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Cancers 14(5), 1261 (2022). doi:10.3390/cancers14051261, Published by MDPI, Basel

Background: Childhood cancer patients are at increased risk of second primary neoplasms (SPNs). We assessed incidence and risk factors for early SPNs with a focus on cancer predisposition syndromes (CPSs). Patients and methods: This cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPNs) diagnosed before age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardised incidence ratios (SIRs) and absolute excess risks (AERs) using Swiss population cancer incidence data, and cumulative incidence of SPNs. We calculated hazard ratios (HRs) of risk factors for SPNs using Fine and Gray competing risk regression. Results: Among 8074 childhood cancer patients, 304 (4%) were diagnosed with a CPS and 94 (1%) developed early SPNs. The incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population (SIR = 10.6, 95% confidence interval [CI]: 8.7-13.1) and the AER was 179/100,000 person-years (CI: 139-219). Cumulative incidence of SPNs 20 years after FPN diagnosis was 23% in patients with CPSs (CI: 12-41%) and 2.7% in those without (CI: 2.0-3.6%). Risk factors for SPNs were CPSs (HR = 7.8, CI: 4.8-12.7), chemotherapy (HR = 2.2, CI: 1.1-4.6), radiotherapy (HR = 1.9, CI = 1.2-2.9), haematopoietic stem cell transplantation (HR = 1.8, CI: 1-3.3), and older age (15-20 years) at FPN diagnosis (HR = 1.9, CI: 1.1-3.2). Conclusion: CPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening.

This article provides an overview of the integrative medicine approach in pediatric oncology that combines conventional medicine with complementary therapies. As a practice example, the division of pediatric oncology from the Children's Hospital St. Gallen describes their use and experience of two different methods of integrative medicine on a daily basis. However, this review article also shows the lack of studies dedicated to integrative medicine in pediatric oncology, particularly regarding efficacy and safety of the different applications.Cet article donne un aperçu sur l’approche de la médecine intégrative en oncologie pédiatrique. Celle-ci combine la médecine conventionnelle avec des thérapies complémentaires. À l’exemple de l’hôpital pédiatrique de Saint-Gall, nous présentons le modèle d’intégration de médecine complémentaire au quotidien dans un service d’oncologie pédiatrique, ainsi que deux champs d’application. Toutefois, cet article de synthèse montre également l’absence d’études dédiées à la médecine intégrative en oncologie pédiatrique, notamment en ce qui concerne l’efficacité et la sécurité des différents traitements.

Background & aims Poor diet may increase the risk that childhood cancer survivors (CCS) will suffer from chronic disease. We compared adherence to national dietary recommendations between CCS, their siblings and the Swiss population, identified determinants of adherence, and assessed the association of adherence with cardiovascular disease (CVD) risk profiles. Methods As part of the Swiss Childhood Cancer Survivor Study (SCCSS), a questionnaire was sent to all Swiss resident CCS aged

Purpose To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. Patients and Methods Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. Results At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% ± 4% and 73% ± 4%, respectively (all survival rates in this abstract are calculated and displayed with ±95% CI). EFS/OS rates by histology were 60% ± 5%/72% ± 5% in rhabdomyosarcoma, 62% ± 10%/69% ± 10% for Ewing tumors of soft tissues, 84% ± 12%/90% ± 10% for synovial sarcoma, and 67% ± 38%/83% ± 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% ± 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% ± 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. Conclusion Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Munster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).

During the last decade much progress has been made toward better understanding of the underlying reasons causing thromboembolism in children. A considerable number of acquired and hereditary thrombotic risk factors have been identified which may also have an impact on therapeutic decisions and prognosis concerning outcome and the risk of a second event. However, indications for therapeutic interventions, such as thrombolysis and prophylactic anticoagulation with respect to the different clinical conditions and their combination with other risk factors, are not yet well defined. The following article describes the causes, clinical presentation and management of thrombosis in neonates, infants and older children, focusing on the clinically most relevant conditions.

The formation of a high-ploidy is rare in Ewing tumor (ET) and is in contrast to some other childhood tumors such as neuroblastoma. In a series of 37 Ewing tumors analyzed by conventional cytogenetics, 4 of the 34 tumors with an abnormal clone (11.8%) demonstrated the presence of a high-ploidy clone, with a chromosome number that ranged from hypotriploid to pentaploid. All 4 contained a t(11;22)(q24;q12) and the karyotypes had further aberrations of the type that would be generally expected in ET. Numerical aberrations represented the majority of the karyotypic events identified and gain of chromosome 8 and loss of chromosomes 3, 10, 16, 19, and 22 occurred in at least 3 tumors. However, no single mechanism could be implicated to explain the karyotypic picture of the 4 cases. It is proposed that high-ploidy subgroups exist in ET and it would be potentially erroneous to group these and other cases together when determining their clinical implications.

