Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for Mind metastases. Early clinical trials with SRS proved that tumor Regulate prices are exceptional to total Mind radiotherapy (WBRT) by itself. Therefore, WBRT moreover SRS was widely adopted for individuals by using a confined number of brain metastases (“restricted amount” customarily signifies 1-4). Subsequent trials focused on answering regardless of whether WBRT upfront was needed in the slightest degree. Depending on present-day randomized controlled trials (RCTs) and meta-analyses comparing SRS by yourself to SRS furthermore WBRT, adjuvant WBRT leads to improved intracranial Manage; having said that, in the cost of neurocognitive performing and quality of life. These adverse consequences of WBRT might also negatively impact on survival in younger sufferers. Dependant on the outcomes of those scientific tests, procedure has shifted to SRS on your own in clients which has a confined number of metastases. Furthermore, RCTs are assessing the role of SRS alone in patients with >4 brain metastases. New developments in SRS contain fractionated SRS for big tumors and The combination of SRS with qualified systemic therapies that cross the blood Mind barrier and/or stimulate an immune reaction. We current On this review the current large amount evidence and rationale supporting SRS given that the regular of look after patients with constrained brain metastases, and emerging applications of SRS.
Brain metastases are a significant cause of morbidity and mortality in patients with metastatic cancer, with an incidence of up to 65% during the course of illness [1, 2]. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer . Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. The development of brain metastases was viewed as an oncologic terminal event.
As systemic therapies have become more efficacious in patients with metastatic disease, improved survival rates are now being observed. In addition, the patterns of disease progression are shifting such that the incidence of brain metastases is increasing while extra-cranial disease remains controlled. This phenomena is likely a consequence of the central nervous system (CNS) being a sanctuary site from drug penetration. As a result, the management of brain metastases has become a major focus of research, with the intent to improve intra-cerebral control and decrease neurologic deaths.
Although the purpose of neurosurgery were set up during the 1990s as a way to realize neighborhood Handle and prolong survival, it had been reserved for your minority of patients presenting with a single metastasis and no other condition beyond the brain [4-7]. However missing was a focal ablative non-invasive treatment that could be applied efficiently to some much broader inhabitants of people with brain metastases. This set the stage for the event of stereotactic radiosurgery (SRS). SRS is a focused ablative radiation cure shipped with sub-millimeter precision to your tumor localized in three-dimensions in 1-five fractions.
The focus of this overview is always to summarize The present significant amount proof to make clear the purpose of SRS as best management for sufferers presenting with minimal Mind metastases. Moreover, we provide an outline of the emerging applications of SRS since it proceeds to evolve into a treatment method alternative to WBRT, With all the intent To optimize neurcognitive function and quality of life (QOL).
PATHOPHYSIOLOGY OF BRAIN METASTASES
Circulating tumor cells (CTCs) can disseminate from a Principal tumor mass to variety distant colonies through implantation at an ectopic website, such as the brain [eight-10]. To do so needs CTCs to arrest inside the circulation, extravasate through the bloodstream or lymphatics in the brain, and endure and proliferate [eleven-thirteen]. The whole process of metastatic colonization will involve a immediate interaction of CTCs with endothelial cells and astrocytes from the brain microenvironment. By way of example, CTCs that have arrested within the capillary mattress immediate regional endothelial cells to remodel the adjacent natural environment to advertise tumour mobile progress and invasion [fourteen-16]. Additional, metastatic tumour cells recruit systemic stromal cells, like fibroblasts, to assist with early colonization , and co-opt area stromal cells, which include reactive astrocytes and microglia, to market tissue invasion [15, eighteen, 19]. Astrocytes inside the tumour microenvironment can also Participate in a job in protecting tumour cells from chemotherapy-induced cytotoxicity, through a nonetheless to be outlined mechanism demanding mobile-cell Make contact with [twenty, 21]. Tumour cells, by way of launch of migration inhibitory issue, interleukin-8, and plasminogen activator inhibitor one, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-mobile proliferation in vitro [22-24]. These molecular processes stand for novel and understudied doable therapeutic targets for your treatment of intracranial metastatic ailment.
