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Stereotactic radiosurgery SRS Financials is a longtime non-invasive ablative therapy for brain metastases. Early medical trials with SRS proved that tumor Command rates are outstanding to entire brain radiotherapy (WBRT) by itself. As a result, WBRT plus SRS was greatly adopted for people by using a restricted number of Mind metastases (“restricted variety” customarily suggests one-four). Subsequent trials focused on answering no matter if WBRT upfront was vital in any way. According to recent randomized controlled trials (RCTs) and meta-analyses comparing SRS on your own to SRS in addition WBRT, adjuvant WBRT brings about far better intracranial Regulate; nevertheless, with the expense of neurocognitive functioning and quality of life. These adverse outcomes of WBRT may additionally negatively influence on survival in younger individuals. Dependant on the outcomes of these reports, treatment has shifted to SRS by yourself in clients which has a minimal amount of metastases. In addition, RCTs are analyzing the role of SRS by yourself in clients with >four Mind metastases. New developments in SRS include things like fractionated SRS for giant tumors and the integration of SRS with targeted systemic therapies that cross the blood Mind barrier and/or promote an immune reaction. We existing During this overview The existing higher level evidence and rationale supporting SRS since the conventional of look after patients with restricted brain metastases, and emerging programs 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 function of neurosurgery had been established during the 1990s as a means to obtain nearby Management and prolong survival, it absolutely was reserved with the minority of sufferers presenting with an individual metastasis and no other ailment over and above the Mind [4-7]. Even now missing was a focal ablative non-invasive treatment that would be utilized proficiently to some Considerably broader inhabitants of patients with brain metastases. This set the stage for the event of stereotactic radiosurgery (SRS). SRS can be a centered ablative radiation treatment sent with sub-millimeter precision into the tumor localized in three-dimensions in 1-5 fractions.

The focus of this evaluate will be to summarize the current large amount proof to make clear the purpose of SRS as ideal management for individuals presenting with limited Mind metastases. On top of that, we provide an overview with the emerging apps of SRS as it continues to evolve right into a therapy alternative to WBRT, Using the intent To optimize neurcognitive perform and quality of life (QOL).

PATHOPHYSIOLOGY OF Mind METASTASES

Circulating tumor cells (CTCs) can disseminate from the primary tumor mass to kind distant colonies by way of implantation at an ectopic web page, including the Mind [eight-ten]. To take action calls for CTCs to arrest in the circulation, extravasate with the bloodstream or lymphatics in the Mind, and endure and proliferate [11-13]. The process of metastatic colonization involves a direct conversation of CTCs with endothelial cells and astrocytes during the Mind microenvironment. For instance, CTCs which have arrested in the capillary mattress direct community endothelial cells to remodel the adjacent environment to market tumour mobile progress and invasion [14-16]. Further more, metastatic tumour cells recruit systemic stromal cells, for instance fibroblasts, to help with early colonization , and co-opt nearby stromal cells, such as reactive astrocytes and microglia, to market tissue invasion [15, eighteen, 19]. Astrocytes in the tumour microenvironment might also play a job in safeguarding tumour cells from chemotherapy-induced cytotoxicity, through a nonetheless being defined system necessitating cell-mobile Speak to [20, 21]. Tumour cells, by release of migration inhibitory factor, interleukin-eight, 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 depict novel and understudied feasible therapeutic targets for the cure of intracranial metastatic illness.

