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Purpose: Gamma knife radiosurgery (GKRS) for orbital cavernous hemangioma (OCH) has emerged as a promising method due to its significant clinical improvement and low incidence of complications. This study aimed to evaluate the safety and efficacy of GKRS for the treatment of OCH., Methods: In accordance with the PRISMA framework, we searched PubMed, Cochrane Central, and Embase for studies reporting outcomes of GKRS for OCH. Studies reporting complications, visual improvement, proptosis, tumor reduction rate, and tumor progression rate for OCH following GKRS were included., Results: Six studies, out of 1856 search results, with 100 patients were included. Among them, only 5 minor complications were related to GKRS, including 3 with orbital pain and 2 with periorbital chemosis. Thus, the complication rate was 13% (95% CI, 7-25%). Visual acuity and visual field improvement rates after GKRS were 80% (95% CI, 63-96%) and 71% (95% CI, 47-95%) respectively. Proptosis improved in 94% of cases (95% CI, 83-100%). The tumor reduction rate was 77% after GKRS (95% CI, 69-85%)., Conclusion: GKRS for OCH appears to be a safe technique, as evidenced by the rate of clinical improvement and radiological improvement. However, studies are limited by an absence of a control group. Additional studies are needed to evaluate the relative efficacy of GKRS as compared with alternative surgical modalities for OCH., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The aim of the study was to investigate whether morphology (i.e. compact/diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients receiving Stereotactic Radiosurgery (SRS) for unruptured bAVMs. This retrospective study included 262 adult patients with unruptured bAVMs who underwent upfront SRS. Hemorrhagic events were defined as evidence of blood on CT or MRI. The morphology of bAVMs was evaluated using automated segmentation which calculated the proportion of vessel, brain tissue, and cerebrospinal fluid in bAVMs on T2-weighted MRI. Compactness index, defined as the ratio of vessel to brain tissue, categorized bAVMs into compact and diffuse types based on the optimal cutoff. Cox proportional hazard model was used to identify the independent factors for post-SRS hemorrhage. The median clinical follow-ups was 62.1 months. Post-SRS hemorrhage occurred in 13 (5.0%) patients and one of them had two bleeds, resulting in an annual bleeding rate of 0.8%. Multivariable analysis revealed bAVM morphology (compact versus diffuse), bAVM volume, and prescribed margin dose were significant predictors. The post-SRS hemorrhage rate increased with larger bAVM volume only among the diffuse nidi (1.7 versus 14.9 versus 30.6 hemorrhage per 1000 person-years in bAVM volume < 20 cm 3 versus 20-40 cm 3 versus > 40 cm 3 ; p = 0.022). The significantly higher post-SRS hemorrhage rate of Spetzler-Martin grade IV-V compared with grade I-III bAVMs (20.0 versus 3.3 hemorrhages per 1000 person-years; p = 0.001) mainly originated from the diffuse bAVMs rather than the compact subgroup (30.9 versus 4.8 hemorrhages per 1000 person-years; p = 0.035). Compact and smaller bAVMs, with higher prescribed margin dose harbor lower risks of post-SRS hemorrhage. The post-SRS hemorrhage rate exceeded 2.2% annually within the diffuse and large (> 40 cm 3 ) bAVMs and the diffuse Spetzler-Martin IV-V bAVMs. These findings may help guide patient selection of SRS for the unruptured bAVMs., (© 2024. The Author(s).)

Background and Objectives: The pathophysiology of vestibular schwannoma (VS) pseudoprogression after Gamma Knife radiosurgery (GKRS) remains unclear. Radiological features in pretreatment magnetic resonance images may help predict VS pseudoprogression. This study used VS radiological features quantified using an automated segmentation algorithm to predict pseudoprogression after GKRS treatment., Methods: This is a retrospective study comprising 330 patients with VS who received GKRS. After image preprocessing and T2W/contrast-enhanced T1-weighted image (CET1W) image generation, with fuzzy C-means clustering, VSs were segmented into solid and cystic components and classified as solid and cystic. Relevant radiological features were then extracted. The response to GKRS was classified into "nonpseudoprogression" and "pseudoprogression/fluctuation". The Z test for two proportions was used to compare solid and cystic VS for the likelihood of pseudoprogression/fluctuation. Logistic regression was used to assess the correlation between clinical variables and radiological features and response to GKRS., Results: The likelihood of pseudoprogression/fluctuation after GKRS was significantly higher for solid VS compared with cystic VS (55% vs 31%, P < .001). For the entire VS cohort, multivariable logistic regression revealed that a lower mean tumor signal intensity (SI) in T2W/CET1W images was associated with pseudoprogression/fluctuation after GKRS ( P = .001). For the solid VS subgroup, a lower mean tumor SI in T2W/CET1W images ( P = .035) was associated with pseudoprogression/fluctuation after GKRS. For the cystic VS subgroup, a lower mean SI of the cystic component in T2W/CET1W images ( P = .040) was associated with pseudoprogression/fluctuation after GKRS., Conclusion: Pseudoprogression is more likely to occur in solid VS compared with cystic VS. Quantitative radiological features in pretreatment magnetic resonance images were associated with pseudoprogression after GKRS. In T2W/CET1W images, solid VS with a lower mean tumor SI and cystic VS with a lower mean SI of cystic component were more likely to have pseudoprogression after GKRS. These radiological features can help predict the likelihood of pseudoprogression after GKRS., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Purpose: To examine the differential effects of SRS and TKI on EGFR-mutated NSCLC patients with brain metastases (BMs) and outcomes following continuation of the same TKI agent in case of new BMs., Methods: This study included 608 NSCLC patients (2,274 BMs) while meta-analyses included 1,651 NSCLC patients (> 3,944 BMs). Overall survival (OS) and intracranial progression free survival (iPFS) were estimated using Kaplan-Meier methods. Hazard ratios (95% CI) of prognostic factors were estimated using Cox regression models., Results: The median OS/iPFS (95% CI) (months) for patients with wildtype EGFR/ALK, EGFR mutations, and ALK rearrangements were 17.7 (12.9-23.6)/12.1 (9.8-15.6), 28.9 (23.8-33.3)/17.7 (14.8-21.2), and 118.0 (not reached)/71.7 (15.1-not reached), respectively. In EGFR-mutated patients, meta-analyses combining our data showed significantly improved OS and iPFS of patients who received SRS and TKI (OS:35.1 months, iPFS:20.0 months) when compared to those who have SRS alone (OS:20.8 months, iPFS:11.8 months) or TKI alone (OS:24.3 months, iPFS:13.8 months). Having SRS for newly diagnosed BMs while keeping the existing TKI agent yielded OS (30.0 vs. 32.1 months, p = 0.200) non-inferior to patients who started combined SRS and TKI therapy for their newly diagnosed NSCLC with BMs. Multivariable analyses showed that good performance score and TKI therapy were associated with improved outcomes., Conclusions: Combined SRS and TKI resulted in favorable outcomes in EGFR-mutated NSCLC patients with newly diagnosed BMs. Continuation of the same TKI agent plus SRS in case of new brain metastases yielded good clinical outcomes and may be considered a standard-of-care treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Whole brain radiation therapy (WBRT) for brain metastases (BMs) is a common cause of radiation-induced leukoencephalopathy; however the safety of alternative stereotactic radiosurgery (SRS) remains unclear. This study examined the incidence of leukoencephalopathy in patients treated with SRS alone versus WBRT plus SRS for BMs with a focus on the relationship between prognostic factors and leukoencephalopathy., Methods: Analysis was performed between 2002 and 2021. The total enrollment was 993 patients with the distribution: WBRT plus SRS (n = 291) and SRS only (n = 702). Leukoencephalopathy was graded from 0 to 3 for changes in white matter indicated by the MRI after WBRT or SRS. Patient characteristics and SRS dosimetric parameters were reviewed to identify factors that contributed to the incidence of leukoencephalopathy or overall survival., Results: The incidence of leukoencephalopathy was consistently higher in WBRT plus SRS group than in SRS alone group (p < 0.001). Leukoencephalopathy was also associated with a larger total tumor volume (≧28cm 3 ; p = 0.028) and age (> 77 years; p = 0.025). Nonetheless, the SRS integral dose to skull in the subgroup of WBRT plus SRS treatment was not demonstrated significance in development of leukoencephalopathy (p = 0.986 for integral dose 1-2 J, p = 0.776 for integral dose > 2 J)., Conclusions: This study revealed that SRS is safe for oligo-BMs in terms of leukoencephalopathy development. Patient age and total tumor volume were identified as important factors in assessing the development of leukoencephalopathy. The additional of SRS (even at an integral dose > 2 J) did not increase the incidence of leukoencephalopathy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Metastases extending to the pituitary gland and cavernous sinus are extremely rare; however, advances in neuroimaging have increased the reported incidence. Stereotactic radiosurgery (SRS) affords the precise delivery of focused radiation to minimize adverse radiation effects. This study assessed the efficacy and safety of SRS in the treatment of pituitary and cavernous sinus metastases., Methods: Analysis was performed on 23 patients with pituitary and cavernous sinus metastases who underwent treatment using SRS between 1996 and 2021. The cohort was categorized into 2 groups in terms of metastasis location: pituitary involvement (Group 1, n = 11) and cavernous sinus involvement (Group 2, n = 12). Overall survival, local tumor control, and distal tumor control rates were compared between the two groups using Kaplan-Meier analysis., Results: The median age of the cohort was 52.2 years and the median tumor volume was 4.5 mL. Overall survival rates were as follows: 1 year (72.9%), 2 years (51.8%), and 3 years (45.3%). Local tumor control rates were as follows: 1 year (82.3%), 2 years (82.3%), and 3 years (65.9%). Visual deficit and hypopituitarism were the most common presentations in Group 1, whereas cranial nerve deficit was the most common presentation in Group 2., Conclusions: SRS appears to be a safe and effective therapy for the treatment of pituitary and cavernous sinus metastases. GKRS is a relatively simple procedure, which places minimal stress on the patient, thereby facilitating further anti-cancer treatment. Considering the limited survival duration in cases of metastasis, it is very likely that post-GKRS complications (e.g., new onset cranial nerve deficit and hypopituitarism) would not become an issue before patient passes away., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Stereotactic radiosurgery (SRS) is an effective treatment for brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). However, factors associated with the development of post-SRS leptomeningeal metastasis (LM) remain unclear. The authors analyzed the incidence and risk factors of LM development in patients with NSCLC and BMs after SRS and examined the survival outcomes and prognostic factors after LM development., Methods: This retrospective study included patients with NSCLC treated with SRS for MRI-diagnosed BM from 2002 to 2021. The authors recorded various clinical and demographic data, including age, sex, tumor histology, molecular profile of tumors, extracranial disease status, previous craniotomy, Karnofsky Performance Status, systemic treatments, tumor volume, and number of BMs. The management and survival outcomes after LM diagnosis were also recorded., Results: LM developed in 13.7% of patients with NSCLC and BMs after SRS treatment. Large initial tumor volume and more than 5 BM lesions, but not EGFR mutation status and post-SRS treatment, were associated with LM development after SRS. Multivariate analysis revealed that chemotherapy and targeted therapy after LM were associated with better survival in patients with LM after SRS., Conclusions: This study is the first to evaluate the risk factors for LM in a relatively large cohort of patients with NSCLC after SRS. In patients with BMs harboring risk factors for subsequent LM, such as initial tumor volume and number of metastatic lesions, aggressive therapies with high CNS penetrating ability should be considered.