SRS was at first a really source intense therapy supplied only at specialised centers and indicated only for metastatic clients with a very good existence expectancy. The problem lay in prognosticating patients properly and Consequently the Radiation Therapy Oncology Team (RTOG) recursive partitioning analysis (RPA) [28, 29] was produced. Based upon the patient's Karnofsky Effectiveness Position (KPS), age, status of the key tumor and presence of extracranial disorder, patients have been grouped into course one, two or 3 with corresponding median survivals of 7.one, four.2 and a pair of.three months, respectively. Even though A significant progress at some time, the RPA is now considered overly simplistic as present oncologic determination creating is much more intricate incorporating molecular, histological, scientific and radiographic condition qualities. You can find now far more innovative classification tools, including the diagnosis-precise graded prognostic evaluation (DS-GPA). This technique supplies histology-certain estimates of survival and can separate, for instance, one of the most favorable breast cancer patients having an anticipated survival of 25 months (great KPS and luminal B variety breast most cancers) in the the very least favorable clients with the envisioned survival of 3 months (poor KPS and basal-like breast most cancers) . Even with developments in prognostication of sufferers with Mind metastases, physicians remain largely not able to properly predict extensive-phrase survivors. A analyze inquiring specialist physicians to estimate survival of the 150 individuals with information about most cancers style, amount of Mind metastases, neurological presentation, further-cranial sickness standing, KPS, RPA class, prior full-brain radiotherapy, and synchronous or metachronous presentation, showed that a lot more than forty five% of predictions had been off by in excess of six months and 18% were off by over twelve months . Even further advances in prognostic exams like the “liquid biopsy” (a non-invasive blood test which can detect tumor DNA or RNA fragments or CTCs) are necessary and in advancement . These Incorporate Sophisticated client and tumor unique genomic information into the equation, as a way to realize personalised survival predictions.
Surgical procedures proceeds to become an essential treatment method option for individuals with confined brain metastases. It really is indicated when metastases are huge (>3-four cm), or each time a pathologic diagnosis is required. Additionally, surgical procedure is desired from the presence of major edema requiring extended superior dose dexamethasone, or to potentially reverse neurological deficits. In any other case, The existing proof indicates the efficacy of SRS is adequate to obtain resilient local Command that is definitely corresponding to surgical treatment. Though there are no RCTs directly evaluating The 2, numerous trials have already been noted evaluating SRS to SRS with WBRT (Table one), which is A serious concentration of this evaluation.
HR: hazard ratio, WHO: planet health Group, KPS: Karnofsky functionality status, WBRT: complete Mind radiotherapy, SRS: stereotactic radiosurgery, yr: yr, mos: months, NS: not significant, NR: not recorded, NA: not relevant, HVLT-R: Hopkins Verbal Studying Take a look at revised.
Patients from the observation team had both surgical procedure by yourself or SRS by itself. Practical result wasn't analyzed individually by surgical treatment or SRS by yourself.
The first RCTs assessing SRS mimicked the look of your Preliminary surgical experiments for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific studies verified that SRS enhanced regional Manage, and also a survival advantage in chosen clients with only one Mind metastasis was shown. These trials have been successful in shifting the paradigm from WBRT alone to WBRT additionally SRS for clients presenting with minimal brain metastases and an excellent performance status.
The following number of clinical trials were being meant to answer if WBRT was in any respect needed, and when compared SRS by itself to SRS with adjuvant WBRT. A few RCTs are claimed in individuals presenting with around 4 metastases [35-37] as well as a forth in abstract kind . Aoyama et al. documented the main RCT, randomizing 132 patients to SRS alone (sixty five sufferers) or WBRT additionally SRS (67 individuals). The main endpoint was brain tumor recurrence. Even though the one-12 months neighborhood Handle price was higher with SRS by itself at seventy three%, added local control with adjuvant WBRT at 89%, was noticed. Additionally, adjuvant WBRT diminished the rate of distant intra-cranial relapse at one 12 months from 64% to forty two%. On the other hand, these gains in intra-cranial Management did not translate into a benefit with respect to cognition, based on Mini-Psychological Status Test (MMSE), nor survival. Additionally, individuals experienced better costs of necrosis and leukoencephalopathy within the WBRT arm. The demo was Hence effective in furnishing the 1st degree one evidence to explain the relative affect of SRS alone vs . SRS with WBRT.