SRS was to begin with a really source intense therapy presented only at specialised facilities and indicated only for metastatic individuals with a fantastic lifestyle expectancy. The obstacle lay in prognosticating patients properly and Consequently the Radiation Therapy Oncology Group (RTOG) recursive partitioning Investigation (RPA) [28, 29] was developed. Depending on the individual's Karnofsky General performance Status (KPS), age, status of the primary tumor and presence of extracranial sickness, clients were grouped into class one, two or 3 with corresponding median survivals of 7.1, four.2 and a pair of.three months, respectively. Whilst a major advancement at time, the RPA is currently regarded overly simplistic as latest oncologic decision producing is way more intricate incorporating molecular, histological, medical and radiographic ailment characteristics. You will discover now a lot more refined classification equipment, such as the diagnosis-specific graded prognostic evaluation (DS-GPA). This technique presents histology-precise estimates of survival and might independent, for instance, probably the most favorable breast cancer sufferers using an anticipated survival of twenty five months (fantastic KPS and luminal B form breast most cancers) in the minimum favorable clients with an expected survival of three months (bad KPS and basal-like breast cancer) . In spite of advancements in prognostication of clients with brain metastases, physicians remain largely not able to accurately predict extensive-phrase survivors. A study inquiring specialist medical professionals to estimate survival of a one hundred fifty people with details about most cancers type, amount of Mind metastases, neurological presentation, added-cranial disorder position, KPS, RPA class, prior complete-Mind radiotherapy, and synchronous or metachronous presentation, confirmed that more than 45% of predictions ended up off by over six months and eighteen% were off by a lot more than twelve months . Further improvements in prognostic assessments including the “liquid biopsy” (a non-invasive blood test that will detect tumor DNA or RNA fragments or CTCs) are essential As well as in enhancement . These combine advanced affected person and tumor certain genomic facts into your equation, to be able to accomplish customized survival predictions.

Operation proceeds being a significant procedure selection for people with confined Mind metastases. It can be indicated when metastases are large (>3-four cm), or any time a pathologic analysis is necessary. Furthermore, surgical treatment is desired inside the presence of sizeable edema demanding extended significant dose dexamethasone, or to likely reverse neurological deficits. Usually, The present evidence indicates the efficacy of SRS is sufficient to achieve tough neighborhood Regulate that's comparable to medical procedures. Although there are no RCTs directly evaluating the two, a number of trials have been noted comparing SRS to SRS with WBRT (Desk 1), which is A serious aim of the evaluation.

HR: hazard ratio, WHO: world overall health Corporation, KPS: Karnofsky performance position, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not significant, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Studying Test revised.

Clients inside the observation team had possibly surgical procedure by yourself or SRS alone. Practical consequence was not analyzed independently by surgical treatment or SRS alone.

The very first RCTs assessing SRS mimicked the look of the Preliminary surgical experiments for brain metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific studies verified that SRS enhanced nearby Regulate, and a survival benefit in chosen individuals with only one brain metastasis was proven. These trials have been thriving in shifting the paradigm from WBRT alone to WBRT additionally SRS for sufferers presenting with minimal Mind metastases and a great effectiveness position.

Another number of scientific trials were intended to solution if WBRT was in any way needed, and as opposed SRS alone to SRS with adjuvant WBRT. A few RCTs are already described in individuals presenting with around 4 metastases [35-37] as well as a forth in abstract type . Aoyama et al. noted the initial RCT, randomizing 132 sufferers to SRS on your own (65 patients) or WBRT plus SRS (sixty seven people). The principal endpoint was Mind tumor recurrence. Even though the 1-yr regional Handle charge was large with SRS on your own at seventy three%, added neighborhood Manage with adjuvant WBRT at 89%, was observed. Furthermore, adjuvant WBRT lessened the speed of distant intra-cranial relapse at 1 yr from sixty four% to 42%. However, these gains in intra-cranial control didn't translate into a bonus with respect to cognition, dependant on Mini-Psychological Status Test (MMSE), nor survival. Additionally, sufferers had better costs of necrosis and leukoencephalopathy inside the WBRT arm. The demo was Consequently profitable in offering the first amount 1 proof to clarify the relative impact of SRS by yourself versus SRS with WBRT.