Objective: The goal of this study was to assess the safety and efficacy of single-session Gamma Knife radiosurgery (GKRS) for orbital cavernous hemangiomas (OCHs)., Methods: Patients who presented with an OCH between September 1999 and May 2022 and were treated with single-session GKRS were included in this single-center cohort study., Results: There were 23 patients (7 males and 16 females) in this study. The median margin dose was 12 Gy (range 11-13 Gy). The median clinical and radiological follow-ups were 45 months (range 5-190 months) and 45 months (range 6-190 months), respectively. Nine (69.2%) of 13 patients with visual acuity impairment had improvement in best corrected visual acuity. Of the 8 patients with visual field defects, 5 patients (62.5%) had complete resolution. Tumor regression was observed in 22 patients (95.7%). The mean relative reduction in tumor volume was 82.6% ± 23.7%. The relative reductions in tumor volume were 33%, 49%, 72%, 84%, and 89% at 6, 12, 24, 36, and 48 months, respectively. Adverse effects of radiation were not observed., Conclusions: GKRS appears to be safe and efficacious for treating OCHs over long-term follow-up. The treatment is associated with a high rate of regression in OCHs and remarkable improvement in both visual acuity and visual field deficits.

Objective: Tyrosine kinase inhibitors (TKIs) is the first-line treatment for EGFR-positive non-small cell lung cancer (NSCLC); however, its applicability to patients with wild-type NSCLC remains an issue of contention. This study compared the effects of gamma knife radiosurgery (GKRS) alone versus combining GKRS and TKIs in treating two genetic forms of NSCLC., Methods: This retrospective study examined 479 NSCLC patients with 1982 brain metastases who underwent GKRS and for whom imaging follow-up data or death records were available. All our patients were consecutive. All gene mutations were confirmed by lung biopsy. The three main endpoints in this study were overall survival (OS), local intracranial tumor control (LC), and distal intracranial tumor control (DC)., Results: There were 296 NSCLC patients with EGFR positive: TKI treatment (n = 262) and without TKI treatment (n = 34). GKRS + TKIs was more effective than GKRS alone in terms of OS (HR 0.53, p = 0.085) and DC (HR 0.51, p < 0.001). There were 150 NSCLC patients with wild-type EGFR: TKI treatment (n = 50) and without TKI treatment (n = 100). GKRS + TKIs was less effective than GKRS alone in terms of OS (HR 1.82, p = 0.049) and DC (HR: 1.40, p = 0.011). We observed no difference in terms of LC in both genetic groups., Conclusions: Combining GKRS with TKIs proved effective in EGFR positive NSCLC patients; however, we do not observe the similar results when combining GKRS with TKIs for patients with wild-type NSCLC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The goal of the study was to define and quantify brain arteriovenous malformation (bAVM) compactness and to assess its effect on outcomes after Gamma Knife radiosurgery (GKRS) for unruptured bAVMs., Methods: Unsupervised machine learning with fuzzy c-means clustering was used to differentiate the tissue constituents of bAVMs on T2-weighted MR images. The percentages of vessel, brain, and CSF were quantified. The proposed compactness index, defined as the ratio of vasculature tissue to brain tissue, categorized bAVM morphology into compact, intermediate, and diffuse types according to the tertiles of this index. The outcomes of interest were complete obliteration and radiation-induced changes (RICs)., Results: A total of 209 unruptured bAVMs treated with GKRS were retrospectively included. The median imaging and clinical follow-up periods were 49.2 and 72.3 months, respectively. One hundred seventy-three bAVMs (82.8%) achieved complete obliteration after a median latency period of 43.3 months. The rates of RIC and permanent RIC were 76.1% and 3.8%, respectively. Post-GKRS hemorrhage occurred in 14 patients (6.7%), resulting in an annual bleeding risk of 1.0%. Compact bAVM, smaller bAVM volume, and exclusively superficial venous drainage were independent predictors of complete obliteration. Diffuse bAVM morphology, larger bAVM volume, and higher margin dose were independently associated with RICs., Conclusions: The compactness index quantitatively describes the compactness of unruptured bAVMs. Moreover, compact bAVMs may have a higher obliteration rate and a smaller risk of RICs than diffuse bAVMs. This finding could help guide decision-making regarding GKRS treatment for patients with unruptured bAVMs.

In kinship tests, the investigating of the forensic STRs usually provides decisive information to resolve relationship cases. We describe a parentage case with 3 genetic incompatibilities (D6S1043, D18S51 and D2S1338) between the child and alleged parent. With 90 STR loci and 100 SNP loci, the massively parallel sequencing (MPS)-based genotyping results support the certainty of parentage, and the mismatched alleles were considered to be mutations. MPS can provide additional allele sequence structures that can be used to infer the origins of the mutations. SNPs as supplementary markers can provide effective information to give an unequivocal statement of the parentage., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations., Methods: Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses., Results: The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97)., Conclusions: Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.

