since the end of therapy of the 5th relapse, he is alive for 11½ years. Our experience further supports that aggressive surgery can help to achieve long-term survival even in patients with multiple osteosarcoma relapses.

Purpose The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of individual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. Patients and Methods Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. Results After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P < .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P < .001). Children reported the highest rates of grade 3 or 4 neutropenia (P < .001) and thrombocytopenia (P < .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P < .001). Conclusion These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes.

Background The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. Patients and methods Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. Results The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age

Thiamine-responsive megaloblastic anemia (TRMA) is a rare disorder typically characterized by megaloblastic anemia, non-type I diabetes and sensorineural deafness. It is caused by various mutations in the SLC19A2 gene that impair the encoded thiamine transporter. So far, only 70 affected individuals mainly from consanguineous families of Middle and Far Eastern origin with a wide spectrum of signs and symptoms, variable onset of disease, and primarily homozygote mutations in SLC19A2 have been reported. We present the first genuine central European descendent with combined heterozygote mutations in SLC19A2, an Austrian boy suffering from pancytopenia and non-type I diabetes. Both manifestations resolved completely under continuous oral thiamine supplementation. Our observation underlines that despite its rarity, TRMA must be considered as an important differential diagnosis in native central European patients with suggestive signs and symptoms. An early molecular genetic verification of the diagnosis provides a sound basis for a successful and simple treatment that helps to prevent severe sequelae.

Background: Local recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. Patients and methods: We analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR. Results: Median follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery. Conclusions: Patient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the future

This study was conducted to investigate presentation, treatment, and outcome in very young children with osteosarcoma.The authors retrospectively analyzed the data of 2706 consecutive COSS patients with newly diagnosed osteosarcoma and identified 28 (1.0%) patients aged younger than 5 years at diagnosis. Demographic, diagnostic, tumor, treatment-related variables, response, and survival data were analyzed.Of the 28 preschoolers, 27 presented with high-grade central osteosarcoma of an extremity, and 1 had a secondary osteosarcoma of the orbit. This analysis focused on the 27 patients with extremity tumors. The size of the primary was large (≥one-third of the involved bone) in 20 of 27 patients. Primary metastases were detected in 4 of 27 children. All patients received multiagent chemotherapy, and 11 of 18 analyzed tumors responded well (90% necrosis) to neoadjuvant chemotherapy. Limb-sparing surgery was performed in 9 cases, ablative procedures were performed in 15, and, in 3 cases, no local surgery was performed. With a median follow-up of 4 years (6.2 years for survivors), 13 patients were alive. Four patients never achieved a complete remission, and 11 developed recurrences; 14 of these 15 patients died. Five-year overall and event-free survival probabilities were 51% (standard error of the mean [SE], 10%) and 48% (SE, 10%). Better survival was correlated with good response to chemotherapy and later time period of diagnosis.Osteosarcoma is extremely rare in preschool children. These patients often have large tumors that may require mutilating resections. Prognosis is in the range of that reported for older patients.

Leo Kager1, Ulrike Pötschger2, Stefan Bielack31St. Anna Children’s Hospital, Vienna, Austria; 2Children’s Cancer Research Institute, Vienna, Austria; 3Klinikum Stuttgart, Olgahospital, Pediatrics 5 – Oncology, Hematology, Immunology, Stuttgart, GermanyAbstract: Osteosarcoma is the most common primary malignant tumor of bone. The disease, however, is very rare with less than 2,000 expected patients at all age groups per year within the European Union and the United States of America. With multimodal therapy, which combines multiagent chemotherapy and complete resection of all macroscopically detectable tumors, about 60%–70% of patients with localized osteosarcoma can be cured. The prognosis, however, is still poor for patients with synchronous or metachronous metastatic or nonresectable primary disease, with reported 5-year event-free survival (EFS) rates of less than 30%. Overall, the EFS rate has been rather stable since the introduction of combination chemotherapy including doxorubicin, cisplatin, high-dose methotrexate with leukovorin rescue, and/or ifosfamide. Mifamurtide, a modulator of innate immunity, which activates macrophages and monocytes, which in turn release chemicals with potential tumoricidal effects, may help to control microscopic metastatic disease and has been safely given together with standard adjuvant chemotherapy to patients with high-grade osteosarcoma. Results of the recently published intergroup study 0133 trial from the Children’s Cancer and Pediatric Oncology Groups suggest that mifamurtide is a medicine that deserves further investigation in this orphan disease.Keywords: orphan drug, orphan disease, outcome innate immunity, immunotherapy

The congenital hypoplastic-dysplastic kidney is characterized by a significant reduction of renal mass, an abnormal parenchymal differentiation and is associated with anomalies of the whole urinary tract. Not much is known about the ability for regeneration in such a kidney. We report on a 2 year 11 months old boy with an anaplastic Wilms tumor of the left kidney, in whom after tumor-nephrectomy an unexpected functional and sonographically documented morphological regeneration of the contralateral hypoplastic-dysplastic kidney occurred. The regeneration of this kidney is especially notable, because it occurred during nephrotoxic chemotherapy and radiotherapy.

Lessons from the analysis of children with TCF3-PBX1 ALL could help to identify treatment components essential for this leukemia subtype. Of 859 children with ALL who were treated in ALL-BFM trials in Austria, 31 (3.6%) had a TCF3-PBX1 ALL. The 5-year event-free survival rate for these 31 patients was 90%+/-5%. Patients with TCF3-PBX1 ALL treated on the ALL-BFM 86 trial had a poorer outcome than patients with TCF3-PBX1 ALL treated on later trials. These data document that contemporary ALL-BFM treatment is highly effective in children with TCF3-PBX1 ALL. Implementation of early dose-intensified remission induction may be an essential treatment component.

10512 Background: EURAMOS-1 (NCT00134030) is an international study in osteosarcoma including two Phase III randomized controlled trials that investigated postoperative treatment optimization on th...

Purpose The outlook for patients with osteosarcoma who present with synchronous regional bone metastases (skip metastases), either in the primary bone site or transarticular, is considered to be extremely poor. This study was conducted to further investigate the prognostic implication of skip metastases in osteosarcoma. Patients and Methods The authors retrospectively analyzed the collected data of 1,765 consecutive patients with newly diagnosed high-grade osteosarcoma of bone who were registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies and identified 24 patients (1.4%) with unequivocally proven skip metastases. All 24 patients were treated by an aggressive surgical approach coupled with polychemotherapy. Demographic, diagnostic, tumor, and treatment-related variables and response and survival data were analyzed. Results Skip metastases were identified preoperatively in 11 of 24 patients by bone scan, eight of 22 patients by plain x-ray, 15 of 18 patients by magnetic resonance imaging, and five of 10 patients by computed tomography. A complete surgical remission (CSR) of all clinically detectable tumor sites was achieved in 22 of 24 patients during front-line therapy. With a median follow-up time of 4.4 years (8 years for survivors) from diagnosis, 12 patients were alive, all of whom were in continuous CSR. Survival did correlate with location of skip metastases and histologic response to neoadjuvant chemotherapy. Conclusion Synchronous regional bone metastases are rare in osteosarcoma, and preoperative detection relies on appropriate diagnostic imaging. Aggressive multimodal therapy holds the promise to achieve prolonged survival, especially in patients in whom these metastases occur within the same bone as the primary lesion and whose tumors respond well to chemotherapy.