Rather then the standard endpoint of survival or intra-cranial control, Chang et al. took a distinct tactic and evaluated neurocognition as the first endpoint. Importantly, the validated Hopkins Verbal Learning Take a look at-Revised (HVLT-R) assessment Device, was used to measure neurocognitive functioning rather than the MMSE which is not a delicate check for neurocognition . Fifty-8 sufferers have been randomized to SRS on your own (n = 30) or WBRT additionally SRS (n = 28). Early stopping policies were invoked for the interim Assessment, along with the study concluded that SRS on your own was favored with regard to the chance of neurocognitive decline at 4 months article-treatment. This reward was recognized Regardless of the one year regional Command and distant brain Command prices favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial Management results were being in keeping with the outcomes through the Aoyama review, but what wasn't envisioned was the survival gain noticed within the SRS on your own arm. The median survival was 15 months inside the SRS alone arm and 6 months within the SRS with WBRT arm (p = 0.003). This survival final result caused the trial to go through significant scrutiny with quite a few arguing the survival edge for SRS on your own was a result of imbalances among the two arms, as far more sufferers taken care of with SRS in addition WBRT experienced better added-cranial (far more liver and adrenal metastases) and intracranial ailment (more substantial quantity of Mind metastases) .

The ecu Group for Exploration and Procedure of Most cancers (EORTC) also took a distinct strategy with their Main endpoint focusing on functional independence . They used, even so, the more clinically familiar World Health and fitness Corporation (WHO) general performance standing (PS) scale, and measured time to WHO PS deterioration to much more than two. This RCT concluded the addition of WBRT didn't Enhance the median length of useful independence (SRS by itself: ten.0 months vs SRS as well as WBRT: 9.five months). The secondary end result of QOL, measured Using the validated EORTC-QLQC30 Software, was observed to be even worse in people who obtained WBRT in a number of QOL domains . Importantly, these final results had been noticed Regardless of adjuvant WBRT lessening the 2-calendar year neighborhood failure rate (31% to 19%), distant Mind failure (forty eight% to 33%), and the necessity for salvage therapies (51% vs. sixteen%). No significant discrepancies in survival were noticed albeit the trial wasn't run to address survival.

These four trials have founded the part of SRS by itself since the conventional of care in clients having a minimal quantity of brain metastases, but they may have not been created to Appraise the impact of WBRT on Total survival.

The inclusion requirements through the RCTs evaluating SRS by itself to SRS furthermore WBRT have been very similar (Desk 1), nonetheless, the first endpoints had been fully distinctive, and no demo was meant to evaluate All round survival. To higher make clear the results of local Command, distant Mind control and survival, a meta-Examination (MAL) was done by Tsao, Xu and Sahgal in 2012 . They described hazard ratios for area control and distant Mind Manage favoring adjuvant WBRT at 2.61 and a couple of.fifteen, respectively, but have been unable to combine the survival final results on account of constraints in how the information ended up described. Sahgal et al. then done someone individual info (IPD) MAL of precisely the same RCTs aimed at evaluating procedure consequences on survival, and execute sub-group analyses . With regard to In general survival, a procedure result was observed favoring SRS by itself in individuals ≤fifty several years. In older patients, no survival disadvantage was observed with SRS by yourself. With respect to distant Mind Command, a cure influence was also observed with risk reductions in the event of new Mind metastases in older patients handled with WBRT, but no advantage in the youthful sufferers (≤50 decades) dealt with with WBRT. As envisioned, nearby Command was enhanced with extra WBRT in all age teams. The concordance amongst a survival detriment and lack of gain in distant brain Command Even with treatment with WBRT, inside the young individuals, led the authors to hypothesize that exposure into the acknowledged harms of WBRT (discussed in detail under) may negatively affect affected person survival. This speculation is provocative, and remains to get validated.

Essentially the most convincing demo design and style to verify the adverse consequences of WBRT is always to randomize clients with no visualized brain metastases to observation or WBRT. This has actually been carried out in scientific tests evaluating prophylactic cranial irradiation (PCI) in each modest cell lung most cancers (SCLC) [forty four, forty five] and non-small cell lung cancer (NSCLC) [46, forty seven]. PCI, not dissimilar into the addition of WBRT to SRS, continues to be proven to lessen the chance of intra-cranial relapse. On the other hand, this attain comes in the cost of a detrimental impact on QOL. For example, considerable improves in exhaustion, hunger loss, nausea and vomiting and leg weakness were observed in individuals with substantial stage SCLC at 6 and 12 weeks post PCI . In addition, in regionally Innovative NSCLC sufferers, a increased decrease in HVLT-R actions of quick and delayed recall had been observed even as much as 1 calendar year write-up-PCI . With regard to extended-time period adverse outcomes of WBRT, a devastating consequence is usually the event of leukoencephalopathy. Without a doubt, radiation-induced dementia charges have already been noted to become as higher as eleven% in prolonged-term Mind metastases survivors (>twelve months) immediately after WBRT , and noted to get increased in individuals treated with WBRT and SRS in contrast to SRS by itself [35, fifty].

