Winward Choy

The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments

Meningiomas are mostly benign, slow-growing tumors of the CNS that originate from arachnoidal cap cells. While monosomy 22 is the most frequent genetic abnormality found in meningiomas, a multitude of other aberrant chromosomal alterations, signaling pathways, and growth factors have been implicated in its pathogenesis. Losses on 22q12.2, a region encoding the tumor suppressor gene merlin, represent the most common genetic alterations in early meningioma formation. Malignant meningioma progression, however, is associated with more complex karyotypes and greater genetic instability. Cytogenetic studies of atypical and anaplastic meningiomas revealed gains and losses on chromosomes 9, 10, 14, and 18, with amplifications on chromosome 17. However, the specific gene targets in a majority of these chromosomal abnormalities remain elusive. Studies have also implicated a myriad of aberrant signaling pathways involved with meningioma tumorigenesis, including those involved with proliferation, angiogenesis, and autocrine loops. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. Despite advancements in our understanding of meningioma pathogenesis, the conventional treatments, including surgery, radiotherapy, and stereotactic radiosurgery, have remained largely stagnant. Surgery and radiation therapy are curative in the majority of lesions, yet treatment remains challenging for meningiomas that are recurrent, aggressive, or refractory to conventional treatments. Future therapies will include combinations of targeted molecular agents as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas.

Heat shock protein vaccines against glioblastoma: from bench to bedside

Current adjuvant treatment regimens available for the treatment of glioblastoma are widely ineffective and offer a dismal prognosis. Advancements in conventional treatment strategies have only yielded modest improvements in overall survival. Immunotherapy remains a promising adjuvant in the treatment of GBM through eliciting tumor specific immune responses capable of producing sustained antitumor response while minimizing systemic toxicity. Heat shock proteins (HSP) function as intracellular chaperones and have been implicated in the activation of both innate and adaptive immune systems. Vaccines formulated from HSP-peptide complexes, derived from autologous tumor, have been applied to the field of immunotherapy for glioblastoma. The results from the phase I and II clinical trials have been promising. Here we review the role of HSP in cellular function and immunity, and its application in the treatment of glioblastoma.

Prognostic factors for post-operative seizure outcomes after cavernous malformation treatment

Although patients with cerebral cavernous malformations may remain asymptomatic, they often present with neurological symptoms of headache, hemorrhage and, most commonly, seizure. A review of articles published between 1985 and 2009 was performed to elucidate the prognostic factors which may predict post-operative seizure control. The following characteristics were found to consistently correlate with a more favorable post-operative seizure-free outcome: (i) extent of resection of the cavernous malformation and its surrounding hemosiderin rim; (ii) single or sporadic seizures compared to chronic epilepsy; (iii) illness duration less than 1 or 2 years; and (iv) size of cavernous malformation less than 1.5 cm. Radiosurgery may achieve post-operative seizure-free rates ranging from 25% to 64.3%, and may be an alternative to surgical resection for deep or eloquent cavernous malformations, or those in patients with co-morbidities. There was no clear association between post-operative seizures and either lesion location, age, or gender. Prognostic features of cavernous malformations should be utilized for both guidance of lesion treatment, and prediction of post-operative seizure outcomes.

Chromosomal alterations, prognostic factors, and targeted molecular therapies for malignant meningiomas

Meningiomas are the second most common intracranial neoplasm in adults and originate from arachnoidal cap cells. Malignant meningiomas are resistant to conventional treatments such as surgery, chemotherapy, and radiotherapy. Unlike benign meningiomas, atypical and anaplastic tumors generally display more complex karyotypes associated with aggressive behavior. While these chromosomal anomalies are associated with greater malignancy in meningiomas, the specific genes involved remain unknown. Malignant meningiomas are characterized by increased tumor aggressiveness, rapid recurrence, local invasion, atypical histological appearance, and a high mitotic index. Potential prognostic factors include extent of resection, treatment with radiotherapy or stereotactic radiosurgery, Ki-67/MIB-1 labeling index, p53 overexpression, percentage of tumor cells in the S-phase, telomerase activity, and numerous genetic expression profiles. A greater understanding of prognostic factors and molecular markers involved in critical signaling pathways may aid in the identification of novel therapeutic targets. As such, further studies are needed to establish reliable prognostic factors and develop more effective treatments for malignant meningiomas.

Predictors of recurrence following resection of intracranial chordomas

Management of intracranial chordomas remains challenging, despite improvements in microsurgical techniques and radiotherapy. Here, we analyzed the prognostic factors associated with improved rates of tumor control in patients with intracranial chordomas, who received either gross (GTR) or subtotal resections (STR). A retrospective review was performed to identify all patients who were undergoing resection of their intracranial chordomas at the Ronald Reagan University of California Los Angeles Medical Center from 1990 to 2011. In total, 57 patients undergoing 81 resections were included. There were 24 females and 33 males with a mean age of 44.6 years, and the mean tumor diameter was 3.36 cm. The extent of resection was not associated with recurrence. For all 81 operations, the 1 and 5 year progression free survival (PFS) was 87.5 and 40.4%, and 88.0 and 33.6% for STR and GTR, respectively (p=0.90). Adjuvant radiotherapy was associated with improved rates of PFS (hazard ratio [HR] 0.20; p=0.009). Additionally, age >45 years (HR 5.88; p=0.01) and the presence of visual deficits (HR 7.59; p=0.03) were associated with worse rates of tumor control. Tumor size, sex, tumor histology, and recurrent tumors were not predictors of recurrence. Younger age, lack of visual symptoms on presentation and adjuvant radiotherapy were associated with improved rates of tumor control following surgery. However, GTR and STR produced comparable rates of tumor control. The surgical management of intracranial chordomas should take a conservative approach, with the aim of maximal but safe cytoreductive resection with adjuvant radiation therapy, and a major focus on quality of life.

