Immunological recovery following HLA-matched CD3+ TCR αß+/CD19+ depleted hematopoietic stem cell transplantation in children.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. METHODS: Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαß+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαß+, and CD19+B-cells infused was 12.7 × 106 /kg, 16.8 × 103 /kg, and 96 × 103 /kg bodyweight. RESULTS: With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal. CONCLUSIONS: Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.

Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions.

Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK-fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.

Management of children and adolescents with gray zone lymphoma: A case series.

BACKGROUND: Data on management of gray zone lymphoma (GZL) in children and adolescents are scarce. PROCEDURE: This retrospective study assessed clinical characteristics and outcome in six Austrian patients with GZL less than 18 years of age (male-to-female ratio: 1:1; median age: 15.8 years). RESULTS: Two patients each had a classical Hodgkin lymphoma (cHL)-like and composite GZL subtype, and one patient each had a large B-cell non-Hodgkin lymphoma (LBCL)-like and sequential GZL subtype. All had advanced disease with mediastinal and extranodal involvement. Five patients received an LBCL- and one patient a cHL-directed polychemotherapy ± radiotherapy. Out of the former patients, three survived, including two who relapsed and underwent high-dose chemotherapy with autologous stem cell rescue. The latter patient survived. CONCLUSIONS: GZL remains a diagnostic and therapeutic challenge, necessitating the development of novel treatment concepts performed in a prospective setting.

Determinants of utilization of cryopreservation of germ cells in adolescent cancer patients in four European countries.

Infertility is a relevant late-effect following cancer treatment; yet, a large proportion of survivors cannot recall having been informed of this risk. In an intervention study, we examined if and how supportive patient information material on fertility/fertility-preserving measures influences utilization of cryopreservation in adolescent cancer patients. The control group, recruited 03/2014-01/2016, received the usual patient education at initial diagnosis. The intervention group, recruited 04/2016-10/2017, received patient education supported by a fertility flyer and brochure. Patients and parents were each asked questions on utilization of cryopreservation in a questionnaire 3 and 6 months after initial diagnosis. Patient core and therapy data were obtained from medical records. Overall, cryopreservation rates showed no significant difference between the control (32.7%, n = 37/113) and intervention group (36.6%, n = 37/101). In the control group, cryopreservation was associated with gender (OR 0.100, CI 0.023-0.427), age (OR 1.559, CI 1.077-2.258) and recalling information on fertility protection (OR 33.663, CI 2.100-539.574); in the intervention group, cryopreservation was related to gender (OR 0.093, CI 0.026-0.330) and the estimated infertility risk (OR 43.665, CI 2.157-883.974).Conclusion: Cryopreservation rates did not overall increase following the intervention; however, the individual risk seemed to be brought into attention more: Those at risk, including younger patients, cryopreserved at higher rates.What is Known:•Infertility is a relevant late-effect following adolescent cancer.•Guidelines recommend to offer fertility protection before cancer treatment.•A relevant proportion of adolescents with cancer are not aware of this risk.•Fertility protection seems under-used in cancer patients at risk for infertility.What is New:•Information material on fertility and protection in adolescents did not increase overall rates of cryopreservation.•Cryopreservation rates were improved according to individual risk for infertility.•Our flyers and brochures on fertility in cancer patients are available in various languages.

Fertility education for adolescent cancer patients: Gaps in current clinical practice in Europe.

OBJECTIVE: As adolescent cancer patients may suffer from infertility following treatment, fertility counselling is essential. Our aim was to explore the current situation in four European countries in terms of (I) education about the risk for infertility, (II) counselling on fertility preservation, (III) patients' knowledge on fertility, (IV) sufficiency of information and (V) uptake of cryopreservation. METHODS: In total, 113 patients (13-20 years) at 11 study centres completed a self-report questionnaire three and six months after cancer diagnosis. Multivariate logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: As many as 80.2% of participants reported having received education about the risk for infertility prior to treatment, 73.2% recalled counselling on fertility preservation. Only 52.3% stated they felt sufficiently informed to make a decision. Inability to recall counselling on fertility preservation (OR = 0.03, CI: 0.00-0.47) and female gender (OR = 0.11, CI: 0.03-0.48) was associated with lower use of cryopreservation, whereas older age was associated with higher use. CONCLUSION: Fertility counselling was available to a relatively high proportion of patients, and it did influence the utilisation of cryopreservation. However, many patients did not feel sufficiently informed. Further improvement is needed to enable adolescent cancer patients to make an informed decision on fertility preservation.

Fertility knowledge and associated empowerment following an educational intervention for adolescent cancer patients.

