Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer.

Focused ultrasound (FUS) combined with intravascularly circulating microbubbles can transiently increase the permeability of the blood-brain barrier (BBB) to enable targeted therapeutic delivery to the brain, the clinical testing of which is currently underway in both adult and pediatric patients. Aside from traditional cancer drugs, this technique is being extended to promote the delivery of immunomodulating therapeutics to the brain, including antibodies, immune cells, and cytokines. In this manner, FUS approaches are being explored as a tool to improve and amplify the effectiveness of immunotherapy for both primary and metastatic brain cancer, a particularly challenging solid tumor to treat. Here, we present an overview of the latest groundbreaking research in FUS-assisted delivery of immunomodulating agents to the brain in pre-clinical models of brain cancer, and place it within the context of the current immunotherapy approaches. We follow this up with a discussion on new developments and emerging strategies for this rapidly evolving approach.

Current and Emerging Systems for Focused Ultrasound-Mediated Blood-Brain Barrier Opening.

With an ever-growing list of neurological applications of focused ultrasound (FUS), there has been a consequent increase in the variety of systems for delivering ultrasound energy to the brain. Specifically, recent successful pilot clinical trials of blood-brain barrier (BBB) opening with FUS have generated substantial interest in the future applications of this relatively novel therapy, with divergent, purpose-built technologies emerging. With many of these technologies at various stages of pre-clinical and clinical investigation, this article seeks to provide an overview and analysis of the numerous medical devices in active use and under development for FUS-mediated BBB opening.

Outcomes of Hypofractionated Stereotactic Radiotherapy for Small and Moderate-Sized Brain Metastases: A Single-Institution Analysis.

Background: Stereotactic radiosurgery (SRS) is the standard treatment for limited intracranial metastases. With the advent of frameless treatment delivery, fractionated stereotactic radiotherapy (FSRT) has become more commonly implemented given superior control and toxicity rates for larger lesions. We reviewed our institutional experience of FSRT to brain metastases without size restriction. Methods: We performed a retrospective review of our institutional database of patients treated with FSRT for brain metastases. Clinical and dosimetric details were abstracted. All patients were treated in 3 or 5 fractions using LINAC-based FSRT, did not receive prior cranial radiotherapy, and had at least 6 months of MRI follow-up. Overall survival was estimated using the Kaplan-Meier method. Local failure and radionecrosis cumulative incidence rates were estimated using a competing risks model with death as the competing risk. Univariable and multivariable analyses using Fine and Gray's proportional subdistribution hazards regression model were performed to determine covariates predictive of local failure and radionecrosis. Results: We identified 60 patients and 133 brain metastases treated at our institution from 2016 to 2020. The most common histologies were lung (53%) and melanoma (25%). Most lesions were >1 cm in diameter (84.2%) and did not have previous surgical resection (88%). The median duration of imaging follow-up was 9.8 months. The median survival for the whole cohort was 20.5 months. The local failure at 12 months was 17.8% for all lesions, 22.1% for lesions >1 cm, and 13.7% for lesions ≤1 cm (p = 0.36). The risk of radionecrosis at 12 months was 7.1% for all lesions, 13.2% for lesions >1 cm, and 3.2% for lesions ≤1 cm (p = 0.15). Conclusions: FSRT is safe and effective in the treatment of brain metastases of any size with excellent local control and toxicity outcomes. Prospective evaluation against single-fraction SRS is warranted for all lesion sizes.

Optimal Management of Calvarial Lymphoma: A Meta-Analysis.

