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BackgroundDrug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual’s mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual’s mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations.MethodsThe present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels forALK,BRCA1,EGFR, andERBB2/HER2.ResultsResults indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%,p p = 0.0001) and [A+B] cybrids (24.67%,p = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B],p = 0.0270). (4) The expression levels decreased forALKin L (p p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased forEGFRin [A+B] cybrids (p = 0.0246) compared to untreated cybrids.ConclusionOur findings suggest that an individual’s mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment.

Background Brain arteriovenous malformations (AVMs) are rare, potentially devastating cerebrovascular lesions that can occur in both children and adults. AVMs are largely sporadic and the basic disease biology remains unclear, limiting advances in both detection and treatment. This study aimed to investigate human brain AVMs for endothelial‐to‐mesenchymal transition (EndMT), a process recently implicated in cerebral cavernous malformations (CCMs). Methods We used 29 paraffin‐embedded and 13 fresh/frozen human brain AVM samples to profile expression of panels of EndMT‐associated proteins and RNAs. CCMs, a cerebrovascular disease also characterized by abnormal vasculature, were used as a primary comparison, given that EndMT specifically contributes to CCM disease biology. AVM‐derived cell lines were isolated from three fresh, surgical AVM samples and characterized by protein expression. Results We observed high collagen deposition, high PAI‐1 expression, and expression of EndMT‐associated transcription factors such as KLF4, SNAI1, and SNAI2 and mesenchymal‐associated markers such as VIM, ACTA2, and S100A4. SMAD‐dependent TGF‐β signaling was not strongly activated in AVMs and this pathway may be only partially involved in mediating EndMT. Using serum‐free culture conditions, we isolated myofibroblast‐like cell populations from AVMs that expressed a unique range of proteins associated with mature cell types and with EndMT. Conditioned medium from these cells led to increased proliferation of HUVECs and SMCs. Conclusions Collectively, our results suggest a role for EndMT in AVM disease. This may lead to new avenues for disease models to further our understanding of disease mechanisms, and to the development of improved diagnostics and therapeutics.

Benign spinal tumors are rare clinical conditions, including meningiomas, schwannomas, and neurofibromas. Although these tumors are usually treated with open surgical resection, spinal stereotactic radiosurgery may be a safe and effective alternative to surgery in selected patients.

Background We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). Methods We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3–5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. Results From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51–86 y). The median target volume was 60 cm3 (range, 14.7–137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1–2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2–12.6 mo). No grades 3–5 ARE occurred. With a median follow-up of 13.8 months (range 1.7–64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6–10.5); overall survival, 14.8 months (95% CI: 10.9–19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5–33.5) versus 11.3 months (95% CI: 8.9–17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2–48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9–17.6) for no ARE (P = 0.08). Conclusions The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1–2 and did not statistically impact survival.

Head and neck paragangliomas (HNPs) are rare, usually benign hyper vascularized neuroendocrine tumors that traditionally have been treated by surgery, with or without endovascular embolization, or, more recently stereotactic radiosurgery (SRS). The aim of our study is to determine the clinical and radiographic effectiveness of SRS for treatment of HNPs. A systematic search of electronic databases was performed, and 37 articles reporting 11,174 patients (1144 tumors) with glomus jugulare (GJT: 993, 86.9%), glomus tympanicum (GTT: 94, 8.2%), carotid body tumors (CBTs: 28, 2.4%), and glomus vagale (GVT: 16, 1.4%) treated with SRS definitively or adjuvantly were included. The local control (LC) was estimated from the pooled analysis of the series, and its association with SRS technique as well as demographic and clinical factors was analyzed. The median age was 56 years (44-69 years). With a median clinical and radiological follow-up of 44 months (9-161 months), LC was 94.2%. Majority of the patients (61.0%) underwent Gamma Knife Radiosurgery (GKS), but there was no statistically significant difference in LC depending upon the SRS technique (p = 0.9). Spearmen's correlation showed that LC was strongly and negatively correlated with multiple parameters, which included female gender (r = - 0.4, p = 0.001), right-sided tumor (r = - 0.3, p = 0.03), primary SRS (r = - 0.5, p ≤ 0.001), and initial clinical presentation of hearing loss (r = - 0.4, p = 0.001). To achieve a LC ≥ 90%, a median marginal dose (Gy) of 15 (range, 12-30 Gy) was required. The results corroborate that SRS in HNPs is associated with good clinical and radiological outcome.

The development of cavernous malformations many years following conventionally fractionated brain irradiation is well recognized and commonly reported. However, cavernous malformation induction following stereotactic radiosurgery (SRS) is largely unreported. Herein, we describe two cases of cavernous malformation formation years following SRS for brain metastases. A 20-year-old woman with breast cancer brain metastases received treatment with whole brain radiotherapy (WBRT), then salvage SRS 1.4 years later for progression of a previously treated metastasis. This lesion treated with SRS had hemorrhagic enlargement 3.0 years after SRS. Resection revealed a cavernous malformation. A 25-year-old woman had SRS for a brain metastasis from papillary thyroid carcinoma. Resection of a progressive, hemorrhagic lesion within the SRS field 2 years later revealed both recurrent carcinoma as well as cavernous malformation. As patients with brain metastases live longer following SRS, our cases highlight that the differential diagnosis of an enlarging enhancing lesion within a previous SRS field includes not only cerebral necrosis and tumor progression but also cavernous malformation induction.

