Trustworthy Direction by SRS Financials

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Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor Regulate prices are top-quality to complete Mind radiotherapy (WBRT) by itself. Due to this fact, WBRT plus SRS was broadly adopted for patients by using a confined number of brain metastases (“restricted variety” customarily suggests one-four). Subsequent trials centered on answering whether WBRT upfront was needed in the slightest degree. According to latest randomized controlled trials (RCTs) and meta-analyses comparing SRS on your own to SRS furthermore WBRT, adjuvant WBRT ends in far better intracranial Command; nonetheless, for the expenditure of neurocognitive performing and Standard of living. These adverse consequences of WBRT may also negatively influence on survival in more youthful individuals. Dependant on the outcomes of those studies, treatment method has shifted to SRS by itself in clients by using a confined number of metastases. Also, RCTs are evaluating the function of SRS on your own in clients with >four brain metastases. New developments in SRS consist of fractionated SRS for large tumors and The combination of SRS with focused systemic therapies that cross the blood brain barrier and/or stimulate an immune reaction. We current With this overview The present large degree evidence and rationale supporting SRS because the standard of look after sufferers with confined Mind 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.

Even though the purpose of neurosurgery had been set up in the nineteen nineties as a means to attain local Command and extend survival, it had been reserved to the minority of patients presenting with only one metastasis and no other ailment beyond the Mind [4-seven]. Nevertheless lacking was a focal ablative non-invasive procedure that can be used proficiently to a Substantially broader population of sufferers with Mind metastases. This set the phase for the development of stereotactic radiosurgery (SRS). SRS is usually a targeted ablative radiation cure delivered with sub-millimeter precision to your tumor localized in three-Proportions in one-5 fractions.

The main focus of the assessment will be to summarize the current large amount evidence to explain the function of SRS as exceptional administration for sufferers presenting with confined Mind metastases. Moreover, we provide an summary on the emerging programs of SRS since it continues to evolve right into a cure different to WBRT, Together with the intent to maximize neurcognitive functionality and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from the Major tumor mass to variety distant colonies by way of implantation at an ectopic website, including the Mind [8-10]. To do so requires CTCs to arrest within the circulation, extravasate within the bloodstream or lymphatics to the Mind, and survive and proliferate [11-thirteen]. The process of metastatic colonization will involve a direct conversation of CTCs with endothelial cells and astrocytes in the brain microenvironment. For example, CTCs that have arrested throughout the capillary bed immediate regional endothelial cells to remodel the adjacent ecosystem to advertise tumour mobile expansion and invasion [fourteen-sixteen]. Further more, metastatic tumour cells recruit systemic stromal cells, for instance fibroblasts, to help with early colonization , and co-decide area stromal cells, like reactive astrocytes and microglia, to market tissue invasion [fifteen, 18, 19]. Astrocytes inside the tumour microenvironment might also Engage in a task in defending tumour cells from chemotherapy-induced cytotoxicity, through a however for being outlined mechanism requiring mobile-cell Make contact with [twenty, 21]. Tumour cells, by means of launch of migration inhibitory issue, interleukin-eight, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-mobile proliferation in vitro [22-24]. These molecular processes characterize novel and understudied achievable therapeutic targets to the therapy of intracranial metastatic condition.