BACKGROUND: Calvarial lymphoma is an exceedingly rare phenomenon; the clinical presentation and imaging pattern mimic many diseases of the central nervous system. Several treatment approaches have been undertaken with variable use of surgery plus adjuvant chemotherapy and radiation; an optimal treatment algorithm has yet to be defined. The aim of this study was to better characterize management strategies and patient outcomes. METHODS: An illustrative case was presented and a meta-analysis was carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. MEDLINE and Embase were searched for cases of calvarial lymphoma. Outcomes between patients who underwent open surgery and biopsy only were compared directly. RESULTS: In an analysis from 1976 to 2019, 62 patients with a median age of 60 were included. The most common presentations were subcutaneous scalp mass (89%), headaches (26%), and focal neurological deficits (21%). Osteolytic changes on computed tomography were seen in 69% of patients with extension into either the intracranial or extracranial space in 97% of cases. Surgical excision was performed in 41 patients with a remission rate of 85% and a recurrence rate of 5%, which did not vary significantly from patients treated nonsurgically (remission in 75%, P = 0.479; recurrence in 0%, P = 1.000) CONCLUSIONS: In patients presenting with a progressively enlarging scalp mass, calvarial lymphoma should be in the differential diagnosis, as it can be effectively managed with a biopsy followed by chemotherapy and radiation. The role for open surgery may be limited.

Predictors of Postoperative Complications in Vestibular Schwannoma Surgery-A Population-Based Study.

OBJECTIVE: To investigate preoperative patient demographics and comorbidities in relation with postsurgical complications following vestibular schwannoma surgery. STUDY DESIGN: Retrospective population-based cohort study. SETTING: All hospitals in the Canadian province of Ontario. PATIENTS: This study includes 1,456 patients who underwent vestibular schwannoma surgery from April 1, 2002 to March 31, 2018 in Ontario, Canada. INTERVENTION/OUTCOME MEASURES: For all surgical patients, the demographic data, preoperative comorbidities, and postoperative complications were evaluated. Postoperative complications were examined immediately following surgery in the hospital as well as 1 year following the hospital discharge. RESULTS: The most common comorbidities in this cohort were hypertension (30.22%), diabetes (9.48%), asthma (13.53%), and chronic obstructive pulmonary disease (6.73%). Diabetes was the most impactful comorbidity and was associated with higher risk of myocardial infarction (RR = 4.58, p < 0.01), pneumonia (RR = 1.80, p = 0.02), dysphagia (RR = 1.58, p < 0.01), and meningitis (RR = 3.62, p < 0.01). Analysis of surgical approaches revealed that the translabyrinthine approach, compared with the open craniotomy approach, was negatively associated with postoperative complications including pneumonia (RR = 0.43, p < 0.01), urinary tract infection (RR = 0.55, p = 0.01), dysphagia (RR = 0.66, p < 0.01), and readmission (RR = 0.45, p < 0.01). CONCLUSION: This study examines patient demographics, preoperative comorbidities, and postoperative complications in patients who have undergone vestibular schwannoma surgery. The results highlight associations between patient characteristics and postoperative outcomes that can aid in preoperative decision-making and counselling.

Practice patterns in the management of recurrent and residual non-functioning pituitary adenomas: Results from a Canada-wide survey.

BACKGROUND: There is no consensus regarding the management and postoperative follow-up of non-functioning pituitary adenomas (NFAs) in the setting of recurrent or residual disease. Subsequent treatment options include continued follow-up, re-resection or radiotherapy. To address this gap and better understand current practice patterns, we surveyed neurosurgeons and radiation oncologists in Canada. METHODS: Neurosurgeons and radiation oncologists (ROs) across Canada were invited to complete a standardized online questionnaire. Summary statistics were computed, and Fisher's Exact tests were performed to assess significance. Qualitative analyses were performed through open and axial coding. RESULTS: Thirty-three participants completed the questionnaires, with neurosurgeons representing a majority of respondents (n = 20 vs n = 13). When treating giant (>3 cm) tumors, 90.9% of neurosurgeons in practice for less than 10 years reported using an endoscopic approach, as compared to only 66.7% of neurosurgeons in practice for 10 years of more. Additionally, neurosurgeons who were newer to practice had a greater tendency to advocate for stereotactic radiosurgery (SRS) or re-resection (54.5% and 36.4%, respectively), as compared to older surgeons who showed a higher propensity (22.2%) to advocate for observation. The presence of cavernous sinus extension appeared to encourage ROs to offer radiotherapy sooner (61.4%), as compared to 40% of neurosurgeons. CONCLUSIONS: Our results identified both variations and commonalities in practice amongst Canadian neurosurgeons. Approaches deviated in the setting of residual tumor based on years of practice. This work provides a critical foundation for future studies aiming to define evidence-based best practices in the management of NFAs.

