Marginal Dose Research Articles

Does Adjuvant Gamma Knife Stereotactic Radiosurgery Have a Role in Treating Optic Nerve Sheath Meningiomas?

Meningiomas arising from or adjacent to the optic nerve sheath meningioma (ONSM) are management challenges because of their risk of visual loss. Stereotactic radiosurgery (SRS) is a minimally invasive modality that can be added as adjuvant treatment for patients whose tumor has progressed or recurred after initial resection. The authors retrospectively reviewed 2,030 meningioma patients who underwent SRS between 1987 and 2022. In total, 7 patients (4 females; median age = 49) were found with tumors originating from the optic nerve sheath. None of the patients had tumors that engulfed the optic nerve as such tumors typically undergo fractionated radiation therapy (FRT) to preserve vision. The clinical history, visual function, and radiographic and neurological findings were characterized. Outcome measures included visual status, tumor control, and the need for additional management. All patients underwent either initial gross total (n = 1) or partial surgical resection (n = 6) before SRS. Two patients with progressive tumor growth also had SRS after failing additional fractionated radiation after surgery (54 Gy, 30 fractions for both patients). The median time between the date of surgery and the SRS procedure date was 38 months. The Leksell Gamma Knife was used to deliver a margin dose of 12 Gy (range: 8-14 Gy) to a median cumulative tumor volume of 3.3 cc (range: 1.2-18 cc). The median maximal optic nerve radiation dose was 6.5 Gy (range: 1.9-8.1 Gy). After SRS, the median follow-up time was 130 months (range: 26-169 months). Two patients showed local tumor progression at 20 and 55 months after SRS. Four had stable visual function, 2 experienced improved visual acuity, and 1 patient had visual deterioration. Meningiomas arising from (but not engulfing the optic nerve) represent management quandaries after failed initial surgical removal. In this experience, salvage SRS was associated with tumor control and vision preservation in 5 of 7 patients. Additional experience with this strategy may further define the role of SRS both as a salvage and primary option.

Stereotactic radiosurgery outcome for deep-seated cerebral arteriovenous malformations in the brainstem and thalamus/basal ganglia: systematic review and meta-analysis.

Deep-seated unruptured AVMs located in the thalamus, basal ganglia, or brainstem have a higher risk of hemorrhage compared to superficial AVMs and surgical resection is more challenging. Our systematic review and meta-analysis provide a comprehensive summary of the stereotactic radiosurgery (SRS) outcomes for deep-seated AVMs. This study follows the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. We conducted a systematic search in December 2022 for all reports of deep-seated arteriovenous malformations treated with SRS. Thirty-four studies (2508 patients) were included. The mean obliteration rate in brainstem AVM was 67% (95% CI: 0.60-0.73), with significant inter-study heterogeneity (tau2 = 0.0113, I2 = 67%, chi2 = 55.33, df = 16, p-value < 0.01). The mean obliteration rate in basal ganglia/thalamus AVM was 65% (95% CI: 0.58-0.72) with significant inter-study heterogeneity (tau2 = 0.0150, I2 = 78%, chi2 = 81.79, df = 15, p-value < 0.01). The presence of deep draining veins (p-value: 0.02) and marginal radiation dose (p-value: 0.04) were positively correlated with obliteration rate in brainstem AVMs. The mean incidence of hemorrhage after treatment was 7% for the brainstem and 9% for basal ganglia/thalamus AVMs (95% CI: 0.05-0.09 and 95% CI: 0.05-0.12, respectively). The meta-regression analysis demonstrated a significant positive correlation (p-value < 0.001) between post-operative hemorrhagic events and several factors, including ruptured lesion, previous surgery, and Ponce C classification in basal ganglia/thalamus AVMs. The present study found that radiosurgery appears to be a safe and effective modality in treating brainstem, thalamus, and basal ganglia AVMs, as evidenced by satisfactory rates of lesion obliteration and post-surgical hemorrhage.

Low-Dose Radiosurgery for Brain Metastases in the Era of Modern Systemic Therapy.

Dose selection for brain metastases stereotactic radiosurgery (SRS) classically has been based on tumor diameter with a reduction of dose in the settings of prior brain irradiation, larger tumor volumes, and critical brain location. However, retrospective series have shown local control rates to be suboptimal with reduced doses. We hypothesized that lower doses could be effective for specific tumor biologies with concomitant systemic therapies. This study aims to report the local control (LC) and toxicity when using low-dose SRS in the era of modern systemic therapy. We reviewed 102 patients with 688 tumors managed between 2014 and 2021 who had low-margin dose radiosurgery, defined as ≤14 Gy. Tumor control was correlated with demographic, clinical, and dosimetric data. The main primary cancer types were lung in 48 (47.1%), breast in 31 (30.4%), melanoma in 8 (7.8%), and others in 15 patients (11.7%). The median tumor volume was 0.037cc (0.002-26.31 cm 3 ), and the median margin dose was 14 Gy (range 10-14). The local failure (LF) cumulative incidence at 1 and 2 years was 6% and 12%, respectively. On competing risk regression analysis, larger volume, melanoma histology, and margin dose were predictors of LF. The 1-year and 2-year cumulative incidence of adverse radiation effects (ARE: an adverse imaging-defined response includes increased enhancement and peritumoral edema) was 0.8% and 2%. It is feasible to achieve acceptable LC in BMs with low-dose SRS. Volume, melanoma histology, and margin dose seem to be predictors for LF. The value of a low-dose approach may be in the management of patients with higher numbers of small or adjacent tumors with a history of whole brain radio therapy or multiple SRS sessions and in tumors in critical locations with the aim of LC and preservation of neurological function.

