CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis.

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Ultrasound Evaluation of Thyroid Gland Pathologies After Radiation Therapy and Chemotherapy to Treat Malignancy During Childhood.

The purpose of this study was to evaluate correlations between treatment of malignancy by radiation therapy during childhood and the occurrence of thyroid gland pathologies detected by ultrasonography in follow-up examinations.Reductions of thyroid gland volume below 2 standard deviations of the weight-specific mean value, occurrence of ultrasonographically detectable thyroid gland pathologies, and hypothyroidism were retrospectively assessed in 103 children and adolescents 7 months to 20 years of age (median: 7 years of age) at baseline (1997-2013) treated with chemoradiation therapy (with the thyroid gland dose assessable) or with chemotherapy alone and followed by ultrasonography and lab…

Long-Term Outcome of Preemptive Immunotherapy Based on Post-Transplant Chimerism and MRD Monitoring after Allogeneic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia: A Single Center Experience

Abstract Introduction: Mixed chimerism (MC) and minimal residual disease (MRD) strongly predict risk for relapse in children with acute lymphoblastic leukemia (ALL) following allogeneic stem cell transplantation (allo-SCT). Preemptive immunotherapy (IT), e.g. withdrawal of immunosuppression (WD-IS) or donor lymphocyte infusion (DLI) guided by chimerism and MRD monitoring can prevent impending relapse in allo-SCT recipients. In this study we retrospectively analyzed chimerism and MRD monitoring and the effect of preemptive IT in all pts undergoing allo-SCT for ALL in our institution. Patients: Between January 2005 and July 2014, a total of 89 children and adolescents (median age 11.5; range …

Massive pulmonary embolism in a young boy with T-cell leukaemia. Successful thrombolytic therapy by recombinant tissue plasminogen activator (rtPA).

SummaryAcute pulmonary embolism (PE) is a serious complication in association with malignant diseases. We describe the successful treatment of PE applying a systemic thrombolytic therapy in a 4-year-old boy with acute lymphoblastic leukaemia.The thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 0.1 mg/ kg bodyweight per hour for six hours was continued for six days without important side effects. In particular no bleeding complications were observed. Computed tomography with contrast revealed a remarkable regression of the central PE. Without further delays the chemotherapy was resumed.

Loneliness predicts suicidal ideation and anxiety symptoms in long-term childhood cancer survivors.

Abstract Background/Objective Long-term childhood cancer survivors (CCS) are at risk for adverse late effects. However, not all of them are well understood. The present study addressed loneliness, a previously under-researched mental health risk in cancer survivor populations. We assessed the prevalence of loneliness and its impact on psychological symptoms over time. Method: A registry-based sample of N = 633 adult long-term CCS underwent medical and psychological assessments and took part in a follow-up survey 2.5 years later. Psychological symptoms (somatic, anxiety, depression symptoms, and suicidal ideation) were measured using the Patient Health Questionnaire. We calculated linear reg…

What's past is prologue: Recalled parenting styles are associated with childhood cancer survivors' mental health outcomes more than 25 years after diagnosis

Abstract Background With the increased survival rates of childhood cancer, long-term survivors' well-being over the life span has come into focus. A better understanding of the determinants of childhood cancer survivors' (CCS) mental health outcomes contributes to the identification of vulnerable individuals as well as to the development of evidence-based prevention and intervention efforts. It has been noted that psychosocial factors such as parental rearing behavior shape individual differences in mental health. There is also evidence that parents show altered parenting behavior in the face of childhood cancer, e. g. that they express more emotional support, but also more worries. However…

HGG-03. THE GLYCOSPHINGOLIPIDS METABOLISM IS A NOVEL TARGET IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA

Abstract H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) is a rare malignant brain tumour entity in children and adults with a median overall survival of around 12 months. Genomic and proteomic analysis may help to identify new target structures, however not all relevant targets are covered by these analyses. Glycosphingolipids and particularly gangliosides play a major role in brain development and have been involved in the pathology of brain tumours. The conversion of ceramide to glucosylceramide via glucosylceramide synthase (GCS) is one of the first steps in the synthesis of glycosphingolipids. Therefore, targeting GCS will inhibit their synthesis. Here we analysed the glycosph…

