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Background and Objectives: In a previous conducted study functional outcome of young patients with bone sarcoma located around the knee was longitudinally evaluated during the first 2 years postoperatively. Functional outcome improved significantly over the first 2 years. The purpose of this descriptive study was to evaluate the functional outcome of these patients at long-term follow-up of 7 years. Methods: Functional outcome was assessed with the TESS, MSTS, Baecke questionnaire, and three functional performance tests: time up and down stairs (TUDS), various walking activities (VWA), and the 6-min walking test (6MWT). Linear Mixed Model has been employed for

A better understanding of the reconstitution of the B-cell compartment during and after treatment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) will help to assess the immunological status and needs of post-treatment BCP-ALL patients. Using 8-colour flow cytometry and proliferation-assays, we studied the composition and proliferation of both the B-cell precursor (BCP) population in the bone marrow (BM) and mature B-cell population in peripheral blood (PB) during and after BCP-ALL therapy. We found a normal BCP differentiation pattern and a delayed formation of classical CD38dim -naive mature B-cells, natural effector B-cells and memory B-cells in patients after chemotherapy. This B-cell differentiation/maturation pattern was strikingly similar to that during initial B-cell development in healthy infants. Tissue-resident plasma cells appeared to be partly protected from chemotherapy. Also, we found that the fast recovery of naive mature B-cell numbers after chemotherapy was the result of increased de novo BCP generation, rather than enhanced B-cell proliferation in BM or PB. These results indicate that post-treatment BCP-ALL patients will eventually re-establish a B-cell compartment with a composition and B-cell receptor repertoire similar to that in healthy children. Additionally, the formation of a new memory B-cell compartment suggests that revaccination might be beneficial after BCP-ALL therapy.

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

Background Outcomes for younger patients with R/R cHL are poor, particularly for those without complete metabolic response (CMR) before autologous transplant (auto-HCT). CheckMate 744 ( NCT02927769 ) is an ongoing phase 2 study for CAYA with R/R cHL, evaluating a risk-stratified, response-adapted approach using nivolumab plus BV, and for patients without CMR, BV plus bendamustine. In the initial analysis of the standard-risk cohort (R2), the regimen was well tolerated with high CMR rates before consolidation with high-dose chemotherapy plus auto-HCT. We report primary analysis data. Patients 5–30 years old; had first-line treatment without auto-HCT. Design Risk stratification has been described (Harker-Murray, ASH 2018). Patients received 4 induction cycles of nivolumab plus BV; patients without CMR by blinded independent central review (BICR) received BV plus bendamustine intensification. Patients with CMR at any time could proceed to consolidation off study. Response was per Lugano 2014 criteria. Primary endpoint: CMR rate (Deauville ≤3) per BICR any time before consolidation. Results 44 patients were treated in R2 (median follow-up: 20.9 months); 43 received 4 induction cycles and 11 received intensification. Median age was 16 years (range, 9–30); 24 (55%) patients had primary refractory cHL. CMR rate (90% CI) any time before consolidation was 88% (77–95) and 89% (78–95) per BICR and investigator, respectively; objective response rate (ORR) was 98% by either assessment. After 4 cycles of induction, CMR was 59% and 66% per BICR and investigator, respectively; ORR (90% CI) was 82% (70–91) and 89% (78–95), respectively. One-year progression-free survival rate by BICR was 91% (90% CI, 77–96). During induction, 8 patients (18%) experienced grade (G) 3–4 treatment-related adverse events (TRAEs); the most common any-grade TRAEs were nausea and hypersensitivity (20% each). One TRAE led to discontinuation (G3 anaphylaxis). Most treatment-related immune-mediated AEs were G1–2 (1 patient had 2 G3 infusion-related reactions). Conclusions This risk-stratified, response-adapted approach offers a well-tolerated salvage strategy with high CMR rates and no new safety signals for CAYA with R/R cHL. Most patients avoided bendamustine prior to consolidation. Further follow-up may confirm durability of disease control. Funding BMS. Previous presentation ASCO 2020

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50–60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAFV600E transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAFV600E protein are not presented by HLA class I molecules. Given that the BRAFV600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.

Activation of B-cell receptor (BCR) signaling is an important mechanism of the development and growth of B-cell lymphomas. Bruton’s tyrosine kinase (BTK) is a key component of BCR signaling and functions as an important regulator of cell proliferation and cell survival in various B-cell lymphomas. BTK inhibitors, especially ibrutinib, have shown promising anti-tumor activity in preclinical and clinical studies. High response rates of ibrutinib were reported in patients with a variety of B-cell non-Hodgkin lymphoma (B-NHL) such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, clinical evidence shows primary and acquired resistance to BTK inhibitors in patients. Understanding the molecular mechanisms underlying BTK inhibitors’ resistance is of paramount importance. In this review, we highlight the potential resistant mechanisms, which include mutational resistance in BTK, mutational resistance in other proteins than in BTK, chromosomal abnormalities, activation of prosurvival pathways, B-cell lymphoma 2 (BCL-2) family members mediated resistance, and tumor microenvironment mediated resistance. We also discuss the strategies that are utilized to overcome BTK inhibitors’ resistance: non-covalent inhibitors of BTK, alternate kinase inhibitors, combination therapies with other oncogenic inhibitors, BCL-2 inhibitors, anti-CD20 antibodies, anti-CD19 chimeric antigen receptor (CAR) T cells, CD19/CD3 bispecific antibody, or with inhibitors targeting other cellular processes.

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAF(V600E) driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAF(V600E) can be a source of neoantigens capable of eliciting effective antitumor CD8(+) T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8(+) T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8(+) T cell density in n = 101 LCH-lesions, with BRAF(V600E) mutated lesions displaying significantly lower CD8(+) T cell:CD1a(+) LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8(+) T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAF(V600E) protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAF(V600E) derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAF(V600E) expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAF(V600E) transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAF(V600E) protein are not presented by HLA class I molecules. Given that the BRAF(V600E) mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.