Excessive N-methyl-D-aspartate (NMDA) receptor stimulation, similar to the pathophysiology inherent to Parkinson's dementia , has actually been postulated as just one system outlining the adverse neurocognitive results of WBRT. Like a strategy to mitigate the danger, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a sizable randomized placebo managed trial involving 554 people. At 24 weeks, 64% of sufferers devoid of memantine and 54% with memantine experienced cognitive function failure based upon assessment While using the HVLT-R. Although the Most important endpoint didn't arrive at importance mainly because of the substantial attrition level, there was a solid trend (p = 0.059) supporting memantine remedy. Examination of secondary endpoints showed that memantine drastically prolonged the time to cognitive drop and yielded exceptional benefits for government perform, processing speed and delayed recognition at 24 weeks. Eventually, these info demonstrate many people undergo cognitive dysfunction with WBRT, and that pharmacologic approaches to mitigate the danger by focusing on equivalent pathways associated with Parkinson's dementia could be worthy of additional investigation.

Additional Perception into WBRTs’ system of injury has come from a the latest Period two trial assessing hippocampal avoidance WBRT (HA-WBRT). Innovative fashionable radiation technologies was applied to limit dose publicity to your hippocampus to not more than eighty% from the prescribed 30Gy in 10 fractions . This non-randomized phase two trial measured neurocognitive functionality using the HVLT-R, and when compared outcomes to historic controls taken care of with traditional WBRT from a RTOG demo databases. HA-WBRT resulted in a very seven% decrease while in the indicate relative HVLT-R delayed recall, which was drastically decrease compared to the 30% decline obtained from historic controls. Despite the fact that this examine is encouraging regarding limiting toxicity from WBRT, a randomized demo is necessary to totally have an understanding of the therapeutic value Within this technologically advanced sort of WBRT.

In 2012, the American Culture for Therapeutic Radiation Oncology revealed an evidence-primarily based guideline by using a series of recommendations over the administration of brain metastases . Because that time, the proof from clinical trials has manufactured it obvious that the preferred up-front radiation therapy selection for individuals with limited Mind metastases is SRS by yourself. In fact, the American Culture for Radiation Oncology (ASTRO) has not too long ago produced a definitive advice within their Opt for Properly campaign and endorse to not routinely add adjuvant WBRT to SRS for confined brain metastases . Furthermore, the a short while ago revised Nationwide Detailed Cancer Community (NCCN) suggestions now aid SRS on your own even further than Individuals people with “constrained” metastases, and don't specify an upper limit for the volume of metastases . The latter is forward imagining; metastasis counting is likely irrelevant and what matters is usually the suitability from the client for SRS [fifty seven-fifty nine]. As a result, the onus is no longer on individuals who address with SRS by yourself to justify the omission of WBRT; rather it truly is on individuals that take care of with WBRT in the SRS acceptable affected person.

WHAT ABOUT THE Client WITH Extra Substantial Mind METASTASES?

Former technical limits in SRS engineering restricted the appliance of SRS to clients with only some brain metastases. Breakthroughs in fastened frame and frameless SRS systems now let cure of numerous metastases in only one session [sixty, 61].