Technical report: Rapid intraoperative reconstruction of cranial implants using additively manufactured moulds.

During craniotomies, a portion of the calvarium or skull is removed to gain access to the intracranial space. When it is not possible to re-implant the flap, surgeons may repair the defect intraoperatively or at a later date. With larger defects being more difficult to repair intraoperatively, we investigated a method for the creation of patient-specific moulds for ad hoc bone flap reconstruction using rapid prototyping. Patient-specific moulds were created based on light scanned models of the defect, using custom software and rapid prototyping. Polymethylmethacrylate bone implants were created for three retrospective craniotomy cases and evaluated based on original flap and skull reconstruction accuracy. Bone implants created using our moulding method reconstruct the original flap and skull with an average reconstruction accuracy of 0.82 and 1.3 mm, respectively. Average skull reconstruction accuracy obtained by surgeons performing freehand implant reconstruction was 1.49 mm. Time needed to generate moulds was between 2 h and 45 min and 6 h and 20 min. Improvements to current printing technology will make this procedure technically feasible for future cranial procedures.

Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study.

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of "sonicated" and "unsonicated" tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

Unilateral Lumbar Facet Dislocation: Case Report and Review of the Literature.

BACKGROUND: Facet dislocations of the lumbar spine, particularly without neurologic injury, are rare occurrences after major trauma. Although there are documented cases of lumbosacral dislocation in the published literature, strictly lumbar unilateral facet dislocation is rare. CASE DESCRIPTION: We report a case of a unilateral facet dislocation at L4-L5 after a single vehicle motorcycle accident. This injury was treated with posterior open reduction and instrumented stabilization with good results. CONCLUSIONS: Given the rarity of this injury pattern, the management of this type of injury is not established. Careful imaging to make the diagnosis is crucial, and we recommend a surgical treatment in the form of an open reduction and instrumented stabilization. In our case, we achieved good outcomes with a posterior approach.

High-Intensity Focused Ultrasound Ablation Therapy of Gliomas.

Ultrasound in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of biological effects, including thermal ablation of brain tumors. Therapeutic ultrasound has been studied for many years, but only within the last decade has the technology reached a point where it is safe and practical for clinical adoption. Using large, multi-element arrays, ultrasound can be focused through the skull, and combined with MRI for image guidance and real-time thermometry, to create lesions in the brain with millimeter accuracy. Using this technology, true non-invasive surgery can be accomplished with immediate tumor killing. Combining the ablative capabilities of focused ultrasound with its other unique effects, such as blood-brain barrier disruption and radiosensitization, may eventually result in change of the current glioma treatment paradigm.

Opening the Blood-Brain Barrier with MR Imaging-guided Focused Ultrasound: Preclinical Testing on a Trans-Human Skull Porcine Model.

Purpose To develop and test a protocol in preparation for a clinical trial on opening the blood-brain barrier (BBB) with magnetic resonance (MR) imaging-guided focused ultrasound for the delivery of chemotherapy drugs to brain tumors. Materials and Methods The procedures were approved by the institutional animal care committee. A trans-human skull porcine model was designed for the preclinical testing. Wide craniotomies were applied in 11 pigs (weight, approximately 15 kg). A partial human skull was positioned over the animal's brain. A modified clinical MR imaging-guided focused ultrasound brain system was used with a 3.0-T MR unit. The ultrasound beam was steered during sonications over a 3 × 3 grid at 3-mm spacing. Acoustic power levels of 3-20 W were tested. Bolus injections of microbubbles at 4 µL/kg were tested for each sonication. Levels of BBB opening, hemorrhage, and cavitation signal were measured with MR imaging, histologic examination, and cavitation receivers, respectively. A cavitation safety algorithm was developed on the basis of logistic regression of the measurements and tested to minimize the risk of hemorrhage. Results BBB openings of approximately 1 cm3 in volume were visualized with gadolinium-enhanced MR imaging after sonication at an acoustic power of approximately 5 W. Gross examination of histologic specimens helped confirm Evans blue (bound to macromolecule albumin) extravasation, and hematoxylin-eosin staining helped detect only scattered extravasation of red blood cells. In cases where cavitation signals were higher than thresholds, sonications were terminated immediately without causing hemorrhage. Conclusion With a trans-human skull porcine model, this study demonstrated BBB opening with a 230-kHz system in preparation for a clinical trial. © RSNA, 2016 Online supplemental material is available for this article.

Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival.

BACKGROUND: Malignant brain tumors have a dismal prognosis, with residual tumor remaining after surgery necessitating adjuvant chemoradiotherapy. The blood-brain barrier hinders many chemotherapeutic agents, resulting in modest treatment efficacy. We previously demonstrated that targeted natural killer (NK)-92 cells could be delivered to desired regions of the brain using MRI-guided focused ultrasound and Definity microbubbles. Targeted NK-92 cells have advantages over many systemic therapies including their specific cytotoxicity to malignant cells (particularly those expressing the target antigen), ability to spare healthy cells, and being unaffected by efflux channels. METHODS: We investigated whether longitudinal treatments with targeted NK-92 cells, focused ultrasound, and microbubbles could slow tumor growth and improve survival in an orthotopic HER2-amplified rodent brain tumor model using a human breast cancer line as a prototype. The HER2 receptor, involved in cell growth and differentiation, is expressed by both primary and metastatic brain tumors. Breast cancers with HER2 amplification have a higher risk of CNS metastasis and poorer prognosis. RESULTS: Early intensive treatment with targeted NK-92 cells and ultrasound improved survival compared with biweekly treatments or either treatment alone. The intensive treatment paradigm resulted in long-term survival in 50% of subjects. CONCLUSIONS: Many tumor proteins could be exploited for targeted therapy with the NK-92 cell line; combined with the mounting safety evidence for transcranial ultrasound, these results may soon be translatable to a highly targeted treatment option for patients with brain tumors.

Cavitation-based third ventriculostomy using MRI-guided focused ultrasound.

OBJECT: Transcranial focused ultrasound is increasingly being investigated as a minimally invasive treatment for a range of intracranial pathologies. At higher peak rarefaction pressures than those used for thermal ablation, focused ultrasound can initiate inertial cavitation and create holes in the brain by fractionation of the tissue elements. The authors investigated the technical feasibility of using MRI-guided focused ultrasound to perform a third ventriculostomy as a possible noninvasive alternative to endoscopic third ventriculostomy for hydrocephalus. METHODS: A craniectomy was performed in male pigs weighing 13-19 kg to expose the supratentorial brain, leaving the dura mater intact. Seven pigs were treated through the craniectomy, while 2 pigs were treated through ex vivo human skulls placed in the beam path. Registration and targeting was done using T2-weighted MRI sequences. For transcranial treatments a CT scan was used to correct the beam from aberrations due to the skull and maintain a small, high-intensity focus. Sonications were performed at both 650 kHz and 230 kHz at a range of intensities, and the in situ pressures were estimated both from simulations and experimental data to establish a threshold for tissue fractionation in the brain. RESULTS: In craniectomized animals at 650 kHz, a peak pressure ≥ 22.7 MPa for 1 second was needed to reliably create a ventriculostomy. Transcranially at this frequency the ExAblate 4000 was unable to generate the required intensity to fractionate tissue, although cavitation was initiated. At 230 kHz, ventriculostomy was successful through the skull with a peak pressure of 8.8 MPa. CONCLUSIONS: This is the first study to suggest that it is possible to perform a completely noninvasive third ventriculostomy using ultrasound. This may pave the way for future studies and eventually provide an alternative means for the creation of CSF communications in the brain, including perforation of the septum pellucidum or intraventricular membranes.

