Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Removing barriers to accessing medical cannabis for paediatric patients.

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.

Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation.

ABSTRACT: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.

Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

The Impact of Exercise on Cardiotoxicity in Pediatric and Adolescent Cancer Survivors: A Scoping Review.

Childhood and adolescent cancer survivors are disproportionately more likely to develop cardiovascular diseases from the late effects of cardiotoxic therapies (e.g., anthracycline-based chemotherapy and chest-directed radiotherapy). Currently, dexrazoxane is the only approved drug for preventing cancer treatment-related cardiac damage. While animal models highlight the beneficial effects of exercise cancer treatment-related cardiac dysfunction, few clinical studies have been conducted. Thus, the objective of this scoping review was to explore the designs and impact of exercise-based interventions for managing cancer treatment-related cardiac dysfunction in childhood and adolescent cancer survivors. Reviewers used Joanna Briggs Institute's methodology to identify relevant literature. Then, 4616 studies were screened, and three reviewers extracted relevant data from six reports. Reviewers found that exercise interventions to prevent cancer treatment-related cardiac dysfunction in childhood and adolescent cancer survivors vary regarding frequency, intensity, time, and type of exercise intervention. Further, the review suggests that exercise promotes positive effects on managing cancer treatment-related cardiac dysfunction across numerous indices of heart health. However, the few clinical studies employing exercise interventions for childhood and adolescent cancer survivors highlight the necessity for more research in this area.

EMPOWER Retinoblastoma: Engaging Patient Partners in Solving the Top 10 Priorities for Eye Cancer Research in Canada.

While it is recognized that research priorities should reflect and integrate the perspectives and needs of patients along with those of health professionals and researchers, it remains challenging to actualize such priorities into tangible research projects. Targeted dissemination is required to catalyze research on these priorities. To create awareness of and inspire action toward actualizing the top 10 retinoblastoma research priorities in Canada, Canadian Retinoblastoma Research Advisory Board (CRRAB) members developed a wide range of dissemination tools and processes. These resources, co-produced with patients, were instrumental to CRRAB sharing the top 10 priorities internationally to mobilize action toward solving them.

Clinician views on and ethics priorities for authorizing medical cannabis in the care of children and youth in Canada: a qualitative study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Perspectives of pediatric oncologists and palliative care physicians on the therapeutic use of cannabis in children with cancer.

BACKGROUND: Children with cancer are increasingly using cannabis therapeutically. AIM: The purpose of this study was to determine the perspectives and practices of pediatric oncologists and palliative care physicians regarding the use of cannabis for medical purposes among children with cancer. METHODS: A self-administered, voluntary, cross-sectional, deidentified online survey was sent to all pediatric oncologists and palliative care physicians in Canada between June and August 2020. Survey domains included education, knowledge, and concerns about cannabis, views on its effectiveness, and the importance of cannabis-related research. Data were analyzed using descriptive statistics. RESULTS: In total, 122/259 (47.1%) physicians completed the survey. Although 62.2% of the physicians completed some form of training about medical cannabis, nearly all (95.8%) desired to know more about the dosing, side effects, and safety of cannabis. Physicians identified a potential role of cannabis in the management of nausea and vomiting (85.7%), chronic pain (72.3%), cachexia/poor appetite (67.2%), and anxiety or depression (42.9%). Only four (0.3%) physicians recognized cannabis to be potentially useful as an anticancer agent. Nearly all physicians reported that cannabis-related research for symptom relief is essential (91.5%) in pediatric oncology, whereas 51.7% expressed that future studies are necessary to determine the anticancer effects of cannabis. CONCLUSIONS: Our findings indicate that most pediatric oncologists and palliative care physicians recognize a potential role for cannabis in symptom control in children with cancer. Well-conducted studies are required to create evidence for cannabis use and promote shared decision making with pediatric oncology patients and their caregivers.

A Case Series of TERC Variant Telomere Biology Disorders in Unrelated Families From Atlantic Canada.

