Browsing by Author "Shih, Chie-Schin"

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    Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial
    (Springer Nature, 2021-01) Fisher, Michael J.; Shih, Chie-Schin; Rhodes, Steven D.; Armstrong, Amy E.; Wolters, Pamela L.; Dombi, Eva; Zhang, Chi; Angus, Steven P.; Johnson, Gary L.; Packer, Roger J.; Allen, Jeffrey C.; Ullrich, Nicole J.; Goldman, Stewart; Gutmann, David H.; Plotkin, Scott R.; Rosser, Tena; Robertson, Kent A.; Widemann, Brigitte C.; Smith, Abbi E.; Bessler, Waylan K.; He, Yongzheng; Park, Su-Jung; Mund, Julie A.; Jiang, Li; Bijangi-Vishehsaraei, Khadijeh; Robinson, Coretta Thomas; Cutter, Gary R.; Korf, Bruce R.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
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    Characteristics of children ≤36 months of age with DIPG: A report from the international DIPG registry
    (Oxford University Press, 2022) Bartlett, Allison L.; Lane, Adam; Chaney, Brooklyn; Yanez Escorza, Nancy; Black, Katie; Cochrane, Anne; Minturn, Jane; Bartels, Ute; Warren, Kathy; Hansford, Jordan; Ziegler, David; Diez, Blanca; Goldman, Stewart; Packer, Roger; Kieran, Mark; DeWire-Schottmiller, Mariko; Erker, Craig; Monje-Deisseroth, Michelle; Wagner, Lars; Koschmann, Carl; Dorris, Kathleen; Shih, Chie-Schin; Hassall, Tim; Fisher, Paul; Wang, Stacie S.; Tsui, Karen; Sevlever, Gustavo; Zhu, Xiaoting; Dexheimer, Phillip; Asher, Anthony; Fuller, Christine; Drissi, Rachid; Jones, Blaise; Leach, James; Fouladi, Maryam; Pediatrics, School of Medicine
    Background: Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. Methods: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. Results: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. Conclusions: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.
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    Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry
    (Oxford University Press, 2022) Erker, Craig; Lane, Adam; Chaney, Brooklyn; Leary, Sarah; Minturn, Jane E.; Bartels, Ute; Packer, Roger J.; Dorris, Kathleen; Gottardo, Nicholas G.; Warren, Katherine E.; Broniscer, Alberto; Kieran, Mark W.; Zhu, Xiaoting; White, Peter; Dexheimer, Phillip J.; Black, Katie; Asher, Anthony; DeWire, Mariko; Hansford, Jordan R.; Gururangan, Sridharan; Nazarian, Javad; Ziegler, David S.; Sandler, Eric; Bartlett, Allison; Goldman, Stewart; Shih, Chie-Schin; Hassall, Tim; Dholaria, Hetal; Bandopadhayay, Pratiti; Samson, Yvan; Monje, Michelle; Fisher, Paul G.; Dodgshun, Andrew; Parkin, Sarah; Chintagumpala, Murali; Tsui, Karen; Gass, David; Larouche, Valerie; Broxson, Emmett; Garcia Lombardi, Mercedes; Shiqi Wang, Stacie; Ma, Jie; Hawkins, Cynthia; Hamideh, Dima; Wagner, Lars; Koschmann, Carl; Fuller, Christine; Drissi, Rachid; Jones, Blaise V.; Leach, James; Fouladi, Maryam; Pediatrics, School of Medicine
    Background: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). Methods: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). Results: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. Conclusion: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
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    Comparison of multi-shot and single shot echo-planar diffusion tensor techniques for the optic pathway in patients with neurofibromatosis type 1
    (Springer, 2019-04) Ho, Chang Y.; Deardorff, Rachael; Kralik, Stephen F.; West, John D.; Wu, Yu-Chien; Shih, Chie-Schin; Radiology and Imaging Sciences, School of Medicine
    Purpose Diffusion tensor imaging (DTI) may be helpful in assessing optic pathway integrity as a marker for treatment in neurofibromatosis type 1 (NF1) patients with optic gliomas (OG). However, susceptibility artifacts are common in typical single-shot echo planar imaging (ssDTI). A readout-segmented multi-shot EPI technique (rsDTI) was utilized to minimize susceptibility distortions of the skull base and improve quantitative metrics. Methods Healthy controls, children with NF1 without OG, and NF1 with OG ± visual symptoms were included. All subjects were scanned with both rsDTI and ssDTI sequences sequentially. Diffusion metrics and deterministic fiber tracking were calculated. Tract count, volume, and length were also compared by a two-factor mixed ANOVA. Results Five healthy controls, 7 NF1 children without OG, and 12 NF1 children with OG were imaged. Six OG patients had visual symptoms. Four subjects had no detectable optic pathway fibers on ssDTI due to susceptibility, for which rsDTI was able to delineate. Tract count (p < 0.001), tract volume (p < 0.001), and FA (P < 0.001) were significantly higher for rsDTI versus ssDTI for all subjects. MD (p < 0.001) and RD (p < 0.001) were significantly lower for rsDTI vs ssDTI. Finally, MD, AD, and RD had a significantly lower difference in NF1 children with visual symptoms compared to NF1 children without visual symptoms only on ssDTI scans. Conclusion DTI with readout-segmented multi-shot EPI technique can better visualize the optic pathway and allow more confident measurements of anisotropy in NF1 patients. This is shown by a significant increase in FA, tract count, and volume with rsDTI versus ssDTI.