The very first significant future review assessing SRS alone for various Mind metastases was claimed in 2014 . Close to 1200 sufferers with 1-10 SRS eligible metastases have been handled with SRS alone applying Gamma Knife know-how (Elekta AB, Stockholm, Sweden). The Investigation was broken down in accordance with the 455 individuals with one metastases, 531 sufferers with 2 to four metastases and 208 with 5 to ten metastases. Survival, distant brain relapse, and local Regulate charges were not noticeably diverse in patients with five to ten metastases as opposed to two to 4 metastases. These results are of big significance because they obstacle the dogma that individuals with a lot more than four metastases won't take pleasure in SRS on your own as a consequence of shortened survival and may inevitably fall short in other places from the Mind. Consequently, this demo offers proof to guidance SRS by yourself in good KPS sufferers with up to 10 metastases, furnished the individual tumor volume is no more than 10 mL and < 3 cm in longest diameter, and the full cumulative volume of all tumors inside the Mind is ≤fifteen mL. Several randomized trials are now evaluating WBRT alone compared to SRS by itself in comparable sufferers, As well as in development is actually a trial assessing SRS on your own as opposed to WBRT as well as SRS Strengthen in patients with 10 to 20 metastases.

Focused THERAPIES IN COMBINATION WITH BRAIN RADIATION

As compared to conventional chemotherapy, many specific agents have increased penetration from the blood-Mind barrier and produce response from the brain. Remarkable advancements in disease Manage are now being observed even for histologies which include melanoma which were Beforehand considered not merely radioresistant but chemoresistant. Table 2 [sixty three-75] summarizes picked scientific trials assessing the efficacy of focused therapies alone or in combination with radiation therapy in the treatment of Mind metastases. Although, with qualified therapies by yourself some amazing reaction costs are observed, progression-free-survival (PFS) fees are usually shorter (< eight months). These final results are certainly not too dissimilar from what has been obtained with WBRT by yourself [33, fifty three]. The exception is in EGFR mutant non-tiny cell lung cancers addressed that has a tyrosine kinase inhibitor. While in the research by Wu et al. one example is, the median PFS was >15 months in EGFR mutant tumours addressed with erlotinib.

Table two. Summary of chosen trials of specific therapy by yourself or together with brain radiation for your therapy of Mind metastases.

PFS: progression no cost survival, nPFS: neurologic development totally free survival, OS: Total survival, NSCLC: non-small cell lung cancer, EGFR: epidermal advancement aspect receptor, WBRT: total brain radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not significant, NR: not recorded, NA: not applicable

Couple of trials have merged focused therapies with radiation, and these are also summarized in Table 2. Whilst, randomized evidence remains to be lacking, There exists suggestion from retrospective details that The mixture may produce improved results. Within the retrospective Assessment of a prospective cohort of patients addressed with SRS for melanoma brain metastases, the team that acquired ipilimumab had a noticeably more time median survival (21.3 vs 4.9 months) . On the other hand, caution really should be exercised as concurrent focused therapy and radiation procedure might not be as innocuous as Beforehand considered. The RCT analyzing SRS with WBRT on your own, vs . together with erlotinib or temozlomide, described substantially bigger Quality three to five toxicity premiums in the combination arm; more importantly, survival was worse even though it didn't achieve statistical significance . A significant limitation of this review was the focused therapy was not biomarker-driven and may partially account for your poor survival noticed. Caution also needs to be taken as there is evidence that brain metastases and first tumors may harbor distinct genetic alterations. In one study of 86 matched brain metastases and primary tumors, clinically useful alterations in fifty three% of Mind metastases weren't detected in the first tumor .

The rising proof implies that qualified therapies will play a substantial purpose in the remedy of brain metastases. We postulate that Despite the fact that specific brokers is probably not powerful in managing gross sickness in the brain, They could be productive in running micro-metastatic disease in the Mind. Therefore, a sensible approach may be to mix qualified therapies with SRS on your own, beating the limitation of SRS in addressing micrometastatic sickness from the Mind and leading to less distant brain failures. The next few years will produce interesting info as there are a number of trials in development utilizing this strategy.