SRS was initially an exceedingly source intensive therapy made available only at specialized centers and indicated just for metastatic patients with a superb life expectancy. The problem lay in prognosticating clients efficiently and Consequently the Radiation Therapy Oncology Team (RTOG) recursive partitioning Assessment (RPA) [28, 29] was produced. Dependant on the affected person's Karnofsky Effectiveness Position (KPS), age, position of the primary tumor and presence of extracranial condition, sufferers ended up grouped into course one, two or 3 with corresponding median survivals of 7.one, four.two and a couple of.three months, respectively. Whilst An important improvement at time, the RPA is currently deemed overly simplistic as recent oncologic final decision earning is much more complicated incorporating molecular, histological, clinical and radiographic illness qualities. You'll find now much more advanced classification tools, such as the analysis-unique graded prognostic evaluation (DS-GPA). This technique offers histology-specific estimates of survival and will separate, as an example, one of the most favorable breast cancer people having an anticipated survival of 25 months (great KPS and luminal B form breast cancer) in the the very least favorable sufferers by having an anticipated survival of three months (bad KPS and basal-like breast cancer) . Even with innovations in prognostication of people with Mind metastases, medical professionals remain mainly struggling to properly forecast very long-time period survivors. A study inquiring expert physicians to estimate survival of the 150 people with information about cancer kind, number of brain metastases, neurological presentation, additional-cranial disease position, KPS, RPA class, prior full-brain radiotherapy, and synchronous or metachronous presentation, confirmed that over 45% of predictions were being off by over six months and eighteen% have been off by over 12 months . Further more advancements in prognostic exams such as the “liquid biopsy” (a non-invasive blood take a look at that could detect tumor DNA or RNA fragments or CTCs) are necessary and in enhancement . These Blend Highly developed client and tumor certain genomic information in to the equation, in order to realize personalized survival predictions.

Surgery carries on to be a significant treatment choice for patients with minimal brain metastases. It can be indicated when metastases are big (>three-4 cm), or each time a pathologic analysis is needed. Furthermore, surgical procedures is desired in the existence of significant edema requiring prolonged superior dose dexamethasone, or to probably reverse neurological deficits. Usually, The present evidence indicates which the efficacy of SRS is sufficient to realize long lasting regional Command that's comparable to medical procedures. Although there aren't any RCTs specifically evaluating the two, many trials are reported comparing SRS to SRS with WBRT (Desk 1), and is a major focus of the overview.

HR: hazard ratio, WHO: planet wellness organization, KPS: Karnofsky general performance standing, WBRT: complete brain radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not significant, NR: not recorded, NA: not relevant, HVLT-R: Hopkins Verbal Learning Examination revised.

Patients in the observation group experienced either operation on your own or SRS by yourself. Useful final result wasn't analyzed independently by medical procedures or SRS on your own.

The initial RCTs evaluating SRS mimicked the look with the initial surgical studies for Mind metastases, and evaluated the addition of SRS to WBRT [33, 34]. These reports verified that SRS enhanced neighborhood Regulate, along with a survival benefit in chosen individuals with just one brain metastasis was revealed. These trials were prosperous in shifting the paradigm from WBRT by itself to WBRT plus SRS for individuals presenting with constrained Mind metastases and a fantastic performance status.

The next series of clinical trials had been intended to solution if WBRT was in any respect important, and as opposed SRS by itself to SRS with adjuvant WBRT. A few RCTs are actually reported in patients presenting with as much as 4 metastases [35-37] as well as a forth in abstract type . Aoyama et al. noted the primary RCT, randomizing 132 clients to SRS by yourself (65 people) or WBRT additionally SRS (67 people). The primary endpoint was Mind tumor recurrence. Even though the 1-year local Command level was high with SRS by itself at seventy three%, further neighborhood Handle with adjuvant WBRT at 89%, was observed. Also, adjuvant WBRT lessened the speed of distant intra-cranial relapse at one 12 months from 64% to forty two%. Having said that, these gains in intra-cranial Regulate did not translate into an advantage with regard to cognition, depending on Mini-Mental Standing Exam (MMSE), nor survival. What's more, clients had bigger costs of necrosis and leukoencephalopathy from the WBRT arm. The trial was thus thriving in giving the initial amount 1 proof to clarify the relative effects of SRS by yourself versus SRS with WBRT.

