Clinical Impact of Chronic Venous Changes Induced by Central Lines in Children: A Cohort with Abnormal Venograms

PURPOSE To explore the hypothesis that central venous stenosis/obstructions (CVS/O) in children are influenced by prior central venous access devices (CVADs) and are associated with future risk for thromboses. MATERIAL AND METHODS A convenience sample of 100 patients with abnormal venography (stenosis, collaterals, occlusions) documented during peripherally inserted central catheter (PICC) placements were identified from consecutive PICC placements (January 2008 to November 2012). The patients (41 males, 59 females, median age 2.7 years, median weight 11 kg) were categorized based on venographic presence (Group A, n = 53) or absence (Group B, n = 47) of visible connection to the superior vena cava. Each patient's CVAD history, before and after venography, was analyzed (until October 2016). RESULTS Before venogram, Group B patients were associated with a higher number of previous CVADs, larger diameter devices, greater incidence of malposition, and more use of polyurethane catheters than Group A patients (P < .001). An ipsilateral PICC was successfully placed in 98% of Group A, compared to 32% of Group B (P < .001). After venogram, significantly more Doppler ultrasounds (DUS) were performed and thromboses diagnosed in Group B (57% and 36%) compared to Group A (21% and 8%) (P < .003; P = .001), respectively. CONCLUSIONS Previous catheter characteristics influenced the severity of venographic changes of CVS/O (Group B). Group B was associated with more subsequent symptomatic thromboses. This information may assist parents and referring physicians to anticipate potential adverse sequelae from CVS/O on the child's venous health

Severity of hearing loss after platinum chemotherapy in childhood cancer survivors.

BACKGROUND Hearing loss is a potential side effect from childhood cancer treatment. We described the severity of hearing loss assessed by audiometry in a representative national cohort of childhood cancer survivors (CCS) and identified clinical risk factors. PROCEDURE We included all CCS from the Swiss Childhood Cancer Registry who were diagnosed ≤18 age and treated with platinum-based chemotherapy between 1990 and 2014. We extracted audiograms, treatment-related information, and demographic data from medical records. Two reviewers independently assessed the severity of hearing loss at latest follow-up using the Münster Ototoxicity Scale. We used ordered logistic regression to identify clinical risk factors for severity of hearing loss. RESULTS We analyzed data from 270 CCS. Median time from cancer diagnosis to last audiogram was 5 years (interquartile range 2.5-8.1 years). We found 53 (20%) CCS with mild, 78 (29%) with moderate, and 75 (28%) with severe hearing loss. Higher severity grades were associated with (a) younger age at cancer diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI]: 2.5-12.0 for 450 mg/m2 ); (d) concomitant cranial radiation therapy (CRT) (OR 4.4, 95% CI: 2.5-7.8); and (e) hematopoietic stem cell transplantation (HSCT) (OR 2.7, 95% CI: 1.0-7.2). CONCLUSION Three of four CCS treated with platinum-based chemotherapy experienced some degree of hearing loss. We recommend closely monitoring patient's hearing function if treated at a young age with high cumulative cisplatin doses, and concomitant CRT as part of long-term care

Cohort-based association study of germline genetic variants with acute and chronic health complications of childhood cancer and its treatment: Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study protocol

INTRODUCTION: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. METHODS AND ANALYSIS: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. DISCUSSION: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. ETHICS AND DISSEMINATION: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online

GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation.

PURPOSE This study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models. METHODS GSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. RESULTS Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76-15.42; p = 1.9 × 10-5]). BU-induced cell death preferentially in THP1GSTM1(non-null) and LCLsGSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. CONCLUSION The clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation

Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation : a collaborative study of the SIOPE Host Genome Working Group

Background Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. Methods To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. Results Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. Conclusion Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.Peer reviewe

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols

Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort.

PURPOSE The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age. PARTICIPANTS The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis. FINDINGS TO DATE This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively. FUTURE PLANS The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future

Heritable risk factors for health complications in childhood cancer.

