Faculty Bibliography

BACKGROUND: Embolization before stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVM) has been shown to negatively affect obliteration rates, but its impact on the risks of radiosurgery-induced complications and latency period hemorrhage is poorly defined. OBJECTIVE: To determine, in a case-control study, the effect of prior embolization on AVM SRS outcomes. METHODS: We evaluated a database of AVM patients who underwent SRS. Propensity score analysis was used to match the case (embolized nidi) and control (nonembolized nidi) cohorts. AVM angioarchitectural complexity was defined as the sum of the number of major feeding arteries and draining veins to the nidus. Multivariate Cox proportional hazards regression analyses were performed on the overall study population to determine independent predictors of obliteration and radiation-induced changes. RESULTS: The matching process yielded 242 patients in each cohort. The actuarial obliteration rates were significantly lower in the embolized (31%, 49% at 5, 10 years, respectively) compared with the nonembolized (48%, 64% at 5, 10 years, respectively) cohort (P = .003). In the multivariate analysis for obliteration, lower angioarchitectural complexity (P < .001) and radiologically evident radiation-induced changes (P = .016) were independent predictors, but embolization was not significant (P = .744). In the multivariate analysis for radiologic radiation-induced changes, lack of prior embolization (P = .009) and fewer draining veins (P = .011) were independent predictors. CONCLUSION: The effect of prior embolization on AVM obliteration after SRS may be significantly confounded by nidus angioarchitectural complexity. Additionally, embolization could reduce the risk of radiation-induced changes. Thus, combined embolization and SRS may be warranted for appropriately selected nidi. ABBREVIATIONS: AVM, arteriovenous malformationRBAS, radiosurgery-based AVM scoreSRS, stereotactic radiosurgeryVRAS, Virginia Radiosurgery AVM Scale.

Cervical-petrous internal carotid artery (CP-ICA) pseudoaneurysms are rare and have different etiologies, presentations, and treatment options. A middle-aged patient with a history of chronic otitis media presented with acute otorrhagia and was found to have a left-sided CP-ICA pseudoaneurysm. The patient was a poor surgical candidate with difficult arterial access. The pseudoaneurysm was treated with stand-alone coiling via a left brachial approach with persistent contrast filling seen only in the aneurysm neck at the end of the procedure. The patient re-presented 12 days later with repeat hemorrhage and rapid enlargement of the neck remnant, and was treated with a covered stent via a transcervical common carotid artery cut-down. A covered stent may provide a more definitive treatment for CP-ICA pseudoaneurysms compared with standalone coiling.

PURPOSE/OBJECTIVE:Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. While acute post-SBRT urinary symptoms are well recognized, the late genitourinary toxicity of SBRT has not been fully described. Here, we characterize the clinical features of late urinary symptom flare and recommend conservative symptom management approaches that may alleviate the associated bother. METHODS:Between February 2008 and August 2011, 216 men with clinically localized prostate cancer were treated definitively with SBRT at Georgetown University Hospital. Treatment was delivered using the CyberKnife with doses of 35-36.25 Gy in five fractions. The prevalence of each of five Common Terminology Criteria for Adverse Events (CTCAE) graded urinary toxicities was assessed at each follow-up visit. Medication usage was documented at each visit. Patient-reported urinary symptoms were assessed using the American Urological Association (AUA) symptom score and the Expanded Prostate Cancer Index Composite (EPIC)-26 at 1, 3, 6, 9, 12, 18, and 24 months. Late urinary symptom flare was defined as an increase in the AUA symptom score of ≥5 points above baseline with a degree of severity in the moderate to severe range (AUA symptom score ≥15). The relationship between the occurrence of flare and pre-treatment characteristics were examined. RESULTS:For all patients, the AUA symptom score spiked transiently at 1 month post-SBRT. Of the 216 patients, 29 (13.4%) experienced a second transient increase in the AUA symptom score that met the criteria for late urinary symptom flare. Among flare patients, the median age was 66 years compared to 70 for those without flare (p = 0.007). In patients who experienced flare, CTCAE urinary toxicities including dysuria, frequency/urgency, and retention peaked at 9-18 months, and alpha-antagonist utilization increased at 1 month post-treatment, rose sharply at 12 months post-treatment, and peaked at 18 months (85%) before decreasing at 24 months. The EPIC urinary summary score of flare patients declined transiently at 1 month and experienced a second, more protracted decline between 6 and 18 months before returning to near baseline at 2-year post-SBRT. Statistically and clinically significant increases in patient-reported frequency, weak stream, and dysuria were seen at 12 months post-SBRT. Among flare patients, 42.9% felt that urination was a moderate to big problem at 12 months following SBRT. CONCLUSION/CONCLUSIONS:In this study, we characterize late urinary symptom flare following SBRT. Late urinary symptom flare is a constellation of symptoms including urinary frequency/urgency, weak stream, and dysuria that transiently occurs 6-18 months post-SBRT. Provision of appropriate anticipatory counseling and the maintenance of prophylactic alpha-antagonists may limit the bother associated with this syndrome.