Enhancing drug delivery for boron neutron capture therapy of brain tumors with focused ultrasound.

BACKGROUND: Glioblastoma is a notoriously difficult tumor to treat because of its relative sanctuary in the brain and infiltrative behavior. Therapies need to penetrate the CNS but avoid collateral tissue injury. Boron neutron capture therapy (BNCT) is a treatment whereby a (10)B-containing drug preferentially accumulates in malignant cells and causes highly localized damage when exposed to epithermal neutron irradiation. Studies have suggested that (10)B-enriched L-4-boronophenylalanine-fructose (BPA-f) complex uptake can be improved by enhancing the permeability of the cerebrovasculature with osmotic agents. We investigated the use of MRI-guided focused ultrasound, in combination with injectable microbubbles, to noninvasively and focally augment the uptake of BPA-f. METHODS: With the use of a 9L gliosarcoma tumor model in Fisher 344 rats, the blood-brain and blood-tumor barriers were disrupted with pulsed ultrasound using a 558 kHz transducer and Definity microbubbles, and BPA-f (250 mg/kg) was delivered intravenously over 2 h. (10)B concentrations were estimated with imaging mass spectrometry and inductively coupled plasma atomic emission spectroscopy. RESULTS: The tumor to brain ratio of (10)B was 6.7 ± 0.5 with focused ultrasound and only 4.1 ± 0.4 in the control group (P < .01), corresponding to a mean tumor [(10)B] of 123 ± 25 ppm and 85 ± 29 ppm, respectively. (10)B uptake in infiltrating clusters treated with ultrasound was 0.86 ± 0.10 times the main tumor concentration, compared with only 0.29 ± 0.08 in controls. CONCLUSIONS: Ultrasound increases the accumulation of (10)B in the main tumor and infiltrating cells. These findings, in combination with the expanding clinical use of focused ultrasound, may offer improvements in BNCT and the treatment of glioblastoma.

Focused ultrasound delivers targeted immune cells to metastatic brain tumors.

Natural killer (NK) cells are cytotoxic lymphocytes involved in innate immunity. NK-92, a human NK cell line, may be targeted to tumor-associated antigens in solid malignancies where it exhibits antitumor efficacy, but its clinical utility for treating brain tumors is limited by an inability to cross the blood-brain barrier (BBB). We investigated the potential for focused ultrasound (FUS) to deliver targeted NK-92 cells to the brain using a model of metastatic breast cancer. HER2-expressing human breast tumor cells were implanted into the brain of nude rats. The NK-92-scFv(FRP5)-zeta cell line expressing a chimeric HER2 antigen receptor was transfected with superparamagnetic iron oxide nanoparticles before intravenous injection, before and following BBB disruption using focused ultrasound (551.5 kHz focused transducer, 0.33 MPa average peak rarefaction pressure) in the presence of a microbubble contrast agent. Baseline and posttreatment 1.5T and 7T MR imaging was done, and histology used to identify NK-92 cells post-mortem. Contrast-enhanced MRI showed reproducible and consistent BBB disruption. 7T MR images obtained at 16 hours posttreatment revealed a significant reduction in signal indicating the presence of iron-loaded NK-92 cells at the tumor site. The average ratio of NK-92 to tumor cells was 1:100 when NK cells were present in the vasculature at the time of sonication, versus 2:1,000 and 1:1,000 when delivered after sonication and without BBB disruption, respectively. Our results offer a preclinical proof-of-concept that FUS can improve the targeting of immune cell therapy of brain metastases.

Proteins involved in regulating bone invasion in skull base meningiomas.

