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Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children.

Malignant mesothelioma is a neoplasm of serosal surfaces, most commonly affecting the pleura. The peritoneum, pericardium, and tunica vaginalis are less frequently involved. Malignant mesothelioma with EWSR1-ATF1 fusion in young adults was recently reported in the literature. Here, we present two pediatric cases of EWSR1-ATF1 translocation-associated malignant mesothelioma in the peritoneum and pericardium respectively. Both cases lacked a known exposure history. Microscopy in both cases showed predominantly epithelioid morphology with ample eosinophilic cytoplasm, and immunohistochemistry was positive for pan-keratin, calretinin, and WT1. Both cases showed EWSR1-ATF1 gene rearrangement by RNA sequencing, which was instrumental in confirming the diagnosis of malignant mesothelioma and to exclude more common pediatric sarcomas, especially in the context of limited sampling.

The use of cannabis for medical purposes by pediatric patients is expanding across Canada; however, supporting evidence, federal regulations and treatment guidelines are lacking. To understand factors affecting treatment decisions in this landscape, we sought to delineate clinician perspectives, ethics priorities and values for cannabis authorization.We sampled participants purposefully through Canadian Childhood Cannabinoid Clinical Trials listservs, which include the majority of pediatric oncologists and palliative care physicians practising in Canada, among many other pediatric physicians and clinicians. Inclusion criteria were being a practising clinician in Canada, involvement in the care of children and willingness to be interviewed regardless of stance on medical cannabis. In November and December 2020, we conducted semistructured interviews focusing on principles, values and priorities, including medical, professional, regulatory, evidentiary and social considerations, for authorizing medical cannabis to children. Interviews were recorded, transcribed and analyzed by means of deductive and inductive thematic methods.We conducted 18 interviews with a diverse group of clinicians representing a range of specialties within pediatric care, including neurology, palliative care, oncology, family medicine and pharmacology. The interviews yielded 4 themes and 12 subthemes related to a priori (medical, professional, regulatory, evidentiary and social themes) and emergent themes. The 4 themes of access, relationships and relational autonomy (autonomy within relationships), medically appropriate use and research priorities were grounded in principles of harm reduction. Participants described problematic authorization procedures that negatively affect patient use. Principles associated with relational autonomy were highlighted as a feature of open clinical communication. Benefits of appropriate medical uses weighed positively over risks, even in the context of potential effects on neurodevelopment. Participants expressed that more research is essential to align medical cannabis with biomedical standards.Clinicians reported pursuing ethical use of medical cannabis for pediatric patients and prioritizing their safety under principles of harm reduction. There is a need for evidence about neurodevelopmental risks, support for research, treatment guidelines and greater knowledge about stakeholder perspectives to alleviate burdens related to use of medical cannabis for pediatric patients in Canada.

Key points Children with chronic debilitating illness and pain are increasingly using cannabis for medical purposes, particularly when conventional treatment options have limited benefit or substantial adverse effects. Caregivers are becoming aware of evidence that suggests medical cannabis provides

PURPOSE This study investigated therapeutic potential of integrated genome and transcriptome profiling of metastatic sarcoma, a rare but extremely heterogeneous group of aggressive mesenchymal malignancies with few systemic therapeutic options. METHODS Forty-three adult patients with advanced or metastatic non-GI stromal tumor sarcomas of various histology subtypes who were enrolled in the Personalized OncoGenomics program at BC Cancer were included in this study. Fresh tumor tissues along with blood samples underwent whole-genome and transcriptome sequencing. RESULTS The most frequent genomic alterations in this cohort are large-scale structural variation and somatic copy number variation. Outlier RNA expression as well as somatic copy number variations, structural variations, and small mutations together suggest the presence of one or more potential therapeutic targets in the majority of patients in our cohort. Point mutations or deletions in known targetable cancer genes are rare; for example, tuberous sclerosis complex 2 provides a rationale for targeting the mammalian target of rapamycin pathway, resulting in a few patients with exceptional clinical benefit from everolimus. In addition, we observed recurrent 17p11-12 amplifications, which seem to be a sarcoma-specific event. This may suggest that this region harbors an oncogene(s) that is significant for sarcoma tumorigenesis. Furthermore, some sarcoma tumors carrying a distinct mutational signature suggestive of homologous recombination deficiency seem to demonstrate sensitivity to double-strand DNA–damaging agents. CONCLUSION Integrated large-scale genomic analysis may provide insights into potential therapeutic targets as well as novel biologic features of metastatic sarcomas that could fuel future experimental and clinical research and help design biomarker-driven basket clinical trials for novel therapeutic strategies.

