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Adomas Bunevicius, Vytenis Deltuva, Sarunas Tamasauskas, Arimantas Tamasauskas, Edward R. Laws Jr., and Robertas Bunevicius

Object

A low triiodothyronine (T3) state is highly prevalent and is associated with a poor prognosis in critically ill patients. The authors investigated, in patients undergoing brain tumor surgery, the direct association of a perioperative low T3 syndrome with clinical outcomes and also with symptoms of depression and anxiety.

Methods

Ninety consecutive patients (71% women, median age 55 years), on admission for brain tumor surgery, were evaluated for sociodemographic and clinical characteristics. Their thyroid function profile was assessed on the morning of brain tumor surgery and on the morning after brain tumor surgery. Patients with free T3 concentrations of 3.1 pmol/L or less were considered to have low T3 syndrome. The patients were evaluated for symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) before and after surgery and for clinical outcomes using the Glasgow Outcome Scale (GOS) at discharge.

Results

After brain tumor surgery, free T3 concentrations decreased (p < 0.001) and the proportion of patients with low T3 levels increased from 38% to 54% (p = 0.02). Lower preoperative (rho = 0.30, p = 0.004) and postoperative (rho = 0.33, p = 0.002) free T3 concentrations correlated with low GOS scores at discharge. Preoperative low T3 syndrome (OR 5.49, 95% CI 1.27–23.69, p = 0.02) and postoperative low T3 syndrome (OR 8.73, 95% CI 1.49–51.21, p = 0.02) both increased risk for unfavorable clinical outcomes (GOS scores < 5) at discharge, after adjusting for age, sex, histological diagnosis of brain tumor, preoperative functional impairment, previous treatment for brain tumor, and depressive symptoms. Preoperative low T3 syndrome increased the risk for preoperative (HADS-depression subscale score ≥ 11; OR 4.12, 95% CI 1.16–14.58, p = 0.03) but not postoperative depressive symptoms independently from sociodemographic and clinical factors.

Conclusions

Low T3 syndrome is a strong independent predictor of unfavorable clinical outcomes and depressive symptoms, and its diagnosis and preoperative management should be considered in patients undergoing neurosurgery for the treatment of brain tumors.

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Adomas Bunevicius, Darrah Sheehan, Mary Lee Vance, David Schlesinger, and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) is used for the management of residual or recurrent Cushing’s disease (CD). Increasing experience and technological advancements of Gamma Knife radiosurgery (GKRS) systems can impact the outcomes of CD patients. The authors evaluated the association of their center’s growing experience and the era in which GKRS was performed with treatment success and adverse events in patients with CD.

METHODS

The authors studied consecutive patients with CD treated with GKRS at the University of Virginia since installation of the first Gamma Knife system in March 1989 through August 2019. They compared endocrine remission and complication rates between patients treated before 2000 (early cohort) and those who were treated in 2000 and later (contemporary cohort).

RESULTS

One hundred thirty-four patients with CD underwent GKRS during the study period: 55 patients (41%) comprised the early cohort, and 79 patients (59%) comprised the contemporary cohort. The contemporary cohort, compared with the early cohort, had a significantly greater treatment volume, radiation prescription dose, maximal dose to the optic chiasm, and number of isocenters, and they more often had cavernous sinus involvement. Endocrine remission rates were higher in the contemporary cohort when compared with the early cohort (82% vs 66%, respectively; p = 0.01). In a Cox regression analysis adjusted for demographic, clinical, and SRS characteristics, the contemporary GKRS cohort had a higher probability of endocrine remission than the early cohort (HR 1.987, 95% CI 1.234–3.199; p = 0.005). The tumor control rate, incidence of cranial nerve neuropathy, and new anterior pituitary deficiency were similar between the two groups.

CONCLUSIONS

Technological advancements over the years and growing center experience were important factors for improved endocrine remission rates in patients with CD. Technological aspects and results of contemporary Gamma Knife systems should be considered when counseling patients, planning treatment, and reporting treatment results. Studies exploring the learning curve for GKRS are warranted.

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Adomas Bunevicius, Karen Lavezzo, Leah Shabo, Jesse McClure, and Jason P. Sheehan

OBJECTIVE

Quality of life (QOL) is an important endpoint measure of cancer treatment. The authors’ goal was to evaluate QOL trajectories and prognostic value in cancer patients treated with stereotactic radiosurgery (SRS) for brain metastases.