Purpose: Our purpose was to determine whether the coverage of brain parenchyma within the 12 Gy radiosurgical volume (V12) correlates with the development of radiation-induced changes (RICs) in patients with unruptured cerebral arteriovenous malformations (AVM) after undergoing stereotactic radiosurgery (SRS)., Methods and Materials: This study conducted regular follow-up examinations of 165 patients with unruptured AVMs who had previously undergone SRS. The RICs identified in T2-weighted magnetic resonance imaging (MRI) scans at any time point in the first 3 years after SRS were labeled "early RICs." The RICs identified in T2-weighted MRI scans at 5-year follow-up brain images were labeled "late RICs." Fully automated segmentation was used to analyze the MRI scans from these patients, whereupon the volume and proportion of brain parenchyma within the V12 was calculated. Logistic regression analysis was used to characterize the factors affecting the incidence of early and late RICs of any grade after SRS., Results: The median duration of follow-up was 70 months (range, 36-222). Early RICs were identified in 124 of the 165 patients with the highest grades as followed: grade 1 (103 patients), grade 2 (19 patients), and grade 3 (2 patients). Only 103 patients had more than 5 years follow-up, and late RICs were identified in 70 of 103 patients. Seventeen of 70 patients with late RICs were symptomatic. The median volume and proportion of brain parenchyma within the V12 was 22.4 cm 3 (range, 0.6-63.9) and 58.7% (range, 18.4-76.8). Univariate analysis revealed that AVM volume and the brain volume within the V12 were correlated with the incidence of both early and late RICs after SRS. Multivariable analysis revealed that only the brain volume within the V12 was significantly associated with the incidence of early and late RICs after SRS., Conclusions: In patients with unruptured AVM, the volume of brain parenchyma within the V12 was an important factor associated with the incidence of early and late RICs after SRS. Before SRS, meticulous radiosurgical planning to reduce brain parenchyma coverage within the V12 could reduce the risk of complications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Gamma Knife radiosurgery (GKRS) is a common treatment modality for vestibular schwannoma (VS). The ability to predict treatment response is important in patient counseling and decision-making. The authors developed an algorithm that can automatically segment and differentiate cystic and solid tumor components of VS. They also investigated associations between the quantified radiological features of each component and tumor response after GKRS., Methods: This is a retrospective study comprising 323 patients with VS treated with GKRS. After preprocessing and generation of pretreatment T2-weighted (T2W)/T1-weighted with contrast (T1WC) images, the authors segmented VSs into cystic and solid components by using fuzzy C-means clustering. Quantitative radiological features of the entire tumor and its cystic and solid components were extracted. Linear regression models were implemented to correlate clinical variables and radiological features with the specific growth rate (SGR) of VS after GKRS., Results: A multivariable linear regression model of radiological features of the entire tumor demonstrated that a higher tumor mean signal intensity (SI) on T2W/T1WC images (p < 0.001) was associated with a lower SGR after GKRS. Similarly, a multivariable linear regression model using radiological features of cystic and solid tumor components demonstrated that a higher solid component mean SI (p = 0.039) and a higher cystic component mean SI (p = 0.004) on T2W/T1WC images were associated with a lower SGR after GKRS. A larger cystic component proportion (p = 0.085) was associated with a trend toward a lower SGR after GKRS., Conclusions: Radiological features of VSs on pretreatment MRI that were quantified using fuzzy C-means were associated with tumor response after GKRS. Tumors with a higher tumor mean SI, a higher solid component mean SI, and a higher cystic component mean SI on T2W/T1WC images were more likely to regress in volume after GKRS. Those with a larger cystic component proportion also trended toward regression after GKRS. Further refinement of the algorithm may allow direct prediction of tumor response.

Objectives: There are limited data on the natural history of chronic hepatitis B virus (HBV) infection in Asian American children. The aim of the present study was to describe a single-center experience of chronic HBV infection in Chinese American patients in New York City., Methods: A retrospective chart review was conducted for patients with chronic HBV infection who had pediatric visits from 2006 to 2017. Clinical and laboratory data were collected to characterize the status of HBV infection and its disease course both cross-sectionally and longitudinally. Available maternal charts were reviewed., Results: Of the total 353 patients, 72 patients (20%) were US-born. Positive hepatitis B envelope antigen (HBeAg) was documented in 208 patients (58%). Three phases of chronic HBV infection were categorized for 329 patients: immune-tolerant 112 (34%), HBeAg-positive immune-active 47 (14%), and inactive carrier 82 (25%). The remaining 88 patients (27%) did not fit into a particular category with 26 of 88 patients meeting the criteria for inactive carrier except for mildly elevated alanine aminotransferase. Age and liver enzyme levels were significantly different between HBeAg-positive and HBeAg-negative groups (P < 0.05). Among 179 patients followed for ≥5 years, the spontaneous seroconversion rate was 38%. In eight patients with linked maternal data, all children completed the HBV vaccine series and seven of eight received hepatitis B immunoglobulin. All mothers were HBeAg-positive with high HBV DNA and had no anti-viral therapy during pregnancy., Conclusions: Both immune-tolerant and inactive carrier phases were common for chronic HBV infection with a spontaneous seroconversion rate of 38%. All US-born patients were born in the era of implemented universal immune-prophylaxis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: The present study was to explore the feasibility of developing positron molecular probes for the metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), to evaluate the distribution and pharmacokinetics, and to explore whether the probe can be used for the imaging of malignant tumours with high MALAT-1 expression in vivo., Methods: [68Ga]Ga labelling of MALAT-1 antisense oligonucleotides ([68Ga]Ga-MALAT-1-ASO) was synthesized by the conjugation of MALAT-1-NOTA-ASO and [68Ga] Ga3+. The radiochemical purity was shown by radio-HPLC. Pharmacokinetic studies and cellular uptake studies were performed. The biodistribution and metabolism of [68Ga] Ga-MALAT-1-ASO in normal ICR and MHCC-LM3 xenograft-bearing nude mice were studied in vitro and in vivo., Results: [68Ga]Ga-MALAT-1-ASO was obtained in 98% radiochemical yield from a 10-min synthesis with 100 ± 50 MBq/nmol specific activity and >99% radiochemical purity. The Log D was -2.53 ± 0.19. The tracer displayed excellent stability in vitro. 68Ga-MALAT-1 ASO showed satisfactory binding ability to MHCC-LM3 cells; the biodistribution of [68Ga]Ga-MALAT-1-ASO in MHCC-LM3 tumour-bearing mice demonstrated specific uptake of the radiotracer (3.04 ± 0.11%ID/g). Micro-PET images of the MHCC-LM3 cell xenograft mouse model provided further evidence to support the hypothesis that [68Ga]Ga-MALAT-1-ASO can target tumours in vivo., Conclusions: We conclude that [68Ga]Ga labelling of MALAT-1 ASO is a convenient approach. The high accumulation of [68Ga]Ga-MALAT-1-ASO for tumours expressing MALAT-1 suggests that this radio compound may be used as a potential positron molecular probe. Molecular structure optimization studies need to be more in-depth to further reduce its background uptake and enhance tumour targeting., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Hypothalamic obesity is common among patients with craniopharyngioma. This study examined whether precise stereotactic radiosurgery reduces the risk of hypothalamic obesity in cases of craniopharyngioma with expected long-term survival., Methods: This cohort study included 40 patients who had undergone Gamma Knife radiosurgery (GKRS; n = 22) or fractionated radiotherapy (FRT; n = 18) for residual or recurrent craniopharyngioma. Neurological presentations, tumor volume changes, and BMI values were meticulously reviewed. The median clinical follow-up durations were 9.7 years in the GKRS group and 10.8 years in the FRT group., Results: The median ages at the time of GKRS and FRT were 9.0 years and 10.0 years, respectively. The median margin dose of GKRS was 12.0 Gy (range 10.0-16.0 Gy), whereas the median dose of FRT was 50.40 Gy (range 44.1-56.3 Gy). Prior to GKRS or FRT, the median BMI values were 20.5 kg/m2 in the GKRS cohort and 20.0 kg/m2 in the FRT cohort. The median BMIs after radiation therapy at final follow-up were 21.0 kg/m2 and 24.0 kg/m2 for the GKRS and FRT cohorts, respectively. In the FRT cohort, BMI curves rapidly increased beyond the 85th percentile of the upper limit of the general population. BMI curves in the GKRS cohort increased more gradually, and many of the patients merged into the normal growth curve after adolescence. However, the observed difference was not statistically significant (p = 0.409)., Conclusions: The study compared the two adjuvant radiation modalities most commonly used for recurrent and residual craniopharyngioma. The authors' results revealed that precise radiosurgery dose planning can mediate the subsequent increase in BMI. There is every indication that meticulous GKRS treatment is an effective approach to treating craniopharyngioma while also reducing the risk of hypothalamic obesity.

Clinical tracking of chimeric antigen receptor (CAR) T cells in vivo by positron emission tomography (PET) imaging is an area of intense interest. But the long-lived positron emitter-labeled CAR T cells stay in the liver and spleen for days or even weeks. Thus, the excessive absorbed effective dose becomes a major biosafety issue leading it difficult for clinical translation. In this study we used  68 Ga, a commercially available short-lived positron emitter, to label CAR T cells for noninvasive cell tracking in vivo. CAR T cells could be tracked in vivo by 68 Ga-PET imaging for at least 6 h. We showed a significant correlation between the distribution of 89 Zr and 68 Ga-labeled CAR T cells in the same tissues (lungs, liver, and spleen). The distribution and homing behavior of CAR T cells at the early period is highly correlated with the long-term fate of CAR T cells in vivo. And the effective absorbed dose of 68 Ga-labeled CAR T cells is only one twenty-fourth of 89 Zr-labeled CAR T cells, which was safe for clinical translation. We conclude the feasibility of 68 Ga instead of 89 Zr directly labeling CAR T cells for noninvasive tracking of the cells in vivo at an early stage based on PET imaging. This method provides a potential solution to the emerging need for safe and practical PET tracer for cell tracking clinically.