Background Autism spectrum disorder (ASD) is a neurodevelopmental condition estimated to affect 1 in 66 children in Canada, and 1 in 270 individuals worldwide. As effective therapies for the management of ASD core and associated symptoms are limited, parents are increasingly turning to clinicians for advice regarding the use of medicinal cannabis to manage behavioural disturbances. Objective The objective of this scoping review was to identify and map symptoms, outcomes and adverse events related to medicinal cannabis treatment for ASD-related behaviours. Methods Ovid MEDLINE, Embase, CINAHL, PsycInfo, Web of Science Core Collection, Google Scholar, and grey literature sources were searched up to January 5, 2020 for studies. Included studies met the following criteria: 1) investigate the use of medicinal cannabis, 2) at least 50% participants had ASD, 3) at least 50% of the study population was 0-18 years old, and 4) any study design (published or unpublished). Results We identified eight completed and five ongoing studies meeting the inclusion criteria. All studies reported substantial behaviour and symptom improvement on medicinal cannabis, with 61-93% of subjects showing benefit. In the three studies reporting on concomitant psychotropic medication usage and with cannabis use, up to 80% of participants observed a reduction in concurrent medication use. Adverse events related to cannabis use were reported in up to 27% of participants related, and two participants had psychotic events. Conclusions Early reports regarding medicinal cannabis in pediatric ASD symptom management are presented as positive; the evidence, however, is limited to very few retrospective cohort and observational studies. Evidence of safety and efficacy from prospective clinical trials is needed.

This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the ‘voice of the clinician’ dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies (n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research.

Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families.

Introduction The use of medicinal cannabis in the paediatric age group is increasing despite the lack of evidence for its efficacy or safety. Objective To map the available evidence on the efficacy and safety of medicinal cannabis in children and adolescents. Methods We conducted a scoping review and searched six electronic databases and grey literature. A study was eligible for inclusion when it investigated the efficacy or safety of medicinal cannabis for any condition, more than half of the participants were 0 to 18 years old, and had any study design except single case reports. Results We included 36 studies in our final analysis, 32 of which investigated the efficacy or safety of cannabis in treatment-resistant epilepsy. The remaining 4 studies examined patients with cancer, dysautonomia, Epidermolysis Bullosa, and motor disorders. Conclusions There is a lack of evidence on the efficacy and safety of medicinal cannabis in most paediatric conditions.

PURPOSE Primary spinal low-grade gliomas (LGGs) are rare, can be difficult to treat, and can result in significant morbidity. The management of pediatric spinal LGGs remains controversial. METHODS A national multi-centre retrospective review of spinal LGGs diagnosed in children less than 18 years of age between 1990–2015 was undertaken to examine the clinical features, pathological subtypes, and treatment outcomes. RESULTS Forty-three patients from five institutions were included. The median age of diagnosis was 5.2 years. All patients were symptomatic at diagnosis. Forty-four percent of patients were diagnosed at least 6 months after symptoms developed. Two patients had metastatic disease at diagnosis. The most common histology was pilocytic astrocytoma (48.8%). Molecular information was available for 15/43 patients: 6 patients had BRAF fusions and 4 patients had BRAF V600E mutations. Gross-total resection was achievable in only 6 patients. Twenty-seven patients were treated with surgery-only and the others received chemotherapy and/or focal radiation. Eleven patients were irradiated. No patients were registered in clinical trials for first-line therapy. Twenty-three patients experienced relapse or progression. Patients were followed for a median of 8.3 years (range, 0.5–20.4 years). Five-year progression-free survival (PFS) and overall survival (OS) rates were 48.3% (95% CI, 32.3% to 62.5%) and 89.7% (95% CI, 74.6% to 96.1%) respectively. CONCLUSION There is significant heterogeneity in surgical outcomes and treatment modalities of pediatric spinal LGGs. The PFS and OS rates remain suboptimal, likely due to tumor location. The low clinical trial enrollment rate highlights the paucity of available trials for spinal LGGs.

