Case report: Slipped capital femoral epiphysis: a rare adverse event associated with FGFR tyrosine kinase inhibitor therapy in a child.

We report a case of slipped capital femoral epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib. A 13-year-old boy was diagnosed to have an optic pathway/hypothalamic glioma with signs of increased intracranial pressure and obstructive hydrocephalus requiring placement of ventriculo-peritoneal (VP) shunt. Sequencing of the tumor showed FGFR1-tyrosine kinase domain internal tandem duplication (FGFR1-KD-ITD). He developed hypothalamic obesity with rapid weight gain and BMI >30. At 12 weeks of treatment with erdafitinib, he developed persistent knee pain. X-ray of the right hip showed SCFE. Erdafitinib was discontinued, and he underwent surgical pinning of the right hip. MRI at discontinuation of erdafitinib showed a 30% decrease in the size of the tumor, which has remained stable at 6 months follow-up. Our experience and literature review suggest that pediatric patients who are treated with pan-FGFR TKIs should be regularly monitored for skeletal side effects.

Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.

BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.

PURPOSE: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10-12), immunohistochemistry (86%, P = 4.6 × 10-3), or tumor mutational burden (80%, P = 9.1 × 10-4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD (P = 2.2 × 10-5). CONCLUSION: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Upfront BRAF/MEK inhibitors for treatment of high-grade glioma: A case report and review of the literature.

Background: High-grade gliomas (HGG) with BRAFV600E mutation represent a unique subset of central nervous system tumors. Targeted therapies including BRAF and MEK inhibitors are now being explored as possible new treatment options. Methods: We report an 18-year-old female with a grade 3 pleomorphic xanthoastrocytoma treated upfront with dabrafenib and trametinib. We also conducted a systematic literature review of patients with HGG and BRAFV600E mutations treated with BRAF inhibitors. Results: Despite local recurrences resected surgically, the patient has been on dabrafenib and trametinib for more than 54 months. Thirty-two patients with HGG and BRAFV600E mutations treated with BRAF inhibitors were retrieved through our systematic review of the literature. Only 1 young patient with an anaplastic ganglioglioma was treated upfront with a BRAF inhibitor with a curative intent. Best response reported with radiation therapy and systemic therapy was a stable disease (SD) for 18 patients (56.3%) and progressive disease (PD) for 9 patients (28.1%). Responses to treatment regimens that included BRAF inhibitors were reported in 31 patients and included 4 complete responses (12.9%), 23 partial responses (74.2%), 2 SDs (6.5%), and 2 PDs (6.5%). Conclusions: Our patient had durable disease control with dabrafenib and trametinib. Given favorable responses reported in patients with HGG treated with BRAF inhibitors, we believe that upfront targeted therapy is a possible treatment approach that should be studied in the context of a clinical trial.

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)-A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA.

Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood-brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series.

Neurofibromatosis type 1-associated plexiform neurofibromas can cause debilitating symptoms and be life threatening. Treatment options are limited, given their tendency to regrow following surgery and their propensity to transform into malignant tumours following radiation. Selumetinib is an oral selective inhibitor of RAS-mitogen-activated protein kinase (MAPK) 1 and 2, which has shown efficacy for tumour shrinkage/stabilisation and symptom improvement. We report a national case series of 19 children treated with selumetinib. All patients experienced symptom improvement or stabilisation with an acceptable toxicity profile, including those patients previously treated with trametinib. This real-world experience confirms previous trials showing significant clinical benefit for this patient population.

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.

Management of Inoperable Supra-Sellar Low-Grade Glioma With BRAF Mutation in Young Children.

Pediatric low-grade gliomas (PLGGs) are the most common central nervous system (CNS) tumors in children. The current standard of care for surgically unresectable and/or progressive cases of PLGGs includes combination chemotherapy. PLGGs are molecularly characterized by alterations in the RAS/RAF/MAPK/ERK pathway in a majority of tumors. PLGGs harboring the BRAF-V600E mutation respond poorly to current chemotherapy strategies. We present a case of a two-year-old female with biopsy-proven low-grade glioma (LGG, pilocytic astrocytoma) involving the hypothalamic/optic chiasm region. At presentation, she had obstructive hydrocephalus, bitemporal hemianopia, central hypothyroidism, and right-sided hemiparesis due to the location/mass effect of the tumor. She was initially treated with chemotherapy (vincristine/carboplatin), but her tumor progressed at six weeks of treatment. She was subsequently started on dabrafenib as her tumor was positive for BRAF-V600E mutation. Dabrafenib monotherapy resulted in dramatic improvement in her clinical symptoms and near-complete resolution of tumor. Our experience and review of the literature suggest that LGGs with BRAF-V600E mutations may benefit from upfront targeted therapy in children. There is an urgent need for prospective clinical trials comparing the efficacy of upfront BRAF inhibitors versus standard chemotherapy in PLGGs with BRAF mutations.

Acute Myeloid Leukemia Presenting as a Posterior Fossa Tumor.

Extramedullary leukemia in pediatric acute myeloid leukemia can manifest as a myeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, in a variety of sites, or as leukemic blasts in the cerebrospinal fluid. Isolated MS of the central nervous system is rare. We report a case of acute myeloid leukemia with central nervous system-MS presenting as a posterior fossa mass mimicking a primary intracranial tumor.

Medical cannabis in pediatric oncology: a survey of patients and caregivers.