INTRODUCTION/OBJECTIVES: Fertility preservation is a major concern for adolescent cancer patients; yet, educational gaps remain. Our intervention study examined whether specially designed educational materials regarding fertility preservation increase knowledge and empowerment of patients and parents. METHODS: Eleven paediatric-oncological centres in four European countries agreed to enrol all eligible patients and parents in a questionnaire survey at 3 and 6 months after diagnosis. Treating physicians were surveyed on their medical consultation regarding fertility. RESULTS: Educational intervention increased knowledge in both patients (n = 113 and n = 101 in the control and intervention groups, respectively) and parents (n = 111 and n = 99 in the control and intervention groups, respectively), but the difference did not achieve statistical significance (knowledge difference patients: 5.6% (t0)/13.1% (t1); parents: 6.4% (t0)/3.8% (t1)). Parents of older patients (OR = 1.3, 95%CI = 1.1-1.7) and higher educational groups (OR = 6.2, 95%CI = 2.1-18.3) in the intervention group (OR = 1.9, 95%CI = 1.03-3.7) achieved higher knowledge levels. Empowerment was significantly improved in both patients (p = 0.046, d = 0.27) and parents (p = 0.046, d = 0.48) in the intervention group. DISCUSSION/CONCLUSIONS: In our study, the use of specifically prepared flyers and brochures successfully raised the level of fertility preservation knowledge in parents of older patients as well as parents with higher educational levels. Overall, the intervention improved patient and parent empowerment. Subsequent projects will include simpler information and digital material to particularly reach out to younger and less educated individuals.

Enterovirus infections in pediatric hematologic/oncologic patients.

BACKGROUND: Enteroviruses (EV) are a large group of Picornaviruses associated with respiratory, gastrointestinal, and neurologic symptoms in the immunocompetent host. Little is known about the epidemiologic and clinical impact in pediatric hematologic/oncologic patients. PROCEDURE: From 2001 through 2017, different clinical specimens were collected from pediatric hematologic/oncologic patients and were tested for enteroviral RNA. RESULTS: Of 13 004 specimens collected from 761 patients, 38 (0.3%) obtained from 14 patients (1.8%) tested positive for EV RNA. Viral shedding was observed without viremia and vice versa. None of 80 cerebrospinal fluid specimens obtained from 60 patients with neurologic symptoms were positive for EV RNA. None of 14 patients positive for EV RNA showed EV-specific symptoms. In 11/14 patients, EV RNA was found to be negative in the follow-up specimen. The remaining patient with a severe primary immune deficiency showed repeated positive EV RNA results for >5 years. CONCLUSIONS: In this pediatric hematologic/oncologic cohort, EV infection occurred rarely and without related symptoms. Specimens concurrently obtained from one patient are commonly not in accordance with each other. In the vast majority of patients, EV RNA appears to turn negative in the follow-up specimen. EV infections seem to have a low impact in this patient cohort.

Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience of 20 years.

Haemophagocytic lymphohistiocytosis (HLH) is a possibly life-threatening syndrome of immune dysregulation and can be divided into primary (hereditary) and secondary forms (including malignancy-associated HLH (M-HLH)). We retrospectively analysed epidemiological, clinical, virological and laboratory data from patients with M-HLH treated at our department between 1995 and 2014. Out of 1.706 haemato-/oncologic patients treated at our department between 1995 and 2014, we identified 22 (1.29%) patients with secondary HLH (1.3-18.0, median 10.1 years; malignancy induced n = 2; chemotherapy induced n = 20). Patients with acute myeloblastic leukaemia (AML) developed HLH significantly more often than patients with acute lymphoblastic leukaemia (ALL) (10/55, 18.2% vs. 6/148, 4.1%, p = 0.0021). As possible viral triggers, we detected BKV (53.8% of the tested patients), HHV-6 (33.3%), EBV (27.8%), CMV (23.5%), ADV (16.7%) and PVB19 (16.7%) significantly more frequently than in haemato-/oncologic patients without HLH. Despite lacking evidence of concurrent bacterial infection, C-reactive protein (CRP) and procalcitotnin (PCT) were elevated in 94.7 and 77.7% of the patients, respectively. Ferritin and sIL2R were markedly elevated in all patients. HLH-associated mortality significantly (p = 0.0276) decreased from 66.6% (1995-2004) to 6.25% (2005-2014), suggesting improved diagnostic and therapeutic management. Awareness of HLH is important, and fever refractory to antibiotics should prompt to consider this diagnosis. Elevated ferritin and sIL2R seem to be good markers, while inflammatory markers like CRP and PCT are not useful to discriminate viral triggered HLH from severe bacterial infection. Re-/activation of several viruses may play a role as possible trigger.