Background: The prevalence of metabolic syndrome (MetS) rapidly increased over the past decades. However, little evidence exists about the effects of long-term exposure to ambient air pollution on MetS in children and adolescents., Objective: This study aims to assess the association between long-term ambient air pollution and the prevalence of MetS in a large population of Chinese children and adolescents., Methods: In 2013, a total of 9,897 children and adolescents aged 10 to 18 years were recruited from seven provinces/municipalities in China. MetS was defined based on the recommendation by the International Diabetes Federation (IDF). Satellite based spatio-temporal models were used to estimate exposure to ambient air pollution (including particles with diameters ≤1.0 µm (PM 1 ), ≤2.5 µm (PM 2.5 ), and ≤10 µm (PM 10 ), and nitrogen dioxide (NO 2 )). Individual exposure was calculated according to 94 schools addresses. After adjustment for a range of covariates, generalized linear mixed-effects models were utilized to evaluate the associations between air pollutants and the prevalence of MetS and its components. In addition, several stratified analyses were examined according to sex, weight status, outdoor physical activity time, and sugar-sweetened beverages (SSBs) intake., Results: The prevalence of MetS was 2.8%. The odds ratio of MetS associated with a 10 μg/m 3 increase in PM 1 , PM 2.5 , PM 10 and NO 2 was 1.20 (95%CI: 0.99, 1.46), 1.31 (95%CI: 1.05, 1.64), 1.32 (95%CI: 1.08, 1.62), and 1.33 (95%CI: 1.03, 1.72), respectively. Regarding the MetS components, we observed associations between all pollutants and abdominal obesity. In addition, long-term PM 1 and NO 2 exposures were associated with the prevalence of elevated fasting blood glucose. Stratified analyses detected that the associations between air pollutants and the prevalence of MetS were stronger in boys (P interaction  < 0.05)., Conclusions: We found that long-term exposure to PM 2.5 , PM 10 , and NO 2 were positively associated with the prevalence of MetS in children and adolescents. Our findings may have certain public health implications for some comprehensive strategy of environment improvement and lifestyles changes in order to reduce the burden of non-communicable disease., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Although rare, orbital cavernous hemangioma (OCH) is the most common benign orbital neoplasm in adults and may cause vision disturbance or loss due to optic nerve compression. The conventional treatment is surgical excision, which carries a risk of intraoperative nerve damage, whereas gamma knife radiosurgery (GKRS) can be a safe and effective alternative. Herein, we report the results of four patients with OCH treated with GKRS, and describe the method of treatment including the optic nerve protection., Methods: This retrospective study included four consecutive patients (three women, one man; mean age: 50 ± 14.7 years) with OCH treated with single-session GKRS between 2014 and 2020. Three patients had decreased visual acuity. During GKRS, the prescription dose delivered to the tumor margin was 12 Gy at the 55-58% isodose line. The dose to the optic nerve margin was < 12 Gy. Follow-up included sequential magnetic resonance imaging (MRI) and ophthalmological examinations at 6-month intervals., Results: The median follow-up period was 29.5 ± 23 months (range, 12-63 months). After GKRS, three patients with visual dysfunction had substantial vision improvement; the fourth patient continued to have normal vision without deterioration. Radiological outcomes after GKRS indicated an average tumor shrinkage of 70% ± 10.6% at the 6-month follow-up and 83% ± 2.64% at the 1-year follow-up. No adverse radiation effects were observed., Conclusions: GKRS for OCH achieved favorable clinical outcomes, with substantial tumor volume reduction. OCH can be diagnosed based on characteristic MRI findings. GKRS may be considered a treatment option for OCH in selected cases.

Background: Previous studies have indicated that exposure to green space may benefit human health. However, the available evidence concerning the effects of greenness, especially school-based greenness, on pediatric obesity is scarce., Objective: To explore the association between school-based greenness and adiposity in children and adolescents in China., Method: We conducted a nationwide cross-sectional study of 56,620 children and adolescents (aged 6-18 years) in seven provinces/municipalities across China. School-based greenness was assessed using satellite-derived Normalized Difference Vegetation Index (NDVI) and Soil Adjusted Vegetation Index (SAVI) within 100-, 500-, and 1000-m circular buffers around each school's address. Generalized linear mixed regression models were used to estimate associations of greenness with BMI z-scores (zBMI), waist circumference, and prevalent overweight/obesity. We also explored the potential mediating role of ambient air pollution and physical activity in the greenness-adiposity associations., Result: In the adjusted model, an IQR increase in NDVI -1000m was associated with lower zBMI (β: -0.11, 95% confidence interval[CI]: -0.13,-0.09) and waist circumference (β: -0.64, 95%CI: -0.78,-0.50). Consistently, an IQR increase in NDVI -100m , NDVI -500m , NDVI -1000m was associated with 7-20% lower odds of overweight/obesity in the adjusted models. Air pollutants mediated 6.5-29.1% of the association between greenness and zBMI. No significant mediation effect was observed for physical activity., Conclusion: Higher school-based greenness levels were associated with lower zBMI, waist circumference, and lower odds of overweight and obesity in children and adolescents. Ambient air pollutants may partially mediate the greenness-adiposity associations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We proposed an algorithm to automate the components within the identification of components within the nidus of cerebral arteriovenous malformations (AVMs) which may be used to analyze the relationship between its diffuseness and treatment outcomes following stereotactic radiosurgery (SRS)., Objectives: to determine the impact of the diffuseness of the AVM nidus on SRS outcomes., Methods: This study conducted regular follow-ups of 209 patients with unruptured AVMs who underwent SRS. The diffuseness of the AVM nidus was estimated by quantifying the proportions of vascular nidal component, brain parenchyma, and cerebrospinal fluid in T2-weighted MRIs. We used Cox regression analysis to characterize the association between nidal diffuseness and treatment outcomes in terms of obliteration rate and radiation-induced change (RICs) rate following SRS., Results: The median AVM volume was 20.7 cm3. The median duration of imaging follow-up was 51 months after SRS. The overall AVM obliteration rate was 68.4%. RICs were identified in 156 of the 209 patients (74.6%). The median proportions of the nidus of AVM and brain parenchyma components within the prescription isodose range were 30.2 and 52.2%, respectively. Cox regression multivariate analysis revealed that the only factor associated with AVM obliteration rate after SRS was AVM volume. However, a larger AVM volume (>20 mL) and a larger proportion of brain parenchyma (>50%) within the prescription isodose range were both correlated with a higher RIC rate following SRS., Conclusions: The diffuseness of the nidus indeed appears to affect the RIC rate following SRS in patients with unruptured AVMs., (© 2020 S. Karger AG, Basel.)

Aim: This study assessed treatment outcomes of Helicobacter pylori (H pylori) infection among inner-city children., Methods: This was a retrospective study of patients aged 1-21 years who underwent initial treatment for H pylori infection from 2011 to 2015. We included patients who completed 2 weeks of treatment with documented adequate compliance after H pylori infection was diagnosed. Treatment outcomes were measured based on stool H pylori antigen and/or histology., Results: Of the total 261 patients diagnosed with H pylori, 239 completed the first-line treatment. The regimens used included amoxicillin/clarithromycin/proton pump inhibitor (PPI) in 207/239 patients (86.6%), amoxicillin/metronidazole/PPI in 14/239 patients (5.8%) and other regimens in 18/239 patients (7.5%). H pylori eradication status was tested in 111/207 (53.6%) patients treated with amoxicillin/clarithromycin/PPI, and the eradication was achieved in 84/111(75.7%) patients. The treatment success rates for amoxicillin/metronidazole/PPI and other regimens were 71.4% (5/7) and 63.6% (7/11), respectively. There was no statistical significance of post-treatment stool H pylori antigen results between PPI (n = 31) and no PPI (n = 43) users., Conclusion: The study showed an eradication rate of 75.7% with the regimen amoxicillin/clarithromycin/PPI suggesting significant antibiotic resistance in our population. The use of PPI did not influence post-treatment stool H pylori antigen results., (© 2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Thyroid cancer (TC) is a frequently occurring malignant tumor with a rising steadily incidence. microRNA (miRNA/miR)‑193a‑3p is an miRNA that is associated with tumors, playing a crucial role in the genesis and progression of various cancers. However, the expression levels of miR‑193a‑3p and its molecular mechanisms in TC remain to be elucidated. The present study aimed to probe the expression of miR‑193a‑3p and its clinical significance in TC, including its underlying molecular mechanisms. Microarray and RNA sequencing data gathered from three major databases, specifically Gene Expression Omnibus (GEO), ArrayExpress and The Cancer Genome Atlas (TCGA) databases, and the relevant data from the literature were used to examine miR‑193a‑3p expression. Meta‑analysis was also conducted to evaluate the association between clinicopathological parameters and miR‑193a‑3p in 510 TC and 59 normal samples from the TCGA database. miRWalk 3.0, and the TCGA and GEO databases were used to predict the candidate target genes of miR‑193a‑3p. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and protein‑protein interaction network enrichment analyses were conducted by using the predicted candidate target genes to investigate the underlying carcinogenic mechanisms. A dual luciferase assay was performed to validate the targeting regulatory association between the most important hub gene cyclin D1 (CCND1) and miR‑193a‑3p. miR‑193a‑3p expression was considerably downregulated in TC compared with in the non‑cancer controls (P<0.001). The area under the curve of the summary receiver operating characteristic was 0.80. Downregulation of miR‑193a‑3p was also significantly associated with age, sex and metastasis (P=0.020, 0.044 and 0.048, respectively). Bioinformatics analysis indicated that a low miR‑193a‑3p expression may augment CCND1 expression to affect the biological processes of TC. In addition, CCND1, as a straightforward target, was validated through a dual luciferase assay. miR‑193a‑3p and CCND1 may serve as prognostic biomarkers of TC. Finally, miR‑193a‑3p may possess a crucial role in the genesis and progression of TC by altering the CCND1 expression.

