Junting Zhang

The pediatric preclinical testing program: description of models and early testing results.

The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide.

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53–induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Prognostic factors for long-term outcome of patients with surgical resection of skull base chordomas-106 cases review in one institution.

Skull base chordoma are still challenging. Between May 1993 and June 2005, 106 consecutive patients with skull base chordoma underwent surgical removal at Skull Base Division of Neurosurgery, Beijing Tiantan Hospital, China. Retrospective analysis included medical charts and images. The age of the patients ranged from 7 to 65 years old, with an average age of 35.6 years. Sixty patients were male; the other 46 were female (1.3:1). Follow up data were available in 79 cases ranging from 10 to 158 months (average 63.9 months) after operation. The prognostic factors for recurrence and survival were analyzed with Kaplan‐Meier, Cox regression and t‐test. Overall, 1, 3, 5 and 10 years survival rates were 87.2%, 79.4%, 67.6%and 59.5% respectively. One, 3, 5 and 10 year recurrent rates were 19.1%, 34.7%, 52.9% and 88.3%, respectively. The long term outcome of the skull base chordomas is poor. The previous radiotherapy or surgery, dedifferentiated pathology, and less tumor resection are risk factors for longterm survival and recurrence (p < 0.05). Although there is no statistic significant role of tumor adherent to vital structure for outcome (p = 0.051), it can not exclude its importance for favorable outcome. Gender, age, tumor size and staging are not independent risk factors for outcome. Surgical technique leading to radical tumor resection with less morbidity is advocatory and beneficial for patients with skull base chordoma with long term outcome, if the tumor could be exposed and resected completely, the recurrence rate was very low for most benign chordomas.

The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults

Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets.

Diagnosis and Management of Adult Intracranial Neurenteric Cysts

BACKGROUND:Intracranial neurenteric cysts are rare, benign lesions of the central nervous system. OBJECTIVE:To analyze our experience with these lesions and conduct a review of the literature with the aim of identifying a rational approach to diagnosis and management. METHODS:Seven patients underwent surgical treatment for intracranial neurenteric cysts from July 2000 to December 2008. The general strategy was to perform complete resection whenever possible. The clinical, radiological, operative, and pathological findings of the patients were reviewed retrospectively. RESULTS:This series included 3 women and 4 men. The age of hospitalized patients ranged from 19 to 55 years, with an average age of 34 years. Headache and dizziness were the most common chief symptoms. The imaging spectrum for these lesions is broad, leading to several preoperative misdiagnoses. All 7 lesions were resected by a far lateral transcondylar or retrosigmoid approach. Total tumor resection was achieved in 3 patients. Four patients presented transient fever postoperatively. All patients were healthy and showed no signs of tumor recurrence at their latest follow-up. CONCLUSION:Intracranial neurenteric cysts ventral to the brainstem are rare lesions occurring in young adults. These lesions should be considered in the differential diagnosis for intracranial extra-axial cystic lesions anterior to the brainstem. Total surgical resection seems to be the most effective therapeutic method, although radical resection at the risk of impairing the brainstem is not recommended. This benign lesion has a favorable overall prognosis.

Foramen magnum meningiomas: experiences in 114 patients at a single institute over 15 years.

BACKGROUND Although there has been great development in the anatomical understanding and operative techniques for skull base tumors, controversy still exists regarding the optimal surgical strategies for the FMMs. We report clinical and radiologic features as well as the surgical findings and outcome for patients with FMM treated at our institution over the last 15 years. METHODS We reviewed 114 consecutive cases of FMM operated between May 1993 and June 2008 in the neurosurgery department at Beijing Tiantan Hospital. RESULTS There were 68 female and 46 male patients (mean age, 52.3 years; range, 28-76 years). Foramen magnum meningiomas were classified as anterior (80 cases), anterolateral (24 cases), and posterolateral (10 cases). Mean duration of symptoms was 11.7 months (ranging from 1.5 to 240 months). Cervico-occipital pain (80.7%) and headache and dizziness (42.1%) were the most common presenting symptoms. The preoperative KPS was 72.5 +/- 8.3. Mean maximum diameter of the tumors on MRI was 3.35 cm (range, 1.5-4.7 cm). Posterior midline approach was performed in 10 cases, far-lateral retrocondylar approach in 97 cases, and extended far-lateral approach in 7 cases. Gross total resection was achieved in 86.0% of patients and subtotal resection in 14.0%. Surgical mortality was 1.8%. Follow-up data were available for 93 patients, with a mean follow-up of 90.3 months (range, 1-180 months), of which 59 (63.4%) lived a normal life (KPS, 80-100). CONCLUSION Our experience suggests that most anterior and anterolateral FMMs can be completely resected by a far-lateral retrocondylar approach without resection of the occipital condyle. Complete resection of the tumor should be attempted at the first operation. Postoperative management of FMM is important for the prognosis.

Natural Malignant Transformation of an Intracranial Epidermoid Cyst

Malignant transformation of intracranial epidermoid cyst (EC) is very rare, and when it does occur, the clinical course is aggressive. We present an unusual case of natural malignant transformation of an intracranial EC, without a history of surgery. A 61-year-old woman was diagnosed with an EC in the right cerebellopontine angle and prepontine cistern 6 years before the operation described in this report. Her neurological symptoms deteriorated in the 2 months prior to the present admission. Magnetic resonance imaging revealed an irregular, nodular enhanced lesion in the cerebellopontine angle, prepontine cistern, and temporoparietal lobe. Subtotal resection of the lesion was performed. Pathological examination revealed malignant transformation of the EC. The patient died on postoperative day 36 from brainstem infarction, chemical meningitis, and hydrocephalus. Spontaneous rupture of the EC could have contributed to the malignant transformation. This could have been avoided by early removal of the EC.