METHODS

Patients who underwent Gamma Knife radiosurgery (GKRS) between January 2016 and November 2019 were prospectively evaluated for QOL using the EQ-5D-3L questionnaire before SRS and at follow-up visits. Only patients who had pre-SRS and at least 1 post-SRS QOL assessment were considered.

RESULTS

Fifty-four cancer patients underwent 109 GKRS procedures. The first post-SRS visit was at a median of 2.59 months (range 0.13–21.08 months), and the last post-SRS visit was at 14.72 months (range 2.52–45.21 months) after SRS. There was no statistically significant change in the EQ-5D index score (p = 0.539) at the first compared with last post-SRS visit. The proportion of patients reporting some problems on the EQ-5D dimension of self-care increased during the course of follow-up from 9% (pre-SRS visit) to 18% (last post-SRS visit; p = 0.03). The proportion of patients reporting problems on the EQ-5D dimensions of mobility, usual activities, pain/discomfort, and anxiety/depression remained stable during the course of follow-up (p ≥ 0.106). After adjusting for clinical variables, a higher recursive partitioning analysis (RPA) class (i.e., worse prognostic category) was independently associated with greater odds for EQ-5D index score deterioration (p = 0.050). Upfront whole-brain radiation therapy predicted deterioration of the EQ-5D self-care (p = 0.03) and usual activities (p = 0.024) dimensions, while a greater number of lesions predicted deterioration of the EQ-5D anxiety/depression dimension (p = 0.008). A lower pre-SRS EQ-5D index was associated with shorter survival independently from clinical and demographic variables (OR 18.956, 95% CI 2.793–128.64; p = 0.003).

CONCLUSIONS

QOL is largely preserved in brain metastasis patients treated with SRS. Higher RPA class, upfront whole-brain radiation therapy, and greater intracranial disease burden are independent predictors of post-SRS QOL deterioration. Worse pre-SRS QOL predicts shorter survival. Assessment of QOL is recommended in brain metastasis patients managed with SRS.

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Martin H. Weiss, Gabriel Zada, John D. Carmichael, and William T. Couldwell

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Adomas Bunevicius, Hideyuki Kano, Cheng-Chia Lee, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Nuria Martinez-Moreno, David Mathieu, John Y. K. Lee, Inga Grills, Douglas Kondziolka, Roberto Martinez-Alvarez, Wael A. Reda, Roman Liscak, Yan-Hua Su, L. Dade Lunsford, Mary Lee Vance, and Jason P. Sheehan

OBJECTIVE

The optimal time to perform stereotactic radiosurgery after incomplete resection of adrenocorticotropic hormone (ACTH)–producing pituitary adenoma in patients with Cushing’s disease (CD) remains unclear. In patients with persistent CD after resection of ACTH-producing pituitary adenoma, the authors evaluated the association of the interval between resection and Gamma Knife radiosurgery (GKRS) with outcomes.

METHODS

Pooled data from 10 institutions participating in the International Radiosurgery Research Foundation were used in this study.

RESULTS

Data from 255 patients with a mean follow-up of 65.59 ± 49.01 months (mean ± SD) were analyzed. Seventy-seven patients (30%) underwent GKRS within 3 months; 46 (18%) from 4 to 6 months; 34 (13%) from 7 to 12 months; and 98 (38%) at > 12 months after the resection. Actuarial endocrine remission rates were higher in patients who underwent GKRS ≤ 3 months than when treatment was > 3 months after the resection (78% and 65%, respectively; p = 0.017). Endocrine remission rates were lower in patients who underwent GKRS at > 12 months versus ≤ 12 months after the resection (57% vs 76%, respectively; p = 0.006). In multivariate Cox regression analyses adjusted for clinical and treatment characteristics, early GKRS was associated with increased probability of endocrine remission (hazard ratio [HR] 1.518, 95% CI 1.039–2.218; p = 0.031), whereas late GKRS (HR 0.641, 95% CI 0.448–0.919; p = 0.015) was associated with reduced probability of endocrine remission. The incidence of some degree of new pituitary deficiency (p = 0.922), new visual deficits (p = 0.740), and other cranial nerve deficits (p = 0.610) was not significantly related to time from resection to GKRS.

CONCLUSIONS

Early GKRS is associated with an improved endocrine remission rate, whereas later GKRS is associated with a lower rate of endocrine remission after pituitary adenoma resection. Early GKRS should be considered for patients with CD after incomplete pituitary adenoma resection.