XRT-04. THE ROLE OF STEREOTACTIC RADIOSURGERY FOR MENINGIOMAS IN PEDIATRIC PATIENTS

Abstract Despite the generally benign and slow-growing nature, meningiomas in pediatric populations often exhibit more aggressive behavior. Stereotactic radiosurgery (SRS) is a non-invasive modality that is widely used as an upfront or adjuvant treatment for patients with meningiomas. Due to the rarity of meningiomas in pediatric patients, the outcomes of SRS for childhood meningiomas have never been described. From 1987 to 2022, a total of 2,030 patients with meningiomas underwent SRS at the University of Pittsburgh Medical Center. Nine patients (2 female; incidence rate = 0.44%) with a median age of 14.5 years (range, 9—17 years) at SRS were identified. Three patients (33.3%) had a history of total body irradiation. Seven patients (77.8%) were asymptomatic at the time of SRS presentation. Seven patients (77.8%) had a pre-SRS craniotomy; two patients (22.2%) had pre-SRS fractionated radiotherapy. The median cumulative tumor volume was 3.65 cc (range, 0.01—11.84 cc). The median margin dose prescribed was 14 Gy (range, 11—25 Gy). The median follow-up time was 107 months (range, 24—194 months). Five patients (55.6%) experienced tumor progression at a median of 25 months (range, 13—161 months). Local tumor control at 1-, 5-, and 10 years was 100%, 55.56%, and 55.56%, respectively. After local tumor progression, 2 patients received repeat SRS, 2 patients had surgical resection and 1 was placed on hydroxyurea for an unresectable tumor. At the date of the last clinical follow-up, 5 patients (55.6%) were still alive while 4 patients (44.4%) expired due to the progression of intracranial disease. 1-, 5-, and 10-year survival was 100%, 88.89%, and 64.81%, respectively. Childhood meningioma is a rare tumor that exhibits aggressive behaviors. SRS should be considered as an upfront or adjuvant treatment option in the multi-modal management of childhood meningiomas for optimal tumor control and maximal quality of life preservation.

Vestibular Schwannoma Stereotactic Radiosurgery in Octogenarians: Case Series.

The management of octogenarians with vestibular schwannomas (VS) has received little attention. However, with the increase in octogenarian population, more effort is needed to clarify the value of stereotactic radiosurgery (SRS) in this population. The aim of this study was to evaluate the safety and efficacy of SRS in this patient age group. A retrospective study of 62 patients aged 80 years or older who underwent single-session SRS for symptomatic VS during a 35-year interval was performed. The median patient age was 82 years, and 61.3% were male. SRS was performed as planned adjuvant management or for delayed progression after prior partial resection in 5 patients. SRS resulted in a 5-year tumor control rate of 95.6% with a 4.8% risk of adverse radiation effects (ARE). Tumor control was unrelated to patient age, tumor volume, Koos grade, sex, SRS margin dose, or prior surgical management. Four patients underwent additional management including 1 patient with symptomatic progression requiring surgical resection, 2 patients with symptomatic hydrocephalus requiring cerebrospinal fluid diversion, and 1 patient whose tumor-related cyst required delayed cyst aspiration. Three patients developed ARE, including 1 patient with permanent facial weakness (House-Brackmann grade II), 1 who developed trigeminal neuropathy, and 1 who had worsening gait disorder. Six patients had serviceable hearing preservation before SRS, and 2 maintained serviceable hearing preservation after 4 years. A total of 44 (71%) patients died at an interval ranging from 6 to 244 months after SRS. SRS resulted in tumor and symptom control in most octogenarian patients with VS.

Quantitative Analysis of Parenchymal Effects and Flow of Large Arteriovenous Malformations Managed With Stereotactic Radiosurgery.