Non-Hodgkin’s lymphoma (NHL) results from malignant proliferation of lymphocytes and is generally restricted to lymphoid tissue such as lymph nodes, Peyer’s patches, and spleen. However, pediatric NHL can rarely and solely arise in other anatomical sites, such as the kidney, skin, lung, eye, bone, stomach, or cavities as an effusion. Adult-type lymphomas (chronic lymphocytic leukemia and multiple myeloma) have scarcely been reported in children. Understanding of these rare pediatric B-NHLs is mainly based on small pediatric case series or adult studies. Due to the limited number of cases the exact prevalence of the abovementioned NHL types cannot be easily estimated. Moreover, the index of suspicion is usually low because of the rarity, resulting sometimes in late diagnosis with a significant impact on prognosis. Since these NHL types are often more well-studied in adult population, adult-based therapeutic approaches are also applied in children. Prognosis in pediatric patients may be different from that of adults. So, more international collaborative efforts are needed in order to identify specific prognostic factors, including molecular and cytogenetic variables and define specific pediatric treatment protocols.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern, a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern, and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p &lt, 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.

8013 Background: Outcomes for younger patients (pts) with R/R cHL are poor, particularly for those without complete metabolic response (CMR) before autologous transplant (auto-HCT). Nivolumab + BV has shown 67% CMR and a high 2-y PFS rate as first salvage in adults with R/R cHL. CheckMate 744 (NCT02927769) is an ongoing phase 2 study for CAYA with R/R cHL, evaluating a risk-stratified, response-adapted approach using nivolumab + BV and, for pts without CMR, BV + bendamustine. In the initial analysis of the standard-risk cohort (R2), the regimen was well tolerated with high CMR rates before consolidation with high-dose chemotherapy plus auto-HCT. We report data from the primary analysis. Methods: Pts were aged 5–30 y and had first-line treatment (tx) without auto-HCT. Risk stratification has been described previously (Harker-Murray, ASH 2018). Pts received 4 induction cycles of nivolumab + BV; pts without CMR by blinded independent central review (BICR) received BV + bendamustine intensification. Pts with CMR at any time could proceed to consolidation off study. Response was per Lugano 2014 criteria. Primary endpoint: CMR rate (Deauville ≤3) per BICR any time before consolidation. Results: At database lock, 44 pts were treated in R2 (median follow up: 20.9 mo); 43 received 4 induction cycles and 11 received intensification. Median age was 16 y (range 9–30); 24 (55%) pts had primary refractory cHL and 20 had relapsed cHL. CMR rates and ORR any time before consolidation and after induction are shown in Table. 1-y PFS rate by BICR was 91% (90% CI 77–96). During induction, 8 (18%) pts experienced grade (G) 3–4 tx-related adverse events (TRAEs); the most common any grade TRAEs were nausea and hypersensitivity (20% each). 1 TRAE led to discontinuation (G3 anaphylaxis). Most tx-related immune-mediated AEs were G1–2 (1 pt had 2 G3 infusion-related reactions). Conclusions: This risk-stratified, response-adapted approach offers a well-tolerated salvage strategy with high CMR rates and no new safety signals for CAYA with R/R cHL. Most pts avoided alkylator exposure prior to consolidation. Further follow up may confirm durability of disease control. Clinical trial information: NCT02927769 . [Table: see text]

Summary Background Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, treatment of relapsed or refractory disease remains challenging. The aims of this study were to assess the safety, tolerability, recommended phase 2 dose, and efficacy of brentuximab vedotin in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. Methods This open-label, dose-escalation phase 1/2 study was done at 12 centres across eight countries (France, Germany, Italy, Mexico, The Netherlands, Spain, UK, and USA). We recruited paediatric patients aged 7–18 years with relapsed or refractory classical Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, for whom standard treatment was unavailable or no longer effective. Participants were allocated to receive brentuximab vedotin at 1·4 mg/kg (phase 1) or 1·8 mg/kg (phases 1 and 2) via intravenous infusion once every 3 weeks for up to 16 cycles. Dose escalation was done via a 3+3 design. Key exclusion criteria were stem-cell transplantation less than 3 months before administration of the first dose of study drug, presence of cytomegalovirus infection after allogeneic stem-cell transplantation, previous treatment with an anti-CD30 antibody, and concurrent immunosuppressive or systemic therapy for chronic graft-versus-host disease. Primary outcomes were safety profile in the safety-evaluable population and maximum tolerated dose, recommended phase 2 dose, pharmacokinetics (phase 1), and proportion of patients who achieved best overall response (phase 2; evaluated by an independent review facility) in the response-evaluable population. This trial is registered with ClinicalTrials.gov , number NCT01492088 . Findings Between April 16, 2012, and April 4, 2016, we screened 41 paediatric patients and enrolled 36 (aged 7–18 years), of whom 19 had relapsed or refractory classical Hodgkin's lymphoma and 17 had relapsed or refractory systemic anaplastic large-cell lymphoma. At the data cutoff (Oct 12, 2016), all 36 patients had discontinued study drug treatment; the most common reason was progressive disease (15 patients). The maximum tolerated dose was not reached. The recommended phase 2 dose was 1·8 mg/kg. The proportion of patients who achieved overall response was 47% (95% CI 21–73) for classical Hodgkin's lymphoma and 53% (28–77) for systemic anaplastic large-cell lymphoma. All 36 patients had a treatment-emergent adverse event and 16 patients (44%) had at least one grade 3 or worse treatment-emergent adverse event. The most common treatment-emergent adverse events were pyrexia (16 [44%] of 36) and nausea (13 [36%]). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (four [11%]), increased γ-glutamyl transpeptidase (two [6%]), and pyrexia (two [6%]). 12 (33%) patients had transient, limited-severity peripheral neuropathy. Eight patients (22%) had a serious adverse event; three (8%) had a drug-related serious adverse event. One patient died of cardiac arrest (disease progression of a large huge mediastinal mass, unrelated to the study drug). Paediatric pharmacokinetic profiles were consistent with those from studies of adult patients. Interpretation Brentuximab vedotin has manageable toxicity and is associated with clinically meaningful responses in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, and could allow subsequent stem-cell transplantation in some patients who were initially ineligible for stem-cell transplantation. Funding Millennium Pharmaceuticals Inc.

