Adverse radiation effects in volume-staged radiosurgery for large arteriovenous malformations: a multiinstitutional study.

OBJECTIVE: The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs). METHODS: This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic. RESULTS: Patients received 2-4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7-94.4 cm3), with a median margin dose per stage of 17 Gy (range 12-20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE. CONCLUSIONS: Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

Dose response and architecture in volume staged radiosurgery for large arteriovenous malformations: A multi-institutional study.

BACKGROUND: Optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. Volume-staged stereotactic radiosurgery (VS-SRS) provides an effective option for these high-risk lesions, but optimizing treatment for these recalcitrant and rare lesions has proven difficult. METHODS: This is a multi-centered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. We evaluated near complete response (nCR), obliteration, cure, and overall survival. RESULTS: With a median age of 33 years old at the time of first SRS volume stage, patients received 2-4 total volume stages and a median follow up of 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cc (range: 7.7-94.4 cc) with a median margin dose per stage of 17 Gy (range: 12-20 Gy). Total AVM volume, margin dose per stage, compact nidus, lack of prior embolization, and lack of thalamic location involvement were all associated with improved outcomes. Dose >/= 17.5 Gy was strongly associated with improved rates of nCR, obliteration, and cure. With dose >/= 17.5 Gy, 5- and 10-year cure rates were 33.7% and 76.8% in evaluable patients compared to 23.7% and 34.7% of patients with 17 Gy and 6.4% and 20.6% with <17 Gy per volume-stage (p = 0.004). Obliteration rates in diffuse nidus architecture with <17 Gy were particularly poor with none achieving obliteration compared to 32.3% with doses >/= 17 Gy at 5 years (p = 0.007). Comparatively, lesions with a compact nidus architecture exhibited obliteration rates at 5 years were 10.7% vs 9.3% vs 26.6% for dose >17 Gy vs 17 Gy vs >/=17.5 Gy. CONCLUSION: VS-SRS is an option for upfront treatment of large AVMs. Higher dose was associated with improved rates of nCR, obliteration, and cure suggesting that larger volumetric responses may facilitate salvage therapy and optimize the chance for cure.

Gamma Knife stereotactic radiosurgery for cavernous sinus meningioma: long-term follow-up in 200 patients.

OBJECTIVEThe authors of this study evaluate the long-term outcomes of stereotactic radiosurgery (SRS) for cavernous sinus meningioma (CSM).METHODSThe authors retrospectively assessed treatment outcomes 5-18 years after SRS in 200 patients with CSM. The median patient age was 57 years (range 22-83 years). In total, 120 (60%) patients underwent Gamma Knife SRS as primary management, 46 (23%) for residual tumors, and 34 (17%) for recurrent tumors after one or more surgical procedures. The median tumor target volume was 7.5 cm3 (range 0.1-37.3 cm3), and the median margin dose was 13.0 Gy (range 10-20 Gy).RESULTSTumor volume regressed in 121 (61%) patients, was unchanged in 49 (25%), and increased over time in 30 (15%) during a median imaging follow-up of 101 months. Actuarial tumor control rates at the 5-, 10-, and 15-year follow-ups were 92%, 84%, and 75%, respectively. Of the 120 patients who had undergone SRS as a primary treatment (primary SRS), tumor progression was observed in 14 (11.7%) patients at a median of 48.9 months (range 4.8-120.0 months) after SRS, and actuarial tumor control rates were 98%, 93%, 85%, and 85% at the 1-, 5-, 10-, and 15-year follow-ups post-SRS. A history of tumor progression after microsurgery was an independent predictor of an unfavorable response to radiosurgery (p = 0.009, HR = 4.161, 95% CI 1.438-12.045). Forty-four (26%) of 170 patients who had presented with at least one cranial nerve (CN) deficit improved after SRS. Development of new CN deficits after initial microsurgical resection was an unfavorable factor for improvement after SRS (p = 0.014, HR = 0.169, 95% CI 0.041-0.702). Fifteen (7.5%) patients experienced permanent CN deficits without evidence of tumor progression at a median onset of 9 months (range 2.3-85 months) after SRS. Patients with larger tumor volumes (≥ 10 cm3) were more likely to develop permanent CN complications (p = 0.046, HR = 3.629, 95% CI 1.026-12.838). Three patients (1.5%) developed delayed pituitary dysfunction after SRS.CONCLUSIONSThis long-term study showed that Gamma Knife radiosurgery provided long-term tumor control for most patients with CSM. Patients who underwent SRS for progressive tumors after prior microsurgery had a greater chance of tumor growth than the patients without prior surgery or those with residual tumor treated after microsurgery.