Purpose: Stereotactic radiosurgery (SRS) is a potential re-irradiation treatment for recurrent intracranial ependymoma after prior radiation therapy. The purpose of this study was to examine the efficacy and safety of repeated SRS in the treatment of recurrent intracranial ependymomas., Methods: This is a retrospective study of consecutive patients with residual or recurrent intracranial ependymomas who were treated with SRS between 1993 and 2018. Tumor progression was defined as a ≥ 10% increase in tumor volume. Tumor regression was defined as a ≥ 10% reduction in tumor volume. A tumor that remained within 10% of its original volume was defined as stable. Tumor control comprised tumor regression and stability. Time-dependent analyses were performed using two treatment failure endpoint definitions: (1) evidence of local tumor progression or distant metastasis (single SRS analysis), and (2) lack of tumor response to SRS (repeated SRS analysis). These analyses were adjusted for the competing risk of death., Results: The study comprised 37 patients (65 intracranial ependymomas) who underwent multiple SRS sessions (range: 1-7). Median age was 10.2 years (range: 0.8-53.8 years), and median tumor volume was 1.5 mL (range: 0.01-22.5 mL). The median radiation dose was 13.3 Gy (range: 7.9-22.0 Gy) at a median isodose line of 57% (range: 50-90%). Overall tumor control rates in the single SRS analysis adjusting for the competing risk of death were 53.6%, 30.5%, and 23.6% at 1, 3, and 5 years, respectively. Overall tumor control rates in the repeated SRS analysis adjusting for the competing risk of death were 70.6%, 50.4%, and 43.1% at 1, 3, and 5 years, respectively. Prior gross total resection was the only independent predictor of overall tumor control after SRS (aHR = 25.62 (1.55-422.1), p = 0.02)., Conclusions: Repeated GKRS appeared to be an effective treatment strategy for recurrent or residual intracranial ependymomas, with acceptable complication rates.

Rationale and Objectives: The purpose of this study was to establish and validate radiomics signatures based on ultrasound (US) medicine images to assess the biological behaviors of intrahepatic cholangiocarcinoma (ICC) in a noninvasive manner., Materials and Methods: This study consisted of 128 ICC patients. We focused on evaluating six pathological features: microvascular invasion, perineural invasion, differentiation, Ki-67, vascular endothelial growth factor, and cytokeratin 7. Region of interest (ROI) of ICC was identified by manually plotting the tumor contour on the grayscale US image. We extracted radiomics features from medical US imaging. Then, dimensionality reduction methods and classifiers were used to develop radiomic signatures for evaluating six pathological features in ICC. Finally, independent validation datasets were used to assess the radiomic signatures performance., Results: We extracted 1076 quantitative characteristic parameters on the US medicine images. Based on extracted radiomics features, the best performing radiomic signatures for evaluating microvascular invasion features were produced by hypothetical test + support vector machine (SVM), perineural invasion subgroup were least absolute shrinkage and selection operator + principal component analysis + support vector machine, differentiation subgroup were hypothetical test + decision tree, Ki-67 subgroup were hypothetical test + logistic regression, vascular endothelial growth factor subgroup were hypothetical test + Gradient Boosting Decision Tree (GBDT), and cytokeratin 7 subgroup were hypothetical test + bagging, respectively., Conclusion: Through the high-throughput radiomics analysis based on US medicine images, we proposed radiomics signatures that have moderate efficiency in predicting the biological behaviors of ICC noninvasively., (Copyright © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The emergence of drug resistance in Helicobacter pylori has resulted in a greater need for susceptibility-guided treatment. While the alleles associated with resistance to clarithromycin and levofloxacin have been defined, there are limited data regarding the molecular mechanisms underlying resistance to other antimicrobials. Using H. pylori isolates from 42 clinical specimens, we compared phenotypic and whole-genome sequencing (WGS)-based detection of resistance. Phenotypic resistance correlated with the presence of alleles of 23S rRNA (A2142G/A2143G) for clarithromycin (kappa coefficient, 0.84; 95% confidence interval [CI], 0.67 to 1.0) and gyrA (N87I/N87K/D91Y/D91N/D91G/D99N) for levofloxacin (kappa coefficient, 0.90; 95% CI, 0.77 to 1.0). Phenotypic resistance to amoxicillin in three isolates correlated with mutations in pbp1 , pbp2 , and/or pbp3 within coding regions near known amoxicillin binding motifs. All isolates were phenotypically susceptible to tetracycline, although four bore a mutation in 16S rRNA (A926G). For metronidazole, nonsense mutations and R16H substitutions in rdxA correlated with phenotypic resistance (kappa coefficient, 0.76; 95% CI, 0.56 to 0.96). Previously identified mutations in the rpoB rifampin resistance-determining region (RRDR) were not present, but 14 novel mutations outside the RRDR were found in rifampin-resistant isolates. WGS also allowed for strain lineage determination, which may be important for future studies in associating precise MICs with specific resistance alleles. In summary, WGS allows for broad analyses of H. pylori isolates, and our findings support the use of WGS for the detection of clarithromycin and levofloxacin resistance. Additional studies are warranted to better define mutations conferring resistance to amoxicillin, tetracycline, and rifampin, but combinatorial analyses for rdxA gene truncations and R16H mutations have utility for determining metronidazole resistance., (Copyright © 2020 American Society for Microbiology.)

Purpose: Gamma Knife radiosurgery (GKRS) is a non-invasive procedure for the treatment of brain metastases. This study sought to determine whether radiomic features of brain metastases derived from pre-GKRS magnetic resonance imaging (MRI) could be used in conjunction with clinical variables to predict the effectiveness of GKRS in achieving local tumor control., Methods: We retrospectively analyzed 161 patients with non-small cell lung cancer (576 brain metastases) who underwent GKRS for brain metastases. The database included clinical data and pre-GKRS MRI. Brain metastases were demarcated by experienced neurosurgeons, and radiomic features of each brain metastasis were extracted. Consensus clustering was used for feature selection. Cox proportional hazards models and cause-specific proportional hazards models were used to correlate clinical variables and radiomic features with local control of brain metastases after GKRS., Results: Multivariate Cox proportional hazards model revealed that higher zone percentage (hazard ratio, HR 0.712; P = .022) was independently associated with superior local tumor control. Similarly, multivariate cause-specific proportional hazards model revealed that higher zone percentage (HR 0.699; P = .014) was independently associated with superior local tumor control., Conclusions: The zone percentage of brain metastases, a radiomic feature derived from pre-GKRS contrast-enhanced T1-weighted MRIs, was found to be an independent prognostic factor of local tumor control following GKRS in patients with non-small cell lung cancer and brain metastases. Radiomic features indicate the biological basis and characteristics of tumors and could potentially be used as surrogate biomarkers for predicting tumor prognosis following GKRS.