To determine whether the current 18F-FDG PET response criterion for skeletal involvement in Hodgkin lymphoma (HL) is suitable, we performed a systematic evaluation of the different types of skeletal involvement and their response on PET after 2 cycles of chemotherapy (PET-2). A secondary objective was to observe the influence of the initial uptake intensity (measured as qPET) and initial metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. Methods: The initial PET scans of 1,068 pediatric HL patients from the EuroNet- PHL-C1 trial were evaluated for skeletal involvement by central review. Three types of skeletal lesions were distinguished: PET-only lesions (those detected on PET only), bone marrow (BM) lesions (as confirmed by MRI or BM biopsy), and bone lesions. qPET and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response for skeletal and nodal involvement on PET-2 were compared. Results: Of the 1,068 patients, 139 (13%) showed skeletal involvement (44 PET-only, 32 BM, and 63 bone). Of the 139 patients with skeletal involvement, 101 (73%) became PET-2–negative in the skeleton and 94 (68%) became PET-2–negative in the lymph nodes. The highest number of PET-2–negative scans in the skeleton was 42 (95%) in the 44 PET-only patients, followed by 22 skeletal lesions (69%) in the 32 BM patients and 37 (59%) in the 63 bone patients. Lesions that became PET-2–negative showed a lower initial median qPET (2.74) and MTV (2 cm3) than lesions that remained PET-2– positive (3.84 and 7 cm3, respectively). Conclusion: In this study with pediatric HL patients, the complete response rate for skeletal involvement on PET-2 was similar to that for nodal involvement. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion—comparison with the local skeletal background—is well suited. The initial qPET and MTV of skeletal lesions were predictive of the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response.

BACKGROUND: Traditionally, in ethical guidelines and in research ethics literature, care and research are clearly separated based on their different objectives. In contrast, in paediatric oncology, research and care are closely combined. Currently, it is unknown how relevant actors in paediatric oncology perceive this combination of research and care. We conducted a qualitative study into the experiences of those involved in Dutch paediatric oncology with the intertwinement of research and care and the dual role of paediatric oncologists as researchers and treating physicians. PROCEDURE: A qualitative study approach, using two focus groups and 19 semi-structured, in-depth interviews with paediatric oncologists, research coordinators, parents of children with cancer, and adolescents with cancer. RESULTS: Four themes characterize how actors experience the intertwinement of research and care in paediatric oncology. First, research is considered of major importance, and paediatric oncology professionals convey this message to patients and their parents. Second, there is ambiguity about categorization of studies into cancer therapy as either research or treatment. Third, role conflicts appear within the work of the paediatric oncologists. Finally, the various benefits of combining treatment with research are emphasized. CONCLUSIONS: Research is regarded as a fundamental and indispensable characteristic of paediatric oncology practice. Paediatric oncology professionals, parents, and patients have a very positive outlook on combining research and care, but they may not be sufficiently critical with respect to potential conflicts. Increased reflection on how to optimally combine research and care could serve as an important protection of the interests of children with cancer and their parents

Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0-61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.

Interim FDG-PET is used for treatment tailoring in lymphoma. Deauville response criteria consist of five ordinal categories based on visual comparison of residual tumor uptake to physiological reference uptakes. However, PET-response is a continuum and visual assessments can be distorted by optical illusions. With a novel semi-automatic quantification tool we eliminate optical illusions and extend the Deauville score to a continuous scale. SUVpeak of residual tumors and average uptake of the liver is measured with standardized volumes of interest. The qPET value is the quotient of these measurements. Deauville scores and qPET-values were determined in 898 pediatric Hodgkin’s lymphoma patients after two OEPA chemotherapy cycles. Deauville categories translate to thresholds on the qPET scale: Categories 3, 4, 5 correspond to qPET values of 0.95, 1.3 and 2.0, respectively. The distribution of qPET values is unimodal with a peak representing metabolically normal responses and a tail of clearly abnormal outliers. In our patients, the peak is at qPET = 0.95 coinciding with the border between Deauville 2 and 3. qPET cut values of 1.3 or 2 (determined by fitting mixture models) select abnormal metabolic responses with high sensitivity, respectively, specificity. qPET methodology provides semi-automatic quantification for interim FDG-PET response in lymphoma extending ordinal Deauville scoring to a continuous scale. Deauville categories correspond to certain qPET cut values. Thresholds between normal and abnormal response can be derived from the qPET-distribution without need for follow-up data. In our patients, qPET < 1.3 excludes abnormal response with high sensitivity.

Background Ovarian infiltration in pediatric non-Hodgkin lymphoma (NHL) at presentation is rare and information on outcome is scarce and mainly based on case reports and small series. Procedure Evaluation of clinical characteristics and outcome of ovarian infiltrated pediatric NHL cases of a single center, and an extensive review of the all cases reported so far in literature. Results At presentation, 6/60 female NHL cases of our center had ovarian infiltration, and combining these cases with earlier case reports, a total of 42 cases were identified. Median age at presentation was 10.9 years (range 0–18), and all but one had a B-cell immunophenotype, with 32/42 cases being classified as Burkitt. Bilateral involvement was reported in 26/41 cases, of which 22 were bilaterally ovariectomized as first treatment. All cases were treated with chemotherapy. Relapses were reported in 9/36 and death in 16/36. After follow-up in our center (median 13.4 years), in 2 cases anti-Mullerian hormone (AMH) values were available (2.1 and 0.9 µg/L), in non-ovarian cases median 2.2 µg/L. Conclusions We conclude that in case of ovarian tumors with negative markers, NHL should be considered in order to avoid unnecessary surgery. Pediatr Blood Cancer 2013;60:2054–2059. © 2013 Wiley Periodicals, Inc.

Data on clinical features and outcome in pediatric follicular lymphoma (pFL) are scarce. The aim of this retrospective study including 13 EICNHL and/or i-BFM study group members was to assess clinical characteristics and course in a series of 63 pFL patients. pFL was found to be associated with male gender (3:1), older age (72 % ≥10 years old), low serum LDH levels (

Item does not contain fulltext BACKGROUND: The hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy leading to acute kidney injury in children. In most cases it is triggered by an infection caused by Shiga-like toxin-producing Escherichia coli (STEC). Endothelial damage plays a central role in the pathogenesis of disease. Hemophilia A is a genetic disorder leading to factor VIII (FVIII) deficiency, an important factor in the coagulation system. CASE: Here we describe a hemophilia A patient who developed HUS due to a STEC O26 infection. The patient developed not only acute kidney injury, but also severe gastro-intestinal and neurological complications. Increased amounts of recombinant FVIII (rFVIII) had to be administered during the acute phase of the disease to reach acceptable blood levels of FVIII, in order to control the hemorrhagic colitis and to prevent severe neurological complications. CONCLUSION: The patient's treatment schedule of rFVIII during the HUS period was a serious challenge, and we cannot exclude that it contributed to the severity of the HUS by enhancing the thrombotic microangiopathic process. The role of factor VIII administration in the severe outcome of this disease is discussed.