Assessment of nine candidate DTP-vaccines with reduced amount of antigen and/or without adjuvant as a fourth (booster-) dose in the second year of life

Abstract Background The incidence of local reactions to diphtheria-, tetanus and acellular pertussis (DTaP-) vaccines in infants and toddlers increases with each subsequent dose, and entire thigh swellings (ETS) have been reported. Lowering the amount of antigen or of adjuvant may decrease the reactogenicity of DTaP while maintaining a protective immune response. Objectives Following priming with three doses of a DTaP vaccine during infancy, the safety, reactogenicity and immunogenicity of nine different candidate DTaP-vaccines with reduced amounts of antigen and/or adjuvant given as fourth (booster) dose were evaluated. Methods Study participants were healthy infants aged 15–27 months at t…

Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology

Objective: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). Methods: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. Results: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417…

Pre-Emptive Immunotherapy for Clearance of Molecular Disease in Childhood Acute Lymphoblastic Leukemia after Transplantation

Abstract Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for …

The desire for children among adult survivors of childhood cancer: Psychometric evaluation of a cancer-specific questionnaire and relations with sociodemographic and psychological characteristics.

OBJECTIVE Long-term childhood cancer survivors (CCS) are less likely to become parents than their peers of the same age. Previous research has suggested that besides fertility, this outcome is shaped by psychosocial factors such as emotional motives toward having a child. Drawing from a sample of CCS with survival times >25 years, we present the validation of a questionnaire assessing cancer-specific reproductive motives and concerns. METHODS We evaluated the cancer-specific version of the Leipzig Questionnaire of Motives to have a Child (LKM-C) in a register-based sample of adult CCS (N = 632, 31% had children, 44.5% women). We conducted a confirmatory factor analysis and tested associatio…

Parenting in the face of serious illness: Childhood cancer survivors remember different rearing behavior than the general population

Objective A child's cancer diagnosis and treatment affect the whole family. While it has been recognized that parents are an important resource for their children, little is known about the specifics of parenting in the face of serious illness. Methods We used the Recalled Parental Rearing Behavior Questionnaire in a register-based cohort of adult childhood cancer survivors (CCS) (N = 951) and a representative population sample of the same age range (N = 2042). The questionnaire assesses behavior of mothers and fathers with three scales (emotional warmth, rejection/punishment, and control/overprotection) by querying the (former) child. We compared the two groups using general linear models.…

Prevalence of cardiovascular late sequelae in long-term survivors of childhood cancer: A systematic review and meta-analysis

Background Cardiovascular diseases are well-known late effects of childhood cancer and research on these late effects is a highly important emerging field. We conducted a systematic review with a meta-analysis to give an overview of the current evidence and the prevalence of late cardiovascular events. Procedure We included publications in which the study populations were children and adolescents who survived cancer. Outcome was defined as all cardiovascular clinical and subclinical endpoints or diagnoses appearing at least one year after cancer diagnosis. A systematic overview is presented for all included studies. A quantitative meta-analysis was conducted for hypertension and stroke. Res…

Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: Data from the German CVSS-study.

Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German po…

49P Targeting IGF1R in osteosarcoma

MMR and MMRV vaccines.