In lieu of the traditional endpoint of survival or intra-cranial Regulate, Chang et al. took a special solution and evaluated neurocognition as the principal endpoint. Importantly, the validated Hopkins Verbal Learning Exam-Revised (HVLT-R) evaluation tool, was accustomed to measure neurocognitive performing instead of the MMSE which isn't a delicate check for neurocognition . Fifty-8 people have been randomized to SRS by itself (n = thirty) or WBRT furthermore SRS (n = 28). Early stopping procedures had been invoked for the interim Investigation, and the examine concluded that SRS by itself was favored with regard towards the likelihood of neurocognitive decrease at four months write-up-remedy. This gain was understood Regardless of the one calendar year local Handle and distant Mind Manage costs favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Command results have been in keeping with the effects with the Aoyama examine, but what was not envisioned was the survival benefit observed during the SRS by yourself arm. The median survival was 15 months during the SRS by yourself arm and 6 months during the SRS with WBRT arm (p = 0.003). This survival result prompted the demo to undergo sizeable scrutiny with quite a few arguing the survival gain for SRS by yourself was a results of imbalances amongst the two arms, as far more individuals addressed with SRS in addition WBRT had increased additional-cranial (additional liver and adrenal metastases) and intracranial condition (larger sized volume of Mind metastases) .

The European Corporation for Analysis and Procedure of Cancer (EORTC) also took a special tactic with their Main endpoint concentrating on functional independence . They utilized, having said that, the more clinically acquainted Earth Well being Group (WHO) performance standing (PS) scale, and calculated some time to WHO PS deterioration to greater than 2. This RCT concluded the addition of WBRT didn't Increase the median duration of useful independence (SRS by itself: ten.0 months vs SRS plus WBRT: 9.five months). The secondary consequence of QOL, calculated With all the validated EORTC-QLQC30 Resource, was noticed to become worse in sufferers who gained WBRT in quite a few QOL domains . Importantly, these effects ended up observed In spite of adjuvant WBRT reducing the two-yr neighborhood failure price (31% to 19%), distant brain failure (forty eight% to 33%), and the necessity for salvage therapies (51% vs. sixteen%). No major differences in survival ended up observed albeit the trial wasn't powered to handle survival.

These 4 trials have set up the job of SRS on your own as being the standard of care in clients with a limited variety of Mind metastases, but they've not been intended to evaluate the effect of WBRT on Over-all survival.

The inclusion criteria throughout the RCTs assessing SRS by yourself to SRS moreover WBRT had been related (Desk one), nevertheless, the main endpoints ended up wholly different, and no demo was built to evaluate General survival. To better clarify the outcomes of nearby Handle, distant brain Management and survival, a meta-Evaluation (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They documented hazard ratios for regional Management and distant brain Management favoring adjuvant WBRT at two.61 and a pair of.15, respectively, but had been not able to combine the survival outcomes because of restrictions in the way in which the data were reported. Sahgal et al. then executed somebody affected individual facts (IPD) MAL of a similar RCTs directed at evaluating treatment effects on survival, and conduct sub-team analyses . With respect to In general survival, a therapy effect was noticed favoring SRS by yourself in people ≤fifty several years. In older patients, no survival downside was observed with SRS by itself. With regard to distant brain control, a cure influence was also observed with risk reductions in the event of latest brain metastases in older individuals treated with WBRT, but no profit from the youthful individuals (≤fifty yrs) taken care of with WBRT. As anticipated, local Handle was enhanced with more WBRT in all age teams. The concordance between a survival detriment and insufficient profit in distant brain control Inspite of treatment method with WBRT, during the more youthful people, led the authors to hypothesize that exposure to your identified harms of WBRT (discussed in detail below) may possibly negatively impact client survival. This speculation is provocative, and remains being validated.

By far the most convincing demo layout to substantiate the adverse results of WBRT should be to randomize individuals without visualized brain metastases to observation or WBRT. This has become done in scientific studies assessing prophylactic cranial irradiation (PCI) in both of those little cell lung most cancers (SCLC) [44, 45] and non-smaller mobile lung cancer (NSCLC) [46, 47]. PCI, not dissimilar on the addition of WBRT to SRS, has long been shown to scale back the potential risk of intra-cranial relapse. Having said that, this acquire comes at the cost of a unfavorable impact on QOL. One example is, major will increase in exhaustion, urge for food decline, nausea and vomiting and leg weak spot have been observed in clients with intensive phase SCLC at six and 12 months submit PCI . Moreover, in domestically Innovative NSCLC clients, a increased decline in HVLT-R actions of instant and delayed remember have been noticed even around one 12 months post-PCI . With regard to lengthier-time period adverse results of WBRT, a devastating consequence is usually the development of leukoencephalopathy. In truth, radiation-induced dementia costs happen to be described to become as superior as 11% in lengthy-expression Mind metastases survivors (>12 months) immediately after WBRT , and noted being better in clients treated with WBRT and SRS in contrast to SRS alone [35, 50].

Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, similar to the pathophysiology inherent to Parkinson's dementia , has become postulated as one mechanism outlining the adverse neurocognitive consequences of WBRT. As being a strategy to mitigate the chance, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a large randomized placebo controlled trial involving 554 people. At 24 months, sixty four% of clients devoid of memantine and fifty four% with memantine experienced cognitive operate failure depending on assessment Using the HVLT-R. Although the Most important endpoint didn't get to significance as a result of high attrition price, there was a powerful craze (p = 0.059) supporting memantine procedure. Examination of secondary endpoints showed that memantine significantly extended time to cognitive decline and yielded superior effects for government perform, processing velocity and delayed recognition at 24 months. Eventually, these information show many patients put up with cognitive dysfunction with WBRT, and that pharmacologic techniques to mitigate the chance by focusing on comparable pathways linked to Parkinson's dementia could be worthy of additional investigation.

Further more insight into WBRTs’ system of harm has originate from a modern Phase two trial analyzing hippocampal avoidance WBRT (HA-WBRT). Refined modern radiation know-how was applied to Restrict dose exposure to your hippocampus to no more than eighty% from the prescribed 30Gy in ten fractions . This non-randomized section 2 demo calculated neurocognitive purpose using the HVLT-R, and in contrast results to historic controls treated with typical WBRT from the RTOG trial database. HA-WBRT resulted in a 7% drop within the necessarily mean relative HVLT-R delayed recall, which was drastically lessen compared to thirty% drop obtained from historic controls. While this study is encouraging when it comes to limiting toxicity from WBRT, a randomized demo is necessary to completely comprehend the therapeutic price On this technologically elaborate sort of WBRT.

In 2012, the American Society for Therapeutic Radiation Oncology printed an proof-centered guideline having a number of recommendations over the administration of Mind metastases . Since that point, the evidence from clinical trials has created it obvious that the preferred up-front radiation treatment selection for sufferers with restricted Mind metastases is SRS on your own. The truth is, the American Modern society for Radiation Oncology (ASTRO) has recently made a definitive recommendation in their Pick out Properly campaign and advise to not routinely insert adjuvant WBRT to SRS for constrained Mind metastases . Also, the recently revised Nationwide Comprehensive Cancer Community (NCCN) suggestions now assistance SRS by yourself even beyond All those individuals with “minimal” metastases, and do not specify an upper limit for the quantity of metastases . The latter is ahead pondering; metastasis counting is probably going irrelevant and what matters is in any other case the suitability of your affected person for SRS [fifty seven-fifty nine]. As a result, the onus is now not on those that treat with SRS by itself to justify the omission of WBRT; relatively it really is on people that treat with WBRT within a SRS suited affected individual.

How about THE Affected individual WITH Much more Comprehensive Mind METASTASES?

Former technical limitations in SRS technology limited the application of SRS to patients with only a few brain metastases. Breakthroughs in mounted body and frameless SRS systems now permit remedy of diverse metastases in a single session [60, sixty one].

