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Intracranial tumors, both primary and metastatic, have distinct anatomic and neuroimaging features. Radiotherapy is often used in the management of intracranial tumors. Various techniques used in radiotherapy include external beam radiotherapy and stereotactic radiotherapy. This chapter discusses the use of neuroimaging in tumor delineation and radiation planning and delivery. Evaluation of immobilization, target volumes, normal tissue volumes, plan review, and quality assurance is required to safely deliver radiotherapy. The practical review of radiotherapy in high-grade glioma is used to demonstrate these facets of patient care. Neuroimaging and clinical evaluation are used to evaluate for disease recurrence following treatment completion. On standard magnetic resonance imaging, it may be difficult to differentiate between pseudo-progression, true disease progression, and radiation necrosis. A multitude of imaging techniques are now available to assist in making this distinction. The progress in neuroimaging has improved radiation planning and delivery and will continue to do so in the future.

Purpose The adrenal glands are common sites of metastatic disease in lung cancer and can be highly symptomatic. Current treatment approaches for adrenal oligometastases, including surgical resection and chemoembolization, are invasive and can be associated with considerable morbidity. More recently, stereotactic body radiotherapy (SBRT) has shown promising tumor control rates in primary lung cancer and oligometastases of various sites, but relatively less data exist on the efficacy of SBRT for adrenal metastases. The purpose of this study is to assess tumor regression pattern, local control, overall survival, pain relief, and treatment morbidity in patients treated with SBRT for adrenal metastases from lung cancer.

The preferential use of intensity-modulated radiotherapy (IMRT) over conventional radiotherapy (CRT) in the treatment of head and neck cancer has raised concerns regarding dose to non-target tissue. The purpose of this study was to compare dose-volume characteristics with the brachial plexus between treatment plans generated by IMRT and CRT using several common treatment scenarios.The brachial plexus was delineated on radiation treatment planning CT scans from 10 patients undergoing IMRT for locally advanced head and neck cancer using a Radiation Therapy Oncology Group-endorsed atlas. No brachial plexus constraint was used. For each patient, a conventional three-field shrinking-field plan was generated and the dose-volume histogram (DVH) for the brachial plexus was compared with that of the IMRT plan.The mean irradiated volumes of the brachial plexus using the IMRT vs the CRT plan, respectively, were as follows: V50 (18±5 ml) vs (11±6 ml), p = 0.01; V60 (6±4 ml) vs (3±3 ml), p = 0.02; V66 (3±1 ml) vs (1±1 ml), p = 0.04, V70 (0±1 ml) vs (0±1 ml), p = 0.68. The maximum point dose to the brachial plexus was 68.9 Gy (range 62.3-78.7 Gy) and 66.1 Gy (range 60.2-75.6 Gy) for the IMRT and CRT plans, respectively (p = 0.01).Dose to the brachial plexus is significantly increased among patients undergoing IMRT compared with CRT for head and neck cancer. Preliminary studies on brachial plexus-sparing IMRT are in progress.

Perfusion-based functional brain imaging techniques such as fMRI and optical intrinsic signal (OIS) imaging are becoming increasingly important in both neuroscience research and intraoperative brain mapping. Recent studies have applied a spectroscopic approach to OIS imaging data, which we will call “two-dimensional optical spectroscopy” (2DOS), generating images of functional changes in hemoglobin oxygenation and blood volume. This improvement comes at the cost of several assumptions. Whereas the “gold standard” technique of fiber spectroscopy decomposes reflected light over a spectral axis, 2DOS retains both spatial dimensions by acquiring images at several wavelengths, sacrificing spectral resolution for the extra spatial dimension. Furthermore, 2DOS data are acquired interleaved within or between trials, but combined during the spectroscopic analysis as if acquired simultaneously. Thus far, the few studies employing this approach have assumed both that the reduced spectral resolution is tolerable, and that sufficient trial averaging can compensate for the temporally staggered data acquisition. To test these assumptions, we compared 2DOS results to those produced by traditional fiber spectroscopy by observing the hemodynamic response to hindpaw electrical stimulation over the primary somatosensory cortex in anesthetized rats. Comparisons revealed low fitting residuals and a high level of correlation between the two, but noteworthy differences in response magnitudes. Inspection of individual timecourses revealed a lower signal-to-noise ratio for 2DOS data. For visualization and interpretation of the 2DOS images, we present a parameterized visualization strategy, in which oxy-, deoxy-, and total hemoglobin are assigned to individual color channels. The resulting composite image conveniently displays the evolution of hemodynamic responses through parenchymal and vascular compartments in space and time.