INTRODUCTION/BACKGROUND:CT-guided, frameless radiosurgery is an alternative treatment to traditional catheter-angiography targeted, frame-based methods for intracranial arteriovenous malformations (AVMs). Despite the widespread use of frameless radiosurgery for treating intracranial tumors, its use for treating AVM is not-well described. METHODS:Patients who completed a course of single fraction radiosurgery at The University of North Carolina or Georgetown University between 4/1/2005-4/1/2011 with single fraction radiosurgery and received at least one follow-up imaging study were included. All patients received pre-treatment planning with CTA ± MRA and were treated on the CyberKnife (Accuray) radiosurgery system. Patients were evaluated for changes in clinical symptoms and radiographic changes evaluated with MRI/MRA and catheter-angiography. RESULTS:Twenty-six patients, 15 male and 11 female, were included in the present study at a median age of 41 years old. The Spetzler-Martin grades of the AVMs included seven Grade I, 12 Grade II, six Grade III, and one Grade IV with 14 (54%) of the patients having a pre-treatment hemorrhage. Median AVM nidal volume was 1.62 cm(3) (0.57-8.26 cm(3)) and was treated with a median dose of 1900 cGy to the 80% isodose line. At median follow-up of 25 months, 15 patients had a complete closure of their AVM, 6 patients had a partial closure, and 5 patients were stable. Time since treatment was a significant predictor of response, with patients experience complete closure having on average 11 months more follow-up than patients with partial or no closure (p = 0.03). One patient experienced a post-treatment hemorrhage at 22 months. CONCLUSION/CONCLUSIONS:Frameless radiosurgery can be targeted with non-invasive MRI/MRA and CTA imaging. Despite the difficulty of treating AVM without catheter angiography, early results with frameless, CT-guided radiosurgery suggest that it can achieve similar results to frame-based methods at these time points.

BACKGROUND:Changes in tumor volume are seen on magnetic resonance imaging within weeks after stereotactic radiosurgery (SRS), but it remains unclear what clinical outcomes early radiological changes portend. OBJECTIVE:We hypothesized that rapid, early reduction in tumor volume post-SRS is associated with prolonged local control and favorable clinical outcome. METHODS:A retrospective review of patients treated with CyberKnife SRS for brain metastases at the University of North Carolina from 2007 to 2009 was performed. Patients with at least 1 radiological follow-up, minimal initial tumor volume of 0.1 cm, no previous focal radiation, and no recent whole-brain radiation therapy were eligible for inclusion. RESULTS:Fifty-two patients with 100 metastatic brain lesions were analyzed and had a median follow-up of 15.6 months (range, 2-33 months) and a median of 2 (range, 1-8) metastatic lesions. In treated metastases in which there was a significant tumor volume reduction by 6 or 12 weeks post-SRS, there was no local progression for the duration of the study. Furthermore, patients with metastases that did not reduce in volume by 6 or 12 weeks post-SRS were more likely to require corticosteroids (P = .01) and to experience progression of neurological symptoms (P = .003). CONCLUSION/CONCLUSIONS:Significant volume reductions of brain metastases measured at either 6 or 12 weeks post-SRS were strongly associated with prolonged local control. Furthermore, early volume reduction was associated with less corticosteroid use and stable neurological symptoms.

