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Diogo Cordeiro, Zhiyuan Xu, Gautam U. Mehta, Dale Ding, Mary Lee Vance, Hideyuki Kano, Nathaniel Sisterson, Huai-che Yang, Douglas Kondziolka, L. Dade Lunsford, David Mathieu, Gene H. Barnett, Veronica Chiang, John Lee, Penny Sneed, Yan-Hua Su, Cheng-chia Lee, Michal Krsek, Roman Liscak, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Wael A. Reda, Nuria Martinez-Moreno, Roberto Martinez-Alvarez, Kevin Blas, Inga Grills, Kuei C. Lee, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman and Jason P. Sheehan

OBJECTIVE

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.

METHODS

Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.

RESULTS

At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.

In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

CONCLUSIONS

Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

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Hideyuki Kano, Antonio Meola, Huai-che Yang, Wan-Yuo Guo, Roberto Martínez-Alvarez, Nuria Martínez-Moreno, Dusan Urgosik, Roman Liscak, Or Cohen-Inbar, Jason Sheehan, John Y. K. Lee, Mahmoud Abbassy, Gene H. Barnett, David Mathieu, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

For some jugular foramen schwannomas (JFSs), complete resection is possible but may be associated with significant morbidity. Stereotactic radiosurgery (SRS) is a minimally invasive alternative or adjunct to microsurgery for JFSs. The authors reviewed clinical and imaging outcomes of SRS for patients with these tumors.

METHODS

Nine participating centers of the International Gamma Knife Research Foundation identified 92 patients who underwent SRS between 1990 and 2013. Forty-one patients had prior subtotal microsurgical resection. The median interval between previous surgery and SRS was 15 months (range 0.5–144 months). Eighty-four patients had preexisting cranial nerve (CN) symptoms and signs. The median tumor volume was 4.1 cm3 (range 0.8–22.6 cm3), and the median margin dose was 12.5 Gy (range 10–18 Gy). Patients with neurofibromatosis were excluded from this study.

RESULTS

The median follow-up was 51 months (range 6–266 months). Tumors regressed in 47 patients, remained stable in 33, and progressed in 12. The progression-free survival (PFS) was 93% at 3 years, 87% at 5 years, and 82% at 10 years. In the entire series, only a dumbbell shape (extension extracranially via the jugular foramen) was significantly associated with worse PFS. In the group of patients without prior microsurgery (n = 51), factors associated with better PFS included tumor volume < 6 cm3 (p = 0.037) and non–dumbbell-shaped tumors (p = 0.015). Preexisting cranial neuropathies improved in 27 patients, remained stable in 51, and worsened in 14. The CN function improved after SRS in 12% of patients at 1 year, 24% at 2 years, 27% at 3 years, and 32% at 5 years. Symptomatic adverse radiation effects occurred in 7 patients at a median of 7 months after SRS (range 5–38 months). Six patients underwent repeat SRS at a median of 64 months (range 44–134 months). Four patients underwent resection at a median of 14 months after SRS (range 8–30 months).

CONCLUSIONS

Stereotactic radiosurgery proved to be a safe and effective primary or adjuvant management approach for JFSs. Long-term tumor control rates and stability or improvement in CN function were confirmed.

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I. Jonathan Pomeraniec, Hideyuki Kano, Zhiyuan Xu, Brandon Nguyen, Zaid A. Siddiqui, Danilo Silva, Mayur Sharma, Hesham Radwan, Jonathan A. Cohen, Robert F. Dallapiazza, Christian Iorio-Morin, Amparo Wolf, John A. Jane Jr., Inga S. Grills, David Mathieu, Douglas Kondziolka, Cheng-Chia Lee, Chih-Chun Wu, Christopher P. Cifarelli, Tomas Chytka, Gene H. Barnett, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKRS) is frequently used to treat residual or recurrent nonfunctioning pituitary macroadenomas. There is no consensus as to whether GKRS should be used early after surgery or if radiosurgery should be withheld until there is evidence of imaging-defined progression of tumor. Given the high incidence of adenoma progression after subtotal resection over time, the present study intended to evaluate the effect of timing of radiosurgery on outcome.

METHODS

This is a multicenter retrospective review of patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery followed by GKRS from 1987 to 2015 at 9 institutions affiliated with the International Gamma Knife Research Foundation. Patients were matched by adenoma and radiosurgical parameters and stratified based on the interval between last resection and radiosurgery. Operative results, imaging data, and clinical outcomes were compared across groups following early (≤ 6 months after resection) or late (> 6 months after resection) radiosurgery.

RESULTS

After matching, 222 patients met the authors’ study criteria (from an initial collection of 496 patients) and were grouped based on early (n = 111) or late (n = 111) GKRS following transsphenoidal surgery. There was a greater risk of tumor progression after GKRS (p = 0.013) and residual tumor (p = 0.038) in the late radiosurgical group over a median imaging follow-up period of 68.5 months. No significant difference in the occurrence of post-GKRS endocrinopathy was observed (p = 0.68). Thirty percent of patients without endocrinopathy in the early cohort developed new endocrinopathies during the follow-up period versus 27% in the late cohort (p = 0.84). Fourteen percent of the patients in the early group and 25% of the patients in the late group experienced the resolution of endocrine dysfunction after original presentation (p = 0.32).