Introduction Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods Patients with histologically-confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson’s Chi-square and Fisher’s exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001 to 0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02 to 0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001 to 0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1 to 79.6] months vs 5.45 [1.8 to 26.3], p = 0.0092) and OS (median 56.73 months [7.8 to 104.5] vs 14.83 [3.8 to 29.1], p = 0.0252). Conclusion Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

OBJECTIVE Cavernous sinus meningioma (CSM) can affect visual function and require expeditious treatment to prevent permanent visual loss. Authors of this retrospective study sought to determine the factors associated with visual functional outcomes in CSM patients treated with surgery, stereotactic radiosurgery (SRS), or stereotactic radiation therapy (SRT), alone or in combination. METHODS Consecutive patients with CSM who had presented at an academic tertiary care hospital from 2000 to 2018 were identified through retrospective chart review. Visual function—visual eye deficit (VED), optic disc (OD) appearance, intraocular pressure (IOP), and extraocular movement (EOM)—was assessed before and after treatment for CSM. VED with visual acuity (VA) ≤ 20/200 and visual field defect ≥ −11 dB, pale OD appearance in the ipsilateral or contralateral eye, increased ipsilateral IOP, and/or EOM restriction were defined as a poor visual functional outcome. Multivariable logistic regression was used to evaluate the associations between pretreatment visual functional assessment and posttreatment visual outcomes. RESULTS The study cohort included 44 patients (73% female; median age 55 years), with a median clinical follow-up of 14 months. Ipsilateral VED improved, remained stable, or worsened, respectively, in 0%, 33.4%, and 66.6% of the patients after subtotal resection (STR) alone; in 52.6%, 31.6%, and 15.8% after STR plus radiation treatment; in 28.5%, 43.0%, and 28.5% after gross-total resection (GTR) alone; and in 56.3%, 43.7%, and 0% after radiation treatment (SRS or SRT) alone. Contralateral VED remained intact in all the patients after STR alone and those with radiation treatment (SRS or SRT) alone; however, it improved, remained stable, or worsened in 10.5%, 84.2%, and 5.3% after STR plus radiation treatment and in 43.0%, 28.5%, and 28.5% after GTR alone. EOM remained intact, fully recovered, remained stable, and worsened, respectively, in 0%, 50%, 50%, and 0% of the patients after STR alone; in 36.8%, 47.4%, 15.8%, and 0% of the patients after STR with radiation treatment; in 57.1%, 0%, 28.6%, and 14.3% of the patients after GTR alone; and in 56.2%, 37.5%, 6.3%, and 0% of the patients after radiation treatment (SRS or SRT) alone. In multivariable analyses adjusted for age, tumor volume, and treatment modality, initial ipsilateral poor VED (OR 10.1, 95% CI 1.05–97.2, p = 0.04) and initial ipsilateral pale OD appearance (OR 21.1, 95% CI 1.6–270.5, p = 0.02) were associated with poor ipsilateral VED posttreatment. Similarly, an initial pale OD appearance (OR 15.7, 95% CI 1.3–199.0, p = 0.03), initial poor VED (OR 21.7, 95% CI 1.2–398.6, p = 0.03), and a higher IOP in the ipsilateral eye (OR 55.3, 95% CI 1.7–173.9, p = 0.02) were associated with an ipsilateral pale OD appearance posttreatment. Furthermore, a higher initial ipsilateral IOP (OR 35.9, 95% CI 3.3–400.5, p = 0.004) was indicative of a higher IOP in the ipsilateral eye posttreatment. Finally, initial restricted EOM was indicative of restricted EOM posttreatment (OR 20.6, 95% CI 18.7–77.0, p = 0.02). CONCLUSIONS Pretreatment visual functional assessment predicts visual outcomes in patients with CSM and can be used to identify patients at greater risk for vision loss.

CyberKnife stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) administers nonisometric, conformational high-dose radiation to the trigeminal nerve with risk of subsequent hypoesthesia.We performed a retrospective, single-institution review of 66 patients with TGN treated with CyberKnife SRS to compare outcomes from 2 distinct treatment periods: standard dosing (n = 38) and reduced dosing (n = 28). Standard and reduced dosing permitted a maximum brainstem dose of 45 Gy and 25 Gy, respectively, each with a prescription dose of 60 Gy. Primary and secondary outcomes were Barrow Neurologic Institute pain and numbness scores. Maximum brainstem dose, prepontine nerve length, and treatment history were recorded for their predictive contributions by logistic regression.After matching, patients in the standard dosing and reduced dosing groups were followed for a median of 25 months and 19.5 months, respectively. Mean trigeminal nerve length was 8.55 mm in the standard dosing group and 9.46 mm in the reduced dosing group. Baseline rates of poorly controlled pain were 97% and 88%, respectively, which improved to 23.4% and 8.3%, respectively (P0.001 for both). The baseline rates of bothersome numbness were null in both groups, and increased to 25% in the standard group (P = 0.006) and to 21% in the reduced group (P = 0.07). Regression analyses suggested that reduced brainstem exposure (P = 0.01), as well as a longer trigeminal nerve (P = 0.01), were predictive of durable pain control.These outcomes demonstrate that a lower maximum brainstem dose can provide excellent pain control without affecting facial numbness. Longer nerves may achieve better long-term outcomes and help optimize individual plans.

Surgery is the primary treatment for acromegaly. However, surgery may not be curative of some tumors, particularly invasive macroadenomas. Adjuvant radiation, specifically robotic stereotactic radiosurgery (rSRS), may improve the endocrine outcome. We retrospectively reviewed hormonal and radiological data of 22 acromegalic patients with invasive macroadenomas treated with rSRS at Stanford University Medical Center between 2000 and 2016. Prior to treatment, the tumor's median maximal diameter was 19 mm (2.5-50 mm). Cavernous sinus invasion occurred in 19 patients (86.3%) and compression of the optic chiasm in 2 (9.0%). At last follow up, with an average follow up of 43.2 months, all patients had a reduction in their IGF-1 levels (median IGF-1% upper limit of normal (ULN) baseline: 136% vs last follow up: 97%; p = 0.05); 9 patients (40.9%) were cured, and 4 (18.1%) others demonstrated biochemical control of acromegaly. The median time to cure was 50 months and the mean interval to cure or biochemical control was 30.3 months (± 24 months, range 6-84 months). Hypopituitarism was present in 8 patients (36.3%) and new pituitary deficits occurred in 6 patients with a median latency of 31.6 ± 14.5 months. At final radiologic follow-up, 3 tumors (13.6%) were smaller and 19 were stable in size. The mean biologically effective dose (BED) was higher in subjects cured compared to those with persistent disease, 163 Gy3 (± 47) versus 111 Gy3 (± 43), respectively (p = 0.01). No patient suffered visual deterioration. Robotic SRS is a safe and effective treatment for acromegaly: radiation-induced visual complications and hypopituitarism is rare.