Background: Remission rate is associated with higher dose of Gamma Knife Radiosurgery (GKRS; Gamma Knife: Elekta AB, Stockholm, Sweden) for acromegaly, but the dose ≥25 Gy is not always feasible when the functioning adenoma is close to optic apparatus., Objective: To evaluate the efficacy and safety of low-dose (<25 Gy) GKRS in the treatment of patients with acromegaly., Methods: Single-center retrospective review of acromegaly cases treated with GKRS between June 1994 and December 2016. A total of 76 patients with the diagnosis of acromegaly who were treated with low-dose GKRS were selected for inclusion. Patients were treated with a median margin dose, isodose line, and treatment volume of 15.8 Gy, 57.5%, and 4.8 mL, respectively. Any identifiable portion of the optic apparatus was limited to a radiation dose of 10 Gy. All patients underwent full endocrine, ophthalmological, and imaging evaluation prior to and after GKRS treatments, and results of these were analyzed., Results: Biochemical remission was achieved in 33 (43.4%) patients. Actuarial remission rates were 20.3%, 49.9%, and 76.3% at 4, 8, and 12 yr, respectively. Absence of cavernous sinus invasion (P = .042) and lower baseline insulin-like growth factor-1 levels (P = .019) were significant predictors of remission. New hormone deficiencies were found in 9 (11.8%) patients. Actuarial hormone deficiency rates were 3%, 14%, and 22.2% at 4, 8, and 10 yr, respectively. Two (2.6%) patients who achieved initial remission experienced recurrence. No optic complications were encountered., Conclusion: Reasonable remission and new hormone deficiency rates can be achieved with low-dose GKRS for acromegaly. These rates may be comparable to those with standard GKRS margin doses., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Purpose: To evaluate the outcomes of patients who underwent Gamma Knife radiosurgery (GKRS) for the treatment of cavernous sinus (CS) meningiomas., Methods: We retrospectively reviewed the clinical and radiological outcomes of 95 patients with CS meningiomas at Taipei Veterans General Hospital between 1993 and 2011. The study cohort comprised 27 men and 68 women with a median age of 50 years (range 29-79 years). The median pre-GKRS tumor volume was 6.6 ml (range 0.9-35.7 ml). The median margin dose was 12 Gy (range 11-21 Gy). The clinical factors related to favorable outcomes were assessed., Results: The median follow-up period was 59 (range 12-209) months. At the final follow-up, the tumor volume regressed in 70 patients (74%) and progressed in eight (8%). Kaplan-Meier analysis revealed that the progression-free survival rates at 5 and 10 years were 92.7% and 81.2%, respectively. Three patients (3.2%) experienced exacerbated cranial nerve dysfunction following radiosurgery. Confined tumors were found to be an independent prognostic factor for tumor control and shorter times to regression in the multivariable analyses. No risk factor for tumor progression was identified in either the univariate or multivariate analyses., Conclusions: GKRS provides good long-term tumor control and is associated with low cranial nerve-related morbidity development rates in patients with small- to medium-sized CS meningiomas. Confined tumor could be an independent prognostic factor for tumor control and shorter times to regression in multivariate analysis. Life-long follow-up is mandatory in such settings, even for outpatients with shrunken or stabilized tumors.

Objective: There is a lack of consensus regarding whether if residual non-functional macroadenomas (NFM) should undergo empirical stereotactic radiosurgery (SRS) or be monitored until tumor progression before SRS treatment. The aim of this study is to compare the risks and benefits of empirical versus progression-guided SRS for NFM after subtotal resection., Methods: This is a retrospective study of consecutive NFM patients who subtotal surgical resection followed by SRS between 1999 and 2014. Patients were dichotomized into two groups: empirical SRS (SRS without evidence of tumor progression) and progression-guided SRS (SRS after demonstration of tumor progression) groups. Tumor response was categorized into: (1) regression, ≥ 10% decrease in tumor volume; (2) stable, < 10% increase or decrease in tumor volume; and (3) progression, ≥ 10% increase in tumor volume. Tumor control comprised stable tumor response and tumor regression., Results: Of the 112 patients who underwent SRS for NFM, 106 patients were treated for residual NFM after surgical resection, and included in the final analysis. The empirical SRS and progression-guided SRS groups comprised 46 and 60 patients, respectively. Overall tumor control rate was 88.7%. Higher rate of tumor control was achieved in the empirical SRS group compared to the progression-guided SRS group (95.65% vs. 83.33%, p = 0.047). Rates of new visual field deficit, cranial neuropathy and endocrinopathy were comparable between the two groups. Empirical SRS group had higher rates of progression-free survival compared to progression-guided SRS group (p = 0.015). Actuarial progression-free survival rates for the empirical SRS group were 93.2%, 93.2%, and 81.5% at 3, 5, and 10 years after SRS. Actuarial progression-free survival rates for the progression-guided SRS were 86.4%, 82.1%, and 68.4% at 3, 5, and 10 years after SRS., Conclusion: Empirical SRS offers higher rates of tumor control and progression-free survival compared to progression-guided SRS in patients with residual NFM after surgical resection. Rates of new hypopituitarism and cranial neuropathies were comparable between the two groups.

Nonconjugated red fluorescent polymers have been increasingly studied to improve the biocompatibility and penetration depth over conventional fluorescent materials. However, the accessibility of such polymers remains challenging due to the scarcity of nonconjugated fluorophores and lacking relevant mechanism of red-shifted fluorescence. Herein, we discovered that the combination of hydrogen bonding and π-π stacking interactions provides nonconjugated poly(amide-imide) with a large bathochromic shift (>100 nm) from blue-green fluorescence to red emission. The amphiphilic PEGylated poly(amide-imide) derived from in situ PEGylation self-assembled into nanovesicles in water, which isolated the aminosuccinimide fluorophore from the solvents and suppressed the hydrogen bonds formation between aminosuccinimide fluorophores and water. Therefore, the fluorescence of PEGylated poly(amide-imide) in water was soundly retained. Furthermore, the strong hydrogen bonding and hydrophobic interactions with water provided PEGylated poly(amide-imide) with a reversible thermoresponsiveness and presented a concentration-dependent behavior. Finally, accompanied by the excellent biostability and photostability, PEGylated poly(amide-imide) exhibited as a good candidate for cell imaging.

Background: Gamma knife radiosurgery (GKRS) is a common treatment for cerebral arterio-venous malformations (AVMs), particularly in cases where the malformation is deep-seated, large, or in eloquent areas of the brain. Unfortunately, these procedures can result in radiation injury to brain parenchyma. The fact that every AVM is unique in its vascular morphology makes it nearly impossible to exclude brain parenchyma from isodose radiation exposure during the formulation of a GKRS plan. Calculating the percentages of the various forms of tissue exposed to specific doses of radiation is crucial to understanding the clinical responses and causes of brain parenchyma injury following GKRS for AVM., Methods: In this study, we developed a fully automated algorithm using unsupervised classification via fuzzy c-means clustering for the analysis of T2 weighted images used in a Gamma knife plan. This algorithm is able to calculate the percentages of nidus, brain tissue, and cerebrospinal fluid (CSF) within the prescription isodose radiation exposure region., Results: The proposed algorithm was used to assess the treatment plan of 25 patients with AVM who had undergone GKRS. The Dice similarity index (SI) was used to determine the degree of agreement between the results obtained using the algorithm and a visually guided manual method (the gold standard) performed by an experienced neurosurgeon. In the nidus, the SI was (74.86 ± 1.30%) (mean ± standard deviation), the sensitivity was (83.05 ± 11.91)%, and the specificity was (86.73 ± 10.31)%. In brain tissue, the SI was (79.50 ± 6.01)%, the sensitivity was (73.05 ± 9.77)%, and the specificity was (85.53 ± 7.13)%. In the CSF, the SI was (69.57 ± 15.26)%, the sensitivity was (89.86 ± 5.87)%, and the specificity was (92.36 ± 4.35)%., Conclusions: The proposed clustering algorithm provides precise percentages of the various types of tissue within the prescription isodose region in the T2 weighted images used in the GKRS plan for AVM. Our results shed light on the causes of brain radiation injury after GKRS for AVM. In the future, this system could be used to improve outcomes and avoid complications associated with GKRS treatment., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the safety and efficacy of SRS treatment of central neurocytomas (CNCs), cavernous sinus hemangiomas (CSHs), and glomus tumors (GTs); and to compare upfront stereotactic radiosurgery (SRS) and adjuvant SRS in the treatment of these hypervascular tumors., Methods: This was a retrospective review of consecutive CNCs, CSHs, and GTs treated with SRS between 1993 and 2017. Tumor response was categorized based on volumetric analysis on magnetic resonance imaging: (1) tumor regression [> 10% decrease in tumor volume (TV)]; (2) stable tumor (≤ 10% change in TV); or (3) tumor progression (> 10% increase in TV)., Results: Sixty hypervascular tumors (CNC: 28; CSH: 16; GT: 16) underwent SRS between 1993 and 2017. Margin doses were 13 Gy, 12 Gy, and 14 Gy for CNCs, CSHs, and GTs, respectively. Tumor regression was observed in 54 tumors (90%) with initial SRS after a median follow-up of 82 months. Relative reductions in TVs for CNCs were 38%, 52%, and 73% at 12, 24, and 48 months, respectively. Relative reductions in TVs for CSHs were 51%, 68%, and 88% at 12, 24, and 48 months, respectively. Relative reductions in TVs for GTs were 22%, 31%, and 47% at 12, 24, and 48 months, respectively. Upfront SRS was performed in 26 patients (43%). No difference in relative TV reductions were found between upfront and adjuvant SRS. Adverse radiation effects were observed in five patients. No mortality was encountered., Conclusion: SRS for hypervascular tumors is associated with high rates of tumor regression with low risk of complications. No significant difference in rates of relative TV reduction were found between upfront and adjuvant SRS. Hence, upfront SRS may be considered in select patients.