Summary. Background: Use of age-adjusted reference values is crucial for correct diagnosis and management of thrombotic and hemorrhagic disease in children. They vary with utilized reagents and analyzers. Objectives: We established reference values with the Sysmex CA-1500 System and in parallel with the Behring BCS System using reagents from Siemens Healthcare Diagnostics Products GmbH. Methods: After informed consent, blood samples were obtained from 218 healthy children and 52 healthy adults, grouped as 1–6 months (n =2 9), 7–12 months (n = 25), 1–5 years (n = 57), 6–10 years (n =5 7), 11–18 years (n = 50) and > 19 years (n = 52). Results: Most coagulation parameters demonstrate good comparability between analyzers with the exception of PT and APTT. Single coagulation factors fibrinogen, factor (F) II, FIX, FXI and XII were significantly decreased in the youngest children; the strongest age dependency was found for coagulation inhibitors Protein Ca nd S, both signif icantly decreased in infancy and young childhood. We confirmed that high levels of von Willebrand factor are found in the youngest children without increased levels of FVIII followed by decreased von Willebrand levels in the subsequent age group. In children with blood group O a less distinct increase in time was found, compared with individuals with one of the other blood groups. Conclusions: The correlation between the CA-1500 and the BCS system was remarkable. Differences were most pronounced between children < 12 months and older children and adults, confirming the phenomenon of developmental hemostasis. The rationale for age-related changes in the hemostatic system remains unraveled. Our results underline the need for age-specific reference ranges.

Abstract 5215 Introduction. Currently, the 5-year survival for childhood NHL is ∼80%. Because of this high survival rate and since treatment is administered in a growing and developing individual, long-term side effects are an important issue. Studies on endocrine long-term effects in survivors of childhood non-Hodgkin lymphoma (NHL) are scarce and often limited by small sample sizes, or by the fact that data of NHL survivors have been combined with that of survivors of other malignancies. Aim of this study was to investigate the long-term endocrine effects of treatment for childhood NHL. Methods. A single centre cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 yrs (9–40 yrs) and time after cessation of therapy 12 yrs (4–30 yrs). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMDTB) and lumbar spine (BMDLS) were measured. Bone mineral apparent density of the lumbar spine (BMADLS) was calculated to correct for bone size. Thyroid stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), Inhibin-B and anti-müllerian hormone (AMH) levels were measured. Results were compared with Dutch controls. Results. Height was lower in survivors at follow-up (mean SDS −0.36, P=0.002), but further analysis showed that shorter stature was already present at diagnosis (mean SDS −0.28, P=0.023). BMI, percentage fat, BMC, BMDTB, BMDLS and BMADLS were not different from controls. LBM was lower in survivors (mean SDS −0.47, P=0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three out of 20 adult females had low AMH levels and 55% (23/42) of adult males had low Inhibin-B levels. Conclusion. Twelve years after cessation of therapy, survivors of NHL did not develope adiposity, osteopenia or osteoporosis or thyroid disease. Male NHL survivors seem to be at risk for infertility. Disclosures: No relevant conflicts of interest to declare.

The Group Medical Appointment (GMA) is a novel consultation form in which patients undergo individual consultations in each other's presence. To compare participants' experiences with GMA and Individual Medical Appointments (IMA), the usual standard of care, our team recently implemented the GMA for children aged 0-18 years with haemophilia or von Willebrand's disease. Participants' experiences with GMA were measured using a standardized QUOTE-questionnaire. Of 100 addressed families, 53 participated in GMA. Of these 53 families, 38 parents (72%) and 14 adolescents (82%) filled in the questionnaire about the GMA. Patients not on prophylaxis were defined as less experienced and patients on prophylaxis, as experienced. Although parents were satisfied with both GMA and IMA (median score 8.0 vs. 9.0 of 10), a significant difference was demonstrated between less experienced and experienced parents. After GMA, less experienced parents were significantly more satisfied (median score 8.0 vs. 5.0; P-value 0.006), felt more social support (82% vs. 30%; P-value 0.005) and reported additional learning effects with regard to disease and treatment (64% vs. 0%; P-value

Context: Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported.Objective: Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied.Patients: We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia.Results: The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578H-LHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin.Conclusions: Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up until now to be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant. (J Clin Endocrinol Metab 96: E1197-E1205, 2011)

Data on incidence, characteristics, and prognosis in stage I childhood anaplastic large cell lymphoma are scarce. Of 463 patients enrolled in the international ALCL99 trial, 36 (8%) had stage I disease and were treated with a prephase chemotherapy, followed by either 3 chemotherapy courses in case of initial complete resection (6 patients) or otherwise by 6 courses of chemotherapy (30 patients). Disease localization was to the peripheral lymph nodes in 26, soft tissue mass in 8, and solitary bone and bronchial disease in 1 patient each. Of the 6 patients with complete resection, none experienced relapse, whereas of the 30 remaining stage I patients, 9 (30%) relapsed, including in all cases a new site of disease involvement and including 3 of 5 anaplastic lymphoma kinase–negative patients. In summary, the failure rate for incompletely resected stage I disease was similar to that for patients with stage II and stage III/IV disease. Whether anaplastic lymphoma kinase negativity contributed to this moderate outcome has to be proven prospectively. This study was registered at www.clinicaltrials.gov as NCT00006455.