Hemangioblastomas are rare, benign, vascular tumors of the central nervous system (CNS), often associated with von-hippel lindau (VHL) disease. Current therapeutic options include microsurgical resection or stereotactic radiosurgery (SRS). With no randomized controlled studies and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. We completed a Pubmed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year progression free survival (PFS). The pooled 5-year PFS across all eligible studies was 88.4%. No difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease. Adverse events were associated with increasing marginal dose, independent of tumor volume. VHL status, sex, radiosurgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. Multiple studies show excellent tumor control at 5-year follow up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.

PurposeTo determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.Materials and methodsIn this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2cm, were enrolled in a phase 1, 3+3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400mg orally once daily for 14days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30days.ResultsFrom 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12months (range, 1-64months), Kaplan-Meier overall survival was 13months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2months after SRS.ConclusionsThe MTD of vorinostat with concurrent SRS was established as 400mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.

Embolization has been proposed to reduce the size of the arteriovenous malformation (AVM) nidus in advance of radiosurgical treatment. Embolization followed by radiosurgery for brain AVMs, however, is controversial.We assessed the impact of embolization on nidal size before radiosurgical treatment and evaluated cure rates and complications by using embolization followed by radiosurgery.A retrospective review of our institutional AVM database identified 91 patients treated from 1995 to 2009 with embolization followed by radiosurgery. Pre- and postembolization AVM volumes were measured with angiography, and the modified radiation-based AVM scores (RBAS) also were calculated pre- and postembolization. RBAS determined from pre-embolization volumes were correlated with postradiosurgical obliteration.Median AVM volume declined from 18.8 mL (interquartile range, 10.2-32.2 mL) to 9.9 mL (3.1-19.2 mL) after embolization, P0.00003. Median RBAS scores decreased from 2.6 mL (1.8-3.9 mL) to 1.8 mL (1.0-2.8 mL), P0.00003. Two of 91 (2.2%) had new fixed deficits after embolization; however, no patient had new disabling deficits (modified Rankin Scale score2). A total of 71 of 91 (79%) have had3 years' follow-up, and 40 (56%) had complete obliteration, with 38 (53%) having excellent outcomes (complete obliteration without neurologic decline). Excellent outcome was seen in 90% of patients with modified RBAS score1, 66% of patients with score 1-1.5, 50% patients with score 1.5-2, and 43% of patients with score2.These data suggest that embolization of brain AVMs can safely and effectively reduce the treatment volume before radiosurgery. Combined therapy with embolization and radiosurgery does not appear to adversely affect rates of excellent outcome.

OBJECTIVEColorectal cancer (CRC) and other gastrointestinal (GI) cancers are believed to have greater radioresistance than other histologies. The authors report local control and toxicity outcomes of stereotactic radiosurgery (SRS) to spinal metastases from GI primary cancers.METHODSA retrospective single-center review was conducted of patients with spinal metastases from GI primary cancers treated with SRS from 2004 to 2017. Patient demographics and lesion characteristics were summarized using medians, interquartile ranges (IQRs), and proportions. Local failure (LF) was estimated using the cumulative incidence function adjusted for the competing risk of death and compared using Gray’s test for equality. Multivariable analyses were conducted using Cox proportional hazard models, adjusting for death as a competing risk, on a per-lesion basis. Patients were stratified in the Cox model to account for repeated measures for clustered outcomes. Median survival was calculated using the Kaplan-Meier method.RESULTSA total of 74 patients with 114 spine lesions were included in our analysis. The median age of the cohort was 62 years (IQR 53–70 years). Histologies included CRC (46%), hepatocellular carcinoma (19%), neuroendocrine carcinoma (13%), pancreatic carcinoma (12%), and other (10%). The 1- and 2-year cumulative incidence rates of LF were 24% (95% confidence interval [CI] 16%–33%) and 32% (95% CI 23%–42%), respectively. Univariable analysis revealed that older age (p = 0.015), right-sided primary CRCs (p = 0.038), and single fraction equivalent dose (SFED; α/β = 10) < 20 Gy (p = 0.004) were associated with higher rates of LF. The 1-year cumulative incidence rates of LF for SFED < 20 Gy10 versus SFED ≥ 20 Gy10 were 35% and 7%, respectively. After controlling for gross tumor volume and prior radiation therapy to the lesion, SFED < 20 Gy10 remained independently associated with worse LF (hazard ratio 2.92, 95% CI 1.24–6.89, p = 0.014). Toxicities were minimal, with pain flare observed in 6 patients (8%) and 15 vertebral compression fractures (13%).CONCLUSIONSSpinal metastases from GI primary cancers have high rates of LF with SRS at a lower dose. This study found that SRS dose is a significant predictor of failure and that prescribed SFED ≥ 20 Gy10 (biological equivalent dose ≥ 60 Gy10) is associated with superior local control.

Postoperative stereotactic radiosurgery (SRS) has less detrimental effect on cognition and quality of life compared with whole brain radiation therapy (WBRT) and is increasingly used for resected brain metastases (BMs). Postoperative SRS techniques are not standardized, and there is a concern for a different pattern of failure after postoperative SRS compared with WBRT. We aim to study the efficacy, toxicity, and failure pattern of postoperative SRS.We retrospectively reviewed outcomes of patients with resected BMs treated with postoperative SRS between 2007 and 2018. Overall survival and cumulative incidences of local failure, overall distant intracranial failure (distant parenchymal failure, nodular leptomeningeal disease [nLMD], classical leptomeningeal disease [cLMD]), and adverse radiation effect were reported. Neurologic death was determined for patients with leptomeningeal disease (LMD).A total of 442 patients with 501 resected BMs were treated over 475 total SRS courses. Median clinical follow-up and overall survival after SRS were 10.1 months (interquartile range, 3.6-20.7 months) and 13.9 months (95% confidence interval [CI], 11.8-15.2 months), respectively. At 12 months, event rates were 7% (95% CI, 5%-10%) for local failure, 9% (95% CI, 7%-12%) for adverse radiation effect, 44% (95% CI, 40%-49%) for overall distant intracranial failure, 37% (95% CI, 33%-42%) for distant parenchymal failure, and 13% (95% CI, 10%-17%) for LMD. The overall incidence of LMD was 15.8% (53% cLMD, 46% nLMD). cLMD was associated with shorter survival than nLMD (2.0 vs 11.2 months, P.01) and a higher proportion of neurologic death (67% vs 41%, P = .02). A total of 15% of patients ultimately received WBRT.We report the largest clinical experience of postoperative SRS for resected BMs, showing excellent local control and low toxicity. Intracranial failure was predominantly distant, with a rising incidence of LMD.