How to improve obliteration rates during volume-staged stereotactic radiosurgery for large arteriovenous malformations.

OBJECTIVEThe management of large-volume arteriovenous malformations (AVMs) with stereotactic radiosurgery (SRS) remains challenging. The authors retrospectively tested the hypothesis that AVM obliteration rates can be improved by increasing the percentage volume of an AVM that receives a minimal threshold dose of radiation.METHODSIn 1992, the authors prospectively began to stage anatomical components in order to deliver higher single doses to AVMs > 15 cm3 in volume. Since that time 60 patients with large AVMs have undergone volume-staged SRS (VS-SRS). The median interval between the first stage and the second stage was 4.5 months (2.8-13.8 months). The median target volume was 11.6 cm3 (range 4.3-26 cm3) in the first-stage SRS and 10.6 cm3 (range 2.8-33.7 cm3) in the second-stage SRS. The median margin dose was 16 Gy (range 13-18 Gy) for both SRS stages.RESULTSAVM obliteration after the initial two staged volumetric SRS treatments was confirmed by MRI alone in 4 patients and by angiography in 11 patients at a median follow-up of 82 months (range 0.4-206 months) after VS-SRS. The post-VS-SRS obliteration rates on angiography were 4% at 3 years, 13% at 4 years, 23% at 5 years, and 27% at 10 years. In multivariate analysis, only ≥ 20-Gy volume coverage was significantly associated with higher total obliteration rates confirmed by angiography. When the margin dose is ≥ 17 Gy and the 20-Gy SRS volume included ≥ 63% of the total target volume, the angiographically confirmed obliteration rates increased to 61% at 5 years and 70% at 10 years.CONCLUSIONSThe outcomes of prospective VS-SRS for large AVMs can be improved by prescribing an AVM margin dose of ≥ 17 Gy and adding additional isocenters so that ≥ 63% of the internal AVM dose receives more than 20 Gy.

Tip Design for Safety of Steerable Needles for Robot-Controlled Brain Insertion.

BACKGROUND: Current practice in neurosurgical needle insertion is limited by the straight trajectories inherent with rigid probes. One technique allowing curvilinear trajectories involves flexible bevel-tipped needles, which bend during insertion due to their asymmetry. In the brain, safety will require avoidance of the sharp tips often used in laboratory studies, in favor of a more rounded profile. Steering performance, on the other hand, requires maximal asymmetry. Design of safe bevel-tipped brain needles thus involves management of this tradeoff by adjusting needle gauge, bevel angle, and fillet (or tip) radius to arrive at a design that is suitably asymmetrical while producing strain, strain rate, and stress below the levels that would damage brain tissue. METHODS: Designs with a variety of values of needle radius, bevel angle, and fillet radius were evaluated in finite-element simulations of simultaneous insertion and rotation. Brain tissue was modeled as a hyperelastic, linear viscoelastic material. Based on the literature available, safety thresholds of 0.19 strain, 10 s-1 strain rate, and 120 kPa stress were used. Safe values of needle radius, bevel angle, and fillet radius were selected, along with an appropriate velocity envelope for safe operation. The resulting needle was fabricated and compared with a Sedan side-cutting brain biopsy needle in a study in the porcine model in vivo (N=3). RESULTS: The prototype needle selected was 1.66 mm in diameter, with bevel angle of 10° and fillet radius of 0.25 mm. Upon examination of postoperative CT and histological images, no differences in tissue trauma or hemorrhage were noted between the prototype needle and the Sedan needle. CONCLUSIONS: The study indicates a general design technique for safe bevel-tipped brain needles based on comparison with relevant damage thresholds for strain, strain rate, and stress. The full potential of the technique awaits the determination of more exact safety thresholds.