Stereotactic radiosurgery (SRS) of larger arteriovenous malformations (AVM) is associated with an elevated incidence of adverse radiation effects (ARE). To date, volume-response and dose-response models have been used to predict such effects. To understand radiological outcomes and their hemodynamic effects on the regional brain. A retrospective analysis was conducted at our institution using a prospective registry of patients managed between 2014 and 2020. We included patients with AVM with a nidus larger than 5 cc who received either single-session or volume-staged Gamma Knife radiosurgery. AVM volume changes, volumes of parenchymal response, and obliteration were analyzed and correlated with transit times and diameters of feeding arteries and draining veins. Sixteen patients underwent single-session SRS, and 9 patients underwent volume-staged SRS. The average AVM volume was 12.6 cc (5.5-23). The AVM locations were predominantly lobar (80%) and 17 (68%) were in critical locations. The mean margin dose was 17.2 Gy (15-21), and the median V12Gy was 25.5 cc. Fourteen (56%) AVMs had a transit time shorter than 1 second. The median vein-artery ratio (sum diameter of the veins/sum diameter of feeding arteries) was 1.63 (range, 0.60-4.19). Asymptomatic parenchymal effects were detected in 13 (52%) patients and were symptomatic in 4 (16%) patients. The median time to ARE was 12 months (95% CI 7.6-16.4). On univariate analysis, significant predictors of ARE were lower vein-artery ratio ( P = .024), longer transit time ( P = .05), higher mean dose ( P = .028), and higher D95 ( P = .036). Transit times and vessel diameters are valuable predictors of the subsequent parenchymal response after SRS. A more quantitative understanding of blood flow is critical for predicting the effects on the regional brain after AVM radiosurgery.

Association between mixed exposure of polycyclic aromatic hydrocarbons and telomere length in general population: NHANES 2001-2002.

Although an association between single polycyclic aromatic hydrocarbons (PAHs) adult exposure and telomere length has been reported, the evidence of mixed PAHs (1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene, 2-phenanthrene, and 1-pyrene) exposure and telomere length in the adult general population is still not clear. A total of 1460 adults over the age of 20 years provided urine information on 8 PAHs and selected covariates from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Bayesian nuclear machine regression (BKMR) was conducted to analyze these associations of telomere length in multiple PAH-exposed environments. Linear regression is mainly used for correlation analysis of PAHs with selected covariate adjustments. Restricted cubic spline (RCS) is used to estimate the correlation between selected PAHs and telomere length. After adjusting for potential covariates, PAHs mixed exposure was negatively associated with telomere length. The linear regression results showed that 2-napthol and 2-fluorene were negatively correlated with telomere length. Telomere length decreased by 1.0% in the fully adjusted model per increment of one unit in the base-10-logarithm-transformed 2-napthol and 2-fluorene concentrations (P = 0.030 and 0.049, respectively). However, the other 6 PAH metabolites were not significantly different. In addition, RCS results showed that 2-napthol has a marginal dose effect relationship with telomere length. Our present study suggested that PAHs are negatively associated with telomere length in the general population of the USA. Considering that the low level of PAHs exposure in the general population can also induce reduced telomere length and potential health risks, future research is needed to explore potential mechanisms.

Stereotactic radiosurgery for recurrent skull base polymorphous adenocarcinoma invading the cavernous sinus: illustrative case.

Polymorphous adenocarcinomas (PACs) are rare tumors arising from the salivary glands. Radical resection and postoperative radiotherapy are the mainstays of treatment. However, complete tumor resection is not always achievable when the tumor invades the skull base. Stereotactic radiosurgery (SRS) could be a less invasive alternative for treating skull base PACs. A 70-year-old male with a history of surgery for a right palatine PAC presented with right visual impairment, diplopia, and ptosis. Imaging studies revealed tumor recurrence invading the right cavernous sinus (CS). SRS using a gamma knife was performed for this recurrence, prescribing a marginal dose of 18 Gy at a 50% isodose line. Five months after SRS, his symptoms were relieved, and the tumor was well-controlled for 55 months without any adverse events. To the best of the authors' knowledge, this is the world's first case of recurrent skull base PAC invading the CS that was successfully treated with salvage SRS. Thus, SRS may be an applicable treatment option for skull base PACs.

Single-Session Gamma Knife Radiosurgery for Patients With 20 or More Brain Metastases.

Stereotactic radiosurgery (SRS) is a widely accepted treatment modality for brain metastases. The role of SRS in patients with higher numbers of metastases remains controversial. To define outcomes in patients with ≥20 brain metastases managed using single-session SRS. This single-institution retrospective cohort study studied 75 patients (26 non-small-cell lung cancer, 21 small-cell lung cancer, 14 breast cancer, and 14 melanoma) undergoing single-session SRS. The median number of tumors per patient was 24, and the median cumulative tumor volume was 3.70 cc. The median margin dose prescribed to each individual tumor was 16 Gy. The median integral cranial dose was 5492 mJ. The median beam on time was 160 minutes. Univariate and multivariate analyses were performed with significance set at P < .05. The median overall survival after SRS was 8.8 months (patients with non-small-cell lung cancer), 4.6 months (patients with small-cell lung cancer), 11.3 months (patients with breast cancer), and 4.1 months (patients with melanoma). Primary cancer type, number of brain metastases, and concurrent immunotherapy were significant factors in predicting survival. Local tumor control rate per patient was 97.3% and 94.6% at 6 and 12 months after SRS, respectively. Thirty-six patients underwent additional SRS for new tumor development with a median time after SRS of 5 months. Three patients experienced adverse radiation events. Single-session SRS is a well-tolerated palliative treatment option even in patients with ≥20 brain metastases, achieving local control rate >90% with low risks of neurotoxicity while continuing concurrent systemic oncological care.