Introduction Pediatric high grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes.Materials and methodsFifty-one patients treated from 1984-2008 at Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progression-free survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and subtotal resection/biopsy subgroup. ResultsMedian OS was 27.6 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or chemoradiation were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent chemoradiation independently correlated with improved PFS, while higher radiation dose (≥ 59.4 Gy), and adjuvant chemotherapy were independently associated with improved OS. DiscussionTotal resection and receiving chemotherapy adjuvant to radiation or chemoradiation are most closely associated with improved PFS and OS. For higher risk incompletely-resected patients, temozolomide use and treatment intensification with concurrent chemoradiation, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes.

We describe the use of near-infrared spectroscopy (NIRS) as a suitable means of assessing hemodynamic changes in the cerebral cortex of awake and behaving monkeys. NIRS can be applied to animals performing cognitive tasks in conjunction with electrophysiological methods, thus offering the possibility of investigating cortical neurovascular coupling in cognition. Because it imposes fewer constraints on behavior than fMRI, NIRS appears more practical than fMRI for certain studies of cognitive neuroscience on the primate cortex. In the present study, NIRS and field potential signals were simultaneously recorded from the association cortex (posterior parietal and prefrontal) of monkeys performing two delay tasks, one spatial and the other non-spatial. Working memory was accompanied by an increase in oxygenated hemoglobin mirrored by a decrease in deoxygenated hemoglobin. Both the trends and the amplitudes of these changes differed by task and by area. Field potential records revealed slow negative potentials that preceded the task trials and persisted during their memory period. The negativity during that period was greater in prefrontal than in parietal cortex. Between tasks, the potential differences were less pronounced than the hemodynamic differences. The present feasibility study lays the groundwork for future correlative studies of cognitive function and neurovascular coupling in the primate.

Brain imaging techniques such as functional magnetic resonance imaging (fMRI) have provided a wealth of information about brain organization, but their ability to investigate fine-scale functional architecture is limited by the spatial specificity of the hemodynamic responses upon which they are based. We investigated the spatiotemporal evolution of hemodynamic responses in rat somatosensory cortex to electrical hindpaw stimulation. We combined the advantages of optical intrinsic signal imaging and spectroscopy to produce high-resolution two-dimensional maps of functional changes in tissue oxygenation and blood volume. Cerebral blood flow changes were measured with laser-Doppler flowmetry, and simultaneously recorded field potentials allowed comparison between hemodynamic changes and underlying neuronal activity. For the first 2 to 3 secs of activation, hemodynamic responses overlapped in a central parenchymal focus. Over the next several seconds, cerebral blood volume changes propagated retrograde into feeding arterioles, and oxygenation changes anterograde into draining veins. By 5 to 6 secs, responses localized primarily in vascular structures distant from the central focus. The peak spatial extent of the hemodynamic response increased linearly with synaptic activity. This spatial spread might be because of lateral subthreshold activation or passive vascular overspill. These results imply early microvascular changes in volume and oxygenation localize to activated neural columns, and that spatial specificity will be optimal within a 2- to 3-sec window after neuronal activation.

Cortical neurons with similar properties are grouped in columnar structures and supplied by matching vascular networks. The hemodynamic response to neuronal activation, however, is not well described on a fine spatial scale. We investigated the spatiotemporal characteristics of microvascular responses to neuronal activation in rat barrel cortex using optical intrinsic signal imaging and spectroscopy. Imaging was performed at 570 nm to provide functional maps of cerebral blood volume (CBV) changes and at 610 nm to estimate oxygenation changes. To emphasize parenchymal rather than large vessel contributions to the functional hemodynamic responses, we developed an ANOVA-based statistical analysis technique. Perfusion-based maps were compared with underlying neuroanatomy with cytochrome oxidase staining. Statistically determined CBV responses localized accurately to individually stimulated barrel columns and could resolve neighboring columns with a resolution better than 400 mum. Both CBV and early oxygenation responses extended beyond anatomical boundaries of single columns, but this vascular point spread did not preclude spatial specificity. These results indicate that microvascular flow control structures providing targeted flow increases to metabolically active neuronal columns also produce finely localized changes in CBV. This spatial specificity, along with the high contrast/noise ratio, makes the CBV response an attractive mapping signal. We also found that functional oxygenation changes can achieve submillimeter specificity not only during the transient deoxygenation ("initial dip") but also during the early part of the hyperoxygenation. We, therefore, suggest that to optimize hemodynamic spatial specificity, appropriate response timing ( using less than or equal to2-3 sec changes) is more important than etiology (oxygenation or volume).