Cell-free DNA (cfDNA) has become a comprehensive biomarker in the fields of non-invasive cancer detection and monitoring, organ transplantation, prenatal genetic testing and pathogen detection. While cfDNA samples can be obtained using a broad variety of approaches, there is an urgent need to standardize analytical tools aimed at assessing its basic properties. Typical methods to determine the yield and fragment size distribution of cfDNA samples are usually either blind to genomic DNA contamination or the presence of enzymatic inhibitors, which can confound and undermine downstream analyses. Here, we present a novel droplet digital PCR assay to identify suboptimal samples and aberrant cfDNA size distributions, the latter typically associated with high levels of circulating tumour DNA (ctDNA). Our assay was designed to promiscuously cross-amplify members of the human olfactory receptor (OR) gene family and includes a customizable diploid locus for the determination of absolute cfDNA concentrations. We demonstrate here the utility of our assay to estimate the yield and quality of cfDNA extracts and deduce fragment size distributions that correlate well with those inferred by capillary electrophoresis and high throughput sequencing. The assay described herein is a powerful tool to establish quality controls and stratify cfDNA samples based on presumed ctDNA levels, then facilitating the implementation of robust, cost-effective and standardized analytical workflows into clinical practice.

Background There is no uniform guideline for postchemotherapy vaccination of children with acute lymphoblastic leukemia (ALL). We evaluated waning immunity to 14 pneumococcal serotypes, pertussis toxin (PT), tetanus toxoid (TT) and varicella, and immunogenicity of postchemotherapy diphtheria, tetanus, pertussis, hepatitis B, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) and pneumococcal vaccination among previously vaccinated children treated for ALL. Methods This was a multicenter trial of children with ALL enrolled 4–12 months postchemotherapy completion. Exclusion criteria included: infant ALL, relapsed ALL, and stem cell transplant recipients. Immunocompetent children were recruited as controls. Postchemotherapy participants received DTaP-IPV-Hib and 13-valent pneumococcal conjugate vaccine (PCV13) concurrently, followed by 23-valent pneumococcal polysaccharide vaccine (PPV23) 2 months later. Serology was measured at baseline, 2 and 12 months postvaccination. Adverse events were captured via surveys. Results At enrollment, postchemotherapy participants (n = 74) were less likely than controls (n = 78) to be age-appropriately immunized with DTaP (41% vs 89%, P, In this multicenter trial, previously vaccinated children treated for acute lymphoblastic leukemia had lower antibody levels than controls to Streptococcus pneumoniae, tetanus toxoid, pertussis toxin, and varicella. Booster vaccination was immunogenic and well tolerated, suggesting benefit of systematic revaccination postchemotherapy.

This cohort study evaluates the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer., Key Points Question Is it feasible and useful to compare the tumor RNA sequencing data of a child or young adult with the tumor RNA sequencing data of thousands of other patients (of all ages) in a research setting? Findings Among 144 tumor samples from children and young adults, comparative RNA sequencing analysis, conducted across 4 precision medicine studies in the United States and Canada, was feasible and potentially useful for 99 of 144 pediatric and young adult cancer samples. In contrast, DNA mutation information was potentially useful for only 34 of 74 samples. Meaning This study’s findings suggest that open sharing and combined analysis of tumor RNA sequencing data from pediatric and young adult patients treated on different clinical trials may represent a feasible approach and may produce useful clinical and biological information for individual patients., Importance Pediatric cancers are epigenetic diseases; therefore, considering tumor gene expression information is necessary for a complete understanding of the tumorigenic processes. Objective To evaluate the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer. Design, Setting, and Participants This cohort study was conducted as a consortium between the University of California, Santa Cruz (UCSC) Treehouse Childhood Cancer Initiative and clinical genomic trials. RNA sequencing (RNA-Seq) data were obtained from the following 4 clinical sites and analyzed at UCSC: British Columbia Children’s Hospital (n = 31), Lucile Packard Children’s Hospital at Stanford University (n = 80), CHOC Children’s Hospital and Hyundai Cancer Institute (n = 46), and the Pacific Pediatric Neuro-Oncology Consortium (n = 24). The study dates were January 1, 2016, to March 22, 2017. Exposures Participants underwent tumor RNA-Seq profiling as part of 4 separate clinical trials at partner hospitals. The UCSC either downloaded RNA-Seq data from a partner institution for analysis in the cloud or provided a Docker pipeline that performed the same analysis at a partner institution. The UCSC then compared each participant’s tumor RNA-Seq profile with more than 11 000 uniformly analyzed tumor profiles from pediatric and young adult patients with cancer, downloaded from public data repositories. These comparisons were used to identify genes and pathways that are significantly overexpressed in each patient’s tumor. Results of the UCSC analysis were presented to clinical partners. Main Outcomes and Measures Feasibility of a third-party institution (UCSC Treehouse Childhood Cancer Initiative) to obtain tumor RNA-Seq data from patients, conduct comparative analysis, and present analysis results to clinicians; and proportion of patients for whom comparative tumor gene expression analysis provided useful clinical and biological information. Results Among 144 samples from children and young adults (median age at diagnosis, 9 years; range, 0-26 years; 72 of 118 [61.0%] male [26 patients sex unknown]) with a relapsed, refractory, or rare cancer treated on precision medicine protocols, RNA-Seq–derived gene expression was potentially useful for 99 of 144 samples (68.8%) compared with DNA mutation information that was potentially useful for only 34 of 74 samples (45.9%). Conclusions and Relevance This study’s findings suggest that tumor RNA-Seq comparisons may be feasible and highlight the potential clinical utility of incorporating such comparisons into the clinical genomic interpretation framework for difficult-to-treat pediatric and young adult patients with cancer. The study also highlights for the first time to date the potential clinical utility of harmonized publicly available genomic data sets.