Background: Aim of our study was to compare functional ability and physical activity in children and young adults who underwent surgery for a malignant bone tumor that was located around the knee. Methods: This cross-sectional study included 82 patients aged 8-25 years with a follow-up of 1-5 years. The functional ability and the amount of physical activity were evaluated by means of questionnaires and objective instruments. Results: Thirty nine patients underwent limb-salvage surgery (24 allograft and 15 endoprosthesis) and 43 underwent ablative surgery (27 amputations and 16 rotationplasty). Patients in the limb-salvage group were significantly older at the time of surgery than patients in the ablative group (mean age 15.2 years vs. 13.2 years, P = 0.03). Apart from significantly better scores for the timed up and down stairs and various walking activities in the limb-salvage group as compared to the ablative surgery group, no significant differences were seen for any of the outcome measures. Conclusions: One to 5 years after limb-salvage and ablative surgery due to a malignant bone tumor children and young adults do, apart from a few activities involving walking and climbing stairs, not differ with respect to overall functional ability and physical activity. J. Surg. Oncol. 2011;103:276-282. (C) 2010 Wiley-Liss, Inc.

Background Pediatric classical Hodgkin lymphoma (cHL) is a clonal disorder in an inflammatory background, also known as the microenvironment. This microenvironment is of major importance for growth and survival of the malignant Hodgkin/Reed Sternberg (HRS) cells. HRS cells and the microenvironment communicate through chemo- and cytokines. Blood biomarkers result from this active crosstalk, and may be a surrogate for lymphoma viability (Steidl et al, JCC 2011). Blood biomarkers are important because they hold the promise to be easily available and cost-effective. One promising biomarker in adult patients with cHL is the "Thymus and Activation-Regulated Chemokine, TARC (Plattell et al, Haematologica 2012). Elevated TARC levels are also described in patients with atopic dermatitis (Hijnen et al, J All Clin Immunol 2004). In adult cHL patients about 85% of patients have significantly elevated levels of TARC in pre-treatment serum or plasma compared to healthy controls (Plattell et al). So far nothing is known about TARC in pediatric cHL patients. To define its value as a diagnostic marker in pediatric cHL patients, we compared TARC levels of pediatric cHL patients with control patients. This study was IRB-approved and registered under Dutch Trial registry number 6876. Methods After providing informed consent, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment. To define normal values of TARC in children, samples were collected from non-cHL randomly selected patients from the hematology, endocrinology and oncology outpatient clinic. Baseline characteristics including history of atopic dermatitis were collected. These control patients were divided in three age groups (0-9,10-14 and 15-18 years). TARC levels were measured by enzyme-linked immunosorbent assay (R&D systems, Human CCL17/TARC Quantikine ELISA Kit). TARC levels of the cHL patients were compared to the control group to obtain ROC curves and calculate the AUC, cross-validated sensitivity and specificity and accuracy of TARC as a diagnostic marker. We hypothesized that pediatric cHL patients had elevated pretreatment TARC levels in both serum and plasma. Analyses were done using SAS V9.4. Results Fourteen cHL patients were included with a median age of 14 (range 11-17) years. Ten (71.4%) were female. Eighty patients were included in the control group with a median age of 12 (range 10 months-18) years. Twenty-nine patients (36.3%) were included in age group 0-9, 25 (31.2%) in age group 10-14 and 26 (32.5%) in age group 15-18. Thirty-nine (48.8%) were female. Patients of the control group had a median TARC value of 71 (range 18-762) pg/ml for plasma and 318 (range 27-1300) pg/ml for serum. TARC plasma and serum levels decreased with age (Spearman correlation -0.26, 2-tailed p=0.0204), but there were no statistically significant pairwise comparisons found between the pre-specified age groups. In the eight control patients (10%) with atopic dermatitis no significantly higher plasma and serum levels were found (plasma median with eczema 97 versus 70 pg/ml without eczema (p=0.71) and serum median with eczema 643 versus 317 pg/ml (p=0.71)). Plasma was collected in 14 cHL patients, and all had elevated TARC levels, with a median plasma level of 18449 (range 1635-55821) pg/mL. Serum samples were collected in 8/14 cHL patients and all had elevated serum TARC levels. Median serum level: 46703 (range 12817-149739) pg/ml. The plasma TARC levels of cHL patients were significantly higher than those of the control group patients (p Conclusion All classical cHL patients had significantly higher TARC levels compared to the 80 control patients. Despite the small sample size of cHL patients, TARC was found to be a sensitive and specific diagnostic marker for pediatric cHL in both plasma and serum. Further research with a bigger sample of cHL patients is necessary to improve the accuracy of the sensitivity, as well as to investigate whether TARC is also a valuable marker for disease response during treatment in pediatric patients with cHL. Disclosures No relevant conflicts of interest to declare.

Introduction: Classical Hodgkin lymphoma (cHL) is among the most common malignancies in adolescents and young adults. High-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (ASCT) are standard for most patients with relapsed/refractory (R/R) disease. Current salvage therapies are associated with excessive toxicity and variable complete remission rates (Harker-Murray et al, Pediatr Blood Cancer 2014). Novel regimens that increase remission rates and reduce late effects of therapy are needed, particularly for young patients. Nivolumab (nivo) is a fully human IgG4 anti-programmed death-1 monoclonal antibody. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate. In a phase 1/2 study of adults with R/R cHL, the combination of nivo + BV was well tolerated, with a high response rate as first salvage regimen (Herrera et al, Blood 2018). CheckMate 744 (AHOD1721; NCT02927769) is the first risk-stratified, response-adapted, phase 2 study of nivo + BV, followed by BV + bendamustine for suboptimal response, in children, adolescents, and young adults with R/R cHL with low or standard risk of relapse. Here we report preliminary, investigator (INV)-assessed results from the standard-risk (R2) cohort. Methods: This open-label study enrolled patients aged 5-30 years with pathologically confirmed cHL, excluding nodular lymphocyte-predominant HL, after failure/non-response to first-line therapy and without prior ASCT. Stratification to R2 was based on refractory disease or early relapse; B symptoms, extranodal disease, or extensive disease with radiation therapy (RT) contraindicated at relapse; relapse in a prior RT field; or stage IIIB or IV at initial diagnosis. Patients in R2 received induction (IND) with 4 cycles of nivo + BV. Patients without complete metabolic response (CMR; Deauville score 1-3) received intensification (INT) with 2-4 cycles of BV + bendamustine. Patients with CMR after IND or INT discontinued study treatment, proceeded to HDCT/ASCT, and entered follow-up. Tumors were assessed by INV and blinded independent central review (BICR) per Lugano 2014 criteria (Cheson et al, J Clin Oncol 2014) every 2 treatment cycles. Treatment decisions were based on BICR assessment. The primary endpoint was CMR rate by BICR prior to HDCT/ASCT. Secondary endpoints included INV-assessed response and safety. Results: At database lock (DBL), 32 patients in R2 had entered IND. Median age was 16 y (range 9-30), 78% were aged Conclusion: For children, adolescents, and young adults with standard-risk R/R cHL prior to ASCT, this risk-stratified, response-adapted approach using nivo, BV, and bendamustine resulted in high CMR rates and was well tolerated, making it a promising novel salvage therapy. Most evaluated patients achieved CMR with IND (nivo + BV); all 6 who went to INT (BV + bendamustine) achieved CMR. Updated results based on a planned interim analysis including more patients and BICR-assessed response data will be presented. Study support: Sponsored by Bristol-Myers Squibb in collaboration with Children's Oncology Group (COG) and EuroNet group. Disclosures Leger: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Brugieres:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Financial support for SIOP meeting in 2016. Galderisi:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Jou:Bristol-Myers Squibb: Employment, Other: company stock ownership.