International audience; We formulated an ultra-small, gadolinium-based nanoparticle (AGuIX) with theranostic properties to simultaneously enhance MRI tumor delineation and radiosensitization in a glioma model. The 9L glioma cells were orthotopically implanted in 10-week-old Fischer rats. The intra-tumoral accumulation of AGuIX was quantified using MRI T1-maps. Rats randomized to intervention cohorts were subsequently treated with daily temozolomide for five consecutive days before radiotherapy treatment. Collectively, a series of 32 rats were divided into untreated (n = 7), temozolomide-only (n = 7), temozolomide and MRT (n = 9), AGuIX and MRT (n = 7), and triple therapy (temozolomide, AGuIX NPs, and MRT; n = 9) cohorts. AGuIX nanoparticles achieved a maximum intra-tumoral concentration (expressed as concentration of Gd3+) at 1 h after intravenous injection, reaching a mean of 227.9 ± 60 lM. This was compared to concentrations of 10.5 ± 9.2 lM and 62.9 ± 24.7 lM in the contralateral hemisphere and cheek, respectively. There was a slower washout in the intra-tumor region, with sustained tumor-to-contralateral ratio of AGuIX, up to 14-fold, for each time point. The combination of AGuIX or temozolomide with MRT improved the median survival time (40 days) compared to the MeST of control rats (25 days) (p < 0.002). There was a trend towards further increased survival when the three treatments were combined (MeST of 46 days). This study demonstrated the selective accumulation of AGuIX in high grade glioma, as well as the potential survival benefits when combined with chemoradiation.

A retrospective data review.To evaluate the efficacy of CyberKnife (CK) stereotactic radiosurgery (SRS) for thyroid spinal metastasis (SMs).Thyroid carcinoma is an infrequent cause of SM. The absolute efficacy of SRS generally and CK in particular remains poorly characterized for thyroid SM. The current study is the first to specifically evaluate the efficacy of CK SRS for thyroid SMs.A retrospective review of patients at our institution between 2003 and 2013 was done. Details about tumor location, radiographic findings before and after CK SRS, tumor recurrence, prescription isodose level, total and maximum dose, number of fractions, and gross tumor volume coverage were similarly collected. For comparison with other studies, the biologically effective dose and the equivalent total dose in 2 Gy fractions were calculated. Each patient was assessed for survival and local disease control from the time of the first CK session and survival analysis was carried out using the Kaplan-Meier method. Risk factors for local failure were assessed using multivariate logistic regression.A total of 12 patients with 32 spinal metastases from thyroid carcinoma that were treated with CK SRS were identified. Survival for 1, 2, and 3 years was 55%, 44%, and 33%, and local control was 67%, 56%, and 34% respectively. The study found that the single strongest factor associated with local control was prior radiotherapy (β-coefficient -27.72, P = 0.01). No complications occurred in the immediate or late follow-up period.This was the first study to specifically investigate the efficacy of CK for treatment of thyroid SMs. Our findings suggest that CK can be safely used to treat spinal SMs from thyroid cancer and is associated with a high rate of local control.4.

Objective/Background: We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma. Methods: We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method. Results: Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2–157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11–43) and 42% (95% CI 22–60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects. Conclusions: SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.

Gross total resection of large intracranial meningiomas (LIMs) can be challenging and cause significant morbidity and mortality. The aim of this systematic review is to determine the clinical effectiveness and safety of stereotactic radiosurgery (SRS) either as primary or adjuvant therapy for LIMs with tumors ≥2.5 cm in maximum dimension (tumor volume ≥8.1 cm3). A total of 452 tumors in 496 patients (350 female [69.3%] and 146 male [30.6%]) with median age 60 years (48–65 years) were included. The median tumor volume at the time of diagnosis was 16.7 cm3 (10–53.3 cm3). The tumors typically were located in the skull base (77.2%), whereas only 14.6% were in the supratentorial space. The median follow-up after SRS was 54 months (18–90 months). In total, 87.8% of patients were treated with single-session (SS) Gamma Knife radiosurgery (GKS), whereas the remaining 12.1% patients received non-SS GKS. Of 452 LIMs assessed for clinical response, 45.1% showed improvement and 15.7% deteriorated after SRS. Radiographic tumor control at last follow-up (2–7.5 years) ranged from 84% to 100%. Overall, radiation-induced toxicity occurred in 23% of patients, with the most common adverse effect being cranial nerve neuropathy (5.5%) and peritumoral edema (5.3%). Subgroup analysis revealed that there is 2-fold greater likelihood of improvement in clinical symptoms in patients with non-SS GKS than SS GKS (odds ratio 2.47; 95% confidence interval 1.38–4.44; P = 0.002). SRS is safe and effective in the treatment of LIMs as primary or adjuvant treatment. Further prospective studies are required to validate our results.

OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.

An estimated 20%25 of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.

Cerebral arteriovenous malformations (AVMs) are vascular lesions consisting of abnormal connections between arteries and veins with no intermediate capillary network. With an annual spontaneous rupture rate of approximately 2–4%, they represent a significant source of hemorrhagic stroke and neurologic morbidity and mortality in young patients. The current treatment paradigms for AVMs include microsurgery, stereotactic radiosurgery (SRS), and embolization, all of which aim to abolish the risk of hemorrhage by obliterating the AVM nidus. Stereotactic radiosurgery is a minimally invasive and effective treatment option that is particularly suitable for small- to medium-sized AVMs located in deep or eloquent brain regions. Obliteration is achieved in 70–80% of cases, following a latency period of approximately 1–3-year posttreatment. SRS carries a unique complication profile including a sustained risk of hemorrhage during the latency period, as well as adverse radiation effects with associated neurologic deficits. AVM lesions vary widely in their natural histories and their suitability for treatment with SRS, based on characteristics such as size, location, and rupture status. For large AVMs, adjunct techniques such as endovascular embolization or volume and dose staging may be utilized to make the lesions appropriate targets for SRS. In the case of unruptured AVMs, early data from recent prospective trials have suggested that conservative medical management may result in better short-term outcomes than interventional treatment. Thus, the risks and complications associated with SRS therapy for individual AVMs must be carefully balanced against the morbidities associated with the natural history of the disease. Here we discuss the salient clinical and pathophysiologic indications for the use of SRS, review data on treatment efficacy and outcomes, and profile the major complications.

