Faculty Bibliography

BACKGROUND:Brain metastases of gastrointestinal origin are a rare occurrence. Radiation therapy (RT) in the form of stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) is an effective established treatment modality in either the definitive or adjuvant setting. The aim of this study is to assess the long-term clinical outcomes of patients with gastrointestinal (GI) brain metastases treated with SRS or WBRT. METHODS:In this single institutional retrospective review, we detail the outcomes of patients diagnosed with metastatic brain tumors from an adenocarcinoma gastrointestinal primary. Patients were treated using stereotactic radiosurgery or whole brain radiation therapy. Initial site control (defined as lesions visualized on imaging at time of treatment), new site control (defined as new intracranial lesions visualized on follow-up imaging), and overall survival were calculated using the Kaplan-Meier method. RESULTS:Thirty-three patients were treated from August 2008 to December 2015. Primary malignancy locations were as follows: 18 colon, 6 esophagus, 4 rectum, 5 other. Median total dose delivered was 25 Gy (18-35 Gy) in a median of 4 fractions for SRS and 30 Gy (10.8-40 Gy) in 10 fractions for WBRT. Crude initial site control at last radiographic follow-up was 64.3% after SRS and 41.7% after WBRT. Eleven of the 28 brain lesions (39.3%) treated with SRS had resection of the SRS-treated lesion prior to radiation therapy. Five of the twelve patients (41.7%) undergoing WBRT underwent cranial resection prior to radiation therapy. Crude new site control at last radiographic follow-up was 46.4% after SRS and 83.3% after WBRT. Kaplan-Meier analysis of overall survival did not show any statistically significant difference between WBRT and SRS (p = 0.424). Median overall survival for SRS patients was 5.2 months (0.5-57.5) and for WBRT patients 4.4 months (0-15). Kaplan-Meier analysis of new site control was significantly improved with WBRT versus SRS (p = 0.017). Total dose, treatment with WBRT, and active extracranial disease were statistically significant on multivariate analysis for new site control (p < 0.05). CONCLUSIONS:Survival and intracranial disease control are poor following RT for brain metastases from GI primaries. In this small series, outcomes are worse than published series for other primary malignancies metastatic to the brain and further research into methods of local control improvement is warranted. Future studies should explore the utility of dose escalation or radiosensitization in this patient population.

Stereotactic body radiation therapy (SBRT) has become a viable treatment option for the many patients who receive a diagnosis of localized prostate cancer each year. Technological advancements have led to tight target conformality, allowing for high-dose-per-fraction delivery without untoward normal tissue toxicity. Biochemical control, now reported up to 5 years, appears to compare favorably with dose-escalated conventionally fractionated radiotherapy. Moreover, toxicity and quality of life follow-up data indicate genitourinary and gastrointestinal toxicities are likewise comparable to conventional radiation therapy. Nevertheless, because of the long natural history of prostate cancer, extended follow-up will be necessary to confirm these impressive initial results. Within this prostate SBRT review, we explore the detailed rationale for SBRT treatment, the diverse SBRT techniques utilized and their unique technical considerations, and finally data for SBRT clinical efficacy and treatment-related toxicity.