Marijuana has been used by many different civilizations for numerous different purposes, including its use for medical indications. Recently, there has been significant media coverage of the efficacy of medical marijuana in the treatment of seizures in children with Dravet syndrome, and this has led many to search for other possible pediatric indications for cannabinoids, including many different indications in pediatric cancer. However, there is very little evidence on safety or efficacy of cannabinoids in children being treated with cancer. This commentary accompanies a recent paper by a group in Israel who have published their experience of medical marijuana in 50 children and adolescents with cancer, showing excellent satisfaction and better symptom control, and without significant adverse drug reactions. This study from Israel is an excellent first step, but prospective well-designed trials of medical marijuana in pediatric oncology are urgently needed.

OBJECTIVE Refractory symptomatic plexiform neurofibromas (PNF) and inoperable refractory low grade gliomas (LGG) pose a clinical challenge that may be life threatening. Phase 1 and 2 clinical trials of MEK inhibition with selumetinib in inoperable PNF and LGG have demonstrated promising results in pediatrics, however access has been limited to enrollment on clinical trial. Phase 1 clinical trial for trametinib a MEK 1 and 2 inhibitor has been completed, publication is pending. Thus we have treated a series of children on a compassionate basis with extensive PN or LGG refractory disease with trametinib, as this is available in Canada. METHODS We have treated children with trametinib on a compassionate basis in our province since 2017. Review of the clinical data regarding this therapy has been IRB approved. RESULTS Two young patients were treated for indication of life threatening extensive PNF and have had tumor shrinkage and improvement of clinical status. Treatment has been complicated by paronychiae, eczema exacerbation, chondrodermatitis nodularis helicis, RSV and influenza B infection and CTCAE grade 2 pneumonia. In spite of the side effects these two patients remain on treatment due to clear benefit from therapy including: improved respiratory compromise, hearing and dysphagia. We will present the data of additional patients treated with trametinib. CONCLUSION Trametinib is an effective therapy for life threatening PNF by changing the natural history of tumor growth in young children. Further data is required in terms of tolerance, efficacy and durability of response in such patients in the setting of clinical trials.

Precision oncology trials for pediatric cancers require rapid and accurate detection of genetic alterations. Tumor variant identification should interrogate the distinctive driver genes and more frequent copy number variants and gene fusions that are characteristics of pediatric tumors. Here, we evaluate tumor variant identification using whole genome sequencing (n = 12 samples) and two amplification-based next-generation sequencing assays (n = 28 samples), including one assay designed to rapidly assess common diagnostic, prognostic, and therapeutic biomarkers found in pediatric tumors. Variant identification by the three modalities was comparable when filtered for 151 pediatric driver genes. Across the 28 samples, the pediatric cancer-focused assay detected more tumor variants per sample (two-sided, P

