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Stereotactic radiosurgery (SRS) is a treatment option in the initial management of patients with brain metastases. While its efficacy has been demonstrated in several prior studies, treatment-related complications, particularly symptomatic radiation necrosis (RN), remains as an obstacle for wider implementation of this treatment modality. We thus examined risk factors associated with the development of symptomatic RN in patients treated with SRS for brain metastases.We performed a retrospective review of our institutional database to identify patients with brain metastases treated with SRS. Diagnosis of symptomatic RN was determined by appearance on serial MRIs, MR spectroscopy, requirement of therapy, and the development of new neurological complaints without evidence of disease progression.We identified 323 brain metastases treated with SRS in 170 patients from 2009 to 2018. Thirteen patients (4%) experienced symptomatic RN after treatment of 23 (7%) lesions. After SRS, the median time to symptomatic RN was 8.3 months. Patients with symptomatic RN had a larger mean target volume (p0.0001), and thus larger V100% (p0.0001), V50% (p0.0001), V12Gy (p0.0001), and V10Gy (p=0.0002), compared to the rest of the cohort. Single-fraction treatment (p=0.0025) and diabetes (p=0.019) were also significantly associated with symptomatic RN.SRS is an effective treatment option for patients with brain metastases; however, a subset of patients may develop symptomatic RN. We found that patients with larger tumor size, larger plan V100%, V50%, V12Gy, or V10Gy, who received single-fraction SRS, or who had diabetes were all at higher risk of symptomatic RN.

Uveal melanoma (UM), the most frequently occurring non-cutaneous melanoma and most common primary intraocular malignancy in adults, arises from the melanocytes of the choroid in approximately 95% of cases. Prompt diagnosis and treatment is vital as primary tumor size is one of the key factors associated with survival. Despite recent advances in management, more than half of the patients develop metastatic disease which portends poor survival. Currently, treatment options for UM include local resection, enucleation, plaque brachytherapy, and/or particle beam radiotherapy (RT). Enucleation was initially the standard of care in the management of UM, but a shift towards eye-preserving therapeutic choices such as RT and local resection has been noted in recent decades. Plaque brachytherapy, a form of localized RT, is the most popular option and is now the preferred treatment modality for a majority of UM cases. In this review we discuss the etiopathogenesis, clinical presentation and diagnosis of UM and place a special emphasis on its therapeutic options. Furthermore, we review the current literature on UM management and propose a functional treatment algorithm for non-metastatic disease.

OBJECTIVEThe authors sought to compare the dosimetric quality of hypofractionated stereotactic radiosurgery in treating sizeable brain tumors across the following treatment platforms: GammaKnife (GK) Icon, CyberKnife (CK) G4, volumetric modulated arc therapy (VMAT) on the Varian TrueBeam STx, double scattering proton therapy (DSPT) on the Mevion S250, and intensity modulated proton therapy (IMPT) on the Varian ProBeam.METHODSIn this retrospective study, stereotactic radiotherapy treatment plans were generated for 10 patients with sizeable brain tumors (> 3 cm in longest diameter) who had been treated with VMAT. Six treatment plans, 20–30 Gy in 5 fractions, were generated for each patient using the same constraints for each of the following radiosurgical methods: 1) GK, 2) CK, 3) coplanar arc VMAT (VMAT-C), 4) noncoplanar arc VMAT (VMAT-NC), 5) DSPT, and 6) IMPT. The coverage; conformity index; gradient index (GI); homogeneity index; mean and maximum point dose of organs at risk; total dose volume (V) in Gy to the normal brain for 2 Gy (V2), 5 Gy (V5), and 12 Gy (V12); and integral dose were compared across all platforms.RESULTSAmong the 6 techniques, GK consistently produced a sharper dose falloff despite a greater central target dose. GK gave the lowest GI, with a mean of 2.7 ± 0.1, followed by CK (2.9 ± 0.1), VMAT-NC (3.1 ± 0.3), and VMAT-C (3.5 ± 0.3). The highest mean GIs for the proton beam treatments were 3.8 ± 0.4 for DSPT and 3.9 ± 0.4 for IMPT. The GK consistently targeted the lowest normal brain volume, delivering 5 to 12 Gy when treating relatively smaller- to intermediate-sized lesions (less than 15–20 cm3). Yet, the differences across the 6 modalities relative to GK decreased with the increase of target volume. In particular, the proton treatments delivered the lowest V5 to the normal brain when the target size was over 15–20 cm3 and also produced the lowest integral dose to the normal brain regardless of the target size.CONCLUSIONSThis study provides an insightful understanding of dosimetric quality from both photon and proton treatment across the most advanced stereotactic radiotherapy platforms.