Gamma Knife radiosurgery for gynecologic metastases to the brain: Analysis of pathology, survival, and tumor control

ObjectiveThis study aims to evaluate the efficacy of stereotactic radiosurgery (SRS) in improving health outcomes of patients with gynecologic brain metastases. MethodsPatients with gynecologic metastases treated with SRS from 2008 to 2020 were retrospectively reviewed. The median age at SRS was 63 years old (cervical 45.5, endometrial 65.5, ovarian 61). The median number of tumors was 3 (range 1–27), and cumulative tumor volume was 2.33 cc (range 0.03–45.63). Median margin dose prescribed was 16 Gy (range 14 Gy – 20 Gy). The median 12 Gy volume was 7.30 cc (range 0.21–74.14 cc). Outcome variables included overall survival (OS) after SRS, local tumor control (LTC), distant tumor control, and adverse radiation effect (ARE). ResultsFifty patients (4 cervical, 25 endometrial, and 21 ovarian cancer) were identified. The OS at 6 and 12 months after SRS was 48%, and 44%, respectively. Eight patients (16%) died from CNS disease progression. The number of brain metastases (p = 0.011) and the Karnofsky Performance Scale (KPS) ≥ 70 (p = 0.020) were significant predictors of OS. LTC rate at 6 and 12 months were 92%, and 87%, respectively. Margin dose ≥16Gy correlated with significantly better local tumor control (p = 0.0001) without increased risk of ARE (p = 0.055). The risk of developing new metastases at 6 and 12 months were 12% and 24% respectively. SRS-induced ARE events occurred in 7 patients. ConclusionIntracranial metastases from gynecologic malignancy can be effectively treated using SRS with low risk of neurotoxicity. Margin dose ≥16Gy can provide significantly better tumor control. Repeat SRS can be utilized to treat new metastases while avoiding the potential cognitive symptoms associated with WBRT.

Stereotactic ablative body radiotherapy with a central high dose using CyberKnife for metastatic lung tumors

BackgroundThe CyberKnife system features a robotically-positioned linear accelerator to deliver real-time image-guided stereotactic ablative body radiotherapy (SABR). It achieves steep dose gradients using irradiation from hundreds of different directions and increases the central dose of the gross tumor volume (GTV) without increasing the marginal dose to the planning target volume. We evaluated the effectiveness and safety of SABR with a central high dose using CyberKnife for metastatic lung tumors.MethodsA total of 73 patients with 112 metastatic lung tumors treated with CyberKnife were retrospectively analyzed. Local control, progression-free survival, and overall survival were calculated using the Kaplan–Meier method. The median age was 69.2 years. The most common primary sites were the uterus (n = 34), colorectum (n = 24), head and neck (n = 17), and esophagus (n = 16). For peripheral lung tumors, the median radiation dose was 52 Gy in 4 fractions, whereas for centrally located lung tumors, it was 60 Gy in 8–10 fractions. The dose prescription was defined as 99% of the solid tumor components of the GTV. The median maximum dose within the GTV was 61.0 Gy. The GTV and planning target volume were enclosed conformally by the 80% and 70% isodose lines of the maximum dose, respectively. The median follow-up period was extended to 24.7 months; it was 33.0 months for survivors.ResultsThe 2-year local control, progression-free survival, and overall survival rates were 89.1%, 37.1%, and 71.3%, respectively. Toxicities of grade ≥ 2 were noted as grade 2 and 3 radiation pneumonitis in one patient each. The two patients with grade 2 or higher radiation pneumonitis had both received simultaneous irradiation at two or three metastatic lung tumor sites. No toxicity of grade ≥ 2 was observed in patients with metastasis in one lung only.ConclusionsSABR with a central high dose using CyberKnife for metastatic lung tumors is effective with acceptable toxicity.Trial registrationNumber: 20557, Name: Stereotactic ablative radiotherapy using CyberKnife for metastatic lung tumor, URL: http://www.radonc.med.osaka-u.ac.jp/pdf/SBRT.pdf, Date of registration: April 1, 2021 (retrospectively registered), Date of enrollment: May 1, 2014.