BACKGROUND:Hypofractionated stereotactic body radiation therapy (SBRT) has been advanced as monotherapy for low-risk prostate cancer. We examined the dose distributions and early clinical outcomes using this modality for the treatment of intermediate-risk prostate cancer. METHODS:Forty-one sequential hormone-naïve intermediate-risk prostate cancer patients received 35-36.25 Gy of CyberKnife-delivered SBRT in 5 fractions. Radiation dose distributions were analyzed for coverage of potential microscopic ECE by measuring the distance from the prostatic capsule to the 33 Gy isodose line. PSA levels, toxicities, and quality of life (QOL) measures were assessed at baseline and follow-up. RESULTS:All patients completed treatment with a mean coverage by the 33 Gy isodose line extending >5 mm beyond the prostatic capsule in all directions except posteriorly. Clinical responses were documented by a mean PSA decrease from 7.67 ng/mL pretreatment to 0.64 ng/mL at the median follow-up of 21 months. Forty patients remain free from biochemical progression. No Grade 3 or 4 toxicities were observed. Mean EPIC urinary irritation/obstruction and bowel QOL scores exhibited a transient decline post-treatment with a subsequent return to baseline. No significant change in sexual QOL was observed. CONCLUSIONS:In this intermediate-risk patient population, an adequate radiation dose was delivered to areas of expected microscopic ECE in the majority of patients. Although prospective studies are needed to confirm long-term tumor control and toxicity, the short-term PSA response, biochemical relapse-free survival rate, and QOL in this interim analysis are comparable to results reported for prostate brachytherapy or external beam radiotherapy. TRIAL REGISTRATION/BACKGROUND:The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009-510).

BACKGROUND:Artificial neural networks (ANNs) excel at analyzing challenging data sets and can be exceptional tools for decision support in clinical environments. The present study pilots the use of ANNs for determining prognosis in neuro-oncology patients. OBJECTIVE:To determine whether ANNs perform better at predicting 1-year survival in a group of patients with brain metastasis compared with traditional predictive tools. METHODS:: ANNs were trained on a multi-institutional data set of radiosurgery patients to predict 1-year survival on the basis of several input factors. A single ANN, an ensemble of 5 ANNs, and logistic regression analyses were compared for efficacy. Sensitivity analysis was used to identify important variables in the ANN model. RESULTS:A total of 196 patients were divided up into training, testing, and validation data sets consisting of 98, 49, and 49 patients, respectively. Patients surviving at 1 year tended to be female (P = .001) and of good performance status (P = .01) and to have favorable primary tumor histology (P = .001). The pooled voting of 5 ANNs performed significantly better than the multivariate logistic regression model (P = .02), with areas under the curve of 84% and 75%, respectively. The ensemble also significantly outperformed 2 commonly used prognostic indexes. Primary tumor subtype and performance status were identified on sensitivity analysis to be the most important variables for the ANN. CONCLUSION/CONCLUSIONS:ANNs outperform traditional statistical tools and scoring indexes for predicting individual patient prognosis. Their facile implementation, robustness in the presence of missing data, and ability to continuously learn make them excellent choices for use in complicated clinical environments.

BACKGROUND:Stereotactic body radiation therapy (SBRT) delivers fewer high-dose fractions of radiation which may be radiobiologically favorable to conventional low-dose fractions commonly used for prostate cancer radiotherapy. We report our early experience using SBRT for localized prostate cancer. METHODS:Patients treated with SBRT from June 2008 to May 2010 at Georgetown University Hospital for localized prostate carcinoma, with or without the use of androgen deprivation therapy (ADT), were included in this retrospective review of data that was prospectively collected in an institutional database. Treatment was delivered using the CyberKnife® with doses of 35 Gy or 36.25 Gy in 5 fractions. Biochemical control was assessed using the Phoenix definition. Toxicities were recorded and scored using the CTCAE v.3. Quality of life was assessed before and after treatment using the Short Form-12 Health Survey (SF-12), the American Urological Association Symptom Score (AUA) and Sexual Health Inventory for Men (SHIM) questionnaires. Late urinary symptom flare was defined as an AUA score ≥ 15 with an increase of  ≥ 5 points above baseline six months after the completion of SBRT. RESULTS:One hundred patients (37 low-, 55 intermediate- and 8 high-risk according to the D'Amico classification) at a median age of 69 years (range, 48-90 years) received SBRT, with 11 patients receiving ADT. The median pre-treatment prostate-specific antigen (PSA) was 6.2 ng/ml (range, 1.9-31.6 ng/ml) and the median follow-up was 2.3 years (range, 1.4-3.5 years). At 2 years, median PSA decreased to 0.49 ng/ml (range, 0.1-1.9 ng/ml). Benign PSA bounce occurred in 31% of patients. There was one biochemical failure in a high-risk patient, yielding a two-year actuarial biochemical relapse free survival of 99%. The 2-year actuarial incidence rates of GI and GU toxicity ≥ grade 2 were 1% and 31%, respectively. A median baseline AUA symptom score of 8 significantly increased to 11 at 1 month (p=0.001), however returned to baseline at 3 months (p=0.60). Twenty one percent of patients experienced a late transient urinary symptom flare in the first two years following treatment. Of patients who were sexually potent prior to treatment, 79% maintained potency at 2 years post-treatment. CONCLUSIONS:SBRT for clinically localized prostate cancer was well tolerated, with an early biochemical response similar to other radiation therapy treatments. Benign PSA bounces were common. Late GI and GU toxicity rates were comparable to conventionally fractionated radiation therapy and brachytherapy. Late urinary symptom flares were observed but the majority resolved with conservative management. A high percentage of men who were potent prior to treatment remained potent two years following treatment.