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Metastatic melanoma is often accompanied by the development of brain metastases, at presentation or during the course of therapy. Local therapies such as surgery and radiation have been considered standard treatments for intracranial disease. However, the emergence of systemic therapies has been changing the treatment paradigm for the management of brain metastases. In patients with BRAF-mutated melanoma, combined BRAF and MEK inhibition has been found to elicit significant clinical responses. Patients who develop resistance to MAP kinase (MAPK) targeted therapy can achieve significant responses upon rechallenge. In this case, a 68-year-old woman with metastatic melanoma who had received multiple treatment courses including combination immunotherapy and combination MAPK-targeted therapy presented with a brainstem metastasis and demonstrated a complete response upon initiation of encorafenib and binimetinib, thereby obviating the need for stereotactic radiosurgery.

Purpose: In radiotherapy, high radiation exposure to optic nerve (ON) can cause optic neuropathy or vision loss. In this study, we evaluated the pattern and extent of the ON movement using MRI, and investigated the potential dosimetric effect of this movement on radiotherapy. Methods: Five volunteers were requested to gaze toward five directions during MRI acquisitions, including neutral (straight forward), left/right (horizontal movement), and up/down (vertical movement). The motion of the ON was analyzed quantitatively. To evaluate the potential dosimetric effect of this motion, the ON motion was hypothetically applied to three patients with perioptic tumors.Results: The motion of ON followed a nearly conical shape among all five subjects. The anterior end of ONs moved with 10.4 ± 2.2 mm and 11.1 ± 1.4 mm horizontally for the left and right eyes, and 9.3 ± 0.8 mm vertically for the right eye. Posterior end of ON has negligible displacement. In the three clinical scenario, the hypothetical movement of ON in this measured range introduced non-negligible dosimetric effect. Conclusion: The range of motion of the anterior portions of the optic nerves is on the order of centimeters, which may need to be considered with extra attention during radiation therapy workflow.

Radiation therapy plays an integral role in the modern management of benign and malignant tumors in the extramedullary space. Necessary components of radiation therapy include patient simulation, immobilization, target delineation, and quality assurance. Radiotherapy is administered in three general circumstances: primary (upfront) treatment for incidental and mildly symptomatic tumors, adjuvant treatment in both subtotal and gross total resections, and treatment of progressive recurrent disease. Advanced radiation modalities include radiosurgery and proton beam radiation. Benign tumors of the extramedullary spine that can be treated with radiation include meningioma, schwannoma, and neurofibroma. Malignant tumors of the extramedullary spine include rare entities such as intradural metastases and more commonly, leptomeningeal disease. We present multiple cases wherein new-age radiosurgical platforms are utilized in the treatment of intradural extramedullary tumors.

D-Band Radio-on-Glass (RoG) modules combining two highly integrated SiGe BiCMOS transceivers (TRX) with a record low-loss glass interposer technology are presented. The ICs operate at 115-155 GHz (Low-Band) and 135-170 GHz (High-Band). In this frequency range, a transmitter P sat up to 13 dBm and an average receiver NF of 8.5 dB is achieved. The integrated module supports TX constellations up to 512-QAM (2.2% EVM at 2 dBm output, 145 GHz) and data-rates up to 42 Gb/s (128-QAM). Measurements mimicking a 250-meter wireless-link demonstrate a maximum data-rate of 36 Gb/s using 64-QAM. The RoG modules represent the first low-cost and highly integrated solution for spectrally efficient backhaul systems in D-Band.

Objective Metastatic melanoma patients often receive palliative radiotherapy (RT) and immunotherapy (IT). However, the immunological interplay between RT dose-fractionation and IT is uncertain, and the optimal treatment strategy using RT and IT in metastatic melanoma remains unclear. Our main objective was to examine the effect of RT dose-fractionation on overall survival (OS). Methods Using the National Cancer Database (NCDB), we classified metastatic melanoma patients who received palliative RT into two dose-fractionation groups - conventionally fractionated RT (CFRT