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Stylianos Pikis, Adomas Bunevicius, Cheng-Chia Lee, Huai-Che Yang, Brad E. Zacharia, Roman Liščák, Gabriela Simonova, Manjul Tripathi, Narendra Kumar, David Mathieu, Rémi Perron, Selcuk Peker, Yavuz Samanci, Jason Gurewitz, Kenneth Bernstein, Douglas Kondziolka, Ajay Niranjan, L. Dade Lunsford, Nikolaos Mantziaris, and Jason P. Sheehan

OBJECTIVE

As novel therapies improve survival for men with prostate cancer, intracranial metastatic disease has become more common. The purpose of this multicenter study was to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) in the management of intracranial prostate cancer metastases.

METHODS

Demographic data, primary tumor characteristics, SRS treatment parameters, and clinical and imaging follow-up data of patients from nine institutions treated with SRS from July 2005 to June 2020 for cerebral metastases from prostate carcinoma were collected and analyzed.

RESULTS

Forty-six patients were treated in 51 SRS procedures for 120 prostate cancer intracranial metastases. At SRS, the mean patient age was 68.04 ± 9.05 years, the mean time interval from prostate cancer diagnosis to SRS was 4.82 ± 4.89 years, and extracranial dissemination was noted in 34 (73.9%) patients. The median patient Karnofsky Performance Scale (KPS) score at SRS was 80, and neurological symptoms attributed to intracranial involvement were present prior to 39 (76%) SRS procedures. Single-fraction SRS was used in 49 procedures. Stereotactic radiotherapy using 6 Gy in five sessions was utilized in 2 procedures. The median margin dose was 18 (range 6–28) Gy, and the median tumor volume was 2.45 (range 0.04–45) ml. At a median radiological follow-up of 6 (range 0–156) months, local progression was seen with 14 lesions. The median survival following SRS was 15.18 months, and the 1-year overall intracranial progression-free survival was 44%. The KPS score at SRS was noted to be associated with improved overall (p = 0.02) and progression-free survival (p = 0.03). Age ≥ 65 years at SRS was associated with decreased overall survival (p = 0.04). There were no serious grade 3–5 toxicities noted.

CONCLUSIONS

SRS appears to be a safe, well-tolerated, and effective management option for patients with prostate cancer intracranial metastases.

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Adomas Bunevicius, Stylianos Pikis, Douglas Kondziolka, Dev N. Patel, Kenneth Bernstein, Erik P. Sulman, Cheng-chia Lee, Huai-che Yang, Violaine Delabar, David Mathieu, Christopher P. Cifarelli, David E. Arsanious, Basem A. Dahshan, Joshua S. Weir, Herwin Speckter, Angel Mota, Manjul Tripathi, Narendra Kumar, Ronald E. Warnick, and Jason P. Sheehan

OBJECTIVE

Molecular profiles, such as isocitrate dehydrogenase (IDH) mutation and O 6-methylguanine-DNA methyltransferase (MGMT) methylation status, have important prognostic roles for glioblastoma patients. The authors studied the efficacy and safety of stereotactic radiosurgery (SRS) for glioblastoma patients with consideration of molecular tumor profiles.

METHODS

For this retrospective observational multiinstitutional study, the authors pooled consecutive patients who were treated using SRS for glioblastoma at eight institutions participating in the International Radiosurgery Research Foundation. They evaluated predictors of overall and progression-free survival with consideration of IDH mutation and MGMT methylation status.

RESULTS

Ninety-six patients (median age 56 years) underwent SRS (median dose 15 Gy and median treatment volume 5.53 cm3) at 147 tumor sites (range 1 to 7). The majority of patients underwent prior fractionated radiation therapy (92%) and temozolomide chemotherapy (98%). Most patients were treated at recurrence (85%), and boost SRS was used for 12% of patients. The majority of patients harbored IDH wild-type (82%) and MGMT-methylated (62%) tumors. Molecular data were unavailable for 33 patients. Median survival durations after SRS were similar between patients harboring IDH wild-type tumors and those with IDH mutant tumors (9.0 months vs 11 months, respectively), as well as between those with MGMT-methylated tumors and those with MGMT-unmethylated tumors (9.8 vs. 9.0 months, respectively). Prescription dose > 15 Gy (OR 0.367, 95% CI 0.190–0.709, p = 0.003) and treatment volume > 5 cm3 (OR 1.036, 95% CI 1.007–1.065, p = 0.014) predicted overall survival after controlling for age and IDH status. Treatment volume > 5 cm3 (OR 2.215, 95% CI 1.159–4.234, p = 0.02) and absence of gross-total resection (OR 0.403, 95% CI 0.208–0.781, p = 0.007) were associated with inferior local control of SRS-treated lesions in multivariate models. Nine patients experienced adverse radiation events after SRS, and 7 patients developed radiation necrosis at 59 to 395 days after SRS.