Expression of EphA2 in Human Astrocytic Tumors: Correlation with Pathologic Grade, Proliferation and Apoptosis

A high expression of EphA2 has been detected in many non-central nervous system tumors; however, the EphA2 expression in brain astrocytic tumors remains unclear. In this study, we investigated the expression of EphA2 mRNA and protein in 90 cases of human astrocytic tumors by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. The proliferative index (PI) of tumor cells was evaluated by Ki-67 immunohistochemistry, and the apoptotic index (AI) was determined by TdT-mediated dUTP nick end labeling assay. The correlation between EphA2 expression, pathologic grade, proliferation and apoptosis of astrocytic tumors was further analyzed. The results showed that 47.8% of cases expressed EphA2 mRNA and 43.3% of cases expressed EphA2 protein. With increasing pathologic grade, the positive rate of EphA2 mRNA and protein, as well as the EphA2 immunoreactivity score (IRS), increased markedly. The PI in the EphA2-positive group was significantly higher than in the EphA2-negative group. In addition, the PI was positively correlated with EphA2 IRS. Although there was no significant difference between the AI in the EphA2-positive group and that in the EphA2-negative group, the AI was inversely correlated with EphA2 IRS. Therefore, EphA2 may be a new biomarker for astrocytic tumors. It may also affect the proliferation and apoptosis of tumor cells and be an attractive therapy target for astrocytic tumors.

Clinical, radiological, and pathological features in 43 cases of intracranial subependymoma.

OBJECT Intracranial subependymomas are rarely reported due to their extremely low incidence. Knowledge about subependymomas is therefore poor. This study aimed to analyze the incidence and clinical, radiological, and pathological features of intracranial subependymomas. METHODS Approximately 60,000 intracranial tumors were surgically treated at Beijing Tiantan Hospital between 2003 and 2013. The authors identified all cases in which patients underwent resection of an intracranial tumor that was found to be pathological examination demonstrated to be subependymoma and analyzed the data from these cases. RESULTS Forty-three cases of pathologically confirmed, surgically treated intracranial subependymoma were identified. Thus in this patient population, subependymomas accounted for approximately 0.07% of intracranial tumors (43 of an estimated 60,000). Radiologically, 79.1% (34/43) of intracranial subependymomas were misdiagnosed as other diseases. Pathologically, 34 were confirmed as pure subependymomas, 8 were mixed with ependymoma, and 1 was mixed with astrocytoma. Thirty-five patients were followed up for 3.0 to 120 months after surgery. Three of these patients experienced tumor recurrence, and one died of tumor recurrence. Univariate analysis revealed that shorter progression-free survival (PFS) was significantly associated with poorly defined borders. The association between shorter PFS and age < 14 years was almost significant (p = 0.51), and this variable was also included in the multivariate analysis. However, multivariate analysis showed showed only poorly defined borders to be an independent prognostic factor for shorter PFS (RR 18.655, 95% CI 1.141-304.884, p = 0.040). In patients 14 years of age or older, the lesions tended to be pure subependymomas located in the unilateral supratentorial area, total removal tended to be easier, and PFS tended to be longer. In comparison, in younger patients subependymomas tended to be mixed tumors involving the bilateral infratentorial area, with a lower total removal rate and shorter PFS. CONCLUSIONS Intracranial subependymoma is a rare benign intracranial tumor with definite radiological features. Long-term survival can be expected, although poorly defined borders are an independent predictor of shorter PFS. All the features that differ between tumors in younger and older patients suggest that they might have different origins, biological behaviors, and prognoses.

Clinical and Pathological Features of Intradural Retroclival Chordoma

OBJECTIVE To investigate the clinical and pathologic characteristics of primary intradural retroclival chordoma and improve the understanding of this rare disease. METHODS A retrospective study was conducted on six cases patients withof an intradural chordoma in the retroclival region who underwent surgery and were confirmed by pathology and imaging. Expression of brachyury, galectin-3, and Ki-67 in paraffin-embedded sections of the specimens was detected by streptavidin-peroxidase immunohistochemistry. RESULTS Lesions were located in the subdural prepontine cistern. Computed tomography scan showed that the bone of the skull base was not destroyed, and findings on magnetic resonance imaging varied, resulting in a misdiagnosis of 50% of the cases in the preoperative imaging. All six cases were classified by their pathology into the classical subtype. They presented a strong positive staining for brachyury and galectin-3, and the Ki-67 labeling index was between 2.5% and 8.2%. Three cases presented no signs of recurrence or regrowth, whereas in the other three patients recurrence or regrowth occurred at 7 ∼ 14 months after initial surgery. Two patients died of this disease. CONCLUSIONS Our study suggests that a positive staining for brachyury, galectin-3, and Ki-67 would be helpful for differential diagnosis, discriminating intradural retroclival chordoma from ecchordosis physaliphora and chordoid meningioma. Our study also shows that within intradural retroclival chordoma, there are significant prognostic differences. Tumors with an abundant blood supply, flake-like cellular arrangement, and a Ki-67 labeling index greater than 5% belong to a rapid-growth type and are prone to short-term recurrence and poorer prognosis.