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    Novel Homozygous Deletion in STRADA Gene Associated With Polyhydramnios, Megalencephaly, and Epilepsy in 2 Siblings: Implications for Diagnosis and Treatment
    (Sage, 2018) Nelson, Katherine; Bell, Jennifer; Jackman, Christopher; Shih, Chie-Schin; Payne, Katelyn; Dlouhy, Stephen; Walsh, Laurence; Neurology, School of Medicine
    Mutations in the STE20-related kinase adaptor α (STRADA) gene have been reported to cause an autosomal recessive neurodevelopmental disorder characterized by infantile-onset epilepsy, developmental delay, and craniofacial dysmorphisms. To date, there have been 17 reported individuals diagnosed with STRADA mutations, 16 of which are from a single Old Order Mennonite cohort and share a deletion of exons 9-13. The remaining individual is of consanguineous Indian descent and has a homozygous single–base pair duplication. We report a novel STRADA gene deletion of exons 7-9 in 2 sisters from nonconsanguineous parents, as well as an improvement in seizure control in 1 sibling following treatment with sirolimus, an m-Tor inhibitor of potential benefit to patients with this genetic mutation.
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    Radiation Induced Cerebral Microbleeds in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy
    (Elsevier, 2018) Kralik, Stephen F.; Mereniuk, Todd R.; Grignon, Laurent; Shih, Chie-Schin; Ho, Chang Y.; Finke, Whitney; Coleman, Peter W.; Watson, Gordon A.; Buchsbaum, Jeffrey; Radiology and Imaging Sciences, School of Medicine
    Purpose Proton beam radiotherapy (PBT) has been increasingly utilized to treat pediatric brain tumors, however, limited information exists regarding radiation induced cerebral microbleeds (CMBs) among these patients. The purpose was to evaluate the incidence, risk factors, and imaging appearance of CMBs in pediatric patients with brain tumors treated with PBT. Methods A retrospective study was performed on 100 pediatric patients with primary brain tumors treated with PBT. CMBs were diagnosed by examining serial MRIs including susceptibility-weighted imaging. Radiation therapy plans were analyzed to determine doses to individual CMBs. Clinical records were used to determine risk factors associated with the development of CMBs in these patients. Results The mean age at time of PBT was 8.1 years. The median follow-up duration was 57 months. The median time to development of CMBs was 8 months (mean 11 months; range 3-28 months). The percentage of patients with CMBs was 43%, 66%, 80%, 81%, 83%, and 81% at 1-year, 2-years, 3-years, 4-year, 5-years, and greater than 5 years from completion of proton radiotherapy. The majority (87%) of CMBs were found in areas of brain exposed to ≥ 30 Gy. Risk factors included maximum radiotherapy dose (P=0.001), percentage and volume of brain exposed to ≥ 30 Gy (P=0.0004; P=0.0005), and patient age at time of PBT (P=0.0004). Chemotherapy was not a significant risk factor (P=0.35). No CMBs required surgical intervention. Conclusion CMBs develop in a high percentage of pediatric patients with brain tumors treated with proton radiotherapy within the first few years following treatment. Significant risk factors for development of CMBs include younger age at time of PBT, higher maximum radiotherapy dose, and higher percentage and volume of brain exposed to ≥ 30 Gy. These findings demonstrate similarities with CMBs that develop in pediatric brain tumor patients treated with photon radiotherapy.