Measles, mumps, rubella and varicella are viral infections which can implicate seriously long-term sequelae of infected individuals or even the unborn child. Vaccines against the individual diseases have long been available. Global measles vaccination is estimated to have prevented more than 20million deaths during 2000-2015. During the same time period, measles incidence decreased from 146 to 36 cases per million populations. Today vaccinations against measles, mumps, rubella and varicella are now carried out mainly with combination vaccines. These are today known as immunogenic and safe. MMRV had similar immunogenicity and overall safety profiles to MMR administered with or without varice…

First experience of the AML-Berlin-Frankfurt-Münster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid

Recently, studies in adults with acute promyelocytic leukemia (APL) showed high cure rates in low-risk patients treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO), while toxicities were significantly reduced compared to the standard treatment with ATRA and chemotherapy. Here we report about first experience with 11 pediatric patients with low-risk APL treated with ATRA and ATO. All patients stayed in molecular remission. All suffered from hyperleukocytosis. Two patients experienced reversible severe side effects. One suffered from osteonecroses at both femurs, seizures, as well as posterior reversible encephalopathy syndrome, the other patient had an abducens paresis.

Mental health and health-related quality of life in preschool-aged childhood cancer survivors. Results of the prospective cohort study ikidS-OEVA.

Objectives Long-term survivors of childhood cancer are at increased risk for sequelae such as poor mental health (MH) or impaired health-related quality of life (HrQoL). We aimed to evaluate early adverse effects on MH and HrQoL in young childhood cancer survivors (YCCS) before school entry. Methods In a nationwide prospective cohort study, children with cancer other than brain tumors diagnosed at preschool age and completed cancer treatments were identified from the German Childhood Cancer Registry. The comparison group was children of the same age without a cancer diagnosis who participated in the prospective population-based health survey ikidS. MH problems and HrQoL were assessed by par…

Inflammatory Characteristics of Monocytes from Pediatric Patients with Tuberous Sclerosis.

Objective  Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1 / tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC. Methods  Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC ( n  = 16) were compared with healthy subjects ( n  = 20). Results  Compared with monocytes from healthy controls, LPS showed a more prominent gene expression pattern in patients with TSC (CCL24, CXCL10, IL…

TRTH-08. HIGH GRADE NEUROEPITHELIAL TUMOR OF THE CENTRAL NERVOUS SYSTEM WITH BCOR ALTERATION IS SENSITIVE TO IGF1R INHIBITION

High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity which was formerly diagnosed with diverse histological diagnoses, for example as ependymoma. This tumor predominantly affects children and has a dismal prognosis. No standard therapies for this entity exist so far. Recently we described the activation of the Sonic hedgehog (SHH) and the WNT signaling pathway in this tumor and described a primary cell culture (PhKh1) isolated from a skull metastasis of a seven years old patient. We also detected a high expression of IGF2, which is known to be required for SHH signaling in medulloblastoma. IGF2 signals …

The safety, reactogenicity and immunogenicity of a 7-valent pneumococcal conjugate vaccine (7VPnC) concurrently administered with a combination DTaP-IPV-Hib vaccine.

To evaluate immune responses, safety and reactogenicity of the concomitant use of DTaP-IPV-Hib and the newly available 7-valent pneumococcal conjugate (7VPnC) vaccines when given as the primary immunization series in early infancy. A total of 231 healthy infants were enrolled at 11 German study centers and randomized to receive either 7VPnC plus DTaP-IPV-Hib vaccines concomitantly into opposite limbs at age 2, 3, 4 and 11-15 months (7VPnC group) or DTaP-IPV-Hib vaccine at the same ages plus a 7VPnC "catch-up vaccination" at ages 6, 7, 8 and 11-15 months (Control group). Blood samples were drawn before and 4 weeks after the first three vaccine doses and 4 weeks after the fourth dose. Local a…

Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity…

Identification of a novel compound heterozygote SCO2 mutation in cytochrome c oxidase deficient fatal infantile cardioencephalomyopathy

UNLABELLED Fatal infantile cardioencephalomyopathy (OMIM No. 604377) is a disorder of the mitochondrial respiratory chain and is characterised by neonatal progressive muscular hypotonia and cardiomyopathy because of severe Cytochrome c oxidase deficiency. Here we report a novel mutation in the Cytochrome c oxidase assembly gene SCO2 in an infant with fatal infantile cardioencephalomyopathy despite normal initial metabolic screening. CONCLUSION In newborns with unexplained muscular hypotonia and cardiomyopathy genetic testing of mitochondrial respiratory chain disorders might be helpful to establish a final diagnosis and guide treatment decisions.