Purpose Pseudarthrosis within the spine tumor population is increased from perioperative radiation and complex stabilization for invasive and recurrent pathology. We report the radiographic and clinical rates of pseudarthrosis following multiple courses of instrumented fusion and perioperative stereotactic radiosurgery (SRS). Methods We performed a single institution review of 418 patients treated with non-isocentric SRS for spine between October 2002 and January 2013, identifying those with spinal instrumentation and greater than six months of follow-up. Surgical history, radiation planning, and radiographic outcomes were documented. Results Eleven patients who met criteria for inclusion underwent 21 sessions of spinal SRS and 16 instrumented operations. Radiographic follow-up was 48.9 months; 3/11 (27%) were with radiographic hardware failure, and one (9%) separate case ultimately warranted externalization due to tumor recurrence. SRS was administered to treat progression of disease in 12/21 (57%) procedures, and residual lesions in 7/11 (64%) procedures. Following first and second SRS, 8/11 (73%) and 2/7 (29%) patients were with symptomatic improvement, respectively. Conclusion Risk of pseudarthrosis following SRS for patients with oncologic spinal lesions will become increasingly apparent with the optimized management of and survival from spinal pathologies. We highlight how the need for local control outpaces the risk of instrumentation failure.

Magnetic particle imaging (MPI) is a novel radiation-free tomographic imaging method that provides a background-free, signal attenuation-free, direct quantification of the spatial distribution of superparamagnetic iron-oxide nanoparticles (SPIONs) with high temporal resolution (milliseconds), high spatial resolution (1 mm), and extreme sensitivity (μmol). The technique is based on nonlinear magnetization of the SPIONs when exposed to an oscillating magnetic field. MPI was first described in 2001. Since then, the technique has been applied to experimental imaging of diseases affecting different organs in the human body. The aim of this paper is to review the potential applications of MPI in the field of neurosurgery.A nonsystematic review of the existing literature on the use of MPI in neurosurgical diseases was performed.MPI has been used for the detection of locoregional invasion of brain tumors, tracking, and monitoring the viability of neural stem cells implanted for neuroregenerative purposes, diagnosis of cerebral ischemia, and diagnosis and morphofunctional assessment of brain aneurysms.MPI is at a preclinical stage. In the future, human-sized MPI scanners, along with the optimal toxicity profile of SPIONs will allow diagnostic applications in neurosurgical diseases.

Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

OBJECT Metastatic disease to the craniovertebral junction (CVJ) is rare but presents unique management challenges. To date, studies on using stereotactic radiosurgery (SRS) for CVJ metastases have been limited to case reports and small case series. The aim of this analysis was to evaluate the utility of SRS in the management of these secondary lesions. METHODS Clinical and radiological information from the charts of 25 patients with metastatic disease of the CVJ who were treated with SRS between 2005 and 2013 at the Stanford CyberKnife Center were retrospectively reviewed. RESULTS Seven male and 18 female patients with a median age of 58 years (range 34–94 years) were identified. The most common primary tumors were breast cancer (n = 5) and non-small cell lung cancer (n = 5), and the most frequent symptom was neck pain (n = 17). The average tumor volume treated was 15.9 cm3 (range 0.16–54.1 cm3), with a mean marginal radiation dose of 20.3 Gy (range 15–25.5 Gy). The median follow-up was 18 months (range 1–81 months), though 1 patient was lost to follow-up. SRS provided radiographic tumor stability in over 80% of patients, offered pain alleviation in nearly two-thirds of patients, and produced no serious complications. Moreover, SRS preserved spinal stability in all but 1 patient, in whom pre-SRS stability was established. There was no evidence of radiation toxicity in the patient population. Median survival was 28 months (range 2–81 months), with survival of 13.3% at 5 years. CONCLUSIONS In the absence of unstable pathological fracture and spinal cord compression, metastatic tumors of the CVJ can be safely and effectively treated with SRS. This treatment option offers palliative pain relief and can halt tumor progression with only a low risk of complications or spinal instability.

Vestibular Schwannomas in Neurofibromatosis Type 2 A 32-year-old man with a family history of neurofibromatosis type 2 presented with balance difficulties and hearing loss. Magnetic resonance imaging revealed bilateral vestibular schwannomas.

Background An understanding of the hearing outcomes is needed for treatment counseling for patients with vestibular schwannomas (VS). Objective To determine long-term hearing results following stereotactic radiosurgery (SRS) for VS and identify any influential variables. Methods Tertiary hospital retrospective cohort. Results There were 579 tumors (576 patients) treated with SRS. Eighty-two percent (473) of tumors had ≥1 yr and 59% (344 ≥3 yr follow-up. In the 244 tumor ears, with measurable hearing before SRS who were followed ≥1 yr, 14% (31) had improved hearing, 13% (29) unchanged hearing, and 74% (158) had worsened hearing. In 175 patients with ≥3 yr follow-up and who had measurable hearing pretreatment, 6% (11 ears) improved hearing, 31% (54 ears) unchanged hearing, and 63% (110 ears) had worsened hearing. Patients with tumors with larger target volumes (P = .040) and with neurofibromatosis type 2 (NF2; P = .017) were associated with poorer hearing (P = .040). Patients with word recognition scores (WRS) of 50% or poorer had tumors with a larger volume (P = .0002), larger linear size (P = .032), and NF2 (P = .045). Traditionally reported hearing outcomes using the Gardner Robertson maintenance of PTA ≤50 db or WRS ≥50% were 48% at 3 yr, which overestimates hearing outcomes compared to the above reporting standards. Conclusion Hearing declines over time in VS treated with SRS in a high proportion of cases. The frequency and magnitude of long-term hearing decline following SRS argues against prophylactic radiation for small tumors in hearing ears with undetermined growth behavior.