Background One in four cases of childhood cancer is incurable. In these cases death can usually be anticipated and therefore preceded by a phase of palliative care. For parents, preparing to let their child die is an extraordinarily painful process. Most struggle to preserve their child. This study identified, from a parental perspective, the main factors that influence the transition from preserving life to letting go. Procedure A multi-centre, qualitative research, study was undertaken during the end-of-life (EoL) phase, comprising single or repeated interviews with 44 parents of 23 children with incurable cancer. Results We discovered that uncertainty, fragmentation and anxiety underpin the preserving life perspective. A perspective of letting go could be supported by a variety of factors. These included: Certainty that the child cannot be cured, postponed grief, the perception of suffering, the ability to disentangle needs and the ability to parent meaningfully. Hope, creating a peaceful parent–child relationship, and the attitude of professionals, could support movements in either direction. Of these, certainty, and in most cases postponed grief, were pre-conditions for the transition towards letting go. Strategies such as not challenging the parents' suppression of grief, creating certainty about the child's condition and supporting parents in efforts to redefine their parental role, supported progress towards accepting a letting go perspective. Conclusions Parents' internal struggle between a preserving frame of mind and one of letting go is influenced by a combination of factors. However, professionals can influence some of these factors in order to facilitate this transition. Pediatr Blood Cancer 2010;54:1000–1008 © 2010 Wiley-Liss, Inc.

Background. This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. Procedure. Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received the TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Center) Children's Quality of Life Questionnaire (TACQOL), patients aged 16 years and older received the TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and the Short Form-36 (SF-36). Three age- and sex-matched normative random samples, drawn from large, nationwide studies, were used for the comparison with healthy controls. Patients were interviewed regarding their most important problems related to the disease and its treatment. Results. Eighty-one patients with a mean age of 16.9 years (SD 4.2) were included (41 female). Limb sparing surgery was executed in 38 patients, ablative surgery in 43 patients. In comparison with healthy controls, patients had significantly poorer HROoL within the domains autonomy and motor function of the TACQOL, gross motor function, cognitive functioning, daily functioning and sexuality of the TAAQOL, and physical functioning, role physical, general health, and the physical and mental component summary scales of the SF-36. Patients reported limitations in physical activities, participation in sports, and cosmetic aspects as the most detrimental consequences of their disease and its treatment. Conclusion. In children and adolescents who underwent surgery for a malignant tumor of the leg physical, functioning was significantly impaired as compared to healthy controls. Pediatr Blood Cancer 2010;54:738-745. (c) 2010 Wiley-Liss, Inc.

Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters.

Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were

Background. To examine the practical applicability, internal consistency, and validity of the Bt-DUX, a disease-specific Health Related Quality of Life (HRQoL) instrument. The Bt-Dux was developed to examine patients’ individual values of their life after a malignant bone tumor of the lower extremity at four domains (cosmetic, social, emotional, and functional). Procedure. Patients were eligible for this cross-sectional, multicenter study if they underwent surgery for a malignant tumor of the leg in a period ranging between 12 and 60 months before the recruitment. Assessments included: Bt-DUX, Toronto Extremity Salvage Score (TESS) Short Form (SF)-36, TNO-AZL Questionnaire for Adult’s Quality of Life (TAAQOL), and TNO-AZL Children’s Quality of Life Questionnaire (TACQOL). Results. Seventy-two patients (35 male, 37 female), mean age 17 (SD 4) years were included. Limb sparing surgery took place in 32 patients and ablative surgery in 40 patients. The Bt-DUX was completed in less than 5min and easy to comprehend. The mean Bt-DUX score was 69.8 (SD 15.5), with Cronbach’s alpha being 0.92. Domain‐total correlations ranged between 0.84 and 0.88 (P