Background Neuroblastoma (NB) is cytogenetically characterized by a number of non-random events. However, knowledge is limited concerning the timing of occurrence and inter-action of many of these events. Methods Karyotypic patterns were obtained from a study group of 49 NB tumors that had been analyzed by conventional cytogenetics combined with FISH and in some instances SKY. Results All chromosomes were involved in a numerical and structural aberration in at least one tumor. There was a positive correlation between the occurrence of MYCN and del(1p) and between del(1p) and 17q. Aberrations involving chromosomes X, 3, 19, and del(1p) could be considered early events, whereas those involving chromosomes 9, 13, 15, 18, 20, and 21 were often late events. Conclusions This study suggests that the karyotypic patterns characterizing NB are complex. There are aberrations that can be grouped into early or late karyotypic events, but others, such as gain of 17q, are variable. © 2004 Wiley-Liss, Inc.

We describe a Hb S/beta-thalassemia (beta-thal) mutation involving an AT transition at codon 132 of the beta-globin gene. The mutation, in the heterozygous state, unlike several other mutations in exon 3, shows no signs of dominant thalassemia but those of a typical beta(0) carrier. Compound heterozygosity with Hb S [beta6(A3)GluVal, GAGGTG] showed a severe clinical picture.

A predisposition to tumor development is currently associated with some, but not all, constitutional chromosomal abnormalities. In a series of 578 children, in which conventional cytogenetic investigation was performed on material from various benign and malignant tumors, four boys and one girl were also found to have constitutional balanced chromosomal rearrangements. The figure of 5 in 578 is notable because the reported incidence of balanced rearrangements in newborns is approximately 1 in 450. Thereby suggesting that some, if not all, children with balanced constitutional chromosomal rearrangements have an increased predisposition for neoplasms developing.

Objectives To describe characteristics of visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (HLH) with focus on diagnostic clues and pitfalls, including the frequency of central nervous system (CNS) involvement, and to determine the efficacy of liposomal amphotericin B (L-AmB). Study design We retrospectively analyzed clinical and laboratory features, diagnostic procedures, and treatment of 13 patients with HLH with imported visceral leishmaniasis, reported to the German HLH reference center (1999-2012). Results The spectrum of presentations was indistinguishable from patients with hereditary HLH or with acquired HLH because of infections with other pathogens. In 8 patients, disease onset occurred before the age of 2 years, coinciding with the typical age of manifestation of primary HLH. Two patients had mild nonspecific CNS findings. Misleading antiviral IgM (n = 6) and autoantibodies (n = 2) led to inaccurate interpretation of the etiology of HLH, sometimes with inappropriate therapeutic consequences. False negative results for Leishmania were obtained by initial bone marrow microscopy in 6/13, serology in 1/12, bone marrow culture in 2/5, and polymerase chain reaction of peripheral blood in 1/3 patients, and all bone marrow samples tested were Leishmania -positive by polymerase chain reaction (n = 7). L-AmB was administered to 12 patients, 5 of whom had no prior HLH-directed immunosuppressive therapy; sodium stibogluconate was administered to 1 patient. Persistent remission was achieved in 11 cases. Two patients required repeated or prolonged L-AmB therapy. Conclusions Awareness of diagnostic pitfalls may save patients from unnecessary toxic treatment. CNS involvement is rare. L-AmB shows efficacy in visceral leishmaniasis-associated HLH.

We have read the paper by Nowak-Gottl and coworkers[1][1] on the meaning of combined prothrombotic defects for recurrence of venous thrombosis in childhood with great interest and congratulate the authors for their work. However, we would like to comment on their findings with regard to Lipoprotein