Using the deformity index of vital structures to predict outcome of patients with large vestibular schwannomas after Gamma Knife radiosurgery

Microsurgery is the mainstay of treatment for large vestibular schwannomas (VS), but the benefits of radiosurgery remain incompletely defined. Here, we aim to use automated volumetric analysis software to quantify the degree of brain stem deformity to predict long-term outcomes of patients with large VS following GKRS. Between 2003 and 2020, 39 patients with large VS (volume > 8cc) undergoing GKRS with a margin dose of 10-12Gy were analyzed. The reconstruction 3D MRI was used to evaluate the extent of deformity for predicting the long-term outcome of patients. Their mean tumor volume was 13.7 ± 6.3cc, and their mean follow-up after GKRS was 86.7 ± 65.3 months. Favorable clinical outcome was observed in 26 (66.7%) patients, while 13 (33.3%) patients had treatment failure. Patients with small tumor volumes, low vital structure deformity indice [(TV/(BSV + CerV) and (TV + EV)/(BSV + CerV)], and long distance of tumor to the central line were more likely to have favorable clinical outcome after GKRS. Significant prognostic value was with tumor shrinkage ratio (< 50%) were CV, CV/TV, TV/CerV, (TV + EV)/(BSV + CerV), and the distance of tumor to the central line. In cox regression, favorable clinical outcome was correlated with the Charlson comorbidity index and cochlear dosage (both p < 0.05). In multivariant analysis, tumor regression was highly correlated with the CV/TV ratio (p < 0.001). The brainstem deformity ratio is likely a useful index to assess the clinical and tumor regression outcomes. Clinical outcomes are multifactorial and the tumor regression was highly correlated with the ratio of cystic components.

SRS for Cavernous Malformations: Myths and Realities.

The optimal management of cavernous malformations (CMs) remains controversial. Over the past decade, stereotactic radiosurgery (SRS) has gained wider acceptance in the management of CMs, especially in those with deep location, eloquence, and where surgery is of high risk. Unlike arteriovenous malformations (AVMs), there is no imaging surrogate endpoint to confirm CM obliteration. Clinical response to SRS can only be gauged by a reduction in long-term CM hemorrhage rates. There is concern that the long-term benefits of SRS and the reduced rehemorrhage rate after a latency period of 2 years may only be a reflection of natural history. Of further concern is the development of adverse radiation effects (AREs), which were significant in the early experimental studies. The lessons learnt from that era have led to the progressive development of well-defined, lower marginal dose treatment protocols that have reported less toxicity (5%-7%) and consequently reduced morbidity. Currently, there is at least Class II, Level B evidence for use of SRS in solitary CMs with previous symptomatic hemorrhage in eloquent areas with high surgical risk. Recent prospective cohort studies observing untreated brainstem and thalamic CMs report significantly higher hemorrhage rates and neurological sequelae than the rates reported from contemporary pooled large natural history meta-analyses. Furthermore, this strengthens our recommendation for early proactive SRS in symptomatic deep-seated CMs due to the higher morbidity associated with observation and microsurgery. The key to successful outcomes for any surgical intervention is patient selection. We hope that our precis on contemporary SRS techniques in the management of CMs will assist this process.

Radiosurgery outcomes in infratentorial juvenile pilocytic astrocytomas.

To assess survival and neurological outcomes for patients who underwent primary or salvage stereotactic radiosurgery (SRS) for infratentorial juvenile pilocytic astrocytomas (JPA). Between 1987 and 2022, 44 patients underwent SRS for infratentorial JPA. Twelve patients underwent primary SRS and 32 patients underwent salvage SRS. The median patient age at SRS was 11.6years (range, 2-84years). Prior to SRS, 32 patients had symptomatic neurological deficits, with ataxia as the most common symptom in 16 patients. The median tumor volume was 3.22cc (range, 0.16-26.6cc) and the median margin dose was 14Gy (range, 9.6-20Gy). The median follow-up was 10.9years (range, 0.42-26.58years). Overall survival (OS) after SRS was 97.7% at 1-year, and 92.5% at 5- and 10-years. Progression free survival (PFS) after SRS was 95.4% at 1-year, 79.0% at 5-years, and 61.4% at 10-years. There is not a significant difference in PFS between primary and salvage SRS patients (p = 0.79). Younger age correlated with improved PFS (HR 0.28, 95% CI 0.063-1.29, p = 0.021). Sixteen patients (50%) had symptomatic improvements while 4 patients (15.6%) had delayed onset of new symptoms related to tumor progression (n = 2) or treatment related complications (n = 2). Tumor volumetric regression or disappearance after radiosurgery was found in 24 patients (54.4%). Twelve patients (27.3%) had delayed tumor progression after SRS. Additional management of tumor progression included repeat surgery, repeat SRS, and chemotherapy. SRS was a valuable alternative to initial or repeat resection for deep seated infratentorial JPA patients. We found no survival differences between patients who had primary and salvage SRS.

Role of Stereotactic Radiosurgery for Cavernous Sinus Hemangiomas - An Individual Patient Data-Based Meta-Analysis.