The main major prospective research evaluating SRS on your own for several brain metastases was documented in 2014 . About 1200 clients with one-10 SRS eligible metastases had been treated with SRS alone utilizing Gamma Knife know-how (Elekta AB, Stockholm, Sweden). The Evaluation was broken down in accordance with the 455 clients with one metastases, 531 sufferers with 2 to 4 metastases and 208 with 5 to ten metastases. Survival, distant brain relapse, and local Command fees weren't noticeably distinct in individuals with five to ten metastases as opposed to two to 4 metastases. These outcomes are of key importance since they problem the dogma that people with much more than 4 metastases will never get pleasure from SRS on your own because of shortened survival and may inevitably fail elsewhere from the brain. For that reason, this trial offers proof to aid SRS by yourself in great KPS people with approximately 10 metastases, furnished the individual tumor quantity is not more than 10 mL and < 3 cm in longest diameter, and the total cumulative volume of all tumors in the brain is ≤15 mL. A number of randomized trials are currently analyzing WBRT by itself versus SRS alone in related clients, As well as in development is really a trial evaluating SRS by itself as opposed to WBRT additionally SRS Improve in people with ten to twenty metastases.

TARGETED THERAPIES Together WITH BRAIN RADIATION

In comparison with classic chemotherapy, various focused agents have increased penetration from the blood-Mind barrier and generate response inside the brain. Extraordinary enhancements in disease Manage are being noticed even for histologies which include melanoma that were Beforehand deemed not merely radioresistant but chemoresistant. Table two [sixty three-75] summarizes selected scientific trials analyzing the efficacy of specific therapies alone or together with radiation therapy during the procedure of Mind metastases. Despite the fact that, with specific therapies on your own some remarkable response rates are noticed, development-absolutely free-survival (PFS) costs are frequently short (< eight months). These benefits are not too dissimilar from what has long been attained with WBRT alone [33, fifty three]. The exception is in EGFR mutant non-little mobile lung cancers treated which has a tyrosine kinase inhibitor. While in the research by Wu et al. for example, the median PFS was >15 months in EGFR mutant tumours handled with erlotinib.

Table two. Summary of selected trials of qualified therapy alone or together with Mind radiation for the therapy of brain metastases.

PFS: development totally free survival, nPFS: neurologic progression no cost survival, OS: General survival, NSCLC: non-smaller mobile lung cancer, EGFR: epidermal advancement aspect receptor, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not considerable, NR: not recorded, NA: not relevant

Couple trials have put together targeted therapies with radiation, and they're also summarized in Desk two. Though, randomized proof remains lacking, There is certainly recommendation from retrospective facts that The mix might result in improved outcomes. Within the retrospective Examination of the future cohort of people dealt with with SRS for melanoma Mind metastases, the team that acquired ipilimumab experienced a noticeably longer median survival (21.three vs four.9 months) . On the other hand, caution has to be exercised as concurrent specific therapy and radiation therapy may not be as innocuous as previously thought. The RCT analyzing SRS with WBRT on your own, compared to in combination with erlotinib or temozlomide, reported significantly greater Quality 3 to 5 toxicity fees in The mix arm; additional importantly, survival was even worse although it didn't arrive at statistical importance . A big limitation of this review was the qualified therapy wasn't biomarker-driven and may partly account for your poor survival observed. Warning also needs to be taken as there is proof that brain metastases and primary tumors may harbor distinctive genetic alterations. In one analyze of 86 matched Mind metastases and primary tumors, clinically informative alterations in fifty three% of brain metastases weren't detected in the principal tumor .

The emerging proof implies that focused therapies will play a significant job while in the cure of brain metastases. We postulate that Despite the fact that focused brokers might not be helpful in controlling gross disease from the brain, They might be efficient in running micro-metastatic condition during the brain. For that reason, a logical approach could possibly be to combine specific therapies with SRS by itself, conquering the limitation of SRS in addressing micrometastatic sickness while in the Mind and leading to less distant brain failures. The following several years will generate fascinating info as There are a selection of trials in development employing this method.