OBJECT/OBJECTIVE:Experience with whole-brain radiation therapy for metastatic tumors in the brain has identified a subset of tumors that exhibit decreased local control with fractionated regimens and are thus termed radioresistant. With the advent of frameless radiosurgery, fractionated radiosurgery (2-5 fractions) is being used increasingly for metastatic tumors deemed too large or too close to crucial structures to be treated in a single session. The authors retrospectively reviewed metastatic brain tumors treated at 2 centers to analyze the dependency of local control rates on tumor radiobiology and dose fractionation. METHODS:The medical records of 214 patients from 2 institutions with radiation-naive metastatic tumors in the brain treated with radiosurgery given either as a single dose or in 2-5 fractions were analyzed retrospectively. The authors compared the local control rates of the radiosensitive with the radioresistant tumors after either single-fraction or fractionated radiosurgery. RESULTS:There was no difference in local tumor control rates in patients receiving single-fraction radiosurgery between radioresistant and radiosensitive tumors (p = 0.69). However, after fractionated radiosurgery, treatment for radioresistant tumors failed at a higher rate than for radiosensitive tumors with an OR of 5.37 (95% CI 3.83-6.91, p = 0.032). CONCLUSIONS:Single-fraction radiosurgery is equally effective in the treatment of radioresistant and radiosensitive metastatic tumors in the brain. However, fractionated stereotactic radiosurgery is less effective in radioresistant tumor subtypes. The authors recommend that radioresistant tumors be treated in a single fraction when possible and techniques for facilitating single-fraction treatment or dose escalation be considered for larger radioresistant lesions.

Prostate cancer (PCa) is the most common type of cancer in men in the United States, which disproportionately affects African American descents. While metastasis is the most common cause of death among PCa patients, no specific markers have been assigned to severity and ethnic biasness of the disease. MicroRNAs represent a promising new class of biomarkers owing to their inherent stability and resilience. In the present study, we investigated potential miRNAs that can be used as biomarkers and/or therapeutic targets and can provide insight into the severity and ethnic biasness of PCa. PCR array was performed in FFPE PCa tissues (5 Caucasian American and 5 African American) and selected differentially expressed miRNAs were validated by qRT-PCR, in 40 (15 CA and 25 AA) paired PCa and adjacent normal tissues. Significantly deregulated miRNAs were also analyzed in urine samples to explore their potential as non-invasive biomarker for PCa. Out of 8 miRNAs selected for validation from PCR array data, miR-205 (p<0.0001), mir-214 (p<0.0001), miR-221(p<0.001) and miR-99b (p<0.0001) were significantly downregulated in PCa tissues. ROC curve shows that all four miRNAs successfully discriminated between PCa and adjacent normal tissues. MiR-99b showed significant down regulation (p<0.01) in AA PCa tissues as compared to CA PCa tissues and might be related to the aggressiveness associated with AA population. In urine, miR-205 (p<0.05) and miR-214 (p<0.05) were significantly downregulated in PCa patients and can discriminate PCa patients from healthy individuals with 89% sensitivity and 80% specificity. In conclusion, present study showed that miR-205 and miR-214 are downregulated in PCa and may serve as potential non-invasive molecular biomarker for PCa.