CONCLUSIONS

In this study, early GKRS was associated with a lower risk of radiological progression of subtotally resected nonfunctioning pituitary macroadenomas compared with expectant management followed by late radiosurgery. Delaying radiosurgery may increase patient risk for long-term adenoma progression. The timing of radiosurgery does not appear to significantly affect the rate of delayed endocrinopathy.

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Mohana Rao Patibandla, Dale Ding, Hideyuki Kano, Zhiyuan Xu, John Y. K. Lee, David Mathieu, Jamie Whitesell, John T. Pierce, Paul P. Huang, Douglas Kondziolka, Caleb Feliciano, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, Danilo Silva, Mahmoud Abbassy, Symeon Missios, Gene H. Barnett, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Due to the complexity of Spetzler-Martin (SM) Grade IV–V arteriovenous malformations (AVMs), the management of these lesions remains controversial. The aims of this multicenter, retrospective cohort study were to evaluate the outcomes after single-session stereotactic radiosurgery (SRS) for SM Grade IV–V AVMs and determine predictive factors.

METHODS

The authors retrospectively pooled data from 233 patients (mean age 33 years) with SM Grade IV (94.4%) or V AVMs (5.6%) treated with single-session SRS at 8 participating centers in the International Gamma Knife Research Foundation. Pre-SRS embolization was performed in 71 AVMs (30.5%). The mean nidus volume, SRS margin dose, and follow-up duration were 9.7 cm3, 17.3 Gy, and 84.5 months, respectively. Statistical analyses were performed to identify factors associated with post-SRS outcomes.

RESULTS

At a mean follow-up interval of 84.5 months, favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RIC) and was achieved in 26.2% of patients. The actuarial obliteration rates at 3, 7, 10, and 12 years were 15%, 34%, 37%, and 42%, respectively. The annual post-SRS hemorrhage rate was 3.0%. Symptomatic and permanent RIC occurred in 10.7% and 4% of the patients, respectively. Only larger AVM diameter (p = 0.04) was found to be an independent predictor of unfavorable outcome in the multivariate logistic regression analysis. The rate of favorable outcome was significantly lower for unruptured SM Grade IV–V AVMs compared with ruptured ones (p = 0.042). Prior embolization was a negative independent predictor of AVM obliteration (p = 0.024) and radiologically evident RIC (p = 0.05) in the respective multivariate analyses.

CONCLUSIONS

In this multi-institutional study, single-session SRS had limited efficacy in the management of SM Grade IV–V AVMs. Favorable outcome was only achieved in a minority of unruptured SM Grade IV–V AVMs, which supports less frequent utilization of SRS for the management of these lesions. A volume-staged SRS approach for large AVMs represents an alternative approach for high-grade AVMs, but it requires further investigation.

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Amitabh Gupta, Zhiyuan Xu, Hideyuki Kano, Nathaniel Sisterson, Yan-Hua Su, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled A. Karim, Nuria Martínez-Moreno, David Mathieu, Brendan J. McShane, Roberto Martínez-Álvarez, Wael A. Reda, Roman Liscak, Cheng-Chia Lee, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing’s disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas.

METHODS

An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12–40.0 Gy) at a median isodose of 50%.

RESULTS

The median endocrine follow-up was 69.5 months (range 9–246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2.

CONCLUSIONS

Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.

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Kyung-Jae Park, Hideyuki Kano, Aditya Iyer, Xiaomin Liu, Daniel A. Tonetti, Craig Lehocky, Andrew Faramand, Ajay Niranjan, John C. Flickinger, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

The authors of this study evaluate the long-term outcomes of stereotactic radiosurgery (SRS) for cavernous sinus meningioma (CSM).

METHODS

The 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).

RESULTS

Tumor 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.

CONCLUSIONS

This 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.

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Hideyuki Kano, John C. Flickinger, Aya Nakamura, Rachel C. Jacobs, Daniel A. Tonetti, Craig Lehocky, Kyung-Jae Park, Huai-che Yang, Ajay Niranjan and L. Dade Lunsford

OBJECTIVE

The 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.

METHODS

In 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.

RESULTS

AVM 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.

CONCLUSIONS

The 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.

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Daniel A. Tonetti, Bradley A. Gross, Kyle M. Atcheson, Brian T. Jankowitz, Hideyuki Kano, Edward A. Monaco III, Ajay Niranjan, John C. Flickinger and L. Dade Lunsford

OBJECTIVE

The authors of this study found that, given the latency period required for arteriovenous malformation (AVM) obliteration after stereotactic radiosurgery (SRS), a study with limited follow-up cannot assess the benefit of SRS for unruptured AVMs.

