Andrew B. Thompson

OBJECTIVE: The most common functioning pituitary adenoma is prolactinoma. Patients with medically refractory or residual/recurrent tumors that are not amenable to resection can be treated with stereotactic radiosurgery (SRS). The aim of this multicenter study was to evaluate the role of SRS for treating prolactinomas.METHODS: This retrospective study included prolactinomas treated with SRS between 1997 and 2016 at ten institutions. Patients’ clinical and treatment parameters were investigated. Patients were considered to be in endocrine remission when they had a normal level of prolactin (PRL) without requiring dopamine agonist medications. Endocrine control was defined as endocrine remission or a controlled PRL level ≤ 30 ng/ml with dopamine agonist therapy. Other outcomes were evaluated including new-onset hormone deficiency, tumor recurrence, and new neurological complications.RESULTS: The study cohort comprised 289 patients. The endocrine remission rates were 28%, 41%, and 54% at 3, 5, and 8 years after SRS, respectively. Following SRS, 25% of patients (72/289) had new hormone deficiency. Sixty-three percent of the patients (127/201) with available data attained endocrine control. Three percent of patients (9/269) had a new visual complication after SRS. Five percent of the patients (13/285) were recorded as having tumor progression. A pretreatment PRL level ≤ 270 ng/ml was a predictor of endocrine remission (p = 0.005, adjusted HR 0.487). An increasing margin dose resulted in better endocrine control after SRS (p = 0.033, adjusted OR 1.087).CONCLUSIONS: In patients with medically refractory prolactinomas or a residual/recurrent prolactinoma, SRS affords remarkable therapeutic effects in endocrine remission, endocrine control, and tumor control. New-onset hypopituitarism is the most common adverse event.

Background: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database.Methods: SEER 18 Custom Data registries were queried for AT/RT (ICD‐0‐3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan‐Meier and Cox proportional hazards regression modeling were performed. Propensity‐score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias.Results: The majority of patients were P = 0.003), whereas trimodality therapy was strongly protective (HR 0.39, P < 0.001). Infants (P = 0.02) and toddlers (HR 0.31, P < 0.001).Conclusion: The current study provides further evidence that trimodality therapy improves clinical outcomes among patients with AT/RT. This finding was most pronounced for younger patients; therefore, further studies are needed to confirm this finding in this vulnerable population.

Computed tomography (CT) derived ventilation algorithms estimate the apparent voxel volume changes within an inhale/exhale CT image pair. Transformation‐based methods compute these estimates solely from the spatial transformation acquired by applying a deformable image registration (DIR) algorithm to the image pair. However, approaches based on finite difference approximations of the transformation's Jacobian have been shown to be numerically unstable. As a result, transformation‐based CT ventilation is poorly reproducible with respect to both DIR algorithm and CT acquisition method. Purpose We introduce a novel Integrated Jacobian Formulation (IJF) method for estimating voxel volume changes under a DIR recovered spatial transformation. The method is based on computing volume estimates of DIR mapped subregions using the hit‐or‐miss sampling algorithm for integral approximation. The novel approach allows for regional volume change estimates that 1) respect the resolution of the digital grid and 2) are based on approximations with quantitatively characterized and controllable levels of uncertainty. As such, the IJF method is designed to be robust to variations in DIR solutions and thus overall more reproducible. Methods Numerically, Jacobian estimates are recovered by solving a simple constrained linear least squares problem that guarantees the recovered global volume change is equal to the global volume change obtained from the inhale and exhale lung segmentation masks. Reproducibility of the IJF method with respect to DIR solution was assessed using the expert‐determined landmark point pairs and inhale/exhale phases from 10 4DCTs available on www.dir-lab.com. Reproducibility with respect to CT acquisition was assessed on the 4DCT and 4D cone beam CT (4DCBCT) images acquired for five lung cancer patients prior to radiotherapy. Results The ten Dir‐Lab 4DCT cases were registered twice with the same DIR algorithm, but with different smoothing parameter. Finite difference Jacobian (FDJ) and IFJ images were computed for both solutions. The average spatial errors (300 landmarks per case) for the two DIR solution methods were 0.98 (1.10) and 1.02 (1.11). The average Pearson correlation between the FDJ images computed from the two DIR solutions was 0.83 (0.03), while for the IJF images it was 1.00 (0.00). For inter‐modality assessment, the IJF and FDJ images were computed from the 4DCT and 4DCBCT of five patients. The average Pearson correlation of the spatially aligned FDJ images was 0.27 (0.11), while it was 0.77 (0.13) for the IFJ method. Conclusion The mathematical theory underpinning the IJF method allows for the generation of ventilation images that are 1) computed with respect to DIR spatial accuracy on the digital voxel grid and 2) based on DIR measured subregional volume change estimates acquired with quantifiable and controllable levels of uncertainty. Analyses of the experiments are consistent with the mathematical theory and indicate that IJF ventilation imaging has a higher reproducibility with respect to both DIR algorithm and CT acquisition method, in comparison to the standard finite difference approach.

Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. The genetic mutations that cause this disease result in elevated levels of vascular endothelial growth factor, which is inhibited by bevacizumab. Previous studies have shown bevacizumab treatment to be effective in reducing symptoms, but study protocols have all used oncological dosing parameters, which carry several well-described serious side effects. This study investigates whether drastically lower dosages of bevacizumab than normally used in oncological treatment could control epistaxis in patients with HHT and medically refractory epistaxis. A prospective, open-label, noncomparative study enrolled six patients receiving 0.125-mg/kg infusions of bevacizumab once every 4 weeks for a total of six infusions. Severity of epistaxis was assessed with the epistaxis severity score, and quality-of-life measures were followed with the 20-item Sino-Nasal Outcome Test and 36-item Short Form surveys. A statistically significant improvement was seen in the control of epistaxis severity and frequency, with minimal negative side effects and high patient satisfaction. Very low dose bevacizumab treatment is an effective method of controlling medically refractory epistaxis in patients with HHT and additional investigation to optimize dosing guidelines is warranted.

Gold nanoparticles hold great promise for studying protein-protein interactions because of their intrinsic optical properties. Pink when in a homogeneous suspension, the solution turns blue-gray when particles are drawn close together, for example, when immobilized proteins specifically interact with each other. However, the nanoparticle stability, size, and method of protein attachment contribute to the unreliable outcome of current assays. To overcome these hurdles, we developed novel and reliable methods first to synthesize homogenous particles of optimal diameter and second to apply a heterologous NTA-Ni-SAM coating for controlled orientation and optimal presentation of histidine-tagged proteins. Both methods were proven to greatly enhance assay sensitivity and specificity by increasing the signal and minimizing the nonspecific binding. Our assay reproducibly detected known protein-protein interactions and unambiguously identified small molecules that inhibited them. We believe our gold nanoparticle bioassay is a versatile and trustworthy new platform for analyzing protein-protein interactions and high-throughput screening of small-molecule inhibitors.