CONCLUSIONS

Post-SRS survival was similar as a function of IDH mutation and MGMT promoter methylation status, suggesting that molecular profiles of glioblastoma should be considered when selecting candidates for SRS. SRS prescription dose > 15 Gy and treatment volume ≤ 5 cm3 were associated with longer survival, independent of age and IDH status. Prior gross-total resection and smaller treatment volume were associated with superior local control.

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Adomas Bunevicius, Mohand Suleiman, Samir Patel, Roberto Martínez Álvarez, Nuria E. Martinez Moreno, Roman Liscak, Jaromir Hanuska, Anne-Marie Langlois, David Mathieu, Christine Mau, Catherine Caldwell, Leonard C. Tuanquin, Brad E. Zacharia, James McInerney, Cheng-Chia Lee, Huai-Che Yang, Jennifer L. Peterson, Daniel M. Trifiletti, Akiyoshi Ogino, Hideyuki Kano, Ronald E. Warnick, Anissa Saylany, Love Y. Buch, John Y. K. Lee, Ben A. Strickland, Gabriel Zada, Eric L. Chang, L. Dade Lunsford, and Jason Sheehan

OBJECTIVE

Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs.

METHODS

From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS.

RESULTS

Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS.

CONCLUSIONS

SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

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David T. Asuzu, Adomas Bunevicius, Rithika Kormath Anand, Mohanad Suleiman, Ahmed M. Nabeel, Wael A. Reda, Sameh R. Tawadros, Khaled Abdel Karim, Amr M. N. El-Shehaby, Reem M. Emad Eldin, Tomas Chytka, Roman Liščák, Kimball Sheehan, Darrah Sheehan, Marco Perez Caceres, David Mathieu, Cheng-chia Lee, Huai-che Yang, Piero Picozzi, Andrea Franzini, Luca Attuati, Herwin Speckter, Jeremy Olivo, Samir Patel, Christopher P. Cifarelli, Daniel T. Cifarelli, Joshua D. Hack, Ben A. Strickland, Gabriel Zada, Eric L. Chang, Kareem R. Fakhoury, Chad G. Rusthoven, Ronald E. Warnick, and Jason P. Sheehan

OBJECTIVE

Resection of meningiomas in direct contact with the anterior optic apparatus carries risk of injury to the visual pathway. Stereotactic radiosurgery (SRS) offers a minimally invasive alternative. However, its use is limited owing to the risk of radiation-induced optic neuropathy. Few SRS studies have specifically assessed the risks and benefits of treating meningiomas in direct contact with the optic nerve, chiasm, or optic tract. The authors hypothesized that SRS is safe for select patients with meningiomas in direct contact with the anterior optic apparatus.

METHODS

The authors performed an international multicenter retrospective analysis of 328 patients across 11 institutions. All patients had meningiomas in direct contract with the optic apparatus. Patients were followed for a median duration of 56 months after SRS. Neurological examinations, including visual function evaluations, were performed at follow-up visits. Clinical and treatment variables were collected at each site according to protocol. Tumor volumes were assessed with serial MR imaging. Variables predictive of visual deficit were identified using univariable and multivariable logistic regression.

RESULTS

SRS was the initial treatment modality for 64.6% of patients, and 93% of patients received SRS as a single fraction. Visual information was available for 302 patients. Of these patients, visual decline occurred in 29 patients (9.6%), of whom 12 (41.4%) had evidence of tumor progression. Visual decline in the remaining 17 patients (5.6%) was not associated with tumor progression. Pre-SRS Karnofsky Performance Status predicted visual decline in adjusted analysis (adjusted OR 0.9, 95% CI 0.9–1.0, p < 0.01). Follow-up imaging data were available for 322 patients. Of these patients, 294 patients (91.3%) had radiographic evidence of stability or tumor regression at last follow up. Symptom duration was associated with tumor progression in adjusted analysis (adjusted OR 1.01, adjusted 95% CI 1.0–1.02, adjusted p = 0.02).

CONCLUSIONS

In this international multicenter study, the vast majority of patients exhibited tumor control and preservation of visual function when SRS was used to treat meningioma in direct contact with the anterior optic pathways. SRS is a relatively safe treatment modality for select patients with perioptic meningiomas in direct contact with the optic apparatus.