A male infant is delivered at a gestational age of 35 weeks by urgent cesarean section for decreased fetal movements lasting more than 24 hours and decreased fetal heart rate variability with major decelerations. The mother is a healthy 35-year-old white, gravida 2 para 0 woman with an uneventful pregnancy except for diet-controlled gestational diabetes mellitus. Thick meconium-stained liquor is noted at birth. The infant is born nonvigorous and undergoes intubation and suctioning below the cords. He develops weak spontaneous respiration and is given free-flow oxygen, but no additional respiratory support is required. Apgar scores are 1, 8, and 8 at 1, 5, and 10 minutes, respectively. Arterial cord gas measurements are as follows: pH 7.00, partial pressure of carbon dioxide 84 mm Hg (11.17 kPa), and base deficit 10 mEq/L. The infant’s weight is 3,485 g (>95th percentile), length is 52 cm, and head circumference is 35 cm (both >90th percentile for gestational age). Clinical examination after birth reveals a palpable left hypochondrial mass and hepatomegaly. Laboratory results of note on day 1 are as follows: platelet count, 49 × 103/μL (49 × 109/L); alanine aminotransferase, 1,880 U/L (31.4 μkat/L); aspartate aminotransferase, 381 U/L (6.36 μkat/L); lactate dehydrogenase, >20,000 U/L (334 μkat/L); international normalized ratio (INR), 2.95; activated partial thromboplastin time, 35.9 seconds; fibrinogen, 84 mg/dL (2.5 μmol/L); D-dimer, greater than 3.5 μ/dL; serum albumin, 1.8 g/dL (18 g/L); serum ferritin, 844 ng/dL serum ammonia, 76.6 μ/dL. Blood and cerebrospinal fluid microbiological cultures and herpes virus polymerase chain reaction are reported negative. Among significant radiologic findings, abdominal ultrasonography on the first day after birth reveals a …

Clinical detection of sequence and structural variants in known cancer genes points to viable treatment options for a minority of children with cancer.1 To increase the number of children who benefit from genomic profiling, gene expression information must be considered alongside mutations.2,3 Although high expression has been used to nominate drug targets for pediatric cancers,4,5 its utility has not been evaluated in a systematic way.6 We describe a child with a rare sarcoma that was profiled with whole-genome and RNA sequencing (RNA-Seq) techniques. Although the tumor did not harbor DNA mutations targetable by available therapies, incorporation of gene expression information derived from RNA-Seq analysis led to a therapy that produced a significant clinical response. We use this case to describe a framework for inclusion of gene expression into the clinical genomic evaluation of pediatric tumors.

Aim: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. Patients & methods: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. Results: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). Conclusion: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification. Original submitted 26 November 2014; Revision submitted 12 May 2015.

BACKGROUND Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

Ultrasensitive methods for rare allele detection are critical to leverage the full potential offered by liquid biopsies. Here, we describe a novel molecular barcoding method for the precise detection and quantification of circulating tumor DNA (ctDNA). The major benefits of our design include straightforward and cost-effective production of barcoded adapters to tag individual DNA molecules before PCR and sequencing, and better control over cross-contamination between experiments. We validated our approach in a cohort of 24 patients with a broad spectrum of cancer diagnoses by targeting and quantifying single-nucleotide variants (SNVs), indels and genomic rearrangements in plasma samples. By using personalized panels targeting a priori known mutations, we demonstrate comprehensive error-suppression capabilities for SNVs and detection thresholds for ctDNA below 0.1%. We also show that our semi-degenerate barcoded adapters hold promise for noninvasive genotyping in the absence of tumor biopsies and monitoring of minimal residual disease in longitudinal plasma samples. The benefits demonstrated here include broad applicability, flexibility, affordability and reproducibility in the research and clinical settings.

Acute graft versus host disease (GVHD) is a significant complication of bone marrow transplantation with approximately half of patients being refractory to steroids. There are numerous second-line systemic immunosuppressive treatments but the overall prognosis is poor and these therapies are associated with high mortality due to infection. An alternative approach to systemic treatment for GVHD is targeted delivery of immunosuppression. We present two pediatric cases with steroid-refractory gastrointestinal GVHD who clinically responded to intra-arterial steroid administration. We also review the literature regarding this treatment modality with a particular emphasis in children. Pediatr Blood Cancer 2014;61:2321–2323. © 2014 Wiley Periodicals, Inc.

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2 ) and temsirolimus (15 mg/m2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m2 , vinblastine 4 mg/m2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months). Conclusion The combination of weekly temsirolimus (15 mg/m2 ) and vinblastine (4 mg/m2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