Objective: This paper describes two different clinical presentations of diffuse cutaneous mastocytosis (DCM), based on the largest series published to date. As far as we are aware, these two variants of clinical presentations have not yet been reported. Design: We undertook a case controlled analysis of 8 children with DCM. Results of laboratory testing including mast cell mediator levels, and clinical symptoms on presentation and during follow-up were analyzed. Results: The levels of relevant mast cell mediators were initially high in all cases but declined sharply later on. There was a reduction of 20% in 2 of the 7 cases, whereas there was a reduction of 80% in the remaining 5. No reduction occurred in 1 case. Clinical improvement followed the same pattern. Conclusions: DCM is a rare variant of cutaneous childhood onset mastocytosis. Various forms show the same or overlapping features at various times. It appears to follow a course similar to that in other types of childhood onset mastocytosis, taking into account the decreased symptoms and the levels of mast cell mediators during follow-up. Obtaining a bone marrow biopsy should be considered only in those cases where there is no improvement or even worsening of signs or symptoms and persistent elevated levels of mast cell mediators.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare variant of Hodgkin's lymphoma (HL) in children. Since specific immunohistochemical staining has become available, NLPHL can be separated from classical Hodgkin's lymphoma (cHL) more accurately. Scarce information is available about pediatric NLPHL treated with chemotherapy only. Therefore, clinical characteristics, treatment, response and outcome of seven pediatric NLPHL patients, median age 9.2 years (range 7.5 - 14.2 years), diagnosed between 1986 - 2003 among 58 HL patients, uniformly treated in a single center with chemotherapy only, were evaluated. The median follow-up time was 4.2 years (range 2.1 - 10.2 years). NLPHL patients were stage I (n = 5), II (n = 2), whereas cHL, median age 11.4 years (range 3.3 - 15.9 years), were stage I (n = 8), II (n = 17), III (n = 9), IV (n = 1). Upfront treatment of NLPHL patients consisted of six courses of epirubicin, bleomycin, vinblastine and dacarbazine (EBVD) without radiotherapy, whereas cHL patients received six courses of EBVD (n = 14) or 4 - 6 courses of EBVD/MOPP (mitoxin, oncovin, procarbazine, prednison; n = 21). Chemotherapy was used as primary treatment thereby aiming to avoid radiotherapy with potential serious side effects to growing jaws and thyroid. All seven patients reached complete remission (CR). Four patients relapsed, of which three locally. These three were salvaged with second-line chemotherapy without radiation therapy (RT) and are in second CR. One patient relapsing with stage III disease was salvaged by EBVD/MOPP followed by autologous BMT and is also in second CR for 36 months. The event-free survival (EFS) is 43% and overall survival (OS) 100%. This study shows that apart from histology, immunohistochemistry (ICH) is required for diagnosing NLPHL. Moreover, it illustrates that although cure of pediatric NLPHL is feasible with chemotherapy only, high dosages of cytotoxic drugs are necessary as salvage treatment in a relatively high proportion of patients after relapse.

Background Complicating malignant hematopoietic proliferations might severely hamper the course of acute lymphoblastic leukemia (ALL) in patients with an otherwise good prognosis. It is important to distinguish whether such neoplastic proliferations represent ALL relapses or secondary treatment-related malignancies. Procedure We present an 11-year-old girl with precursor-B-ALL in whom maintenance treatment was complicated by an isolated ALL relapse in the brain, nodular lymphoproliferations in the liver, and an isolated myelo-monocytic leukemia cutis. All these hemato-oncologic malignancies occurred in the background of a secondary immunodeficiency, most likely caused by cytotoxic treatment. Results and Conclusions Using a stepwise molecular approach, we were able to demonstrate that the liver infiltrates were Epstein–Barr virus (EBV)-positive, contained monoclonal mature B-cells with immunoglobulin heavy chain gene (IGH) gene rearrangements unrelated to the primary ALL, and thus represented a true secondary non-Hodgkin lymphoma (NHL). In contrast, the skin infiltrates consisted of myelo-monocytic cells with clonal IGH and T-cell receptor gamma gene rearrangements, identical to the precursor-B-ALL blasts at diagnosis. Thus, the disease course of the precursor-B-ALL patient was complicated by two different isolated extramedullary relapses (brain and skin) and a secondary EBV+ B-NHL. © 2003 Wiley-Liss, Inc.

Traditionally, in ethical guidelines and in research ethics literature, care and research are clearly separated based on their different objectives. In contrast, in paediatric oncology, research and care are closely combined. Currently, it is unknown how relevant actors in paediatric oncology perceive this combination of research and care. We conducted a qualitative study into the experiences of those involved in Dutch paediatric oncology with the intertwinement of research and care and the dual role of paediatric oncologists as researchers and treating physicians.A qualitative study approach, using two focus groups and 19 semi-structured, in-depth interviews with paediatric oncologists, research coordinators, parents of children with cancer, and adolescents with cancer.Four themes characterize how actors experience the intertwinement of research and care in paediatric oncology. First, research is considered of major importance, and paediatric oncology professionals convey this message to patients and their parents. Second, there is ambiguity about categorization of studies into cancer therapy as either research or treatment. Third, role conflicts appear within the work of the paediatric oncologists. Finally, the various benefits of combining treatment with research are emphasized.Research is regarded as a fundamental and indispensable characteristic of paediatric oncology practice. Paediatric oncology professionals, parents, and patients have a very positive outlook on combining research and care, but they may not be sufficiently critical with respect to potential conflicts. Increased reflection on how to optimally combine research and care could serve as an important protection of the interests of children with cancer and their parents.

A large series of 202 childhood precursor-B cell acute lymphoblastic leukemia (ALL) patients was analyzed by Southern blotting (SB) for cross-lineage rearrangements and/or deletions in the T cell receptor TCRB, TCRG and TCRD loci. In 93% (187/201) of the precursor-B-ALL patients one or more genes were rearranged and/or deleted. TCRB gene rearrangements were found in 35% (69/196), TCRG gene rearrangements in 59% (113/192), TCRD gene rearrangements in 55% (112/202), and isolated monoallelic or biallelic deletions of TCRD loci in 34% (68/202) of the cases. TCRB gene rearrangements involved exclusively the Jbeta2 locus with complete V(D)Jbeta2 joinings in 53% of gene rearrangements and incomplete Dbeta-Jbeta2 gene rearrangements in 33%. TCRG gene rearrangements frequently occurred on both alleles (65% of cases) and in approximately 70% concerned rearrangements to Jgamma1 gene segments. Most rearranged TCRD alleles (80%) represented incomplete Vdelta2-Ddelta3 or Ddelta2-Ddelta3 gene rearrangements, while the remaining TCRD gene rearrangements remained unidentified. Subsequently, we evaluated, whether heteroduplex PCR analysis of rearranged TCRG and TCRD genes can be used for reliable identification of PCR targets for detection of minimal residual disease (MRD). The concordance between SB and heteroduplex PCR analysis for detection of the various types of clonal TCRG and TCRD gene rearrangements ranged between 78% and 87%. The discrepancies could be assigned to the presence of 'atypical' TCRD gene rearrangements or translocations only detectable by SB, but also to efficient PCR-based detection of rearrangements derived from small subclones, which are difficult to detect with SB. Indications for oligoclonality were observed in 38% and 30% of patients with TCRG and TCRD gene rearrangements, respectively, which is comparable to the frequency of oligoclonality in IGH locus. Based on the combined data it was possible to reduce the broad panel of six TCRD and 12 TCRG primer combinations for MRD studies to two TCRD combinations (Vdelta2-Ddelta3 and Ddelta2-Ddelta3) and six TCRG combinations (VgammaI, VgammaII, VgammaIV family-specific primers with Jgamma1.1/2.1 and Jgamma1.3/2.3 primers) resulting in the detection of 80% and 97% of all TCRD and TCRG gene rearrangements, respectively. Finally, the heteroduplex PCR data indicate that MRD monitoring with TCRG and/or TCRD targets is possible in approximately 80% of childhood precursor-B-ALL patients; approximately 55% of patients even have two TCRG and/or TCRD targets.