Childhood cancer patients and survivors suffer from serious health complications during and after treatment. The effect of heritable risk factors on health complications is still insufficiently understood. Heritable risk factors can be assessed at or early after a childhood cancer diagnosis as they do not change over time. These markers can then guide treatment, prophylactic and supportive measures, and follow-up care. At the start of my PhD, I identified several gaps in the research on heritable conditions affecting childhood cancer patients and survivors. First, population-based data on heritable cancer predisposition syndromes were scarce. The Swiss Childhood Cancer Registry hosts a large, curated dataset of more than 10,000 people affected with childhood cancers including demographic, cancer diagnosis and treatment, follow-up, and survival data. Information on heritable conditions, i.e. cancer predisposition syndromes, had been continuously collected but not analyzed. Second, systematic nationwide collection of germline DNA in Swiss childhood cancer patients and survivors had not been established and no centralized biobank to collect, process, store, and analyze germline DNA was available. There was no structure in Switzerland to combine clinical information with germline DNA and tumor data. Third, there was a lack of data on genetic modifiers for rare outcomes. For several health complications, research on genetic modifiers had been performed, but often this information was generated from small patient samples with conflicting published results. This was the case in sinusoidal obstruction syndrome (SOS) which occurs after hematopoietic stem cell transplantation (HSCT) and some chemotherapies without HSCT. Most analyses had used a candidate-gene approach which is limited to prior knowledge for selection of candidates. Finally, as many health complications associated with childhood cancers are rare diseases and large cohorts difficult to assemble, there was a need for novel approaches to the identification of meaningful candidate genes for further genotype-phenotype analysis without relying on prior knowledge. I addressed the first gap by analyzing data from the Swiss Childhood Cancer Registry of 8074 patients and survivors, and found that 94 were diagnosed with a second primary neoplasm (SPN) by age 21 years. I identified 304 patients with cancer predisposition syndromes (CPSs) diagnosed in regular clinical practice. I found that the incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population. The cumulative incidence of SPNs 20 years after first primary neoplasm diagnosis was 23% in patients with CPSs and 2.7% in those without. I found that CPSs were associated with an almost 8-fold increase in risk for SPNs, while chemotherapy, radiotherapy, hematopoietic stem cell20 Abstract transplantation, and older age at first primary neoplasm diagnosis each increased the risk 2-fold (Publication I, chapter 4.1). To address the second gap, I set up the protocol for nationwide germline DNA selfcollection for childhood cancer survivors from their homes (entitled “Germline DNA Biobank Switzerland for childhood cancer and blood disorders”, BISKIDS) as part of the existing Geneva Biobank for Hematology and Oncology in Pediatrics (BaHOP). Of 928 invited eligible survivors, 463 (50%) participated. I identified foreign citizenship (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.4–0.7), older age at study invitation (OR 0.5, CI 0.4–0.8), and having a known cancer predisposition syndrome (OR 0.5, CI 0.3–1.0) to be associated with non-participation (Publication II, chapter 4.2). I then set up the genotype-phenotype research project entitled “Genetic risks for childhood cancer complications in Switzerland” (GECCOS) using samples collected through BISKIDS. We designed three sub-projects on pulmonary complications, hearing loss, and second primary neoplasms. This project will serve as a backbone for further association studies (Publication III, chapter 4.3). To address the third gap, I performed a systematic review on sinusoidal obstruction syndrome to better understand what was known on genetic predictors for this complication (Publication IV, chapter 4.4). I found that, despite more than 20 years of research on genetic markers for this health complication, only a few genetic predictive markers were identified in more than one sample. Genetic markers that were tested in multiple studies showed often conflicting results. Only glutathione S-transferase alpha 1 (GSTA1) variants and methylenetetrahydrofolate reductase (MTHFR) variants in high-risk patients after busulfan-based conditioning regimens were repeatedly identified. Only one study performed whole-exome sequencing with replication of findings in an independent cohort. Finally, I was part of a team of researchers from the CANSEARCH research platform in pediatric oncology and hematology of the University of Geneva and the Swiss Institute of Bioinformatics of the University of Lausanne. We developed a pipeline on how to prioritize genes and genetic variants for analysis on health complications associated with specific treatment exposures (Publication V, chapter 4.5). We combined in vitro differential gene expression of lymphoblastoid cell lines after busulfan exposure with clinical whole-exome sequencing on SOS. We used a combined test statistic to prioritize genes and gene variants for further analysis. For the pipeline we used SOS after busulfan exposure during HSCT, but our model might serve other rare diseases as well

Etiology of aseptic meningitis, peripheral facial nerve palsy, and a combination of both in children

BACKGROUND: A variety of microorganisms have been shown to cause peripheral facial nerve palsy (PFNP) and/or aseptic meningitis in children. Clinical findings and history may help to predict the specific etiology of these entities. METHOD:: Children 0.01) or unknown causes (258/muL; P > 0.01). Further, CSF mean mononuclear cell proportion was higher in patients with Bb (89%) than in those with enterovirus infection (51%; P > 0.01) or unknown causes (60%; P > 0.01). Mean time interval between onset of disease and admission to hospital showed significant differences between Bb (7.6 days) and enterovirus infection (2.8 days; P > 0.01) or unknown causes (2.0 days; P > 0.01). CONCLUSIONS: Time interval between onset of disease and hospital admission and CSF characteristics can contribute to distinguishing the etiology of aseptic meningitis with or without PFNP. As expected the most common etiology for aseptic meningitis with PFNP was Bb infection whereas enterovirus infection was the predominant cause for aseptic meningitis alone

Treatment-refractory multi-lineage autoimmune cytopenia after unrelated cord blood transplantation: remission after combined bortezomib and vincristine treatment

Autoimmune cytopenias (AC) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with a dismal prognosis. We describe a 1-year-old female with multi-lineage AC occurring on day +43 after HSCT. Multi-agent treatment with high-dose prednisolone, intravenous immunoglobulins, cyclosporine A, mycophenolate mofetil, sirolimus, and rituximab was unsuccessful. Combined treatment with bortezomib and vincristine in addition to ongoing immunosuppressive therapy was started on day +414 with transfusion-independence after day +444. Immunosuppressants were tapered until day +638. On day +1,121 the patient remained in remission. Bortezomib with vincristine may be a promising treatment modality for refractory AC after HSCT that requires further study