Hyper- and viscoelastic modeling of needle and brain tissue interaction.

Deep needle insertion into brain is important for both diagnostic and therapeutic clinical interventions. We have developed an automated system for robotically steering flexible needles within the brain to improve targeting accuracy. In this work, we have developed a finite element needle-tissue interaction model that allows for the investigation of safe parameters for needle steering. The tissue model implemented contains both hyperelastic and viscoelastic properties to simulate the instantaneous and time-dependent responses of brain tissue. Several needle models were developed with varying parameters to study the effects of the parameters on tissue stress, strain and strain rate during needle insertion and rotation. The parameters varied include needle radius, bevel angle, bevel tip fillet radius, insertion speed, and rotation speed. The results will guide the design of safe needle tips and control systems for intracerebral needle steering.

Automatic Steering of Manually Inserted Needles.

Bevel-tipped flexible needles can be robotically steered to reach clinical targets along curvilinear paths in 3D. Manual needle insertion allows the clinician to control the insertion speed, ensuring patient safety. This paper presents a control law for automatic 3D steering of manually inserted flexible needles, enabling path-following control. A look-ahead proportional controller for position and orientation is presented. The look-ahead distance is a linear function of insertion speed. Simulations in a 3D brain-like environment demonstrate the performance of the proposed controller. Experimental results also show the feasibility of this technique in 2D and 3D environments.

Needle insertion with duty-cycled rotation into multiple media.

Thin, flexible needles can be steered along nonlinear paths to reach deep anatomical structures within the human body. This study builds upon previous work involving steering of bevel-tipped needles by inserting while rotating in a duty-cycled fashion. Here we investigate how needle material and radius, duty cycle, and tissue stiffness affect needle curvature. Needles were inserted into media while rotated at a specified duty cycle and the curvature was measured. A linear relationship between duty cycle and curvature was observed across all needle materials and radii, and tissue stiffnesses. Following these observations, we developed a model that encapsulates needle and tissue parameters in order to predict the duty cycle needed to achieve a desired curvature.

A biohybrid artificial lung prototype with active mixing of endothelialized microporous hollow fibers.

Acute respiratory distress syndrome (ARDS) affects nearly 150,000 patients per year in the US, and is associated with high mortality ( approximately 40%) and suboptimal options for patient care. Mechanical ventilation and extracorporeal membrane oxygenation are limited to short-term use due to ventilator-induced lung injury and poor biocompatibility, respectively. In this report, we describe the development of a biohybrid lung prototype, employing a rotating endothelialized microporous hollow fiber (MHF) bundle to improve blood biocompatibility while MHF mixing could contribute to gas transfer efficiency. MHFs were surface modified with radio frequency glow discharge (RFGD) and protein adsorption to promote endothelial cell (EC) attachment and growth. The MHF bundles were placed in the biohybrid lung prototype and rotated up to 1,500 revolutions per minute (rpm) using speed ramping protocols to condition ECs to remain adherent on the fibers. Oxygen transfer, thrombotic deposition, and EC p-selectin expression were evaluated as indicators of biohybrid lung functionality and biocompatibility. A fixed aliquot of blood in contact with MHF bundles rotated at either 250 or 750 rpm reached saturating pO(2) levels more quickly with increased rpm, supporting the concept that fiber rotation would positively contribute to oxygen transfer. The presence of ECs had no effect on the rate of oxygen transfer at lower fiber rpm, but did provide some resistance with increased rpm when the overall rate of mass transfer was higher due to active mixing. RFGD followed by fibronectin adsorption on MHFs facilitated near confluent EC coverage with minimal p-selectin expression under both normoxic and hyperoxic conditions. Indeed, even subconfluent EC coverage on MHFs significantly reduced thrombotic deposition adding further support that endothelialization enhances, blood biocompatibility. Overall these findings demonstrate a proof-of-concept that a rotating endothelialized MHF bundle enhances gas transfer and biocompatibility, potentially producing safer, more efficient artificial lungs.