Background Although stereotactic radiosurgery (SRS) is an effective modality in the treatment of brainstem metastases (BSM), radiation-induced toxicity remains a critical concern. To better understand how severe or life-threatening toxicity is affected by the location of lesions treated in the brainstem, a review of all available studies reporting SRS treatment for BSM was performed. Methods Twenty-nine retrospective studies investigating SRS for BSM were reviewed. Results The rates of grade 3 or greater toxicity, based on the Common Terminology Criteria for Adverse Events, varied from 0 to 9.5% (mean 3.4 ± 2.9%). Overall, the median time to toxicity after SRS was 3 months, with 90% of toxicities occurring before 9 months. A total of 1243 cases had toxicity and location data available. Toxicity rates for lesions located in the medulla were 0.8% (1/131), compared with midbrain and pons, respectively, 2.8% (8/288) and 3.0% (24/811). Conclusions Current data suggest that brainstem substructure location does not predict for toxicity and lesion volume within this cohort with median tumor volumes 0.04–2.8 cc does not predict for toxicity.

For medically-refractory trigeminal neuralgia (TN), microvascular decompression (MVD) is the first-line treatment, and has demonstrated the greatest efficacy and durability. However, due to potential surgical complications, a bias may exist against performing MVD in elderly patients. We sought to determine through a quantitative analysis whether MVD in the elderly is a safe and effective procedure for TN. We completed a Pubmed/SCOPUS literature search up to 12/2016 for eligible studies on MVD for TN. Only research articles with age stratification of results were included. In this quantitative analysis, we analyzed the data for the six articles identified in the literature comparing MVD for a group of patients ≥65 years with an elderly group65 years. A total of 1483 were included. 455 patients were ≥65 years (mean 70.8 years, range 65-89 years) and 1028 patients were65 years (mean 53.4 years, range 19-64 years). Composite mean follow-up time was 51.6 months for the elderly group, and 55.1 months for the young group. Following MVD, each group had 1 mortality (p = 0.43). There were 21 serious morbidities in the elderly group (4.62%) and 32 in the young group (3.11%) (p = 0.11). In addition, 15 patients (1.46%) in the elderly group and 24 patients (1.62%) in the young group experienced a cerebrospinal fluid leak (p = 0.23). TN recurrence rates 9.23% in the young group and 13.33% in the elderly group (p = 0.070). In conclusion, for properly-selected surgical candidates, MVD should not be ruled out on the basis of age ≥65 years.

Background: Demarcation of malignant brain tumor boundaries is critical to achieve complete resection and to improve patient survival. Contrast-enhanced brain magnetic resonance imaging (MRI) is the gold standard for diagnosis and pre-surgical planning, despite limitations of gadolinium (Gd)-based contrast agents to depict tumor margins. Recently, solid metal-based nanoparticles (NPs) have shown potential as diagnostic probes for brain tumors. Gold nanoparticles (GNPs) emerged among those, because of their unique physical and chemical properties and biocompatibility. The aim of the present study is to review the application of GNPs for in vitro and in vivo brain tumor diagnosis. Methods: We performed a PubMed search of reports exploring the application of GNPs in the diagnosis of brain tumors in biological models including cells, animals, primates, and humans. The search words were “gold” AND “nanoparticle” AND “brain tumor”. Two reviewers performed eligibility assessment independently in an unblinded standardized manner. The following data were extracted from each paper: first author, year of publication, animal/cellular model, GNP geometry, GNP size, GNP coating (i.e. PEG, gadolinium), blood-brain barrier (BBB) crossing aids, imaging modalities, and therapeutic agents conjugated to the GNPs, Results: The PubMed search provided 100 items. A total of 16 studies, published between the 2011 and 2017, were included in our review. No studies on humans were found. Thirteen studies were conducted in vivo on rodent models. The most common shape was a nanosphere (twelve studies). The size of GNPs ranged between 20 nm and 120 nm. In eight studies, the GNPs were covered in polyethylene glycol (PEG). The BBB penetration was increased by surface molecules (nine studies) or by means of external energy sources (in two studies). The most commonly used imaging modalities were MRI (four studies), surface-enhanced Raman scattering (SERS) (three studies), and fluorescent microscopy (three studies). In two studies, the GNPs were conjugated with therapeutic agents. Conclusion: Experimental studies demonstrated that GNPs might be versatile, persistent and safe contrast agents for multimodality imaging, thus enhancing the tumor edges pre-, intra- and post-operatively improving microscopic precision. The diagnostic GNPs might also be used for multiple therapeutic approaches, namely as “theranostic” NPs.

Giant cell tumors (GCTs) developing from the cranial bones are rare. Occurrence of these tumors in the vicinity of eloquent areas precludes complete excision. Fractionated external beam radiotherapy (FEBRT) has been used for those cases, but with inconsistent outcomes. The authors report a case of a patient with a GCT involving the left occiput which was successfully treated by CyberKnife stereotactic radiosurgery (CK RS). There was improvement in the neurological deficit and occipital pain without adjunctive treatment. This is the first report of stereotactic radiosurgery (SRS) adopted as a primary treatment modality for a cranial GCT.

Trigeminal neuralgia is a debilitating neuropathic condition characterized by recurrent paroxysms of shock-like pain across the distribution of the trigeminal nerve, often brought on by innocuous stimuli. Available therapies presently include symptomatic management using anti-convulsant drugs and invasive surgical procedures to target the pathogenic drivers of disease or ablate the trigeminal nerve. Radiosurgery is a treatment modality that offers a minimally invasive, low-risk alternative that has promising clinical utility in the management of refractory trigeminal neuralgia. Radiosurgical approaches like Gamma Knife (GKS) and Cyberknife (CK) utilize image-guided, algorithm-defined dose contouring to disrupt pathogenic pain signaling by delivering targeted amounts of radiation along different points on the trigeminal nerve. This chapter reviews the structure of radiotherapy paradigms, treatment protocol, major outcomes, associated risks, relative clinical utility, and areas of further research that underlie the use of CK and GKS in managing trigeminal neuralgia.