e21551 Background: Combined BRAF/MEK inhibition results in improved progression free and overall survival in BRAF mutated melanoma, but significant response is not universally observed. TERT promoter activating mutations often co-occur with BRAF mutations and have been associated with aggressive features and poorer prognosis. The TERT promotor inhibits apoptosis via a mechanism dependent upon BRAF mutant MAPK activation. Preclinical data in mouse models suggests that BRAF/TERT genetic duet melanomas are associated with improved response to BRAF/MEK inhibition as compared with BRAF mutant/TERT-WT melanomas. Methods: We performed a single center retrospective analysis of adults with melanoma with confirmed BRAF mutations +/- TERT promoter mutations. Responses and progression free survival in response to BRAF/MEK inhibition was assessed. Differences in RR and PFS were compared using Kaplan-Meier and Log-Rank. Results: 52 cases of BRAF/TERT genetic duet and BRAF mutated/TERT-WT melanomas were assessed. A total of 24 patients received BRAF/MEK inhibitors over the course of treatment meeting criteria for study inclusion; 9 (37.5%) BRAF/TERT genetic duet and 15 (62.5%) BRAF mutated/TERT-WT. BRAF V600E was present in 19/24 (79.2%) and V600K in 5/24 (20.8%). In the genetic duets, TERT -146C > T was present in 4/9 (44.4%), -124C > T in 2/9 (22.2%), -139_-138CC > TT in 2/9 (22.2%), and a SNV in 1/9 (11.1%). Mean age at diagnosis was 56 ± 13.5 years and 62.5% were male. ECOG PFS was 0-1 in 15/24 (62.5%), 2-3 in 6/24 (25%), and unreported in 3/24 (12.5%). Mean LDH at start of therapy was 391 (range 81-1664). At initial diagnosis 20.8% were Stage I, 25% Stage II, 37.5% Stage III, and 16.7% Stage IV. Two or more sites of disease were present in 10/24 (41.7%) and 2/24 (8.3%) had CNS metastases. BRAF/MEK directed therapy was first line in 6/24 (25%) of patients, others received prior immunotherapy. No significant differences between groups were observed in baseline demographics, disease state at diagnosis, or treatment history. In BRAF/TERT genetic duet melanomas CR was observed in 1/9 (11.1%), PR in 7/9 (77.8%), and NR in 1/9 (11.1%). In BRAF mutated/TERT-WT CR was observed in 3/15 (20%), PR in 11/15 (73.3%), and NR in 1/15 (6.7%). BRAF/TERT genetic duets were observed to initially have somewhat better PFS on first exposure to BRAF/MEK directed therapy but the PFS curves crossed at about 5 months with no significant difference observed overall (p = 0.40). Conclusions: This study is the first to report on outcomes of BRAF/MEK directed therapy in BRAF/TERT genetic duet vs BRAF mutated/TERT-WT melanomas in humans. While preclinical data from mouse models observed an improved response to BRAF/MEK inhibition in genetic duet tumors, no significant difference was observed. Our study is limited by small sample size. A multicenter analysis may be of interest to better understand the effects of BRAF inhibition in patients with BRAF/TERT genetic duet melanoma.

Purpose: Renal cell carcinoma (RCC) and melanoma have been considered `radioresistant' due to the fact that they do not respond to conventionally fractionated radiation therapy. Stereotactic radiosurgery (SRS) provides high-dose radiation to a defined target volume and a limited number of studies have suggested the potential effectiveness of SRS in radioresistant histologies. We sought to determine the effectiveness of SRS for the treatment of patients with radioresistant brain metastases. Materials and Methods: We performed a retrospective review of our institutional database to identify patients with RCC or melanoma brain metastases treated with SRS. Treatment response were determined in accordance with the Response Evaluation Criteria in Solid Tumors. Results: We identified 53 radioresistant brain metastases (28\% RCC and 72\% melanoma) treated in 18 patients. The mean target volume and coverage was 6.2 +/- 9.5 mL and 95.5\% +/- 2.9\%, respectively. The mean prescription dose was 20 +/- 4.9 Gy. Forty lesions (75\%) demonstrated a complete/partial response and 13 lesions (24\%) with progressive/stable disease. Smaller target volume (p < 0.001), larger SRS dose (p < 0.001), and coverage (p = 0.008) were found to be positive predictors of complete response to SRS. Conclusion: SRS is an effective management option with up to 75\% response rate for radioresistant brain metastases. Tumor volume and radiation dose are predictors of response and can be used to guide the decision-making for patients with radioresistant brain metastases.

