Elizabeth Vera-Bolanos

A prognostic gene expression signature in infratentorial ependymoma

Patients with ependymoma exhibit a wide range of clinical outcomes that are currently unexplained by clinical or histological factors. Little is known regarding molecular biomarkers that could predict clinical behavior. Since recent data suggest that these tumors display biological characteristics according to their location (cerebral vs. infratentorial vs. spinal cord), rather than explore a broad spectrum of ependymoma, we focused on molecular alterations in ependymomas arising in the infratentorial compartment. Unsupervised clustering of available gene expression microarray data revealed two major subgroups of infratentorial ependymoma. Group 1 tumors over expressed genes that were associated with mesenchyme, Group 2 tumors showed no distinct gene ontologies. To assess the prognostic significance of these gene expression subgroups, real-time reverse transcriptase polymerase chain reaction assays were performed on genes defining the subgroups in a training set. This resulted in a 10-gene prognostic signature. Multivariate analysis showed that the 10-gene signature was an independent predictor of recurrence-free survival after adjusting for clinical factors. Evaluation of an external dataset describing subgroups of infratentorial ependymomas showed concordance of subgroup definition, including validation of the mesenchymal subclass. Importantly, the 10-gene signature was validated as a predictor of recurrence-free survival in this dataset. Taken together, the results indicate a link between clinical outcome and biologically identified subsets of infratentorial ependymoma and offer the potential for prognostic testing to estimate clinical aggressiveness in these tumors.

Adult ependymal tumors: prognosis and the M. D. Anderson Cancer Center experience

Ependymomas in adults are rare and often misdiagnosed. This study reports on a series of adult patients with confirmed ependymoma treated at The University of Texas M. D. Anderson Cancer Center (MDACC). Patients aged >17 and with ependymoma were identified, and clinical data were collected by retrospective chart review. Descriptive statistics were used to describe the clinical data, Kaplan-Meier methods were used to generate survival curves, and Cox proportional hazards models were used to evaluate the association of clinical characteristics with survival. This series included 123 adult patients [51% male; median age 39 years (18-72)]. Forty had tumors in the brain, 80 in the spine, and 3 had both. The majority were Grade I/II lesions (108) vs Grade III (anaplastic; 15). Eighteen patients had tumors that were reclassified as ependymal tumors at MDACC. The most common presenting symptom was pain, with an average of 4 symptoms reported prior to diagnosis. Sixty-three percent of patients had a gross total resection, and 49% received radiation therapy. Average follow-up was 5.5 years, and 13% had died. Median time to recurrence was 21 months (Grade II) brain and 18 months (Grade III). Worse outcome measured by overall and progression-free survival were associated with brain location (P = .01, P = .04) and tumor anaplasia (P = .0025, P = .001). An MIB-1 > 10 was associated with worse outcome (P = .03). Tumor grade and brain location are associated with a worse prognosis. Reclassification of ependymoma by neuropathologists is common. Results of this study have lead to a multicenter study to further define important diagnostic and prognostic variables for adults with ependymoma.

Risk analysis of severe myelotoxicity with temozolomide: The effects of clinical and genetic factors

A benefit of temozolomide (TMZ) is that myelotoxicity is uncommon. Recently, several small series have reported significant myelotoxicity resulting in treatment delays or death. The ability to predict risk of myelotoxicity may influence patient care. We retrospectively reviewed 680 malignant glioma patients and developed a clinical risk formula for myelotoxicity for each gender by logistic regression. The variables that remained were assigned a score of 1 and added together for a final risk score. Women experienced more myelotoxicity than did men (p = 0.015). For males, risk factors included body surface area (BSA) > or = 2 m(2) (odds ratio [OR] = 2.712, p = 0.04), not on steroids (OR = 2.214, p = 0.06), and on bowel medication (OR = 3.955, p = 0.008). For females, final factors included no prior chemotherapy (OR = 3.727, p = 0.001), creatinine > or = 1 mg/dl (OR = 6.08, p = 0.002), platelets < 270,000/mm(3) (OR = 2.438, p = 0.03), BSA < 2 m(2) (OR = 4.178, p = 0.04), not on medication for gastroesophageal reflux disease (OR = 2.942, p = 0.01), and on analgesics (OR = 2.169, p = 0.05). Age was included because of observable trends. Risk of developing myelotoxicity ranged from 0% to 33% (male) and from 0% to 100% (females). Polymorphisms in NQO1 (NAD(P)H dehydrogenase, quinone 1), MGMT (O(6)-methylguanine-DNA methyltransferase), and GSTP1 (glutathione S-transferase pi 1) were related to risk of developing myelotoxicity in a subset of patients. Myelotoxicity with TMZ is a significant clinical issue for those at risk. Use of a clinical model to predict risk and evaluation of identified genetic polymorphisms related to myelotoxicity may allow for individualized dosing, optimizing patient management.

Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients

BACKGROUND Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution. METHODS Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival. RESULTS The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression. CONCLUSIONS We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system.

Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all P < 0.01) were significantly associated with worse progression‐free survival (PFS), while extensive ependymal canal formation was not (P = 0.89). Similar to the PF tumors, microvascular proliferation (P = 0.01) and elevated mitotic rate (P = 0.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (P = 0.03) were associated with worse clinical outcome in ST ependymomas, but hypercellularity (P = 0.57) and necrosis (P = 0.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site‐specific grading criteria be considered in future classification systems.

Clinical course of adult patients with ependymoma: results of the Adult Ependymoma Outcomes Project.

Ependymomas are a rare tumor in adults, and there are limited reports of the clinical course, treatment, and current health status of patients.

The impact of symptom interference using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) on prediction of recurrence in primary brain tumor patients†

Tumor grade, age, extent of resection, and performance status are established prognostic factors for survival in primary brain tumor (PBT) patients. Development of disease‐related symptoms is predictive of tumor recurrence in other cancers but has not been reported in the PBT population.

Congruence of primary brain tumor patient and caregiver symptom report

Evaluating the severity of symptoms in patients with primary brain tumors (PBTs) is important in clinical care and research but may be difficult due to patient neurocognitive (NC) impairment. This study was conducted to evaluate the congruence of symptom reporting in patient and caregiver dyads, examining potential impact of NC impairment and Karnofsky performance status (KPS).

Reliability and validity of the M. D. Anderson Symptom Inventory-Spine Tumor Module

OBJECT Tumors involving the spine have unique associated neurological symptoms. The occurrence of spine-related symptoms has been shown to predict treatment course and survival in several studies conducted in patients with solid tumors and consequent spinal cord dysfunction. Currently, no instrument that measures both neurological and cancer-related symptoms exists for patients with spine tumors. The objective of this study was to develop a reliable and valid self-reporting instrument for patients with spine tumors. METHODS Patients with diagnosed tumors involving the spine (both primary and metastatic) participated in this study. Data collection tools included a patient-completed demographic data sheet, an investigator-completed clinician checklist, and the core M. D. Anderson Symptom Inventory to which were added 16 neurological symptoms (M. D. Anderson Symptom Inventory-Spine Tumor Module [MDASI-SP]). The authors evaluated the reliability and validity of the MDASI-SP in patients with spine tumors. RESULTS One hundred twenty-six patients participated in the study. Participants were primarily white (73%) males (53%) with metastatic spine tumors (76%). They ranged in age from 18-81 years (median 56 years). Cognitive debriefing of the MDASI-SP was conducted showing the instrument was clear, concise, and easily understood by patients. The most severe core symptoms were pain, fatigue, numbness, disturbed sleep, and distress. The most severe spine module symptoms were spine pain, numbness, weakness in the legs, neck stiffness, and changes in bowel or sexual function. The mean symptom severity of items as well as a cluster analysis was used to reduce the number of total items to 18 (5 spine module items). Regression analysis showed that 57.4% of the variability in symptom interference with daily function was explained by the final instrument. Factor analysis was performed to determine the underlying constructs being evaluated by the symptom items. The 18-item MDASI-SP measures 4 underlying constructs including a disease, an autonomic, a constitutional/treatment, and an emotional factor. The internal consistency (reliability) of the MDASI-SP was 0.946, and the instrument was sensitive to disease severity based on the Karnofsky Performance Scale (KPS). The mean symptom severity was 1.52 for those with good KPS scores (80-100) versus 2.46 for those with poor scores (p < 0.01). The instrument was also sensitive to neurological status according to the Frankel grade (p < 0.001) and inpatient status (p < 0.01). CONCLUSIONS The 18-item MDASI-SP demonstrated validity and reliability in patients with spine tumors as a composite measure of disease-related symptoms. This instrument can be used to describe symptom occurrence throughout the disease trajectory and to evaluate interventions designed for symptom management.

The symptom burden of primary brain tumors: evidence for a core set of tumor- and treatment-related symptoms

BACKGROUND A set of symptoms common across cancers has been proposed to enhance quality of care and clinical research in solid tumor patients. Using data from several clinical studies, this study evaluated these symptoms in primary brain tumor patients. METHODS Symptom report data using the MD Anderson Symptom Instrument -Brain Tumor (MDASI-BT) from 621 patients enrolled in 8 clinical studies was used. The prevalence and severity of symptoms were reported as they relate to tumor grade, treatment stage and KPS. RESULTS The sample was primarily white (82.5%) males (59%) with high-grade gliomas (75%). More than 50% of patients reported at least 10 concurrent symptoms, and 40% of patients reporting having at least 3 moderate-to-severe symptoms. Fatigue, drowsiness, difficulty remembering, disturbed sleep, and distress were the most severe symptoms reported by all tumor grades. Functional interference of symptoms with ability to work, perform activities, walk, and enjoy life was reported by more than 25% of patients. CONCLUSIONS These results support a core set of symptoms, common in other solid tumor patients, that may impact clinical care and assessment of treatment benefit. Although only 5 of the Center for Medical Technology Policy list of proposed core symptoms met criteria for inclusion in this sample, 5 of the other proposed core symptoms were also reported in similar frequency as reported in the other cancer populations. This primary brain tumor population differed from other solid tumor patients in that other symptoms, which could be disease related, were more prevalent and thus should also be collected for these patients.