Improvements IN SRS - INDICATIONS AND Apps

As tumors get greater, SRS dosing is counter-intuitively lowered with regard to tumor Management, to maintain safety to the traditional brain tissue; otherwise, the potential risk of radiation necrosis gets prohibitive . Therefore, tumors higher than four cm have generally been excluded from one fraction SRS. If your tumors are non-operable, then these individuals are taken care of with WBRT Regardless of its weak regional Management. The advent of non-invasive head immobilization products, on-board image-steering techniques and advanced radiation shipping program has produce the observe of hypofractionated frameless stereotactic radiotherapy (SRT) [60, 78]. Effectively by fractionating, the protection profile with regard to the normal brain tissue toxicity is improved, and the full tumor dose can be escalated this sort of that doses like 24Gy in three fractions and thirty-40Gy in five fractions at the moment are not unusual. Just one interesting retrospective series claimed greater premiums of Command and reduced premiums of toxicities with hypofractionated SRT (36Gy in six fractions) in comparison with solitary portion SRS . Nonetheless, this exercise remains in its infancy and we are looking for a RCT to find out whether or not solitary fraction SRS needs to be reserved just for smaller metastases (e.g. one-two centimeters), as the info suggest worse local Handle for much larger tumors [eighty, eighty one]. Figure 1 is undoubtedly an illustration of the efficacy of hypofractionated SRT in a significant tumor. This patient would have or else been excluded from one portion SRS and addressed with WBRT upfront (plus or minus a SRS Strengthen), or operated on.

A. MRI of three.6cm proper cerebellar metastases from lung cancer. B. Remarkably conformal procedure approach While using the one hundred% (environmentally friendly line) and 80% (blue line) isodose strains wrapping tightly round the gross tumour (purple colorwash), and setting up focus on quantity (orange colorwash). The brainstem (blue colorwash) is spared from large dose. (B) MRI two months post completion of radiation (30Gy in five fractions). C. Full resolution of your tumour at 1 calendar year.

In write-up-operative individuals, the apply of routinely managing with WBRT is also getting out-of-date. There exists growing use of SRS to your post-operative surgical cavity as a method to spare patients through the adverse consequences of WBRT and to improve neighborhood Manage [eighty two-93]. At the Sunnybrook Odette Cancer Heart, We've got adopted hypofractionated SRT as our standard of care, delivering 30-35Gy in five fractions for the article-operative tumor mattress . Fractionation has the advantage of reducing the adverse effects to the conventional tissues, given that the targets are usually huge and irregularly formed. Our Original final results have demonstrated one year community Manage costs of ∼eighty% in patients who may have possibly recurred and re-operated upon right after past WBRT, or in patients without any prior heritage of WBRT and operated on. You can find an ongoing analyze analyzing publish-surgical cavity solitary fraction SRS by yourself vs . WBRT and may be a apply-defining examine .

In the last several decades, clinical trials have informed us about the suitable administration of clients with Mind metastases. To begin with, SRS was considered an adjunct to WBRT in selected sufferers presenting with a restricted variety of brain metastases. Even so, the job of WBRT has since been questioned as We've discovered of its possible to adversely have an effect on QOL and neurocognition. Therefore, SRS on your own has emerged as The present regular of care with Level 1 evidence to aid its observe. Present-day investigate is centered on the evaluation of broader programs of SRS to a number of clinical cases which were historically considered complete indications for WBRT. One example is, SRS by itself is presently being evaluated during the procedure of five or more brain metastases, and in post-operative people. A whole new era of trials is also rising investigating the effect of targeted therapies concurrent with SRS.

Medical trials in individuals with Mind metastases are A significant problem as summarized from the recent reviews from the Reaction Evaluation in Neuro-Oncology (RANO) Mind metastases team [95, 96]. They recommend for demo style and design and response evaluation that trials be tumor or biomarker precise, that evaluation be according to distinction-enhanced MRI, that baseline and repeated neurocognitive and QOL screening be executed with validated and sensitive devices, that stratification be according to excess-cranial condition status, Which acceptable timing be considered regarding endpoint tests. In the end, the oncology Local community has regarded that the development of Mind metastases is no longer the terminal oncologic function of your past.

CONFLICTS OF INTEREST, Money DISCLOSURES

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

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