Background Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. While hepatitis is a well-known complication during the treatment phase of ALL, the association of abnormal liver biochemistries at initial presentation of leukemia is poorly described. The aim of this study is to examine the prevalence and assess the clinical impact of hepatitis at diagnosis in children with ALL. Procedure All children diagnosed with ALL at BC Children's Hospital between 2001and 2006 were included. Charts were reviewed and data recorded to a computerized spreadsheet. Descriptive statistical analyses were performed. Results One hundred forty-seven ALL patients were identified. Over one third of patients had abnormal liver transaminase values (AST and/or ALT). Of the patients with abnormal transaminases, (52%) had ALT elevations twice the upper limit of normal. Risk factors for elevated transaminases included a high WBC count at diagnosis, older age, bulky disease, and T-cell leukemia. Conjugated hyperbilirubinemia was observed in 3.4% of subjects. Of these cases, 60% received steroids prior to induction chemotherapy and all had rapid resolution of their hyperbilirubinemia to normal levels. Conclusions Elevated transaminases are common at initial presentation of ALL and are likely due to hepatic injury from leukemic infiltrates. Conjugated hyperbilirubinemia at presentation may require treatment modification and dose reduction. A short course of steroids prior to initiation of induction chemotherapy appears to result in rapid resolution of the hyperbilirubinemia with subsequent ability to provide full dosing of induction chemotherapy. Pediatr Blood Cancer. 2010;55:434–439. © 2010 Wiley-Liss, Inc.

Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole-genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding. Identification of oncogenic drivers in recurrent pediatric PTC may facilitate targeted therapy while avoiding repeated RAI.

Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3-125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9-15.9) associated with cisplatin-induced hearing loss in children.

Genital ulceration is a rare manifestation of infectious mononucleosis caused by Epstein-Barr virus (EBV). We report a girl with severe genital ulceration and tissue necrosis during primary EBV infection that required surgical debridement. The excised genital tissue was EBV polymerase chain reaction-positive whereas in situ hybridization was negative. This suggests that the ulceration was likely because of the inflammatory response to the virus and not because of the intense viral infection of the genitalia.

Acute graft versus host disease (GVHD) is a significant complication of bone marrow transplantation with approximately half of patients being refractory to steroids. There are numerous second-line systemic immunosuppressive treatments but the overall prognosis is poor and these therapies are associated with high mortality due to infection. An alternative approach to systemic treatment for GVHD is targeted delivery of immunosuppression. We present two pediatric cases with steroid-refractory gastrointestinal GVHD who clinically responded to intra-arterial steroid administration. We also review the literature regarding this treatment modality with a particular emphasis in children.

A two-year-old boy with an ependymoma was admitted for administration of chemotherapy (cyclophosphamide, methotrexate, etoposide and cisplatin). Previous cycles of the same chemotherapy had been well tolerated, with no hypotension. Independent of medical advice, the patient’s parents had been

Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children.Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay.With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model.This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

Purpose Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. Patients and Methods We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. Results We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10−5 for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate–binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. Conclusion We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

Adverse drug reactions (ADRs) rank as one of the top ten leading causes of death and illness in the developed world. In cancer therapy, more patients are surviving cancer than ever before, but 40% of cancer survivors suffer life-threatening or permanently disabling severe ADRs and are left with long-term sequelae. ADRs are often more frequent and more severe in children, and the consequences for children who experience a severe ADR can be catastrophic. Pharmacogenomics has the potential to improve the safety of these drugs. This review highlights severe ADRs that can occur in cancer therapy that are more frequent and more severe in children, and the pharmacogenomics research that aims to understand, predict, and ultimately prevent these severe reactions.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. While hepatitis is a well-known complication during the treatment phase of ALL, the association of abnormal liver biochemistries at initial presentation of leukemia is poorly described. The aim of this study is to examine the prevalence and assess the clinical impact of hepatitis at diagnosis in children with ALL.All children diagnosed with ALL at BC Children's Hospital between 2001 and 2006 were included. Charts were reviewed and data recorded to a computerized spreadsheet. Descriptive statistical analyses were performed.One hundred forty-seven ALL patients were identified. Over one third of patients had abnormal liver transaminase values (AST and/or ALT). Of the patients with abnormal transaminases, (52%) had ALT elevations twice the upper limit of normal. Risk factors for elevated transaminases included a high WBC count at diagnosis, older age, bulky disease, and T-cell leukemia. Conjugated hyperbilirubinemia was observed in 3.4% of subjects. Of these cases, 60% received steroids prior to induction chemotherapy and all had rapid resolution of their hyperbilirubinemia to normal levels.Elevated transaminases are common at initial presentation of ALL and are likely due to hepatic injury from leukemic infiltrates. Conjugated hyperbilirubinemia at presentation may require treatment modification and dose reduction. A short course of steroids prior to initiation of induction chemotherapy appears to result in rapid resolution of the hyperbilirubinemia with subsequent ability to provide full dosing of induction chemotherapy.

Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted “panel” sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.