Background In the setting of spinal metastases with epidural cord compression, radiosurgery is often only considered when there is sufficient separation between the epidural disease and the spinal cord. However, in patients who are nonsurgical candidates or those who prefer nonoperative management, there may be a benefit from stereotactic body radiation therapy, even when the epidural target is closer than the traditionally referenced 3 mm distance from the spinal cord. The purpose of this retrospective study is to evaluate our institution's experience in treating 20 such patients. Methods We reviewed records of all patients treated with stereotactic body radiation therapy for spinal metastases at our institution from January 2010 to January 2016, with follow-up through December 2016. The primary end point was local progression of disease. Local progression was defined as clear radiographic disease growth on follow-up imaging or worsening clinical symptoms in the absence of evidence for radiation myelopathy. Results Local control was obtained in 55% of patients meeting these criteria without a single case of radiation myelitis. Most patients with disease progression were able to undergo additional local treatment. Conclusions Although local control was less than expected when compared with spine radiosurgery with adequate separation between the target and spinal cord, this treatment appears to be a viable option in the nonsurgical candidate.

OBJECTIVEThe Leksell Gamma Knife Icon (GK Icon) radiosurgery system can utilize cone-beam computed tomography (CBCT) to evaluate motion error. This study compares the accuracy of frame-based and frameless mask-based fixation using the Icon system.METHODSA retrospective cohort study was conducted to evaluate patients who had undergone radiosurgery with the GK Icon system between June and December 2017. Patients were immobilized in either a stereotactic head frame or a noninvasive thermoplastic mask with stereotactic infrared (IR) camera monitoring. Setup error was defined as displacement of the skull in the stereotactic space upon setup as noted on pretreatment CBCT compared to its position in the stereotactic space defined by planning MRI for frame patients and defined as skull displacement on planning CBCT compared to its position on pretreatment CBCT for mask patients. For frame patients, the intrafractionation motion was measured by comparing pretreatment and posttreatment CBCT. For mask patients, the intrafractionation motion was evaluated by comparing pretreatment CBCT and additional CBCT obtained during the treatment. The translational and rotational errors were recorded.RESULTSData were collected from 77 patients undergoing SRS with the GK Icon. Sixty-four patients underwent frame fixation, with pre- and posttreatment CBCT studies obtained. Thirteen patients were treated using mask fixation to deliver a total of 33 treatment fractions. Mean setup and intrafraction translational and rotation errors were small for both fixation systems, within 1 mm and 1° in all axes. Yet mask fixation demonstrated significantly larger intrafraction errors than frame fixation. Also, there was greater variability in both setup and intrafraction errors for mask fixation than for frame fixation in all translational and rotational directions. Whether the GK treatment was for metastasis or nonmetastasis did not influence motion uncertainties between the two fixation types. Additionally, monitoring IR-based intrafraction motion for mask fixation—i.e., the number of treatment stoppages due to reaching the IR displacement threshold—correlated with increasing treatment time.CONCLUSIONSCompared to frame-based fixation, mask-based fixation demonstrated larger motion variations. The variability in motion error associated with mask fixation must be taken into account when planning for small lesions or lesions near critical structures.

Purpose The main objective of this study was to develop a technique to accurately determine the air gap between the end of the proton beam compensator and the body of the patient in proton radiotherapy. Methods Orthogonal x‐ray image‐based automatic coordinate reconstruction was used to determine the air gap between the patient body surface contour and the end of beam nozzle in proton radiotherapy. To be able to clearly identify the patient body surface contour on the orthogonal images, a radiopaque wire was placed on the skin surface of the patient as a surrogate. In order to validate this method, a Rando® head phantom was scanned and five proton plans were generated on a Mevion S250 Proton machine with various air gaps in Varian Eclipse Treatment Planning Systems (TPS). When setting up the phantom in a treatment room, a solder wire was placed on the surface of the phantom closest to the beam nozzle with the knowledge of the beam geometry in the plan. After the phantom positioning was verified using orthogonal kV imaging, the last pair of setup kV images was used to segment the solder wire and the in‐room coordinates of the wire were reconstructed using a back‐projection algorithm. Using the wire as a surrogate of the body surface, we calculated the air gaps by finding the minimum distance between the reconstructed wire and the end of the compensator. The methodology was also verified and validated on clinical cases. Results On the phantom study, the air gap values derived with the automatic reconstruction method were found to be within 1.1 mm difference from the planned values for proton beams with air gaps of 85.0, 100.0, 150.0, 180.0, and 200.0 mm. The reconstruction technique determined air gaps for a patient in two clinical treatment sessions were 38.4 and 41.8 mm, respectively, for a 40 mm planned air gap, and confirmed by manual measurements. There was strong agreement between the calculated values and the automatically measured values, and between the automatically and manually measured values. Conclusions An image‐based automatic method has been developed to conveniently determine the air gap of a proton beam, directly using the orthogonal images for patient positioning without adding additional imaging dose to the patient. The method provides an objective, accurate, and efficient way to confirm the target depth at treatment to ensure desired target coverage and normal tissue sparing.