As opposed to the traditional endpoint of survival or intra-cranial Regulate, Chang et al. took a special approach and evaluated neurocognition as the key endpoint. Importantly, the validated Hopkins Verbal Studying Exam-Revised (HVLT-R) assessment tool, was accustomed to evaluate neurocognitive working versus the MMSE which is not a delicate test for neurocognition . Fifty-8 individuals ended up randomized to SRS alone (n = 30) or WBRT as well as SRS (n = 28). Early stopping regulations were invoked with the interim Assessment, along with the analyze concluded that SRS alone was favored with respect to your chance of neurocognitive drop at 4 months write-up-therapy. This reward was understood Regardless of the 1 12 months nearby Handle and distant Mind Regulate rates favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Handle outcomes had been In step with the final results from the Aoyama review, but what wasn't anticipated was the survival gain noticed in the SRS alone arm. The median survival was 15 months inside the SRS on your own arm and 6 months inside the SRS with WBRT arm (p = 0.003). This survival final result brought about the demo to bear sizeable scrutiny with lots of arguing which the survival edge for SRS by yourself was a results of imbalances amongst the two arms, as additional sufferers dealt with with SRS moreover WBRT experienced increased further-cranial (more liver and adrenal metastases) and intracranial condition (much larger volume of brain metastases) .
The eu Business for Analysis and Remedy of Cancer (EORTC) also took another solution with their Key endpoint specializing in practical independence . They used, nonetheless, the more clinically common Entire world Overall health Business (WHO) overall performance status (PS) scale, and calculated time to WHO PS deterioration to a lot more than 2. This RCT concluded the addition of WBRT didn't Increase the median period of practical independence (SRS by itself: ten.0 months vs SRS plus WBRT: nine.5 months). The secondary consequence of QOL, measured Together with the validated EORTC-QLQC30 Resource, was observed to get even worse in clients who acquired WBRT in quite a few QOL domains . Importantly, these final results have been observed Inspite of adjuvant WBRT minimizing the 2-yr regional failure amount (31% to 19%), distant Mind failure (forty eight% to 33%), and the need for salvage therapies (fifty one% vs. sixteen%). No important discrepancies in survival ended up noticed albeit the demo was not driven to handle survival.
These four trials have set up the role of SRS alone because the regular of care in individuals by using a constrained variety of brain metastases, but they've not been made to Assess the impact of WBRT on Total survival.
The inclusion requirements throughout the RCTs evaluating SRS by itself to SRS moreover WBRT ended up related (Desk 1), nonetheless, the main endpoints were completely different, and no demo was created to Assess General survival. To raised make clear the outcomes of nearby Handle, distant brain Command and survival, a meta-Investigation (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They reported hazard ratios for area Handle and distant brain Manage favoring adjuvant WBRT at two.61 and 2.fifteen, respectively, but have been unable to mix the survival final results because of limits in the way in which the info ended up noted. Sahgal et al. then executed a person individual data (IPD) MAL of a similar RCTs aimed toward assessing remedy results on survival, and accomplish sub-team analyses . With respect to All round survival, a treatment result was noticed favoring SRS on your own in clients ≤50 many years. In more mature individuals, no survival downside was noticed with SRS by yourself. With regard to distant brain Command, a procedure result was also observed with risk reductions in the event of new Mind metastases in older individuals treated with WBRT, but no gain while in the more youthful people (≤50 several years) taken care of with WBRT. As predicted, area control was improved with supplemental WBRT in all age teams. The concordance between a survival detriment and insufficient benefit in distant brain Management despite remedy with WBRT, during the younger sufferers, led the authors to hypothesize that publicity for the acknowledged harms of WBRT (talked about intimately underneath) may perhaps negatively impact individual survival. This speculation is provocative, and remains to become validated.