Successful Unrelated Stem Cell Transplantation in an Infant With Congenital Acute Myelogenous Leukemia FAB M5 Showing Massive Cutaneous Infiltrations--A Challenging Multidisciplinary Approach.

The multidisciplinary management of a male neonate presenting with congenital acute myelogenous leukemia of monoblastic phenotype is reported using conventional chemotherapy, high dose conditioning, and matched unrelated donor stem cell transplantation. These therapies were combined to add a graft versus leukemia effect to the treatment. Although chimerism studies showed a decrease of donor white blood cells, T-cells remained stable of allogeneic origin. We hypothesize that a continuous graft versus leukemia effect results in minimal residual disease negativity for now more than 18 months since stem cell transplantation.

Long-term Remission in a Female With Multiple Relapsed Juvenile Granulosa Cell Tumor.

A 4 ½-year-old female was diagnosed with ovarian juvenile granulosa cell tumor stage IA. After complete tumor resection she received 4 courses of chemotherapy due to unfavorable histopathologic features (high mitotic index, high microvessel density, blood vessel invasion). One year after diagnosis, she experienced paraaortic lymph node relapse treated with surgery, local radiotherapy, and conventional and high-dose chemotherapy. A second, paratracheal lymph node relapse 7 months later necessitated surgical removal and radiotherapy. Subsequently an adjuvant antiangiogenesis-based treatment including paclitaxel, bevacizumab, thalidomide, and pegylated interferon was initiated and continued for 2 years. The female is now in third complete remission 6 years after second relapse.

Sirolimus for the treatment of children with various complicated vascular anomalies.

Vascular anomalies include a heterogeneous group of disorders that are categorized as vascular tumors or vascular malformations. Treatment options include resection, embolization, laser therapy, and sclerotherapy or medical treatment such as propranolol, steroids, interferon, and cytostatic chemotherapy. Mammalian target of rapamycin seems to play a key role in the signal pathway of angiogenesis and subsequently in the development of vascular anomalies. Recently, the successful use of sirolimus has been reported in children with lymphatic malformations and kaposiform hemangioendotheliomas. We report on six patients with different vascular anomalies (kaposiform hemangioendothelioma n = 2, combined lymphatico-venous malformation n = 2, pulmonary lymphangiectasia n = 1, and orbital lymphatic malformation n = 1) who were treated with peroral sirolimus. Three of the children initially presented with a Kasabach-Merrit phenomenon. Median duration of treatment was 10 months; two children are still on treatment. Three children each achieved complete and partial remission. Kasabach-Merrit phenomenon resolved within 1 month in all patients. Treatment with sirolimus was tolerated well; only mild reversible leukopenia was observed. CONCLUSION: Sirolimus proved to be effective in children with complicated lymphatic or lymphatico-venous malformations and kaposiform hemangioendotheliomas. Treatment was tolerated well with acceptable side effects. The optimum length of treatment and possible long-term side effects have to be evaluated. WHAT IS KNOWN: • Vascular anomalies including vascular tumors and vascular malformations may lead to life-threatening conditions.• Some patients are refractory to established treatment and/or are not available for local invasive procedures. WHAT IS NEW: • We reviewed the literature focusing treatment of vascular anomalies inc hildren and adolescents.• Our data support recent studies that sirolimus is an effective treatment option in patients with complicated vascular tumors andmalformations

Is wide resection obsolete for desmoid tumors in children and adolescents? Evaluation of histological margins, immunohistochemical markers, and review of literature.

Desmoid fibromatosis is a benign fibroblastic neoplasm with high recurrence rates predominantly observed in pediatric and adolescent patients. The use of wide resection margins has been discussed controversially in literature. In addition, data on non-surgical treatment is limited as phase III studies are still missing. Nineteen patients under the age of 18 years were identified. Tumor location, surgical treatment for primary or recurrent tumors, resection margins, medical neo-/adjuvant treatment, time to recurrence as well as immunohistochemical markers (estrogen receptor, ER α and ß, progesterone and androgen receptors, somatostatin, Ki-67, c-kit, platelet-derived growth factor receptors, PDGFRs, α and ß, ß-catenin) were evaluated. The mean age at diagnosis was 6.6 years, with a mean follow-up of 114 months. Recurrences were detected in four out of nineteen patients. Surprisingly, the recurrence rate was not influenced by type of resection used (R0, R1/2). All samples were tested negative for ER α, somatostatin, and progesterone receptor. In contrast, a majority of tumors showed positive results for PDGFR α and ß and ß-catenin. No correlation between positive immunohistochemical markers and tumor recurrences was detectable. In conclusion, recurrence rates are not depending on resection type and immunohistochemical markers seem to behave differently in children and adolescents in contrast to adult patients.

Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B.

OBJECTIVES: Although amphotericin B (AmB) and its lipid formulations are used for the treatment of fungal infections of the CNS, the kinetics of AmB in the CSF after intravenous administration of liposomal amphotericin B (LAmB) are not well characterized. PATIENTS AND METHODS: From 14 paediatric haemato-oncological patients (aged 0.4-19.5 years, median 7.6 years), we obtained 30 CSF samples by means of routine punctures (performed for intrathecal treatment of the underlying diseases) at different timepoints after the prophylactic intravenous infusion of LAmB (AmBisome, 3 mg/kg/day). Concurrent serum samples were obtained to calculate the transfer rates. An HPLC method was used for AmB detection. RESULTS: CSF levels of AmB 1-100 h after the intravenous infusion of LAmB were between 10 and 120 ng/mL, except in one case with a level of 529 ng/mL. Concurrent serum levels were about 1000-fold higher, ranging between 3 and 75 µg/mL. CSF levels did not show a clear time-dependent concentration profile, but remained at a steady-state for longer than 48 h after infusion. The transfer rate ranged from 0.02% to 0.92% (median 0.13%) and correlated significantly (r=0.801, P<0.001) with increasing time after infusion. CONCLUSIONS: After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

Unrelated CD3/CD19-depleted peripheral stem cell transplantation for Hurler syndrome.

For patients with mucopolysaccharidosis type IH (MPS1-H; Hurler syndrome), early allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice. One boy and one girl aged 20.5 and 22 months, respectively, with MPS1-H received a conditioning regimen consisting of thiotepa, fludarabine, treosulfan, and ATG. Grafts were peripheral blood stem cells from unrelated donors (10/12 and 11/11 matched), that were manipulated by CD3/CD19 depletion and contained 20.3 and 28.2 × 10(6) CD34+ cells/kg body weight, respectively. Both patients achieved stable hematopoietic engraftment and stable donor chimerism. Neither acute or chronic graft-versus-host disease (GVHD) nor other severe transplant-related complications occurred. At a follow-up of 48 and 37 months, both patients are alive and well with normal levels of α-L-iduronidase and have made major neurodevelopmental progress. Treosulfan-based conditioning offers the advantage of reduced toxicity; the use of unrelated CD3/CD19-depleted peripheral stem cell grafts allows transfusion of high CD34+ cell numbers together with a "tailored" number of CD3+ cells as well as engraftment facilitating cells in order to achieve rapid hematopoietic engraftment while reducing the risk of graft rejection and GVHD. This regimen might be an additional option when unrelated donor HSCT is considered for a patient with MPS1-H.

Age- and gender-related differences in teicoplanin levels in paediatric patients.

OBJECTIVES: Teicoplanin is a glycopeptide antibiotic active against Gram-positive bacteria, including methicillin-resistant staphylococci. While teicoplanin trough levels (TTLs) >10 mg/L are commonly considered appropriate, levels >20 mg/L are aimed for in the treatment of severe infections. Due to toxicity, it is recommended to avoid levels >60 mg/L. PATIENTS AND METHODS: In our institution, the initial dosing schedule of teicoplanin (10-15 mg/kg every 12 h for three loading doses and every 24 h thereafter) is adapted according to TTLs analysed by a fluorescence polarization immunoassay on treatment days 2 to 4. Teicoplanin peak levels (TPLs) are analysed in selected cases 30 min after the end of infusion. In a retrospective analysis we evaluated 1357 TTLs and 333 TPLs from 410 treatment episodes from 2005 to 2011. RESULTS: Initial TTLs were <10 mg/L in 14.1% and <20 mg/L in 72.6% of episodes. Toddlers had significantly lower TTLs, with a 2-fold and 2.5-fold increased risk of having levels <10 mg/L (24.6%) and <20 mg/L (82.6%), respectively. For the entire cohort, follow-up TTLs were less likely to be <10 mg/L and more likely to be >20 mg/L when compared with initial TTLs (P < 0.001, each). Adolescent girls had significantly higher initial TPLs (P = 0.001) and significantly higher follow-up TTLs (P = 0.016) than adolescent boys. In parallel, adolescent girls had initial TPLs >60 mg/L significantly more frequently (P = 0.012) and follow-up TTLs <10 mg/L significantly less frequently (P = 0.005). CONCLUSIONS: More tailored dosing regimens with higher loading doses, especially for toddlers, should be considered. While further pharmacokinetic data in paediatric patients are pending, therapeutic drug monitoring is mandatory.