We present a 4.4-mm2 single-chip synthesized signal source with 125 MHz to 32 GHz continuous frequency coverage with a minimum frequency step smaller than 10 Hz. The chip is fabricated in a 0.18-μm SiGe BiCMOS 1P6M technology. A core fractional-N synthesizer using a 20-MHz reference frequency has four LC-VCOs and a 4- to 8-GHz synthesizable range. Post-synthesis blocks extend the frequency coverage up to 32 GHz and down to 125 MHz through frequency multiplication and division. In different operation modes, the chip, including a balanced 50-ohm load driver, consumes from 284 to 498 mW. The phase noise performance achieves -117.6 dBc/Hz at 1-MHz offset from a 6-GHz output frequency and -83 dBc/Hz in-band noise. The integrated phase noise is -28 dBc and the absolute jitter is 1.05 psRMS at 6-GHz output. The jitter is maintained nearly constant (between 0.9 and 1.2 psRMS) across the whole output frequency range.

A 10-GBd 40-Gb/s coherent optical transport is a promising technology for higher data rate communications by virtue of improved sensitivity and high spectrum efficiency. One of the major challenges in designing a 40-Gb/s coherent quadrature-phase-shift-keying receiver is to achieve high-speed data conversion at around 20-GHz sampling rate with at least 5-bit resolution. With the detailed design framework for the target requirements, this paper presents a 5-bit 20-GS/s flash analog-to-digital converter (ADC) realized in 0.18-m SiGe BiCMOS technology. The ADC includes a track-and-hold amplifier (THA) incorporated with linear distortion compensation, double-interpolation preamplifier, current bias-weighted comparator, and high-speed encoder logic. At 4 V, the THA had a bandwidth that exceeded 23 GHz and an IIP3 of 24 dBm. The ADC achieves a signal-to-noise-plus-distortion ratio of 28.6 dB and a spurious-free dynamic range of 36 dB with a 1-GHz input sinusoid sampled at 20 GS/s. The ADC has a wide resolution bandwidth of 7 GHz, and the figure of merit is 9.54 pJ/conversion-step. The ADC consumes 3.24 W from 4- and 3-V supplies when sampled at 20 GHz. The prototype ADC occupies 8.68 mm2 of silicon area.

Return-to-zero differential phase-shift keying applications require a differential amplifier with high bandwidth, high gain, low noise, and good input impedance match. In this paper, we describe an InGaAs-InP heterostructure bipolar transistor differential transimpedance amplifier with high bandwidth of 47 GHz and high gain of 56 dB-/spl Omega/. The input-referred current noise is less than 35 pA//spl radic/Hz over the measurement range up to 40 GHz.

We realized a monolithic polarization-diversity dual-quadrature coherent receiver with on-chip balanced detection in a silicon photonic integrated circuit with integrated germanium detectors. We tested it using a polarization-division multiplexed quadrature phase-shift keyed signal at 112-Gb/s.

In this paper, we describe an InGaAs/InP heterostructure bipolar transistor differential transimpedance amplifier with high bandwidth of 47 GHz and high gain of 56 dB-ohms.

Recent advances in probe and feedback techniques have brought near-field scanning microscopy (NSOM) to the point where it can be routinely applied to a variety of systems.1 Although many efforts are directed at improving the current spatial resolution of ~12 nm of the current probe designs, the diversity of applications would be greatly increased by the development of a near-field probe with greatly improved photon flux.

We report the first measurements of linear and nonlinear absorption and perpendicular field electro-absorption (Quantum Confined Stark Effect) in GaAs/AlGaAs quantum wells for light propagating parallel to the plane of the layers. This geometry is well-suited for integrated optics. With increasing intensity the absorption is found to saturate at the very low intensity of 300 W/cm 2 . With increasing electric field the absorption edge shifts to longer wavelengths by as much as 40 meV, giving a modulation depth >10 db in a 150 μm long device. The strong dichroism present in this geometry is retained even at high fields, making polarization sensitive electro-optical devices possible. We also demonstrate in the waveguide geometry optical bistability due to the self-electro-optic effect with 20:1 on/off ratio.