TERC variant telomere biology disorders (TBDs) are a rare, heterogenous group of disorders that arise from germline variants in TERC, a gene that encodes for the RNA component of telomerase. Variants in TERC lead to accelerated telomere attrition and can manifest as many different phenotypes. In this case series, we aimed to add to the literature describing TERC variant TBDs by reporting cases from two unrelated families from Atlantic Canada. The first case, a previously described germline TERC variant, n.107G>T (NR_001566.1), was identified in a young woman with myelodysplastic syndrome (MDS) and found to segregate with cytopenias in the family. This case represents a unique phenotypic presentation: this variant has not previously been described in patients with MDS and adds important segregation data to the literature. The second case, a novel TERC n.437T>G variant, was identified in a patient with both aplastic anemia and pulmonary fibrosis manifesting in his early 30s. We report these novel cases of germline TERC variants in order to help clinicians recognize TBDs, as well as to add important supporting information for the pathogenicity of these variants.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Incidence and risk factors of venous thrombotic events in pediatric patients with CNS tumors compared with non-CNS cancer: A population-based cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a well-recognized complication in pediatric cancer patients. It has been demonstrated that the incidence of VTE in pediatric patients with central nervous system (CNS) tumors is lower than that of patients with other cancers. Risk factors for developing cancer-related thrombosis are numerous and can include patient, disease, or treatment-related influences. The present study was designed to assess the VTE incidence in a pediatric oncology population, and to investigate whether intensity of treatment has similar associated with risk of VTE development in patients with and without CNS tumors. METHODS: A retrospective population-based cohort study of pediatric oncology patients in Atlantic Canada was conducted. Data collected from medical records included demographics, cancer type, treatment, presence of central venous catheters (CVC), and presence of thrombosis. Treatment intensity was assessed using the intensity of treatment rating scale (ITR-3). Study period was from January 2000 to December 2017. SPSS version 24 was used for statistical analysis. RESULTS: Of 1262 patients with pediatric cancer, 247 (19.6%) had CNS tumors. VTE occurred in significantly fewer (n = 5, 2%) patients with CNS tumors compared with patients with non-CNS cancers (n = 79, 7.8%) (p = 0.001). The ITR-3 scores did not differ significantly between the CNS and non-CNS groups (p = 0.638). In a multivariate logistic regression analysis, ITR-3 score was associated with VTE (odds ratio [OR]: 1.48, 95% CI: 1.2-1.9), while presence of CNS tumor was protective (OR: 0.26, 95% CI: 0.1-0.6). CONCLUSIONS: We demonstrate that pediatric patients with CNS tumors experience a significantly lower incidence of VTE compared with patients with non-CNS cancer. An increase in the ITR-3 rating significantly increased the odds of developing VTE.

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

Pontine gliomas a 10-year population-based study: a report from The Canadian Paediatric Brain Tumour Consortium (CPBTC).

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. PATIENTS AND METHODS: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). CONCLUSIONS: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.

Effect of different conditioning regimens on survival and engraftment for children with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoeitic stem cell transplantation: A single institution experience.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH), a rare hyperinflammatory immuneregulatory disorder, is a challenge in hematopoietic stem cell transplantation (HSCT) because of the high rate of mixed chimerism, relapse, and graft failure (GF) unless intensive myeloablative regimens are used. However, historically conventional myeloablative regimens (conv MA) are associated with high toxicity and mortality. PROCEDURE: We retrospectively compared transplant outcomes between three preparative regimens of varying intensities: Conv MA (n = 15), reduced-intensity conditioning (RIC, n = 12), and a treosulfan-based reduced-toxicity conditioning (RTC, n = 9). RESULTS: Patients in the RIC cohort had a higher incidence of mixed donor chimerism and five patients (42%) developed secondary GF (P = .002) compared to the other two regimens. There was a higher incidence of veno-occlusive disease and intensive care unit (ICU) admissions in the Conv MA cohort. With the RTC regimen, there was a similar 2-year overall survival (89, 73, and 83%; P = .87), but improved compound EFS (lack of relapse, GF, second transplant or additional donor cell infusions, or death; 89, 73, and 42%, P = .041) in RTC, Conv MA, and RIC regimen, respectively. CONCLUSIONS: The intensity of the preparative regimen has a significant impact on outcome of HSCT for HLH. The newly described treosulfan-based RTC provides for a stable graft with a reasonable toxicity profile.

Canadian Pediatric Neuro-Oncology Standards of Practice.

Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the absence of a clinical trial for seven of the most prevalent brain tumors in children. This allowed description of practice across the country, along with a consensus. This had a multitude of benefits, including understanding practice patterns, allowing for a basis to compare in future research and informing Health Canada of the current management of patients. This also allows all children in Canada to receive equivalent care, regardless of location.

Pediatric CNS Tumor Patients Have Significantly Lower Requirement of Tissue Plasminogen Activator for Episodes of Central Venous Catheter Dysfunction Compared With Other Pediatric Oncology Patients: Results of a Population-based Cohort Study.

PURPOSE: Central venous catheters (CVCs) are an important component of care delivery in pediatric oncology patients. However, CVC dysfunction is a common problem. Tissue plasminogen activator (tPA) is often administered to re-establish function, however, specific experience in pediatric patients with central nervous system (CNS) tumors is lacking. The goal of this study was to investigate the CVC experience and use of tPA for episodes of CVC dysfunction in pediatric patients with CNS tumors in comparison with other patients. METHODS: Medical records of all pediatric oncology patients from the 4 Atlantic provinces in Canada (Nova Scotia, New Brunswick, Prince Edward Island, and Newfoundland and Labrador) were reviewed. Data collected included demographics, treatment, details of CVCs along with CVC dysfunction, and tPA use. RESULTS: The cohort consisted of 1152 pediatric oncology patients, 222 (19.3%) of whom had CNS tumors. CVC dysfunction requiring tPA administration occurred in 12 (5.4%) of patients with CNS tumors compared with 182 (19.6%) of patients with non-CNS tumors (P=0.0001). Multivariate logistic regression analysis showed that administration of tPA for CVC dysfunction was 2.5 times more likely in patients with non-CNS tumors than those with CNS tumors (P=0.012; 95% confidence interval, 1.3-4.9). CONCLUSIONS: Our study showed that pediatric patients with CNS tumors require significantly less frequent administration of tPA for episodes of CVC dysfunction than patients with non-CNS tumors after adjusting for confounding factors. Hypotheses for this include: potential biologic differences of tumors, the role of the blood-brain barrier, or systematic differences in intensity of treatments.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.