Add-on-therapy with bevacizumab in children and adolescents with poor prognosis non-CNS solid tumors.

Bevacizumab is increasingly being used in adult patients with cancer and children with central nervous system (CNS) tumors. Little, however, is known about the efficacy, risks, and benefits of bevacizumab administration in non-CNS tumors of childhood. The aim of the present study was to report on bevacizumab administered as add-on-therapy for poor prognosis non-CNS solid tumors of childhood and adolescence, including a prospective evaluation of side effects of bevacizumab. Seven patients (female: n = 5; median age, 14.5 years) with relapsed (n = 4) or primary metastatic (n = 3) solid non-CNS tumors received bevacizumab at 5-10 mg/kg body weight intravenously every 2-3 weeks. Assessment of cardiac function, thyroid hormone levels, urine analysis, and radiographic responses were carried out every 3 months. The median time of bevacizumab treatment was 10 (range, 5-17) months. Patients received a median of 16 (range, 10-38) bevacizumab infusions. With a median follow-up of 25 (range, 13-38) months, five patients relapsed after 7-25 months and three of them died. Two patients are still in complete remission for 31 and 32 months, respectively. Fraction shortening decreased in two patients. Bevacizumab was associated with new-onset increase in basal thyroid-stimulating hormone (n = 3), mild proteinuria/hematuria (n = 5), intermittent hypertension (n = 2), hypertension requiring antihypertensive medication (n = 3), and epistaxis (n = 2). In two patients, therapy with bevacizumab was terminated because of side effects. Selected patients with relapsed or primary metastatic solid non-CNS tumors of childhood and adolescence might benefit from add-on-therapy with bevacizumab. Although the side effects were usually mild, cardiac monitoring seems to be essential during and after the administration of bevacizumab.

Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms.

BACKGROUND: Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes. METHODS: The study systematically evaluated pedigrees of patients with t-MNs for cancer incidences and the possibility of a hereditary cancer predisposition syndrome. In addition, mutational analyses were performed using constitutional DNA from index patients, and deleterious heterozygous germline mutations were assessed for loss of heterozygosity in sorted leukaemic cells by single nucleotide polymorphism array. RESULTS: A nuclear pedigree was obtained in 51/53 patients with t-MNs resulting in a total of 828 individuals analysed. With a standardised incidence ratio of 1.03 (95% CI 0.74 to 1.39), the tumour incidence of first- degree relatives was not increased. However, six pedigrees were suggestive for a hereditary breast and ovarian cancer syndrome, three of a Li-Fraumeni like syndrome, and three index patients showed multiple primary neoplasms. Mutational analysis revealed two BRCA1 (c.3112G→T, c.5251C→T), one BRCA2 (c.4027A→G), two BARD1 (C557S) and four TP53 germline mutations (g.18508_18761delinsGCC, c.847C→T, c.845_848dupGGCG, c.1146delA) in nine of 53 (17%) index patients with t-MNs. Loss of heterozygosity in leukaemic cells was demonstrated for the BRCA1c.3112G→T and TP53c.845_848dupGGCG mutations, respectively. CONCLUSION: It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.

Parenthood for childhood cancer survivors: unfounded fear of cancer development in offspring and related health behaviors.

Current literature reveals no increased risk for adverse non-hereditary health outcomes in the offspring of childhood cancer survivors (CCS), yet survivors reported concerns regarding their offspring's health. To investigate how the fear of cancer development in offspring influences parental behavior related to health and prevention, survey reports from 256 European adult CCS and 256 age- and sex-matched siblings who participated in a multicenter study on offspring health were analyzed in the present study. Analyses of covariance and chi-square tests were conducted to test for differences between CCS and siblings in outcome variables (all related to healthy parenting behavior). CCS reported higher fear levels (p = 0.044, Partial η2 = 0.01) and less alcohol consumption (p = 0.011, Phi = 0.12) and smoking (p = 0.022, Phi = 0.11) during pregnancy than siblings. In survivor families, children were breastfed less often (p < 0.001, Phi = 0.18). Partial correlation analyses showed that CCS' fear levels decreased with increasing age (r = -0.16, p = 0.014), time since oncological therapy (r = -0.19, p = 0.003), and number of children (r = -0.21, p = 0.001). Overall, due to their own experiences with cancer, many CCS harbor misperceptions regarding the health outcomes of their offspring. Although the fear decreases with increasing distance from the active disease, any fear should be taken seriously, even if unfounded, and combated through targeted educational measures.