Virtually all immunoglobulin kappa (IGK) gene deletions are mediated via rearrangements of the so-called kappa deleting element (Kde). Kde rearrangements occur either to Vkappa gene segments (Vkappa-Kde rearrangements) or to the heptamer recombination signal sequence in the Jkappa-Ckappa intron. Kde rearrangements were analyzed by the polymerase chain reaction (PCR) and heteroduplex analysis in 130 B-lineage leukemias: 63 precursor-B-acute lymphoblastic leukemias (ALL) and 67 chronic B cell leukemias. To obtain detailed information about Kde rearrangements, we sequenced 109 of the 189 detected junctional regions. Vkappa gene family usage in the Vkappa-Kde rearrangements in our series of B-lineage leukemias was comparable to Vkappa gene family usage in functional Vkappa-Jkappa rearrangements in normal and malignant mature B cells, except for a higher frequency of VkappaII family usage in precursor-B-ALL. Junctional region sequencing of the Kde rearrangements in precursor-B-ALL revealed a mean insertion of 4.7 nucleotides and a mean deletion of 9.5 nucleotides, resulting in an extensive junctional diversity, whereas in chronic B cell leukemias the insertion (1.9) and deletion (6.0) were significantly lower. The relatively extensive junctional diversity of the Kde rearrangements in precursor-B-ALL allowed us to design leukemia/patient-specific oligonucleotide probes, which were proven to be useful for detection of minimal residual disease (MRD) with sensitivities of 10(-4) to 10(-5). Kde rearrangements occur in approximately 50% of precursor-B-ALL cases and are likely to remain stable during the disease course, because Kde rearrangements are assumed to be 'end-stage' rearrangements, which cannot easily be replaced by continuing rearrangement processes. These findings indicate that junctional regions of Kde rearrangements in precursor-B-ALL represent new valuable patient-specific PCR targets for detection of MRD.

Ovarian infiltration in pediatric non-Hodgkin lymphoma (NHL) at presentation is rare and information on outcome is scarce and mainly based on case reports and small series.Evaluation of clinical characteristics and outcome of ovarian infiltrated pediatric NHL cases of a single center, and an extensive review of the all cases reported so far in literature.At presentation, 6/60 female NHL cases of our center had ovarian infiltration, and combining these cases with earlier case reports, a total of 42 cases were identified. Median age at presentation was 10.9 years (range 0-18), and all but one had a B-cell immunophenotype, with 32/42 cases being classified as Burkitt. Bilateral involvement was reported in 26/41 cases, of which 22 were bilaterally ovariectomized as first treatment. All cases were treated with chemotherapy. Relapses were reported in 9/36 and death in 16/36. After follow-up in our center (median 13.4 years), in 2 cases anti-Müllerian hormone (AMH) values were available (2.1 and 0.9 µg/L), in non-ovarian cases median 2.2 µg/L.We conclude that in case of ovarian tumors with negative markers, NHL should be considered in order to avoid unnecessary surgery.

Background Few longitudinal data are available concerning quality of life (QoL) and functioning of young patients undergoing surgical procedures for malignant bone tumors around the knee joint. Aim of the present study was to evaluate patients' quality of life, functional ability, and physical activity during a 2-year postoperative period. Methods This prospective study included patients who underwent surgery for a malignant bone tumor around the knee joint between 2004 and 2008. Assessments were done at 3, 6, 9, 12, 18, and 24 months after surgery. QoL was measured with the TNO-AZL Children's or Adult's Quality of Life Questionnaires (TACQOL and TAAQOL), the Short Form-36 (SF-36) and Bone tumor (Bt)-DUX; functional ability with the Toronto Extremity Salvage Scale (TESS), the 6-minute walk test (6 MWT) and four functional performance tests; and physical activity with the Baecke questionnaire and the ActiLog® activity monitor. Statistical analysis included linear mixed model analysis. Results Forty-four patients (27 males, 17 females, mean age 14.9 (SD 4.8) years) were included, 27 (61%) underwent limb-salvage and 17 (39%) ablative surgery. Twenty patients were lost during the 2 years follow-up as a consequence of oncological complications. Over the first year, survivors showed significant improvement of QoL, functional ability and physical activity, except for the mental dimension of the SF-36 and the activity monitor results. Over the second year, these improvements were less pronounced. Conclusions In the first 2 years after bone tumor surgery, survivors improved significantly with respect to QoL, functional ability, and physical activity levels. Pediatr Blood Cancer 2012; 58: 978–985. © 2011 Wiley Periodicals, Inc.

Aim of our study was to compare functional ability and physical activity in children and young adults who underwent surgery for a malignant bone tumor that was located around the knee.This cross-sectional study included 82 patients aged 8-25 years with a follow-up of 1-5 years. The functional ability and the amount of physical activity were evaluated by means of questionnaires and objective instruments.Thirty nine patients underwent limb-salvage surgery (24 allograft and 15 endoprosthesis) and 43 underwent ablative surgery (27 amputations and 16 rotationplasty). Patients in the limb-salvage group were significantly older at the time of surgery than patients in the ablative group (mean age 15.2 years vs. 13.2 years, P = 0.03). Apart from significantly better scores for the timed up and down stairs and various walking activities in the limb-salvage group as compared to the ablative surgery group, no significant differences were seen for any of the outcome measures.One to 5 years after limb-salvage and ablative surgery due to a malignant bone tumor children and young adults do, apart from a few activities involving walking and climbing stairs, not differ with respect to overall functional ability and physical activity.