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Matthew D. Hall, Yazmin Odia, Joshua E. Allen, Rohinton Tarapore, Ziad Khatib, Toba N. Niazi, Doured Daghistani, Lee Schalop, Andrew S. Chi, Wolfgang Oster and Minesh P. Mehta

Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity to DRD2 antagonism. This study reports the first clinical experience with the DRD2/3 antagonist ONC201 as a potential targeted therapy for H3 K27M–mutant DIPG. One pediatric patient (a 10-year-old girl) with H3 K27M–mutant DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use study and began single-agent ONC201 treatment 1 month after completing radiotherapy. The study endpoints were clinical and radiographic response (primary) and toxicities (secondary).

The patient presented with House-Brackmann grade IV facial palsy and unilateral hearing loss. MRI demonstrated a 2.3 × 2.1 × 2.8–cm pontomedullary tumor. Stereotactic biopsy confirmed H3 K27M–mutated DIPG. The tumor was treated with radiotherapy, but 1 month after completion of that treatment, the tumor and neurological symptoms showed only minimal change, and ONC201 treatment was initiated as described above. The tumor volume sequentially decreased by 26%, 40%, and 44% over the next 6 months, and remained stable at 18 months. Ipsilateral hearing normalized and the facial palsy improved to House-Brackmann grade I by 4 months. After 1 year of ONC201 treatment, 2 new lesions were identified outside of the prior high-dose radiotherapy volume. The patient was treated with dexamethasone, bevacizumab, and additional focal radiotherapy to these new tumors. These tumors remained stable in size over the subsequent 6 months on MRI. To date, no adverse events have been observed or reported due to ONC201. The patient remains clinically improved as of the latest follow-up visit, 19 months after starting ONC201 and 22 months from diagnosis. This case supports further investigation of this novel agent targeting H3 K27M–mutated DIPG.

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Matthew C. Tate, Anurahda Banerjee, Scott R. Vandenberg, Tarik Tihan, John H. Chi, Christopher P. Ames and Andrew T. Parsa

This 18-year-old woman presented with headache and diplopia over several months and was found to have an enhancing pineal tumor with resultant obstructive hydrocephalus. Following standard preoperative diagnostic tests, including spinal axis imaging, the patient was taken to the operating room for an endoscopic third ventriculostomy to relieve hydrocephalus and then subsequently underwent a craniotomy for gross-total resection of the pineal mass. The patient was discharged after an uneventful hospital course and received standard adjuvant cranial-spinal radiation and chemotherapy as an outpatient. Follow-up imaging 1 year after surgery demonstrated a metabolically active, lytic lesion in the C-3 vertebral body and new lung lesions suggesting a metastatic pineoblastoma. The patient underwent a C-3 anterior corpectomy and reconstruction without complication as aggressive therapy for presumed metastatic disease. Final pathological results from the vertebral lesion were consistent with radiation-induced reactive changes, not metastatic pineoblastoma as originally suspected. The patient recovered well and remains symptom free. To the authors' knowledge this is the first reported case of reactive changes mimicking metastasis in a single vertebral body following standard therapy for resected primary pineoblastoma.

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John H. Chi, Amith Panner, Kristine Cachola, Courtney A. Crane, Joseph Murray, Russell O. Pieper, C. David James and Andrew T. Parsa


Despite recent advances in cancer immunotherapy, cellular mechanisms controlling expression of tumor-associated antigens are poorly understood. Mutations in cancer cells, such as loss of PTEN, may increase expression of tumor-associated antigens. The authors investigated the relationship between PTEN status and the expression of a glioma-associated antigen, adenosine diphosphate–ribosylation factor 4–like (ARF4L) protein.


Human glioma cell lines with confirmed PTEN status were examined by Northern blot analysis and quantitative polymerase chain reaction. Western blot analysis was used to measure ARF4L protein levels across multiple cell lines.


The loss of PTEN was shown to lead to increased levels of ARF4L protein but no change in transcript levels. Cell lines with serial mutations, including activation of Ras and Akt pathways, also demonstrated increased levels of ARF4L protein, which decreased after treatment with rapamycin. The ARF4L transcript preferentially localized to the polysomal compartment after PTEN loss in glioma or activation of Akt in human astrocytes.


Expression of ARF4L is controlled by the activated Akt/mTOR pathway, which is a downstream effect of the loss of PTEN function. Mutations leading to oncogenesis may impact the regulation and expression of tumor specific antigens. Screening of mutation status in glioma may be helpful in selecting patients for immunotherapy trials in the future.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010