Abnormal expression of microRNA (miR) is associated with the occurrence and progression of various types of cancers, including papillary thyroid carcinoma (PTC). In the present study, the aim was to explore miR‑486‑5p expression and its role in PTC, as well as to investigate the biological function of its potential target genes. The expression levels of miR‑486‑5p and its clinicopathological significance were examined in 507 PTC and 59 normal thyroid samples via The Cancer Genome Atlas (TCGA). Subsequently, the results were validated using data from Gene Expression Omnibus (GEO) and ArrayExpress. Receiver operating characteristic and summary receiver operating characteristic curves were used to assess the ability of miR‑486‑5p in distinguishing PTC from normal tissue. Furthermore, potential miR‑486‑5p mRNA targets were identified using 12 prediction tools and enrichment analysis was performed on the encoding genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of miR‑486‑5p were consistently downregulated in PTC compared with in normal tissue across datasets from TCGA, GEO (GSE40807, GSE62054 and GSE73182) and ArrayExpress (E‑MTAB‑736). The results also demonstrated that miR‑486‑5p expression was associated with cancer stage (P=0.003), pathologic lymph node (P=0.047), metastasis (P=0.042), neoplasm (P=0.012) and recurrence (P=0.016) in patients with PTC. In addition, low expression of miR‑486‑5p in patients with PTC was associated with a worse overall survival. A total of 80 miR‑486‑5p‑related genes were observed from at least 9 of 12 prediction platforms, and these were involved in 'hsa05200: Pathways in cancer' and 'hsa05206: MicroRNAs in cancer'. Finally, three hub genes, CRK like proto‑oncogene, phosphatase and tensin homolog and tropomyosin 3, were identified as important candidates in tumorigenesis and progression of PTC. In conclusion, it may be hypothesized that miR‑486‑5p contributes towards PTC onset and progression, and may act as a clinical target. However, in vitro and in vivo experiments are required to validate the findings of the present study.

Thyroid cancer (TC) is the most common endocrine malignancy, accounting for approximately 90% of all malignancies of the endocrine system. Despite the fact that patients with TC tend to have good prognoses, the high incidence rate and lymph node metastases remain unresolved issues. Autophagy is an indispensable process that maintains intracellular homeostasis; however, the role of autophagy in several steps of the initiation and progression of TC has not yet been elucidated. In this study, we first identified several autophagy-related genes (ARGs) that were provoked in the onset of TC. Subsequently, a bioinformatics analysis hinted that these genes were markedly disturbed in several proliferative signaling pathways. Moreover, we demonstrated that the differentially expressed ARGs were closely related to several aggressive clinical manifestations, including an advanced tumor stage and lymph node metastasis. Our study further selected prognostic ARGs and developed a prognostic signature based on three key genes (ATG9B, BID and B1DNAJB1), which displayed a moderate ability to predict the prognosis of TC. On the whole, the findings of this study demonstrate that ARGs disrupt proliferation-related pathways and consequently lead to aggressive clinical manifestations. These findings provide insight into the potential molecular mechanisms of action of ARGs and their clinical significance, and also provide classification information of potential therapeutic significance.

Background: Diffusion tensor imaging (DTI) is a novel MRI technique that enables noninvasive evaluation of microstructural alterations in white matter of brain. Initially, DTI was used in intra- or inter-hemispheric association bundles. Recent technical advances are overcoming the challenges of imaging small white matter bundles, such as the cranial nerves. In this study, we use DTI to shed more light on the microstructure changes in long-standing trigeminal neuralgia. We also utilize DTI to study the effect of early stereotactic radiosurgery (SRS) on the microstructures of the trigeminal nerve and to predict the effectiveness of early SRS in the treatment of medically refractory trigeminal neuralgia (TN)., Methods: To analyze the presentation of trigeminal nerve, the DTI was reconstructed in 21 cases pre- and post-SRS. DTI parameters recorded include fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), linear anisotropy coefficient (Cl), planar anisotropy coefficient (Cp), and spherical anisotropy coefficient (Cs). Comparisons between ipsilateral (symptomatic) and contralateral (asymptomatic) trigeminal nerves and symptom durations of < 5 and ≧ 5 years were performed., Results: The study cohort comprised 21 patients with TN with a median age of 66 years. Initial adequate facial pain relief (Barrow Neurological Institute facial pain scores I-IIIb) was achieved in 16 (76%) patients. For the pre-SRS DTI findings, ipsilateral trigeminal nerve was associated with higher baseline root entry zone (REZ) Cs compared to contralateral nerve (0.774 vs. 0.743, p = 0.04). Ipsilateral trigeminal nerve with symptoms of < 5 years was associated with higher baseline FA compared to trigeminal nerve with symptoms of ≧ 5 years (0.314 vs. 0.244, p = 0.02). For the post-SRS DTI findings, ipsilateral trigeminal nerves with symptoms of <5 years demonstrated decrease in Cl, while those with symptoms ≧ 5 years demonstrated increase in Cl after SRS at the ipsilateral REZ (- 0.025 vs. 0.018, p = 0.04). At the cisternal segment of ipsilateral trigeminal nerve, symptoms of < 5 years were associated with decreased FA and increased λ 2 , while symptoms of ≧ 5 years were associated with increased FA and decreased λ 2 after SRS (FA - 0.068 vs. 0.031, p = 0.04, λ 2 0.0003 vs. - 0.0002, p = 0.02)., Conclusions: SRS provides high rates of initial pain relief with moderate rates of facial hypoesthesia. Ipsilateral trigeminal nerve was associated with higher baseline REZ Cs, and baseline FA was associated with duration of symptoms. There were significant associations between duration of symptoms and changes in ipsilateral REZ Cl, cisternal segment FA, and cisternal segment λ 2 after SRS. These preliminary findings serve as comparisons for future studies investigating the use of DTI in radiosurgical planning for patients with TN.

Background: Depression is a heterogeneous disorder, with the exact neuronal mechanisms causing the disease yet to be discovered. Recent work suggests it is accompanied by neuro-inflammation, characterized, in particular, by microglial activation. However, microglial activation and its involvement in neuro-inflammation and stress-related depressive disorders are far from understood., Methods: We utilized multiple detection methods to detect the neuro-inflammation in the hippocampus of rats after exposure to chronic mild stress (CMS). Male Sprague Dawley (SD) rats were subjected to chronic mild stressors for 12 weeks. Microglial activation and hippocampal neuro-inflammation were detected by using a combinatory approach of in vivo [18F] DPA-714 positron emission computed tomography (PET) imaging, ionized calcium-binding adapter molecule 1 and translocator protein (TSPO) immunohistochemistry, and detection of NOD-like receptor protein 3 (NLRP3) inflammasome and some inflammatory mediators. Then, the rats were treated with minocycline during the last 4 weeks to observe its effect on hippocampal neuro-inflammation and depressive-like behavior induced by chronic mild stress., Results: The results show that 12 weeks of chronic mild stress induced remarkable depressive- and anxiety-like behavior, simultaneously causing hippocampal microglial activation detected by PET, immunofluorescence staining, and western blotting. Likewise, activation of NLRP3 inflammasome and upregulation of inflammatory mediators, such as interleukin-1β (IL-1β), IL-6, and IL-18, were also observed in the hippocampus after exposure to chronic stress. Interestingly, the anti-inflammatory mediators, such as IL-4 and IL-10, were also increased in the hippocampus following chronic mild stress, which may hint that chronic stress activates different types of microglia, which produce pro-inflammatory cytokines or anti-inflammatory cytokines. Furthermore, chronic minocycline treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation. Similarly, the activation of NLRP3 inflammasome and the increase of inflammatory mediators were not exhibited or significantly less marked in the minocycline treatment group., Conclusion: These results together indicate that microglial activation mediates the chronic mild stress-induced depressive- and anxiety-like behavior and hippocampal neuro-inflammation.

In Gamma Knife forward treatment planning, normalization effect may be observed when multiple shots are used for treating large lesions. This effect can reduce the proportion of coverage of high-value isodose lines within targets. The aim of this study was to evaluate the performance of forward treatment planning techniques using the Leksell Gamma Knife for the normalization effect reduction. We adjusted the shot positions and weightings to optimize the dose distribution and reduce the overlap of high-value isodose lines from each shot, thereby mitigating the normalization effect during treatment planning. The new collimation system, Leksell Gamma Knife Perfexion, which contains eight movable sectors, provides an additional means to reduce the normalization effect by using composite shots. We propose different techniques in forward treatment planning that can reduce the normalization effect. Reducing the normalization effect increases the coverage proportion of higher isodose lines within targets, making the high-dose region within targets more uniform and increasing the mean dose to targets. Because of the increase in the mean dose to the target after reducing the normalization effect, we can set the prescribed marginal dose at a higher isodose level and reduce the maximum dose, thereby lowering the risk of complications., (© 2017 Shuang Ho Hospital-Taipei Medical University. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

This study aims to examine the relationship between high birth weight (HBW) and blood pressure and assess whether HBW leads to increased hypertension during childhood and adolescence. All the participants aged 6-18 years with HBW were selected from a cross-sectional study from seven provinces in China. Nine thousand nine hundred and sixty-two children were randomly sampled with matched data. Basic information of students was collected with a standardized student and guardian questionnaire. High blood pressure was defined according to sex-, age- and height-specific references. Multi-variance logistic regression was used to estimate the odds ratio (OR) of high blood pressure and HBW after adjustment for confounding factors. The overall mean of systolic BP and diastolic BP in HBW group were significantly higher than normal group in both genders and urban/rural area. Corresponding overall prevalence of high BP, elevated SBP and elevated DBP in HBW group were also higher than normal group in both genders, respectively (boys: 19.41% vs 16.16%; 10.12% vs 8.16%; 14.86% vs 12.71%; girls: 14.95% vs 12.66%; 8.19% vs 6.56%; 11.13% vs 9.86%). In addition, birth weight was positively associated with high BP, elevated SBP and elevated DBP in children and adolescents of both sexes (boys: OR 1.25, 1.27, 1.20; girls: OR 1.21, 1.27, 1.15). However, the positive association was attenuated and even reversed after adjustment for potential confounding variables. In this study, HBW may lead to higher childhood blood pressure, but no association between HBW and childhood hypertension was observed.