Abstract 2986 Poster Board II-962 Introduction: The protein C pathway is believed to be a crucial regulator of coagulation. Similar to the adult population, it is of utmost importance in pediatric patients to maintain the balance between pro- and anticoagulatory signals (Petaja and Manco-Johnson 2003). Cancer patients have been shown to have cancer and cancer-therapy associated pathologies of the protein C pathway. (Nijziel, van Oerle et al. 2003; Woodley-Cook, Shin et al. 2006). A test evaluating the response of the protein C pathway after activation of endogenous protein C has been shown to be a sensitive tool to screen for protein C deficiency and APC resistance whereas protein S deficiency is detected less reliably (Toulon, Halbmeyer et al. 2000). This is in line with findings suggesting that any pathology of this assay is related to an increased risk of VTE, independent of the pathology related to the abnormality of the test result (Toulon, Perez et al. 2007). Similarly, patients with idiopathic pregnancy loss were found to have a pathological response independent of the pathology related (Sarig, Lanir et al. 2002). Methods: We therefore evaluated the influence of different variables on the results of the global protein C assay (Pro C Global on a BCS analyzer, Siemens, Marburg, Germany) in 431 children enrolled into the Thrombotect study. The Thrombotect study is a prospective, randomized trial evaluating unfractionated heparin vs low molecular weight heparin vs antithrombin replacement for prevention of thromboembolism in children undergoing asparaginase containing chemotherapy for acute lymphoblasic leukaemia within the BFM protocol. A multivariate linear regression analysis on results obtained before treatment was performed (MedCalc 10.0.1). Results: To date (as of 8/09), 720 children have been randomized in the Thrombotect trial. At the time, we had complete data for laboratory evaluation available for 431 children on day 0 of the treatment protocol. Free protein S, IgG antibodies against cardiolipin or phosphatidlyserine, dRVVT, fibrinogen, the presence of F II G20210A, homocystein concentration, Lp(a) concentration and PAI-1 activity had no predictive value towards the protein C pathway assay result in this multivariate analysis. In contrast, the protein C pathway activity was expectedly shown to be dependent on the presence of the F V Leiden mutation (p Unexpectedly, the protein C pathway activity was also dependent on antithrombin activity (p=0.0166), F XIIc (p=0.0137) and IgM (but not IgG) antibodies against cardiolipin (p=0.0304) and phosphatidylserine (p=0.0006) in this multivariate analysis. Importantly, the association between protein C pathway activity and the “unexpected” predictors were independent of whether or not the results were in the reference range or not (median [95% CI] antithrombin activity 0.95 [0.93-0.97], median F XIIc 0.94 [0.90-0.98], median ACL IgM 2 [2-3] U/ml, median APS IgM 2 [2-3] U/ml). Conclusions: The protein C pathway is believed to be a crucial regulatory element of haemostasis. Our results from a large cohort (n = 431) of children with ALL and thus at risk for thromboembolism indicate that the protein C pathway is -expectedly (such as F V Leiden mutation, protein C activity, F VIIIc) and unexpectedly (such as antithrombin activity and the concentration of antiphospholipid IgM antibodies) - interdependent with many other variables of the coagulation system. These data provide evidence that the protein C pathway ex vivo in children with ALL is targeted by various elements of other haemostasis pathways in a significant manner in multivariate analysis. Disclosures: No relevant conflicts of interest to declare.

Abstract 990 Poster Board I-12 Thromboembolic events (TE) are common complications in association with acute lymphoblastic leukemia (ALL). The incidence, as reported in the literature, is 3.2% on average, but varies from 1.1% to over 30%, which might be explained by different definitions of the events (symptomatic/asymptomatic), diagnostic methods, study designs (prospective/retrospective) and treatment protocols. Pathogenesis and etiology of ALL-related TE have not yet been fully clarified so far and the existing data on the relevance of potentially influencing risk factors are quite inconclusive. The higher risk of TE in patients with ALL and under ALL treatment may be caused by the ALL itself and the applicated chemotherapy, first of all asparaginase but potentially in combination with other drugs, e.g. steroids. The chemotherapy leads to an imbalance of coagulation factors inducing a hypercoagulable state in the patient. Other modulating factors might be the preexistence of hereditary thrombophilia, the existence of an implanted central venous line (CVL) and the potential treatment with antithrombotic prophylaxis. Data on TE were prospectively collected from 2419 patients with ALL (age 1-18 years) enrolled from August 1999 to September 2005 into study ALL-BFM 2000 of the Berlin-Frankfurt-Münster group (Germany, Austria, Switzerland). Patients participating in the “Thrombotect” study (randomized study for evaluation of antithrombotic therapies in ALL) were excluded from the analysis. Among the analyzed patients, 104 TE were documented (4.3%); 41 TE were localized in the CNS (mainly sinus venous thromboses), 63 TE outside of the CNS (lower deep venous system, n=14; upper deep venous system n=40; cardiac, n=6; pulmonary embolisms, n=3). Nine TE were classified as life-threatening (7 cerebral, 2 non-cerebral), 1 patient died from a cerebral infarct with concomitant serious bleeding. About 62% of the TE (n=64) were diagnosed during the 5-week induction treatment with prednisone or dexamethasone, vincristine, daunorubicin, asparaginase, and intrathecal methotrexate, 14% (n=15) during the subsequent consolidation phase, and 24% during later treatment phases. Adolescent patients had a significantly higher risk to develop TE with a rate of 3.4% in patients Several parameters which have potential impact on TE incidence are unknown in this study. These include anticoagulatory prophylaxis by institutional practice, preexisting hereditary thrombophilia as well as the coagulation status at time of diagnosis of ALL, under chemotherapy, and at diagnosis of TE. TE are a rather rare but potentially serious complication of contemporary ALL treatment. Risk factors are numerous. So far, besides age, immunophenotype, and treatment phases robust predictive factors are still missing. Prospective randomized studies are underway to identify risk factors and to develop preventive strategies. Disclosures: No relevant conflicts of interest to declare.