Introduction This study's objective is to compare the overall survivals (OSs) and various parameters of patients with 1-3 versus ≥ 4 brain metastases post-CyberKnife radiosurgery (CKRS) (Accuray, Sunnyvale, California) alone. Methods Charts of 150 patients, from 2009-2014, treated with only CKRS for brain metastases were reviewed retrospectively for overall survival (OS) and patient, tumor, and imaging characteristics. Parameters included demographics, Eastern Cooperative Oncology Group (ECOG) performance scores, number and control of extracranial disease (ECD) sites, cause of death (COD), histology, tumor volume (TV), and post-CKRS whole brain radiotherapy (WBRT). The imaging characteristics assessed were time of complete response (CR), partial response (PR), stable imaging or local failure (LF), and distal brain failure (DBF). Patients and their data were divided into those with 1-3 (group 1) versus ≥ 4 brain metastases (group 2). For each CR and LF patient, absolute neutrophil count (ANC), absolute lymphocyte count (ALC)), and ANC/ALC ratio (NLR) were obtained, when available, at the time of CKRS. Results Both group 1 and group 2 had a median OS of 13 months. The patient median age for the 115 group 1 patients versus the 35 group 2 patients was 62 versus 56 years. Group 1 had slightly more males and group 2, females. The predominant ECOG score for each group was 1 and the number of ECD sites was one and two, respectively. Uncontrolled ECD occurred in the majority of both group 1 and group 2 patients. The main COD was ECD in both groups. The prevalent tumor histology for groups 1 and 2 was non-small cell lung carcinoma. Median TVs were 1.08 cc versus 1.42 cc for groups 1 and 2, respectively. The majority of patients in both groups did not undergo post-CKRS WBRT. Imaging outcomes were LC (CR, PR, or stable imaging) in 93 (80.9%) and 26 (74.3%) group 1 and 2 patients, of whom 32 (27.8%) and six (17.1%) had CR; 38 (33.0%) and 18 (51.4%), PR and 23 (20.0%) and two (5.7%), stable imaging; LF was the outcome in 22 (19.1%) and nine (25.7%) patients, and DBF occurred in 62 (53.9%) and 21 (60.0%), respectively. Uni- and multivariable analyses showed the independent parameters of a lower ECOG score, a greater number of ECD sites and uncontrolled ECD were significantly associated with greater mortality risk with and without accounting for other covariates. At CKRS, 19 group 1 and 2 CR patients had a mean ANC of 5.88 K/µL and a mean ALC of 1.31 K/µL and 13 (68%) of 19 had NLRs ≤ five, while 11 with LFs had a mean ANC of 5.22 K/µL and a mean ALC of 0.93 K/µL and seven (64%) had NLRs > five. An NLR ≤ five and high ALC was associated with a CR and an NLR > five and a low ALC with an LF. Conclusions Median OS post-CKRS was 13 months for both patients with 1-3 brain metastases and with ≥ 4. This is the only study in the literature to evaluate OS in patients with 1-3 and ≥ 4 brain metastases who were treated with CKRS alone. For groups 1 and 2 patients combined, 119 (79.3%) had LC and 38 (25.3%) had CR. The ANC, ALC, and NLR values are likely predictive of CR and LF outcomes.

Introduction This study’s objective is to assess various patient, tumor and imaging characteristics and to compare median overall survival (OS) of 150 patients with 1-12 brain metastases post-CyberKnife radiosurgery (CKRS) (Accuray, Sunnyvale, California) alone. Methods Charts of 150 patients, from 2009-2014, treated with only CKRS for brain metastases were reviewed retrospectively for patient, tumor, and imaging characteristics. Parameters included demographics, Eastern Cooperative Oncology Group (ECOG) performance scores, number and control of extracranial disease (ECD) sites, cause of death (COD), histology, tumor volume (TV), and post-CKRS whole brain radiotherapy (WBRT). The imaging characteristics assessed were time of complete response (CR), partial response (PR), stable imaging or local failure (LF), and distal brain failure (DBF). The primary tumor Ki-67s of the breast carcinoma brain metastasis patients, who had the longest median OS of any group, were recorded when available. Results The predominant age group for the 150-patient cohort was the younger 17-65 years of age category, which was represented by 94 (62.7%). The 150-patient group had slightly more males, 79 (52.7%). The majority of 111 (74%) patients had an ECOG score of 1, 39 (26%) had 1 ECD site and uncontrolled ECD occurred in 112 (74.7%). The main COD was ECD in 106 (70.7%). The prevalent tumor histology was non-small cell lung carcinoma (88 of 150, 58.7%). The most common TV was 0-0.5 ccs (48 of 150, 32%). The majority of 125 (83.3%) patients did not undergo post-CKRS WBRT. Imaging outcomes were local control (LC) (CR, PR, or stable imaging) in 119 (79.3%), of whom 38 (25.3%) had CR, 56 (37.3%) PR and 25 (16.7%) stable imaging; LF was the outcome in 31 (20.7%) and DBF occured in 83 (55.3%). The median OS was 13 months. Patients 17-65 years of age had a median OS of 13 months, while those 66-88 years, had 12 months. Females versus males had median OS of 15 versus 12 months. The most prolonged median OS of 21.5 months occurred in those with an ECOG score of 0. Patients with two ECD sites had a median OS of 14.5 months, while those with controlled ECD, 20.5 months. Patients with breast cancer brain metastases had the longest median OS of 23 months. The median OS for each of three (0-0.5 ccs, 0.6-1.5 ccs, 1.6-4.0 ccs) of four CKRS TV quartiles was 13 months and for those with 4.1-28.5 ccs, 10 months. Median OS for patients with versus without post-CKRS WBRT was 23 versus 12 months. The longest median OS of 18.5 months for post-CKRS imaging outcomes was in patients with CR; those with LF had a median OS of 11.5 months. Of nine patients with breast carcinoma brain metastases with available Ki-67s from primary tumor resections, the Ki-67 values were ≥ 34% for four patients with CR, PR and stable imaging outcomes, and < 34% for five patients with LF. Conclusions An ECOG score of 0, ECD control, breast carcinoma brain metastasis histology. undergoing WBRT post-CKRS and CR imaging outcomes, each resulted in a longer median OS. The Ki-67 proliferation indices from primary breast carcinoma resection correlated well with the brain imaging outcomes in a small preliminary study in the present study's breast carcinoma patients with brain metastases.

Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein–coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays, we identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G protein and arrestin pathways) to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands on the basis of NOPR antagonist J-113,397 [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] to explore structure-activity relationships. Our study shows that NOPR is capable of biased signaling, and further, the NOPR selective ligands MCOPPB [1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-(3R)-3-piperidinyl-1H-benzimidazole trihydrochloride] and NNC 63-0532 [8-(1-naphthalenylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-3-acetic acid, methyl ester] are G protein–biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor.

tereotactic radiosurgery can effectively ablate brain tumors; however, it also has the potential to cause tissue S injury around the tumor site. The acute effects on the brain tissue are usually reversible; they occur

Surgery is the primary treatment for Cushing disease. When surgery is unsuccessful in normalizing hypercortisolism, adjuvant radiation, such as stereotactic radiosurgery, may be useful to improve biochemical control.This retrospective study included a cohort of consecutive patients treated with CyberKnife (CK) radiosurgery for active Cushing disease at Stanford Hospital and Clinics.As first-line treatment, all patients underwent transsphenoidal surgery with histologic demonstration of an adrenocorticotropic hormone-producing pituitary adenoma. CK was performed as adjuvant therapy for persistent or recurrent disease. The median time between surgery and CK was 14 ± 34 months. Before CK, median maximal diameter of tumors was 9 mm (range, 7-32 mm), with cavernous sinus invasion in all patients (100%) and abutment of the optic chiasm in 1 patient (14.2%). With an average follow-up of 55.4 months, normalization of hypercortisolism was achieved in 4 patients (57.1%): 2 patients (28.5%) achieved normalization of the hypothalamic-pituitary-adrenal axis without glucocorticoid replacement, and 2 patients developed hypoadrenalism (28.5%). The median time to biochemical remission was 12.5 months. Hypopituitarism occurred in only 1 patient (14.2%), and no patients had visual complications. Time between surgery and radiotherapy of14 months was associated with a significantly improved biochemical remission rate (P = 0.02).In a cohort of patients with Cushing disease, we demonstrate that CK is an effective treatment with rare complications.

Summary: Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor’s genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration. : Darmanis et al. perform single-cell transcriptomic analyses of neoplastic and stromal cells within and proximal to primary glioblastomas. The authors describe a population of neoplastic-infiltrating glioblastoma cells as well as a putative role of tumor-infiltrating immune cells in supporting tumor growth. Keywords: single cell, RNA-seq, glioma, glioblastoma, GBM, brain, heterogeneity, infiltrating, diffuse, checkpoint

BACKGROUND: This is an updated version of the original Cochrane review published in 2013, Issue 4. Low‐grade gliomas (LGG) constitute a class of slow‐growing primary brain neoplasms. Patients with clinically and radiographically suspected LGG have two initial surgical options, biopsy or resection. Biopsy can provide a histological diagnosis with minimal risk but does not offer a direct treatment. Resection may have additional benefits such as increasing survival and delaying recurrence, but is associated with a higher risk for surgical morbidity. There remains controversy about the role of biopsy versus resection and the relative clinical outcomes for the management of LGG. OBJECTIVES: To assess the clinical effectiveness of biopsy compared to surgical resection in patients with a new lesion suspected to be a LGG. SEARCH METHODS: The following electronic databases were searched in 2012 for the first version of the review: Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11), MEDLINE (1950 to November week 3 2012), Embase (1980 to Week 46 2012). For this updated version, the following electronic databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5), MEDLINE (Nov 2012 to June week 3 2016), Embase (Nov 2012 to 2016 week 26). All relevant articles were identified on PubMed and by using the ’related articles’ feature. We also searched unpublished and grey literature including ISRCTN‐metaRegister of Controled Trials, Physicians Data Query and ClinicalTrials.gov for ongoing trials. SELECTION CRITERIA: We planned to include patients of any age with a suspected intracranial LGG receiving biopsy or resection within a randomized clinical trial (RCT) or controlled clinical trial (CCT). Patients with prior resections, radiation therapy, or chemotherapy for LGG were excluded. Outcome measures included overall survival (OS), progression‐free survival (PFS), functionally independent survival (FIS), adverse events, symptom control, and quality of life (QoL). DATA COLLECTION AND ANALYSIS: A total of 1375 updated citations were searched and critically analyzed for relevance. This was undertaken independently by two review authors. The original electronic database searches yielded a total of 2764 citations. In total, 4139 citations have been critically analyzed for this updated review. MAIN RESULTS: No new RCTs of biopsy or resection for LGG were identified. No additional ineligible non‐randomized studies (NRS) were included in this updated review. Twenty other ineligible studies were previously retrieved for further analysis despite not meeting the pre‐specified criteria. Ten studies were retrospective or were literature reviews. Three studies were prospective, however they were limited to tumor recurrence and volumetric analysis and extent of resection. One study was a population‐based parallel cohort in Norway, but not an RCT. Four studies were RCTs, however patients were randomized with respect to varying radiotherapy regimens to assess timing and dose of radiation. One RCT was on high‐grade gliomas (HGGs) and not LGG. Finally, one RCT evaluated diffusion tensor imaging (DTI)‐based neuro‐navigation for surgical resection. AUTHORS' CONCLUSIONS: Since the last version of this review, no new studies have been identified for inclusion and currently there are no RCTs or CCTs available on which to base definitive clinical decisions. Therefore, physicians must approach each case individually and weigh the risks and benefits of each intervention until further evidence is available. Some retrospective studies and non‐randomized prospective studies do seem to suggest improved OS and seizure control correlating to higher extent of resection. Future research could focus on RCTs to determine outcomes benefits for biopsy versus resection.