Cerebral radiation necrosis (CRN) is a well described possible complication of radiation for treatment of intracranial pathology. However, CRN as sequelae of radiation to extracranial sites is rare. Neutron beam radiation is a highly potent form of radiotherapy that may be used to treat malignant tumors of the salivary glands. This report describes a patient who underwent neutron beam radiation for a parotid adenocarcinoma and who developed biopsy-confirmed temporal lobe radiation necrosis thirty months later. This represents the longest time interval described to date, from initial neutron radiation for extracranial pathology to development of CRN. Two other detailed case studies exist in the literature and are described in this report. These reports as well as our patient’s case are reviewed, and additional recommendations are made to minimize the development of CRN after extracranial neutron beam radiation. Physicians should include the possible diagnosis of CRN in any patient with new neurologic signs or symptoms and a history of head and neck radiation that included planned fields extending to the base of the skull. Counseling of patients prior to neutron beam radiation should include potential neurologic complications associated with CRN and risks of treatment for CRN including neurosurgical intervention.

Conventional treatment of glioblastoma has advanced only incrementally in the last 30 years and still yields poor outcomes. The current strategy of surgery, radiation, and chemotherapy has increased median survival to approximately 15 months. With the advent of molecular biology and consequent improved understanding of basic tumor biology, targeted therapies have become cornerstones for cancer treatment. Many pathways (RTKs, PI3K/AKT/mTOR, angiogenesis, etc.) have been identified in GBM as playing major roles in tumorigenesis, treatment resistance, or natural history of disease. Despite the growing understanding of the complex networks regulating GBM tumors, many targeted therapies have fallen short of expectations. In this paper, we will discuss novel therapies and the successes and failures that have occurred. One clear message is that monotherapies yield minor results, likely due to functionally redundant pathways. A better understanding of underlying tumor biology may yield insights into optimal targeting strategies which could improve the overall therapeutic ratio of conventional treatments.

Purpose To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). Methods and Materials The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64–72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266–800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. Results The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. Conclusions Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.

Purpose Although Radiation Therapy Oncology Group protocols have proposed a limiting dose to the brachial plexus for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, essentially no recommendations exist for the delineation of this structure for treatment planning. Methods and Materials Using anatomic texts, radiologic data, and magnetic resonance imaging, a standardized method for delineating the brachial plexus on 3-mm axial computed tomography images was devised. A neuroradiologist assisted with identification of the brachial plexus and adjacent structures. This organ at risk was then contoured on 10 consecutive patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. Dose–volume histogram curves were generated by applying the proposed brachial plexus contour to the initial treatment plan. Results The total dose to the planning target volume ranged from 60 to 70 Gy (median, 70). The mean brachial plexus volume was 33 ± 4 cm 3 (range, 25.1–39.4). The mean irradiated volumes of the brachial plexus were 50 Gy (17 ± 3 cm 3 ), 60 Gy (6 ± 3 cm 3 ), 66 Gy (2 ± 1 cm 3 ), 70 Gy (0 ± 1 cm 3 ). The maximal dose to the brachial plexus was 69.9 Gy (range, 62.3–76.9) and was ≥60 Gy, ≥66 Gy, and ≥70 Gy in 100%, 70%, and 30% of patients, respectively. Conclusions This technique provides a precise and accurate method for delineating the brachial plexus organ at risk on treatment planning computed tomography scans. Our dosimetric analysis suggest that for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, brachial plexus routinely receives doses in excess of historic and Radiation Therapy Oncology Group limits.

Cortical spreading depression (CSD) is a pronounced depolarization of neurons and glia that spreads slowly across the cortex followed by a period of depressed electrophysiological activity. The vascular changes associated with CSD are a large transient increase in blood flow followed by a prolonged decrease lasting greater than I h. Currently, the profile of functional vascular activity during this hypovolemic period has not been well characterized. Perfusion-based imaging techniques such as functional magnetic resonance imaging (fMRI) assume a tight coupling between changes in neuronal and vascular activity. Under normal conditions, these variables are well correlated. Characterizing the effect of CSD on this relationship is an important step to understand the impact acute pathophysiological events may have on neurovascular coupling. We examine the effect of CSD on functional changes in cerebral blood volume (CBV) evoked by cortical electrophysiological activity for I h following CSD induction. CBV signal amplitude, duration, and time to peak show little recovery at 60 min post-induction. Analysis of spontaneous vasomotor activity suggests a decrease in vascular reactivity may play a significant role in the disruption of normal functional CBV responses. Electrophysiological activity is also attenuated but to a lesser degree. CBV and evoked potentials are not well correlated following CSD, suggesting a breakdown of the neurovascular coupling relationship. (c) 2005 Society of Photo-Optical Instrumentation Engineers.