One of the most convincing demo style to verify the adverse results of WBRT is usually to randomize clients without visualized brain metastases to observation or WBRT. This has become performed in scientific tests analyzing prophylactic cranial irradiation (PCI) in both equally modest cell lung cancer (SCLC) [44, 45] and non-tiny cell lung cancer (NSCLC) [46, 47]. PCI, not dissimilar towards the addition of WBRT to SRS, has long been revealed to lessen the potential risk of intra-cranial relapse. Having said that, this attain comes at the expense of a negative impact on QOL. Such as, sizeable improves in exhaustion, appetite loss, nausea and vomiting and leg weak spot ended up observed in patients with in depth stage SCLC at 6 and 12 months article PCI . Additionally, in regionally Sophisticated NSCLC sufferers, a higher drop in HVLT-R actions of instant and delayed remember have been observed even as many as 1 12 months publish-PCI . With regard to extended-phrase adverse effects of WBRT, a devastating consequence is usually the development of leukoencephalopathy. In truth, radiation-induced dementia charges have been noted to be as substantial as eleven% in extended-term Mind metastases survivors (>12 months) after WBRT , and documented being higher in people dealt with with WBRT and SRS as opposed to SRS by yourself [35, 50].
Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, much like the pathophysiology inherent to Parkinson's dementia , has actually been postulated as 1 system conveying the adverse neurocognitive outcomes of WBRT. As a technique to mitigate the danger, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a significant randomized placebo controlled trial involving 554 clients. At 24 months, 64% of individuals without the need of memantine and 54% with memantine had cognitive operate failure according to assessment With all the HVLT-R. Although the Key endpoint did not reach significance because of the substantial attrition fee, there was a strong pattern (p = 0.059) supporting memantine procedure. Evaluation of secondary endpoints showed that memantine significantly prolonged some time to cognitive drop and yielded top-quality benefits for govt purpose, processing pace and delayed recognition at 24 months. In the end, these knowledge present nearly all clients suffer cognitive dysfunction with WBRT, and that pharmacologic approaches to mitigate the risk by focusing on equivalent pathways linked to Parkinson's dementia can be worthy of further more investigation.
Further insight into WBRTs’ system of injury has originate from a latest Stage two demo assessing hippocampal avoidance WBRT (HA-WBRT). Subtle modern day radiation technologies was placed on Restrict dose publicity towards the hippocampus to not more than 80% from the prescribed 30Gy in 10 fractions . This non-randomized phase two trial measured neurocognitive function using the HVLT-R, and in comparison outcomes to historic controls addressed with common WBRT from a RTOG demo database. HA-WBRT resulted inside of a 7% decrease within the mean relative HVLT-R delayed remember, which was appreciably decreased than the 30% decrease received from historic controls. Whilst this study is encouraging with regard to limiting toxicity from WBRT, a randomized demo is needed to completely fully grasp the therapeutic value In this particular technologically intricate type of WBRT.
In 2012, the American Culture for Therapeutic Radiation Oncology published an evidence-dependent guideline that has a series of recommendations to the administration of Mind metastases . Since that point, the proof from scientific trials has made it very clear that the preferred up-front radiation treatment choice for patients with limited brain metastases is SRS by yourself. Actually, the American Culture for Radiation Oncology (ASTRO) has just lately built a definitive advice in their Opt for Sensibly marketing campaign and advise not to routinely incorporate adjuvant WBRT to SRS for limited Mind metastases . Additionally, the not long ago revised Countrywide Detailed Most cancers Network (NCCN) tips now guidance SRS by itself even past People sufferers with “restricted” metastases, and do not specify an upper Restrict for the number of metastases . The latter is ahead pondering; metastasis counting is probably going irrelevant and what matters is in any other case the suitability on the client for SRS [57-59]. Hence, the onus is not on individuals who treat with SRS on your own to justify the omission of WBRT; fairly it's on those that take care of with WBRT in a SRS acceptable patient.
WHAT ABOUT THE Individual WITH A lot more EXTENSIVE BRAIN METASTASES?
Past specialized restrictions in SRS know-how limited the appliance of SRS to sufferers with only a few Mind metastases. Developments in mounted frame and frameless SRS systems now make it possible for treatment of diverse metastases in only one session [60, 61].