BACKGROUND: There are minimal data regarding the safety and efficacy of cannabis used as an anti-cancer agent or for symptom management in pediatric oncology. We aimed to characterize the prevalence and factors associated with the use of cannabis for the treatment of cancer and management of cancer-related symptoms in children during or after cancer treatment. METHODS: An anonymous 40 question paper survey was offered to patients/caregivers of children with cancer attending a pediatric oncology clinic in a provincially mandated cancer agency between October 2019 and March 2020. RESULTS: There were 64 respondents included in the analysis. Fourteen participants (N=14/64; 22%) reported use of cannabis, of which half used cannabis for either cancer treatment or symptom management, or both. Leukemia (n=9/14; 64%) was the most frequent diagnosis in children whose caregivers reported using cannabis and the majority of them were still receiving active cancer treatment (N= 5/9; 56%). All of the respondents using cannabis (14/14, 100%) experienced symptom improvement. Most of the caregivers procured cannabis from their friends (N=5/14; 36%), and oil was the most commonly used formulation (N=12/14; 86%). Cannabis-related information was received from another parent (N=4/14; 29%) or from a doctor (N=4/14; 29%). The reported monthly expenditure on cannabis varied widely from less than $50 CAD (N=4/14; 29%) to more than $500 CAD (N=3/14; 21%). CONCLUSIONS: Our survey shows that cannabis, mostly oil products, was used by one-fifth of children with cancer during or after the completion of cancer treatment. These findings require validation in a larger nationwide survey.

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

Thromboangiitis Obliterans (Buerger's Disease) in an Adolescent Male.

Arterial occlusive disease of the limb is very rare in children. Buerger's disease (BD) is a nonatherosclerotic, segmental inflammatory arteritis affecting the small and medium-sized vessels of the extremities. We report BD in a 16-year-old male presenting with arterial insufficiency of left foot and history of smoking cigarettes and cannabis for 2 years. BD was diagnosed based on history of smoking in combination with clinical, laboratory, and radiologic findings. Pediatric hemato-oncologists should consider BD in the differential diagnosis in adolescents who smoke cigarettes and/or cannabis and present with vascular insufficiency of the hands and/or feet.

Feeling scared or worried self-report in children receiving cancer treatments using the Symptom Screening in Pediatrics Tool (SSPedi).

INTRODUCTION: The objectives of this study were to describe reports of bother for feeling scared or worried among children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients, and to identify factors associated with it. METHODS: We included children receiving cancer treatments who were 8-18 years of age. Three patient types were enrolled: inpatients receiving active cancer treatment, outpatients receiving maintenance acute lymphoblastic leukemia chemotherapy, and outpatients in survivorship. Amount of bother due to feeling scared or worried yesterday or today was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi) on a 0-4 scale. Risk factors were evaluated using logistic regression. RESULTS: Among the 502 children included, 225 (45.0%) reported any degree of bother (score ≥ 1) and 29 (5.8%) reported severe bother (score ≥ 3) for feeling scared or worried. In multiple regression evaluating any bother, boys were less likely to be bothered (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41-0.87) and inpatients receiving active cancer treatment were more likely to be bothered compared to outpatients in survivorship (OR 3.58, 95% CI 2.00-6.52). The only factor associated with being severely bothered by feeling scared or worried was clinic visit or admission due to fever (OR 4.57, 95% CI 1.24-13.60). DISCUSSION: We found 45% of children receiving cancer treatments reported being bothered by feeling scared or worried. Girls and inpatients receiving active treatment experienced more bother of any degree, while visiting the hospital due to fever was associated with being severely bothered. Future work should identify interventions to prevent or alleviate this symptom.

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.

Intracranial growing teratoma syndrome (iGTS): an international case series and review of the literature.

PURPOSE: Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon of paradoxical growth of a germ cell tumor (GCT) during treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of iGTS in Western countries. METHODS: Pediatric patients from 22 North American and Australian institutions diagnosed with iGTS between 2000 and 2017 were retrospectively evaluated. RESULTS: From a total of 777 cases of central nervous system (CNS) GCT, 39 cases of iGTS were identified for an overall frequency of 5%. Pineal region was a more frequent location for iGTS as compared to cases of GCT without iGTS (p < 0.00001). In patients with an initial tissue diagnosis of GCT, immature teratoma was present in 50%. Serum AFP or ßhCG was detectable in 87% of patients (median values 66 ng/mL and 44 IU/L, respectively). iGTS occurred at a median of 2 months (range 0.5-32) from diagnosis, in the majority of patients. All patients underwent surgical resection, leading to gross total resection in 79%. Following surgery, all patients resumed adjuvant therapy or post treatment follow-up for GCT. At a median follow-up of 5.3 years (range 0.2-11.8), 37 (95%) of patients are alive, including 5 with stable residual mass. CONCLUSION: iGTS occurs in 5% of patients with GCT in Western countries. Tumors of the pineal region and GCT containing immature teratoma appear to be associated with a higher risk of developing iGTS. Complete surgical resection is the mainstay of treatment. Overall survival of patients developing iGTS remains favorable.

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.

Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors.

The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model. Transient opening of the BBB in response to HAV6 peptide administration was quantitatively characterized using both a gadolinium magnetic resonance imaging (MRI) contrast agent and adenanthin (Ade), the intended therapeutic agent. The effects of HAV6 peptide on BBB integrity and the efficacy of concurrent administration of HAV6 peptide and the small molecule inhibitor, Ade, in the growth and progression of an orthotopic medulloblastoma mouse model using human D425 tumor cells was examined. Systemic administration of HAV6 peptide caused transient, reversible disruption of BBB in mice. Increases in BBB permeability produced by HAV6 were rapid in onset and observed in all regions of the brain examined. Concurrent administration of HAV6 peptide with Ade, a BBB impermeable inhibitor of Peroxiredoxin-1, caused reduced tumor growth and increased survival in mice bearing medulloblastoma. The rapid onset and transient nature of the BBB modulation produced with the HAV6 peptide along with its uniform disruption and biocompatibility is well-suited for CNS drug delivery applications, especially in the treatment of brain tumors.