Cavernous sinus haemangiomas (CSHs) are rare vascular malformations arising from the micro-circulation of the cavernous sinus. The current treatment options are micro-surgical excision of CSH, stereotactic radiosurgery (SRS), and fractionated radiation therapy (FRT). We conducted a meta-analysis assessing the effect and complications of SRS in CSH and compared the pooled results after surgical excision of CSH. The aim of the study is to provide valuable insight into the role of SRS in the treatment of CSHs. The literature search revealed a total of 21 articles with 199 patients who met our inclusion criteria, and these were analyzed for this study. There were 138 (69.3%) female and 61 (30.7%) male patients. The mean age at the time of radiosurgery was 48.4 ± 14.9 years. The mean tumor volume at the time of SRS was 17.4 cm3 (range 0.3-138 cm3). Fifty (25%) patients had undergone surgery before SRS, whereas 149 (75%) patients received standalone SRS. A total of 186 (93.5%) patients were treated by gamma knife radiosurgery (GKRS), whereas 13 got treated by Cyberknife. The mean tumor volume in CK-F, GKRS, and GKRS-F groups was 36.6 ± 26.3, 15.4 ± 18.4, and 86.0 ± 19.5 cm3, respectively. The mean marginal dose was 21.8 ± 2.9 Gy, 14.0 ± 1.9 Gy, and 25 ± 0.0 Gy in CK-F, GKRS, and GKRS-F groups, respectively. The mean marginal dose of SRS was 14.6 ± 2.9 Gy. The mean follow-up period after SRS was 35.8 ± 31.6 months. Significant clinical improvement was seen in 106 patients out of 116 (91.4%) after SRS with remarkable shrinkage, 22 patients out of 27 (81.5%) with minimal shrinkage, and nine patients out of 13 (69.2%) with stationary tumor shrinkage. The sixth cranial nerve (CN6) was the most commonly involved nerve in 73 patients (36.7%). 30/65 (89%) experienced an improvement in the abducent nerve function following SRS. 115/120 (95.8%) patients primary treated with SRS experienced clinical improvement, whereas the rest of the five patients remained clinically stable. Radiosurgery SRS is a safe and effective option in patients with CSHs and resulted in more than 50% decrease in tumor volume in 72.4% of the patients.

SRS for Vestibular Schwannomas - Current Status.

Stereotactic radiosurgery (SRS) is an established modality of treatment for vestibular schwannomas (VS). We aim to summarize the evidence-based use of SRS in VSs and address the specific considerations pertaining to the same, along with our own clinical experiences. A thorough review of the literature was done to gather evidence regarding the safety and efficacy of SRS in VSs. Additionally, we have reviewed the senior author's experience in treating VSs (N = 294) between 2009 and 2021 and our experiences with microsurgery in post-SRS patients. Available scientific evidence upholds the role of SRS in VSs, in small-to-medium-sized tumors (5-year local tumor control >95%). The risk of adverse radiation effects remains minimal, while the hearing preservation rates are variable. Our center's post-GammaKnife VS follow-up cohort (sporadic - 157, neurofibromatosis-2 - 14) showed excellent tumor control rates at the last follow-up of 95.5% (sporadic) and 93.8% (neurofibromatosis-2), with a median margin dose of 13 Gy and mean follow-up periods of 3.6 (sporadic) and 5.2 (neurofibromatosis-2) years. Microsurgery in post-SRS VSs poses a formidable challenge due to the resulting thickened arachnoid and adhesions to critical neurovascular structures. Near-total excision is the key to better functional outcomes in such cases. SRS is here to stay as a trusted alternative in the management of VSs. Further studies are required to propose means of accurate prediction of hearing preservation rates and also to compare the relative efficacies of various SRS modalities.

An Extremely Inhomogeneous Gross Tumor Dose is Suitable for Volumetric Modulated Arc-Based Radiosurgery with a 5-mm Leaf-Width Multileaf Collimator for Single Brain Metastasis.