Improvements IN SRS - INDICATIONS AND Apps

As tumors get larger, SRS dosing is counter-intuitively reduced with regard to tumor control, to maintain safety to the conventional Mind tissue; or else, the chance of radiation necrosis results in being prohibitive . Consequently, tumors better than four cm have generally been excluded from one portion SRS. If the tumors are non-operable, then these sufferers are actually treated with WBRT In spite of its lousy area Regulate. The appearance of non-invasive head immobilization devices, on-board image-assistance devices and advanced radiation delivery software program has lead to the apply of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, seventy eight]. Essentially by fractionating, the protection profile with respect to the traditional Mind tissue toxicity is improved, and the full tumor dose might be escalated this sort of that doses like 24Gy in three fractions and thirty-40Gy in five fractions at the moment are not unusual. One particular interesting retrospective series described greater prices of control and decrease charges of toxicities with hypofractionated SRT (36Gy in six fractions) compared to solitary fraction SRS . On the other hand, this observe is still in its infancy and we are needing a RCT to find out if single portion SRS need to be reserved only for small metastases (e.g. one-2 centimeters), as the info suggest even worse area Regulate for larger tumors [80, 81]. Determine 1 is definitely an example of the efficacy of hypofractionated SRT in a large tumor. This patient would've usually been excluded from solitary portion SRS and dealt with with WBRT upfront (as well as or minus a SRS boost), or operated on.

A. MRI of 3.6cm suitable cerebellar metastases from lung most cancers. B. Extremely conformal treatment approach Along with the 100% (environmentally friendly line) and eighty% (blue line) isodose traces wrapping tightly throughout the gross tumour (purple colorwash), and arranging goal quantity (orange colorwash). The brainstem (blue colorwash) is spared from higher dose. (B) MRI 2 months write-up completion of radiation (30Gy in five fractions). C. Finish resolution in the tumour at 1 calendar year.

In article-operative sufferers, the practice of routinely managing with WBRT is usually turning into outdated. There may be rising use of SRS to the article-operative surgical cavity as a way to spare individuals in the adverse consequences of WBRT and to enhance local Regulate [82-93]. For the Sunnybrook Odette Cancer Center, Now we have adopted hypofractionated SRT as our common of treatment, providing 30-35Gy in five fractions to your submit-operative tumor mattress . Fractionation has the advantage of reducing the adverse effects to the conventional tissues, given that the targets are generally huge and irregularly formed. Our Preliminary benefits have shown 1 calendar year neighborhood Management prices of ∼eighty% in patients who may have possibly recurred and re-operated upon just after earlier WBRT, or in people without any prior record of WBRT and operated upon. There exists an ongoing review evaluating submit-surgical cavity one fraction SRS on your own as opposed to WBRT and could be a observe-defining examine .

In the last several many years, clinical trials have informed us about the suitable administration of people with brain metastases. Initially, SRS was considered an adjunct to WBRT in chosen clients presenting with a constrained amount of Mind metastases. On the other hand, the role of WBRT has given that been questioned as We have now acquired of its possible to adversely influence QOL and neurocognition. Due to this fact, SRS by itself has emerged as The existing standard of treatment with Level 1 proof to assistance its apply. Existing investigation is focused on the evaluation of broader applications of SRS to a number of clinical predicaments which were ordinarily thought of complete indications for WBRT. One example is, SRS by yourself is at this time staying evaluated in the remedy of 5 or maybe more brain metastases, As well as in write-up-operative people. A completely new period of trials can be emerging investigating the influence of specific therapies concurrent with SRS.

Medical trials in people with Mind metastases are a major obstacle as summarized from the the latest stories through the Reaction Assessment in Neuro-Oncology (RANO) brain metastases team [95, 96]. They propose for trial style and reaction evaluation that trials be tumor or biomarker particular, that evaluation be depending on contrast-enhanced MRI, that baseline and recurring neurocognitive and QOL screening be performed with validated and delicate instruments, that stratification be determined by further-cranial disease status, Which appropriate timing be thought of regarding endpoint tests. Ultimately, the oncology Local community has acknowledged that the event of brain metastases is no more the terminal oncologic occasion of your past.

CONFLICTS OF Fascination, Money DISCLOSURES

Dr. Arjun Sahgal has acquired honorarium from preceding educational seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also received investigate grants from Elekta AB, or else there aren't any conflicts of interest to disclose.

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