Genetic expression profiles of adult and pediatric ependymomas: Molecular pathways, prognostic indicators, and therapeutic targets

Ependymomas are tumors that can present within either the intracranial or spinal regions. While 90% of all pediatric ependymomas are intracranial, spinal cord ependymomas are more commonly found in patients 20-40 years old. Treatment for spinal lesions has achieved local control rates up to 100% following gross total resection, while pediatric intracranial tumors have 40-60% mortality. Given the inability to effectively treat ependymomas with current standard practices, researchers have focused their efforts on evaluating chromosomal alterations, genetic expression profiles, epigenetic events, and molecular pathways. While these studies have provided critical insight into the potential mechanisms underlying ependymoma pathogenesis, understanding of the intricate interplay between the various pathways involved in tumor initiation, development, and progression will require deeper investigation. However, several potential prognostic markers and therapeutic targets have been identified, providing key areas of focus for future research. The utilization of unique genetic expression profiles based upon patient age, tumor location, tumor grade, and subtype has revealed a multitude of findings warranting further study. Inspection of various molecular pathways associated with ependymomas may establish the foundation for developing novel therapies capable of achieving significant clinical improvements with individualized regimens specifically designed for personalized treatment strategies.

Survival outcomes for radiotherapy treatment of epidermoid tumors with malignant transformation

Epidermoid tumors are intracranial lesions that may occasionally undergo malignant transformation. Although surgical resection is the first-line treatment for malignant epidermoids, postoperative radiotherapy has been intermittently reported with favorable findings. Our analysis identified all previously reported patients with malignant epidermoids treated with surgical resection alone or surgery plus radiotherapy to examine the potential role for this adjuvant therapy. Whereas patients treated with surgery only had an overall survival of 6.6 months, those treated with postoperative radiotherapy demonstrated a statistically significant increase in survival to 12.7 months (log-rank test, p<0.003). Furthermore, the mean dosage of radiation given to this patient population was 52.2 Gy, with no appreciable survival benefit for the utilization of levels of radiation greater than 50 Gy. When determining the management for malignant transformation of epidermoid tumors, the combination of surgical resection and radiotherapy may be associated with improved short-term survival.

Pineal Cyst: A Review of Clinical and Radiological Features

Pineal cysts (PCs) are benign and often asymptomatic lesions of the pineal region that are typically small and do not change in size over time. PCs appear as small, well circumscribed, unilocular masses that either reside within or completely replace the pineal gland. This article reviews and discusses the characteristic features of PCs-clinical, histological, and identifiable by various imaging modalities-which assist clinicians in narrowing the differential diagnosis for pineal lesions.

The tumor biology and molecular characteristics of medulloblastoma identifying prognostic factors associated with survival outcomes and prognosis

Medulloblastomas (MB) are highly aggressive primitive neuroectodermal tumors (PNET) usually located in the posterior fossa. Current treatment for MBs, which includes a combination of surgery, chemotherapy and radiation, remain challenging especially in younger patients. However, advances in the understanding of regulatory pathways in cerebellar development have elucidated possible areas of dysfunction involved in tumorigenesis. Multiple studies have demonstrated the importance of the sonic hedgehog, Wnt, and Notch pathways in MB pathogenesis at the molecular level. While staging and prognosis are often based on the Chang classification system, future algorithms will involve identifying molecular markers in order to allow for more specific risk stratifications of various MB subtypes and provide improved correlation with staging and prognosis. Future development of novel therapies that target the heterogeneity of MB and are tailored to the tumors unique molecular profile may yield improved outcomes for these patients.

The role of CD44 in glioblastoma multiforme

A transmembrane molecule with several isoforms, CD44 is overexpressed in many tumors and promotes tumor formation through interactions with the tumor microenvironment. CD44 has been implicated in malignant processes including cell motility, tumor growth, and angiogenesis. The role of CD44 has been examined in many cancer types. This paper provides, to our knowledge, the first focused review of the role of CD44 in glioblastoma multiforme (GBM), the most common and fatal of primary brain cancers. We summarize research that describes how CD44 promotes GBM aggressiveness by increasing tumor cell invasion, proliferation and resistance to standard chemoradiation therapy. Effects of CD44 inhibition in GBM are also explored. Clinical trials investigating CD44 targeting in CD44-positive solid tumors are underway, and the evidence presented here suggests that CD44 inhibition in GBM may be a promising therapy.