PURPOSE/OBJECTIVE:Respiratory-induced tumor motion of upper gastrointestinal (GI) tumors during radiation therapy is often assessed using a single 4-dimensional computed tomography (4D-CT) and presumed to be representative during fractionated treatment regimens. The purpose of this study was to examine the intra- and interfraction correlations of tumor motion between pretreatment 4D-CT and real-time fiducial-based motion tracking in patients treated with fractionated stereotactic body radiation therapy (SBRT) for upper GI malignancies. METHODS AND MATERIALS/METHODS:Fourteen patients with upper GI tumors underwent fractionated SBRT using the CyberKnife radiosurgical system with Synchrony respiratory motion management. Before treatment, each patient underwent a free-breathing 4D-CT scan and fiducial motion was tracked for each phase of the respiratory cycle. Real-time fiducial positions recorded during delivery of each SBRT fraction were extracted from the CyberKnife planning system. Displacements were compared between those predicted by 4D-CT and those recorded by Synchrony during treatment in the left-right (LR), anteroposterior (AP), and superoinferior (SI) directions. RESULTS:The 4D-CT scans demonstrated little correlation with real-time mean fiducial displacement as determined by Pearson correlation with coefficients of 0.45, 0.52, and 0.63 in the SI, AP, and LR directions, respectively. Cohort-averaged maximum fiducial displacements based on 4D-CT and real-time tracking were measured to be 3.86 ± 1.40 mm versus 10.73 ± 7.03 mm, 2.29 ± 1.02 mm versus 4.44 ± 3.33 mm, and 1.45 ± 0.49 mm versus 2.67 ± 2.49 mm in the SI, AP, and LR directions, respectively. Mean fiducial displacements were greater than that predicted by the maximum displacements on the corresponding 4D-CT scan in 39%, 22%, and 25% of SBRT fractions in the SI, AP, and LR directions, respectively. CONCLUSIONS:Comparison of 4D-CT with real-time fiducial tracking demonstrated significant inter- and intrafractional discrepancies, particularly in the SI direction, which could result in compromise of target coverage when planning with a single free-breathing 4D-CT.

BACKGROUND AND PURPOSE/OBJECTIVE:Radiotherapy of central lung tumors carries a higher risk of treatment-related toxicity and local failure. In the era of aggressive oligometastic management the exploration of the proper dose-fractionation for metastatic central lung tumors is essential. MATERIALS AND METHODS/METHODS:Patients diagnosed with high-risk metastatic lesions of the central pulmonary tree comprised this single-institutional retrospective analysis. "High-risk" central pulmonary lesions were defined as those with abutment and/or invasion of the mainstem bronchus. All patients were treated using the CyberKnife SBRT system in 5 fractions to a total dose of 35 or 40 Gy. RESULTS:Twenty patients were treated from 2008 to 2011 at Georgetown University Hospital. At a median follow up of 19 months, 1-year Kaplan-Meier local control and overall survival was 70 and 75 %, respectively. Late grade 2 or higher atelectasis was the most common treatment-related toxicity and was significantly associated with maximum dose to the mainstem bronchus. Gross endobronchial involvement was associated with significantly lower overall survival. CONCLUSIONS:Five-fraction SBRT to a total dose of 35 or 40 Gy appears to be a safe and effective management strategy for high-risk central pulmonary metastatic lesions, though care should be taken to limit the maximum point dose to the mainstem bronchus.

BACKGROUND:Stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) is considered standard of care in the medically inoperable patient population. Multiple methods of SBRT delivery exist including fiducial-based tumor tracking, which allows for smaller treatment margins and avoidance of patient immobilization devices. We explore the long-term clinical outcomes of this novel fiducial-based SBRT method. METHODS:In this single institutional retrospective review, we detail the outcomes of medically inoperable pathologically confirmed stage I NSCLC. Patients were treated with the Cyberknife SBRT system using a planning target volume (PTV) defined as a 5-mm expansion from gross tumor volume (GTV) without creation of an internal target volume (ITV). Dose was delivered in three or five equal fractions of 10 to 20 Gy. Pretreatment and posttreatment pulmonary function test (PFT) changes and evidence of late radiological rib fractures were analyzed for the majority of patients. Actuarial local control, locoregional control, distant control, and overall survival were calculated using the Kaplan-Meier method. RESULTS: = 0.01). Five-year local control, locoregional control, and overall survival were 87.6, 71.8, and 39.3 %, respectively. CONCLUSIONS:Despite reduced treatment margins and lack of patient immobilization, SBRT with fiducial-based tumor tracking achieves clinically comparable long-term outcomes to other linac-based SBRT approaches.