BACKGROUND: Bone invasive skull base meningiomas are a subset of meningiomas that present a unique clinical challenge due to brain and neural structure involvement and limitations in complete surgical resection, resulting in higher recurrence and need for repeat surgery. To date, the pathogenesis of meningioma bone invasion has not been investigated. We investigated immunoexpression of proteins implicated in bone invasion in other tumor types to establish their involvement in meningioma bone invasion. METHODS: Retrospective review of our database identified bone invasive meningiomas operated on at our institution over the past 20 years. Using high-throughput tissue microarray (TMA), we established the expression profile of osteopontin (OPN), matrix metalloproteinase-2 (MMP2), and integrin beta-1 (ITGB1). Differential expression in tumor cell and vasculature was evaluated and comparisons were made between meningioma anatomical locations. RESULTS: MMP2, OPN, and ITGB1 immunoreactivity was cytoplasmic in tumor and/or endothelial cells. Noninvasive transbasal meningiomas exhibited higher vascular endothelial cell MMP2 immunoexpression compared to invasive meningiomas. We found higher expression levels of OPN and ITGB1 in bone invasive transbasal compared to noninvasive meningiomas. Strong vascular ITGB1 expression extending from the endothelium through the media and into the adventitia was found in a subset of meningiomas. CONCLUSIONS: We have demonstrated that key proteins are differentially expressed in bone invasive meningiomas and that the anatomical location of bone invasion is a key determinant of expression pattern of MMP1, OPN, and ITGB1. This data provides initial insights into the pathophysiology of bone invasion in meningiomas and identifies factors that can be pursued as potential therapeutic targets.

Carotid artery angioplasty and stenting for patients less than 70 years-of-age.

BACKGROUND: Recent studies have suggested that carotid artery angioplasty and stenting (CAS) is a safe alternative to carotid endarterectomy (CEA) in average risk patients <70 years of age. We examined a consecutive series of patients who underwent CAS in order to determine the influence of patient age on outcome. METHODS: A retrospective, longitudinal cohort study of consecutive patients who underwent CAS at St. Michael's Hospital, Canada between January 2001 and November 2010 was performed. The outcome measures were 30-day stroke and 30-day composite death, stroke and acute myocardial infarction (MI). Patients were stratified based on age <70 and ≥ 70 years. RESULTS: One hundred and fifty-nine patients underwent 165 CAS procedures. The 30-day risk of stroke was 3.8% while the composite outcome of death/stroke/MI was 8.2%. When stratified by age <70 and ≥ 70 years, the 30-day stroke rate was 0% versus 7.4% (p=0.03), and the composite outcome of death/stroke/MI was 2.6% versus 13.6% (p=0.02), respectively. CONCLUSIONS: Patients <70 years of age undergoing CAS have a low rate of major complications, comparing favourably with historical CEA adverse event rates, and supporting the recent carotid stenosis literature that in the younger population CAS has a similar complication rate compared to CEA.

The use of film dosimetry of the penumbra region to improve the accuracy of intensity modulated radiotherapy.

Accurate measurements of the penumbra region are important for the proper modeling of the radiation beam for linear accelerator-based intensity modulated radiation therapy. The usual data collection technique with a standard ionization chamber artificially broadens the measured beam penumbrae due to volume effects. The larger the chamber, the greater is the spurious increase in penumbra width. This leads to inaccuracies in dose calculations of small fields, including small fields or beam segments used in IMRT. This source of error can be rectified by the use of film dosimetry for penumbra measurements because of its high spatial resolution. The accuracy of IMRT calculations with a pencil beam convolution model in a commercial treatment planning system was examined using commissioning data with and without the benefit of film dosimetry of the beam penumbrae. A set of dose-spread kernels of the pencil beam model was calculated based on commissioning data that included beam profiles gathered with a 0.6-cm-i.d. ionization chamber. A second set of dose-spread kernels was calculated using the same commissioning data with the exception of the penumbrae, which were measured with radiographic film. The average decrease in the measured width of the 80%-20% penumbrae of various square fields of size 3-40 cm, at 5 cm depth in water-equivalent plastic was 0.27 cm. Calculations using the pencil beam model after it was re-commissioned using film dosimetry of the penumbrae gave better agreement with measurements of IMRT fields, including superior reproduction of high dose gradient regions and dose extrema. These results show that accurately measuring the beam penumbrae improves the accuracy of the dose distributions predicted by the treatment planning system and thus is important when commissioning beam models used for IMRT.