The role of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) in thyroid carcinoma (TC) remains unclear. The current study was aimed to assess the clinical value of HOTAIR expression levels in TC based on publically available data and to evaluate its potential signaling pathways. The expression data of HOTAIR and clinical information concerning TC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Furthermore, 3 online biological databases, Starbase, Cbioportal, and Multi Experiment Matrix, were used to identify HOTAIR-related genes in TC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Panther pathway analyses were then undertaken to study the most enriched signaling pathways in TC (EASE score<0.1, Bonferroni<0.05). The TCGA results demonstrated that the expression level of HOTAIR in TC tissues was significantly increased compared with non-cancerous tissues (p<0.001). HOTAIR over-expression was significantly associated with poor survival in TC patients (p=0.03). Meta-analyses of GEO datasets revealed a trend consistent with the above results on HOTAIR expression levels in TC (SMD=0.23; 95%CI, 0.00-0.45; p=0.047). Finally, the results of functional analysis for HOTAIR-related genes indicated that HOTAIR might participate in tumorigenesis via the Wnt signaling pathway. In conclusion, our study demonstrates that HOTAIR may be involved in thyroid carcinogenesis, and the over-expression of HOTAIR could act as a biomarker associated with a poor outcome in TC patients. Moreover, the Wnt signaling pathway may be the key pathway regulated by HOTAIR in TC., (© Georg Thieme Verlag KG Stuttgart · New York.)

BACKGROUND MiR-101-3p can promote apoptosis and inhibit proliferation, invasion, and metastasis in breast cancer (BC) cells. However, its mechanisms in BC are not fully understood. Therefore, a comprehensive analysis of the target genes, pathways, and networks of miR-101-3p in BC is necessary. MATERIAL AND METHODS The miR-101 profiles for 781 patients with BC from The Cancer Genome Atlas (TCGA) were analyzed. Gene expression profiling of GSE31397 with miR-101-3p transfected MCF-7 cells and scramble control cells was downloaded from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified. The potential genes targeted by miR-101-3p were also predicted. Gene Ontology (GO) and pathway and network analyses were constructed for the DEGs and predicted genes. RESULTS In the TCGA data, a low level of miR-101-2 expression might represent a diagnostic (AUC: 0.63) marker, and the miR-101-1 was a prognostic (HR=1.79) marker. MiR-101-1 was linked to the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and miR-101-2 was associated with the tumor (T), lymph node (N), and metastasis (M) stages of BC. Moreover, 427 genes were selected from the 921 DEGs in GEO and the 7924 potential target genes from the prediction databases. These genes were related to transcription, metabolism, biosynthesis, and proliferation. The results were also significantly enriched in the VEGF, mTOR, focal adhesion, Wnt, and chemokine signaling pathways. CONCLUSIONS MiR-101-1 and miR-101-2 may be prospective biomarkers for the prognosis and diagnosis of BC, respectively, and are associated with diverse clinical parameters. The target genes of miR-101-3p regulate the development and progression of BC. These results provide insight into the pathogenic mechanism and potential therapies for BC.

Aim: This study assessed the Helicobacter pylori (H. pylori) serum antibody test as a diagnostic screening tool in symptomatic inner city children., Methods: This was a retrospective study of patients aged one to 18 years who were referred to our paediatric gastroenterology department from 2009 to 2013. We included all patients who had H. pylori serum antibodies and/or faecal antigens who underwent esophagogastroduodenoscopy (EGD) for histology, with or without a gastric tissue rapid urease test., Results: A total of 395 patients had EGDs carried out to evaluate epigastric pain, heartburn and nausea or vomiting, and their overall socio-economic Z-score was -2.62. The histology was positive for H. pylori infection in 52 of 395 patients (13%), and epigastric pain was documented in 45 of these 52 patients (87%). Compared to histology, the serum H. pylori antibody test had a sensitivity of 88.4% and a specificity of 93.4%. The tissue rapid urease test and faecal antigen test had sensitivities of 89.3% and 55.6% and specificities of 89.9% and 98.9%, respectively., Conclusion: The serum H. pylori antibody test had high sensitivity and specificity, and it was a good diagnostic screening tool in our study. Epigastric pain was strongly associated with a current H. pylori infection in our population., Competing Interests: The authors have no conflicts of interest to declare., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Studies have been reported that cyclin-dependent kinase5 (CDK5) was associated with the development of several cancers. However, the relationship between CDK5 level and clinicopathological factors is still poorly understood in cervical diseases. The aim of the current study was to investigate the expression of CDK5 and its clinical significance in variant cervical lesions., Methods: Immunohistochemistry (IHC) was used to detect CDK5 expression in 54 cases of chronic cervicitis, 42 cases of condyloma acuminate (CA), 38 cases of carcinoma in situ, and 360 cases of cervical cancers [adenocarcinoma, n = 63; squamous cell carcinoma (SCC), n = 263; adenosquamous carcinoma, n = 34]. The clinicopathological characteristics in relation to CDK5 were examined by Pearson's Chi-square test., Results: The positive rates of CDK5 were 27.8, 31.0, 50, 54.0, 58.8, and 62.7 % in chronic cervicitis, CA, carcinoma in situ, adenocarcinoma, adenosquamous carcinoma and SCC, respectively. Statistically analysis showed that CDK5 expression in cervical cancer tissues was higher than non-cervical cancer tissues (inflammation and CA) (P < 0.001). The overexpression of CDK5 was significantly correlated with lymph node metastasis (r = 0.317; P < 0.001), histological type (r = 0.198; P < 0.001), FIGO stage (r = 0.358; P < 0.001), TNM stage (r = 0.329; P < 0.001) and pathological grade (r = 0.259; P < 0.001) in cervical lesions evaluated by Pearson's Chi-square test. Furthermore, the positive relationships were found between CDK5 and lymph node metastasis (P < 0.001), FIGO stage (P < 0.001), TNM stage (P < 0.001) and pathological grade (P < 0.001) in SCC. CDK5 was positively interrelated to TNM stage (P = 0.017) in adenosquamous carcinoma., Conclusions: CDK5 may play a vital role in the development of cervical cancer, which may be a marker for the diagnosis, therapy and prognosis of cervical cancer.

Background: Atypical and anaplastic meningiomas have much higher recurrence rates after surgical resection compared with benign meningiomas, but the role of adjuvant radiosurgery remains unclear. This study was undertaken to evaluate the outcomes of gamma knife radiosurgery for patients with atypical and anaplastic meningiomas., Methods: In this retrospective analysis of a prospectively maintained database, 46 patients with histologically proven atypical or anaplastic meningiomas by current World Health Organization (WHO) criteria underwent postoperative Gamma Knife radiosurgery between 1993 and 2013. The median follow-up period was 32.6 months. The median tumor volume and margin dose were 11.7 mL (range, 2-53 mL) and 13.1 Gy (range, 12.0-16.5 Gy), respectively., Results: Local control at 3 and 5 years was 50.6% and 32.1%, respectively. Gender (P = 0.013) and marginal dose less than or equal to 13 Gy (P = 0.049) were associated with the local control. The 3- and 5-year overall survival for patients with WHO grade II was 97.1% and 88.3%, respectively, compared with 66.7% and 66.7% for patients with WHO grade III meningiomas. Radiation therapy before Gamma Knife radiosurgery (GKRS; P = 0.018) and tumor grade (P = 0.019) were the factors associated with a worse overall survival rate. Fourteen patients (30.4%) developed adverse radiation effects after GKRS treatment, and all were Radiation Therapy Oncology Group grade I., Conclusions: Postoperative GKRS treatment for patients with atypical and anaplastic meningioma is challenging. More aggressive treatment, including of safely maximizing the extent of surgical resection and using a higher margin dose (>13Gy), should be applied to achieve better local control., (Copyright © 2016 Elsevier Inc. All rights reserved.)