Linear relationships between synaptic activity and hemodynamic responses are critically dependent on functional signal etiology and paradigm. To investigate these relationships, we simultaneously measured local field potentials (FPs) and optical intrinsic signals in rat somatosensory cortex while delivering a small number of electrical pulses to the hindpaw with varied stimulus intensity, number, and interstimulus interval. We used 570 and 610 nm optical signals to estimate cerebral blood volume (CBV) and oxygenation, respectively.The spatiotemporal evolution patterns and trial-by-trial correlation analyses revealed that CBV-related optical signals have higher fidelity to summed evoked FPs (ΣFPs) than oxygenation-derived signals. CBV-related signals even correlated with minute ΣFP fluctuations within trials of the same stimulus condition. Furthermore, hemodynamic signals (CBV and late oxygenation signals) increased linearly with ΣFP while varying stimulus number, but they exhibited a threshold and steeper gradient while varying stimulus intensity, suggesting insufficiency of the homogeneity property of linear systems and the importance of spatiotemporal coherence of neuronal population activity in hemodynamic response formation. These stimulus paradigm-dependent linear and nonlinear relationships demonstrate that simple subtraction-based analyses of hemodynamic signals produced by complex stimulus paradigms may not reflect a difference in ΣFPs between paradigms. Functional signal- and paradigm-dependent linearity have potentially profound implications for the interpretation of perfusion-based functional signals.

We investigated the coupling between perfusion-related brain imaging signals and evoked neuronal activity using optical imaging of intrinsic signals (OIS) at 570 and 610 nm. OIS at 570 nm reflects changes in cerebral blood volume (CBV), and the 610 nm response is related to hemoglobin oxygenation changes. We assessed the degree to which these components of the hemodynamic response were coupled to neuronal activity in rat barrel, hindpaw, and forepaw somatosensory cortex by simultaneously recording extracellular evoked field potentials (EPs) and OIS while varying stimulation frequency. In all stimulation paradigms, 10 Hz stimulation evoked the largest optical and electrophysiological responses. Across all animals, the 610 late phase and 570 responses correlated linearly with sigmaEP (P < 0.05) during both whisker deflection and electrical hindpaw stimulation, but the 610 early phase did not (whisker P = 0.27, hindpaw P = 0.28). The signal-to-noise ratio (SNR) of the 610 early phase (whisker 3.1, hindpaw 5.3) was much less than that for the late phase (whisker 14, hindpaw 51) and 570 response (whisker 11, hindpaw 46). During forepaw stimulation, however, the 610 early phase had a SNR (17) higher than that during hindpaw stimulation and correlated well with neuronal activity (P < 0.05). We conclude that the early deoxygenation change does not correlate consistently with neuronal activity, possibly because of its low SNR. The robust CBV-related response, however, has a high SNR and correlates well with evoked cortical activity.

In the original article, the following errors were made. On page 155, in the Abstract, Methods and materials subsection, the first sentence should read “TEN lesions were treated with SBRT in nine patients with lung cancer and followed with post-therapy clinical exams and computed tomography.” On page 157, in the Results, Objective response classification subsection, the third sentence should read “When response was assessed by RECIST criteria at 5 months after therapy completion for the remaining EIGHT patients with NINE lesions, there were six partial responses (PR), three patients with stable disease (SD), and none with progressive disease (PD), resulting in an objective response rate (CR + PR) of 67 %.”

We investigated the relationship between neuronal activity, oxygen metabolism, and hemodynamic responses in rat somatosensory cortex with simultaneous optical intrinsic signal imaging and spectroscopy, laser Doppler flowmetry, and local field potential recordings. Changes in cerebral oxygen consumption increased linearly with synaptic activity but with a threshold effect consistent with the existence of a tissue oxygen buffer. Modeling analysis demonstrated that the coupling between neuronal activity and hemodynamic response magnitude may appear linear over a narrow range but incorporates nonlinear effects that are better described by a threshold or power law relationship. These results indicate that caution is required in the interpretation of perfusion-based indicators of brain activity, such as functional magnetic resonance imaging (fMRI), and may help to refine quantitative models of neurovascular coupling.