Radical surgery and different types of urinary diversion in patients with rhabdomyosarcoma of bladder or prostate--a single institution experience.

Abstract Purpose In a retrospective study we analyzed the outcome of patients treated for rhabdomyosarcoma (RMS) of the bladder/prostate with special attention to radical surgery. Methods In 25 patients with genitourinary RMS (15 bladder/10 prostate) the median age at diagnosis was 4 years [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , and 8 patients had a stage II RMS, 12 stage III and 5 stage IV. In 19/25 (12 bladder/7 prostate), radical surgery and urinary diversion were performed. Urinary diversion comprised 2 continent anal diversions, 11 continent cutaneous diversions, 4 colon conduits and 2 urethral diversions (2 +…

The Relation between Coagulant and Vascular Function in Adult Survivors of Childhood Cancer

PNR-35CNS HGNET-BCOR - MOLECULAR CHARACTERIZATION AND IDENTIFICATION OF POSSIBLE THERAPEUTIC TARGETS OF A NEW BRAIN TUMOR ENTITY

Treatment of relapse after allogeneic stem cell transplantation in children and adolescents with ALL: the Frankfurt experience

Therapy for post-transplant relapse of paediatric ALL is limited. Standardised curative approaches are not available. We hereby describe our local procedure in this life-threatening situation. A total of 101 ALL patients received their first allogeneic stem cell transplantation (SCT) in our institution. After relapse, our primary therapeutic goal was to cure the patient with high-dose chemotherapy or specific immunotherapy (HDCHT/SIT) followed by a second SCT from a haploidentical donor (transplant approach). If this was not feasible, low-dose chemotherapy and donor lymphocyte infusions (LDCHT+DLI) were offered (non-transplant approach). A total of 23 patients suffered a post-transplant rel…

Risk factors for suicidal ideation in a large, registry-based sample of adult long-term childhood cancer survivors

Abstract Introduction Long-term childhood cancer survivors (CCS) are at risk for physical and psychosocial late effects. Previous research has attested to increased rates of suicidal ideation (SI) in CCS, an especially dangerous indicator of distress. However, little was known about risk factors of SI among CCS which go beyond illness- and treatment related variables. Methods A registry-based sample of 916 adult long-term CCS (Mage=34.58 years [SD=5.53], Mage at diagnosis=6.15 years [SD=4.28]) underwent medical assessments and filled out questionnaires. We conducted a linear regression analysis on SI, testing predictors of different areas: sociodemographic, social, physical health and healt…

A combination vaccine against measles, mumps, rubella and varicella.

A new combination vaccine against measles, mumps, rubella and varicella (MMRV) from GlaxoSmithKline Biologicals has recently been approved in Europe. It combines the components from two well-established, live, attenuated vaccines against measles, mumps and rubella. This review presents a summary of the development of this MMRV vaccine from published clinical studies. Seroconversion rates and antibody titers after the first and second dose are similar to those observed after concomitant administration of the MMR and varicella vaccines. Furthermore, the clinical profile of this combination vaccine, in terms of injection- site and general tolerability, is similar to that of the component vacci…

Mortality risk among 5‐year survivors of childhood cancer in Germany—Results from the CVSS study (Cardiac and Vascular late Sequelae in long‐term Survivors of childhood cancer study)

The growing population of long-term childhood cancer survivors is at increased risk for severe, therapy-related late effects and premature mortality. The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS) study is a cohort of patients from Germany diagnosed with a neoplasia prior to 15 years of age in the time period 1980 to 1990. Late mortality was evaluated in a total of 4505 individuals who survived 5 years or more after the initial diagnosis (5-year survivors). Survivors with a second primary tumor were excluded. Standardized mortality ratios (SMRs) were calculated. By December 2014, 400 patients had died. Available cause of death information from 188 i…