Introduction Single or multi-fraction (mf) stereotactic radiosurgery (SRS) is an indispensable treatment option for brain metastases (BMs). The integration of volumetric modulated arc therapy (VMAT) into linac-based SRS is expected to further enhance efficacy and safety and to expand the indications for the challenging type of BMs. However, the optimal treatment design and relevant optimization method for volumetric modulated arc-based radiosurgery (VMARS) remain unestablished with substantial inter-institutional differences. Therefore, this study was conducted to determine the optimal dose distribution suitable for VMARS of BMs, especially regarding dose inhomogeneity of the gross tumor volume (GTV). The GTV boundary, not margin-added planning target volume, was regarded as a basis for planning optimization and dose prescription. Materials and methods This was a planning study for the clinical scenario of a single BM. Eight sphere-shaped objects with diameters of 5-40 mm in 5-mm increments were assumed as GTVs. The treatment system included a 5-mm leaf width multileaf collimator (MLC) Agility® (Elekta AB, Stockholm, Sweden)and a dedicated planning system Monaco® (Elekta AB). The prescribed dose (PD) was uniformly assigned to just cover 98% of the GTV (D98%). Three VMARS plans with different dose inhomogeneities of the GTV were generated for each GTV: the % isodose surfaces (IDSs) of GTV D98%, normalized to 100% at the maximum dose (Dmax), were ≤70% (extremely inhomogeneous dose, EIH); ≈80% (inhomogeneous dose, IH); and ≈90% (rather homogeneous dose, RH). VMARS plans were optimized using simple and similar cost functions. In particular, no dose constraint to the GTV Dmax was assigned to the EIH plans. Results Intended VMARS plans fulfilling the prerequisites were generated without problems for all GTVs of ≥10 mm, whereas 86.4% was the lowest IDS for the D98%for 5-mm GTV. Therefore, additional plans for 9-and 8-mm GTVs were generated, which resulted in 68.6% and 75.1% being the lowest IDSs for the D98%values of 9- and 8-mm GTVs, respectively. The EIH plans were the best in terms of the following: 1) dose conformity, i.e., minimum spillage of PD outside the GTV; 2) moderate, not too excessive, dose attenuation outside the GTV, i.e., appropriate marginal dose 2-mm outside the GTV boundary as a function of GTV size; and 3) lowest dose of the surrounding normal tissue outside the GTV. In contrast, the RH plans were the worst based on all of theaforementioned measures. Conclusions On the assumption of uniform dose assignment to the GTV margin, a very inhomogeneous GTV dose is basically the most suitable for SRS of BMs in terms of 1) superior dose conformity; 2) minimizing the dose of the surrounding normal tissue outside the GTV; and 3) moderate dose spillage margin outside the GTV with a tumor volume-dependent rational increase, i.e., appropriate dose of the common PTV boundary. The concentrically laminated steep dose increase inside the GTV boundary for the EIH plan may also be advantageous for achieving superior tumor response, although early and excessive GTV shrinkage caused by the EIH plan during mfSRS can lead to surrounding brain injury.

Modified Dynamic Conformal Arcs With Forward Planning for Radiosurgery of Small Brain Metastasis: Each Double Arc and Different To-and-Fro Leaf Margins to Optimize Dose Gradient Inside and Outside the Gross Tumor Boundary.

Dynamic conformal arcs (DCA) are a widely used technique for stereotactic radiosurgery (SRS) of brain metastases (BM) using a micro-multileaf collimator (mMLC), while the planning design and method considerably vary among institutions. In the usual forward planning of DCA, the steepness of the dose gradient outside and inside the gross tumor volume (GTV) boundary is simply defined by the leaf margin (LM) setting to the target volume edge. The dose fall-off outside the small GTV tends to be excessively precipitous, especially with an MLC of 2.5-mm leaf width, which is predisposed to the insufficient coverage of microscopic brain invasion and other inherent inaccuracies. Meanwhile, insufficient dose increase inside the GTV boundary, i.e., less inhomogeneous GTV dose, likely leads to inferior and less sustainable tumor response. The more inhomogeneous GTV dose is prone to the steeper dose gradient outside the GTV and vice versa. Herein, we describe an alternative simply modified DCA (mDCA) planning that was uniquely devised to optimize the dose gradient outside and inside the GTV boundary for further enhancing and consolidating local control of small BM. For a succinct exemplification, a 10-mm spherical target was assumed as a GTV for DCA planning using a 2.5-mm mMLC. The benchmark plan was generated by adding a 0-mm LM to the GTV edge byassigning a single fraction of 30 Gy to the isocenter, in which the GTV coverage by 24 Gy with 80% isodose surface (IDS) was 96%, i.e., D96%, while the coverage of GTV + isotropic 2 mm volume by 18 Gy with 60% IDS was 70%, with the D98% being 12 Gy with 40% IDS, viz., too steep dose fall-off outside the GTV boundary. Alternatively, the increase of LM with or without decreasing the isocenter dose enablesthe increase of the GTV + 2 mm coverage by 18 Gy while resulting in an inadequate GTV dose with either a less inhomogeneous dose or an excessive marginal dose. Meanwhile, in the newly devised mDCA planning, everysingle arc was converted to a double to-and-fro arcwith different LM settings under the same spatial arrangement, which enabled GTV + 2 mm volume coverage with 18 Gy while preserving the GTV marginal dose and inhomogeneity similar to those for the benchmark plan. Additionally, the different collimator angle (CA) setting for the to-and-fro arcs led to further trimming of the dose conformity. The limitations of general forward planning with only adjusting the LM for everysingle arc were demonstrated, which can be a contributing factor for local tumor progressionof small BM. Alternatively, the mDCA with each double to-and-fro arc and different LM and CA settings enables optimization of the dose gradient both outside and inside the GTV boundary according to the planners' intent, e.g., moderate dose spillage margin outside the GTV and steep dose increase inside the GTV boundary.