The first big prospective review evaluating SRS by yourself for multiple Mind metastases was reported in 2014 . Somewhere around 1200 clients with one-ten SRS eligible metastases were taken care of with SRS on your own using Gamma Knife engineering (Elekta AB, Stockholm, Sweden). The Examination was broken down according to the 455 individuals with one metastases, 531 people with two to four metastases and 208 with 5 to ten metastases. Survival, distant Mind relapse, and local Manage prices were not drastically diverse in individuals with 5 to 10 metastases vs . two to 4 metastases. These results are of major importance because they challenge the dogma that clients with in excess of 4 metastases won't take advantage of SRS alone as a consequence of shortened survival and can inevitably fail in other places while in the brain. Hence, this trial provides proof to assist SRS on your own in good KPS clients with up to ten metastases, supplied the person tumor volume is not more than ten mL and < 3 cm in longest diameter, and the full cumulative volume of all tumors in the brain is ≤fifteen mL. Numerous randomized trials are now assessing WBRT by yourself versus SRS by yourself in similar sufferers, and in enhancement is actually a demo analyzing SRS alone compared to WBRT moreover SRS Improve in clients with ten to twenty metastases.
Qualified THERAPIES IN COMBINATION WITH BRAIN RADIATION
When compared with classic chemotherapy, several specific agents have better penetration through the blood-brain barrier and produce reaction in the brain. Dramatic advancements in sickness Manage are being observed even for histologies which include melanoma which were Formerly viewed as not merely radioresistant but chemoresistant. Table 2 [63-75] summarizes chosen medical trials assessing the efficacy of specific therapies by itself or in combination with radiation therapy while in the procedure of Mind metastases. Even though, with targeted therapies on your own some amazing response charges are observed, development-totally free-survival (PFS) rates are often small (< 8 months). These outcomes are usually not as well dissimilar from what continues to be obtained with WBRT on your own [33, fifty three]. The exception is in EGFR mutant non-compact cell lung cancers dealt with with a tyrosine kinase inhibitor. In the study by Wu et al. for example, the median PFS was >15 months in EGFR mutant tumours treated with erlotinib.
Desk two. Summary of picked trials of specific therapy on your own or together with Mind radiation with the therapy of brain metastases.
PFS: development absolutely free survival, nPFS: neurologic progression totally free survival, OS: overall survival, NSCLC: non-small cell lung most cancers, EGFR: epidermal progress element receptor, WBRT: whole Mind radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not important, NR: not recorded, NA: not relevant
Number of trials have put together focused therapies with radiation, and these are also summarized in Table two. Although, randomized evidence is still missing, There's suggestion from retrospective details that the combination could produce improved results. In the retrospective Examination of the future cohort of individuals taken care of with SRS for melanoma Mind metastases, the team that received ipilimumab experienced a noticeably for a longer period median survival (21.3 vs four.9 months) . Nevertheless, caution ought to be exercised as concurrent specific therapy and radiation treatment might not be as innocuous as Beforehand thought. The RCT evaluating SRS with WBRT on your own, compared to together with erlotinib or temozlomide, reported appreciably bigger Quality three to 5 toxicity rates in the combination arm; extra importantly, survival was even worse even though it did not attain statistical importance . An important limitation of this analyze was the focused therapy wasn't biomarker-pushed and should partly account for that inadequate survival observed. Caution also has to be taken as You can find evidence that Mind metastases and first tumors may well harbor unique genetic alterations. In a single examine of 86 matched brain metastases and first tumors, clinically insightful alterations in 53% of Mind metastases weren't detected in the principal tumor .
The emerging evidence implies that specific therapies will Engage in an important purpose inside the cure of Mind metastases. We postulate that Whilst qualified agents might not be successful in controlling gross ailment inside the brain, They could be powerful in handling micro-metastatic sickness from the brain. Therefore, a sensible technique might be to mix focused therapies with SRS alone, beating the limitation of SRS in addressing micrometastatic ailment within the Mind and leading to much less distant brain failures. The subsequent couple of years will yield interesting information as There are a variety of trials in development using this system.