BACKGROUND:Achieving durable local control while limiting normal tissue toxicity with definitive radiation therapy in the management of high-risk brain metastases remains a radiobiological challenge. The objective of this study was to examine the local control and toxicity of a 5-fraction stereotactic radiosurgical approach for treatment of patients with inoperable single high-risk NSCLC brain metastases. METHODS:This retrospective analysis examines 20 patients who were deemed to have "high-risk" brain metastases. High-risk tumors were defined as those with a maximum diameter greater than 2 cm and/or those located within an eloquent cortex. Patients were evaluated by a neurosurgeon prior to treatment and determined to be inoperable due to tumor or patient characteristics. Patients were treated using the CyberKnife® SRS system in 5 fractions to a total dose of 30 Gy, 35 Gy, or 40 Gy. RESULTS:Twenty patients with a median age of 65.5 years were treated from April 2010 to August 2014 in 5 fractions to a median total dose of 35 Gy. At a median follow up of 11.3 months local tumor control was observed in 18 of 20 metastases (90 %). Both local failures were observed in patients receiving a lower dose of 30 Gy. Median pre-treatment dexamethasone dose was 10 mg/day and median post-treatment nadir dose was 0 mg/day. Salvage intracranial therapy was required in 45 % of patients. Symptomatic radionecrosis was observed in 4 of 20 patients (20 %), two of which were treated to 40 Gy and the remainder to 35 Gy. Kaplan-Meier 1-year, 2-year, and median survival were calculated to be 45 %, 20 %, and 13.2 months, respectively. CONCLUSIONS:Five-fraction SRS to a total dose of 35 Gy appears to be a safe and effective management strategy for single high-risk NSCLC brain metastases, while a total dose of 40 Gy leads to an excess risk of neurotoxicity.

Spontaneous electrical activity that moves in synchronized waves across large populations of neurons plays widespread and important roles in nervous system development. The propagation patterns of such waves can encode the spatial location of neurons to their downstream targets and strengthen synaptic connections in coherent spatial patterns. Such waves can arise as an emergent property of mutually excitatory neural networks, or can be driven by a discrete pacemaker. In the mouse cerebral cortex, spontaneous synchronized activity occurs for approximately 72 h of development centered on the day of birth. It is not known whether this activity is driven by a discrete pacemaker or occurs as an emergent network property. Here we show that this activity propagates as a wave that is initiated at either of two homologous pacemakers in the temporal region, and then propagates rapidly across both sides of the brain. When these regions of origin are surgically isolated, waves do not occur. Therefore, this cortical spontaneous activity is a bilateral wave that originates from a discrete subset of pacemaker neurons.

Spontaneous, synchronized electrical activity (SSA) plays important roles in nervous system development, but it is not clear what causes it to start and stop at the appropriate times. In previous work, we showed that when SSA in neonatal mouse cortex is blocked by TTX in cultured slices during its normal time of occurrence (E17-P3), it fails to stop at P3 as it does in control cultured slices, but instead persists through at least P10. This indicates that SSA is self-extinguishing. Here we use whole-cell recordings and [Ca2+]i imaging to compare control and TTX-treated slices to isolate the factors that normally extinguish SSA on schedule. In TTX-treated slices, SSA bursts average 4 s in duration, and have two components. The first, lasting about 1 s, is mediated by AMPA receptors; the second, which extends the burst to 4 s and is responsible for most of the action potential generation during the burst, is mediated by NMDA receptors. In later stage (P5-P9) control slices, after SSA has declined to about 4% of its peak frequency, bursts lack this long NMDA component. Blocking this NMDA component in P5-P9 TTX-treated slices reduces SSA frequency, but not to the low values found in control slices, implying that additional factors help extinguish SSA. GABA(A) inhibitors restore SSA in control slices, indicating that the emergence of GABA(A)-mediated inhibition is another major factor that helps terminate SSA.