Immunogenicity of an adjuvanted SARS-CoV-2 trimeric S-protein subunit vaccine (SCB-2019) in SARS-CoV-2-naïve and exposed individuals in a phase 2/3, double-blind, randomized study

BackgroundWe evaluated immunogenicity of SCB-2019, a subunit vaccine candidate containing a pre-fusion trimeric form of the SARS-CoV-2 spike (S)-protein adjuvanted with CpG-1018/alum. MethodsThe phase 2/3, double-blind, randomized SPECTRA trial was conducted in five countries in participants aged ≥ 18 years, either SARS-CoV-2-naïve or previously exposed. Participants were randomly assigned to receive two doses of SCB-2019 or placebo administered intramuscularly 21 days apart. In the phase 2 part of the study, on days 1, 22, and 36, neutralizing antibodies were measured by pseudovirus and wild-type virus neutralization assays to SARS-CoV-2 prototype and variants, and ACE2-receptor-binding antibodies and SCB-2019–binding antibodies were measured by ELISA. Cell-mediated immunity was measured by intracellular cytokine staining via flow cytometry. Results1601 individuals were enrolled between 24 March and 13 September 2021 and received at least one vaccine dose. Immunogenicity analysis was conducted in a phase 2 subset of 691 participants, including 428 SARS-CoV-2-naïve (381 vaccine and 47 placebo recipients) and 263 SARS-CoV-2-exposed (235 vaccine and 28 placebo recipients). In SARS-CoV-2-naïve participants, GMTs of neutralizing antibodies against prototype virus increased 2 weeks post-second dose (day 36) compared to baseline (224 vs 12.7 IU/mL). Seroconversion rate was 82.5 %. In SARS-CoV-2-exposed participants, one SCB-2019 dose increased GMT of neutralizing antibodies by 48.3-fold (1276.1 IU/mL on day 22) compared to baseline. Seroconversion rate was 92.4 %. Increase was marginal post-second dose. SCB-2019 also showed cross-neutralization capability against nine variants, including Omicron, in SARS-CoV-2-exposed participants at day 36. SCB-2019 stimulated Th1-biased cell-mediated immunity to the S-protein in both naïve and exposed participants. The vaccine was well tolerated, no safety concerns were raised from the study. ConclusionsA single dose of SCB-2019 was immunogenic in SARS-CoV-2-exposed individuals, whereas two doses were required to induce immune response in SARS-CoV-2-naïve individuals. SCB-2019 elicited a cross-neutralizing response against emergent SARS-CoV-2 variants at antibody levels associated with clinical protection, underlining its potential as a booster.Clinicaltrials.gov: NCT04672395; EudraCT: 2020-004272-17.

Gamma Knife Radiosurgery for Cushing’s Disease: Evaluation of Biological Effective Dose from a Single-Center Experience

Objective: Gamma knife radiosurgery (GKRS) has served as an adjunctive treatment in Cushing's disease (CD) for decades and has become a vital part of therapy in the management of CD. Biological effective dose (BED) is a radiobiological parameter with time correction, considering the cellular deoxyribonucleic acid repairment. We aimed to investigate the safety and efficacy of GKRS for CD and evaluate the association of BED and treatment outcome. Methods: A cohort study of 31 patients with CD received GKRS in West China Hospital between June 2010 and December 2021. Endocrine remission was defined as normalization of 24 h urinary free cortisol (UFC) or serum cortisol ≤ 50 nmol/L after a 1 mg dexamethasone suppression test. Result: The mean age was 38.6 years old, and females accounted for 77.4%. GKRS was the initial treatment for 21 patients (67.7%), and 32.3% of patients underwent GKRS after surgery due to residual disease and recurrence. The mean endocrine follow-up duration was 22 months. The median marginal dose was 28.0 Gy, and the median BED was 221.5 Gy2.47. Fourteen patients (45.1%) experienced control of hypercortisolism in the absence of pharmacological treatment, and the median duration to remission was 20.0 months. The cumulative rates of endocrine remission at 1, 2, and 3 years after GKRS were 18.9%, 55.3%, and 72.21%, respectively. The total complication rate was 25.8%, and the mean duration from GKRS to hypopituitary was 17.5 months. The new hypopituitary rate at 1, 2, and 3 years were 7.1%, 30.3%, and 48.4%, respectively. A high BED level (BED > 205 Gy2.47) was associated with better endocrine remission than a low BED level (BED ≤ 205 Gy2.47), while no significant differences were found between the BED level and hypopituitarism. Conclusions: GKRS was a second-line therapeutic option for CD with satisfactory safety and efficacy. BED should be considered during GKRS treatment planning, and optimization of BED is a potentially impactful avenue toward improving the efficacy of GKRS.