INNOVATIONS IN SRS - INDICATIONS AND Apps
As tumors get bigger, SRS dosing is counter-intuitively decreased with respect to tumor Management, to maintain basic safety to the traditional brain tissue; usually, the risk of radiation necrosis will become prohibitive . Subsequently, tumors better than 4 cm have commonly been excluded from single portion SRS. Should the tumors are non-operable, then these individuals are handled with WBRT Irrespective of its lousy neighborhood Command. The appearance of non-invasive head immobilization equipment, on-board image-direction systems and Innovative radiation supply application has produce the exercise of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, seventy eight]. Primarily by fractionating, the safety profile with respect to the conventional Mind tissue toxicity is improved, and the entire tumor dose might be escalated these types of that doses like 24Gy in 3 fractions and 30-40Gy in 5 fractions at the moment are commonplace. A person exciting retrospective collection claimed higher prices of Handle and decrease costs of toxicities with hypofractionated SRT (36Gy in six fractions) as compared to single portion SRS . Nevertheless, this apply continues to be in its infancy and we're needing a RCT to find out whether single fraction SRS should be reserved just for compact metastases (e.g. one-two centimeters), as the information propose worse nearby control for larger sized tumors [80, eighty one]. Determine one is undoubtedly an example of the efficacy of hypofractionated SRT in a big tumor. This affected person would have if not been excluded from one portion SRS and addressed with WBRT upfront (plus or minus a SRS Strengthen), or operated upon.
A. MRI of three.6cm appropriate cerebellar metastases from lung cancer. B. Hugely conformal therapy system With all the a hundred% (green line) and 80% (blue line) isodose traces wrapping tightly throughout the gross tumour (pink colorwash), and scheduling concentrate on quantity (orange colorwash). The brainstem (blue colorwash) is spared from significant dose. (B) MRI two months post completion of radiation (30Gy in five fractions). C. Complete resolution of your tumour at one 12 months.
In publish-operative individuals, the practice of routinely managing with WBRT is likewise getting out-of-date. There exists rising use of SRS for the publish-operative surgical cavity as a way to spare individuals in the adverse effects of WBRT and to further improve community Manage [eighty two-ninety three]. On the Sunnybrook Odette Most cancers Heart, We have now adopted hypofractionated SRT as our regular of treatment, delivering thirty-35Gy in five fractions to your publish-operative tumor mattress . Fractionation has the benefit of reducing the adverse results to the traditional tissues, given that the targets are usually significant and irregularly formed. Our initial effects have shown 1 year regional Command costs of ∼80% in sufferers which have either recurred and re-operated upon immediately after prior WBRT, or in individuals without having prior background of WBRT and operated upon. There is an ongoing examine assessing write-up-surgical cavity single fraction SRS by yourself vs . WBRT and could be a practice-defining research .
In the last various many years, scientific trials have educated us about the right management of patients with brain metastases. To begin with, SRS was regarded as an adjunct to WBRT in selected individuals presenting using a constrained amount of Mind metastases. On the other hand, the job of WBRT has since been questioned as we have learned of its prospective to adversely have an effect on QOL and neurocognition. Therefore, SRS on your own has emerged as the current regular of care with Degree 1 evidence to assistance its apply. Present investigation is focused on the evaluation of broader programs of SRS to many medical predicaments that were historically considered complete indications for WBRT. One example is, SRS by yourself is at present becoming evaluated within the treatment of five or even more brain metastases, and in publish-operative people. A brand new period of trials can be emerging investigating the influence of qualified therapies concurrent with SRS.
Clinical trials in clients with Mind metastases are A significant challenge as summarized by the the latest studies in the Response Evaluation in Neuro-Oncology (RANO) brain metastases group [ninety five, 96]. They advocate for trial design and style and response evaluation that trials be tumor or biomarker unique, that evaluation be depending on distinction-Increased MRI, that baseline and repeated neurocognitive and QOL testing be carried out with validated and sensitive devices, that stratification be determined by excess-cranial sickness status, Which correct timing be regarded as with regards to endpoint screening. Ultimately, the oncology Local community has regarded that the development of Mind metastases is no more the terminal oncologic event from the previous.
CONFLICTS OF Desire, Fiscal DISCLOSURES
Dr. Arjun Sahgal has received honorarium from preceding instructional seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also received investigation grants from Elekta AB, otherwise there won't be any conflicts of desire to disclose.