METHODS

The authors reviewed their institutional experience with “ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)–eligible” AVMs treated with SRS between 1987 and 2016, with the primary outcome defined as stroke (ischemic or hemorrhagic) or death (AVM related or AVM unrelated). Patients with at least 3 years of follow-up in addition to those who experienced stroke or died during the latency period were included. Secondary outcome measures included obliteration rates, patients with new seizure disorders, and those with new focal deficits without stroke.

RESULTS

Of 233 patients included in this study, 32 had a stroke or died after SRS over the mean 8.4-year follow-up (14%). Utilizing the 10% stroke or death rate at a mean 2.8-year follow-up for untreated AVMs in ARUBA, the rate in the authors’ study is significantly lower than that anticipated at the 8.4-year follow-up for an untreated cohort (14% vs 30%, p = 0.0003). Notwithstanding obliteration, in this study, annualized rates of hemorrhage and stroke or death after 3 years following SRS were 0.4% and 0.8%, respectively. The overall obliteration rate was 72%; new seizure disorders, temporary new focal deficits without stroke, and permanent new focal deficits without stroke occurred in 2% of patients each.

CONCLUSIONS

After a sensible follow-up period exceeding the latency period, there is a lower rate of stroke/death for patients with treated, unruptured AVMs with SRS than for patients with untreated AVMs.

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Daniel A. Tonetti, Bradley A. Gross, Brian T. Jankowitz, Hideyuki Kano, Edward A. Monaco III, Ajay Niranjan, John C. Flickinger and L. Dade Lunsford

OBJECTIVE

Aggressive dural arteriovenous fistulas (dAVFs) with cortical venous drainage (CVD) are known for their relatively high risk of recurrent neurological events or hemorrhage. However, recent natural history literature has indicated that nonaggressive dAVFs with CVD have a significantly lower prospective risk of hemorrhage. These nonaggressive dAVFs are typically diagnosed because of symptomatic headache, pulsatile tinnitus, or ocular symptoms, as in low-risk dAVFs. Therefore, the viability of stereotactic radiosurgery (SRS) as a treatment for this lesion subclass should be investigated.

METHODS

The authors evaluated their institutional experience with SRS for dAVFs with CVD for the period from 1991 to 2016, assessing angiographic outcomes and posttreatment hemorrhage rates. They subsequently pooled their results with those published in the literature and stratified the results based on the mode of clinical presentation.

RESULTS

In an institutional cohort of 42 dAVFs with CVD treated using SRS, there were no complications or hemorrhages after treatment in 19 patients with nonaggressive dAVFs, but there was 1 radiation-induced complication and 1 hemorrhage among the 23 patients with aggressive dAVFs. In pooling these cases with 155 additional cases from the literature, the authors found that the hemorrhage rate after SRS was significantly lower among the patients with nonaggressive dAVFs (0% vs 6.8%, p = 0.003). Similarly, the number of radiation-related complications was 0/124 in nonaggressive dAVF cases versus 6/73 in aggressive dAVF cases (p = 0.001). The annual rate of hemorrhage after SRS for aggressive fistulas was 3.0% over 164.5 patient-years, whereas none of the nonaggressive fistulas bled after radiosurgery over 279.4 patient-years of follow-up despite the presence of CVD.

CONCLUSIONS

Cortical venous drainage is thought to be a significant risk factor in all dAVFs. In the institutional experience described here, SRS proved to be a low-risk strategy associated with a very low risk of subsequent hemorrhage or radiation-related complications in nonaggressive dAVFs with CVD.

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Seyed H. Mousavi, Ajay Niranjan, Berkcan Akpinar, Edward A. Monaco III, Jonathan Cohen, Jagdish Bhatnagar, Yue-Fang Chang, Hideyuki Kano, Sakibul Huq, John C. Flickinger and L. Dade Lunsford

OBJECTIVE

During the last 25 years, more than 100,000 patients worldwide with trigeminal neuralgia (TN) have undergone stereotactic radiosurgery (SRS) with a standard dose of radiation. However, the radiobiological effect of radiation is determined by the amount of energy delivered to the tissue (integral dose [ID] = mean dose × target volume) and is directly associated with the nerve volume. Although the trigeminal nerve volume varies among patients with TN, the clinical impact of this variation in delivered energy is unknown. The objective of this study was to evaluate the effect of delivered ID on the outcome of TN radiosurgery.

METHODS

The authors evaluated 155 patients with unilateral TN who had undergone SRS as their initial surgical management over a 13-year period. The authors measured the postganglionic ID within the SRS target and retrospectively stratified patients into 3 groups: low (< 1.4 mJ), medium (1.4–2.7 mJ), and high (> 2.7 mJ) ID. Clinical outcomes, which included pain status (scored using the Barrow Neurological Institute Pain Scale) and sensory dysfunction (scored using the Barrow Neurological Institute Numbness Scale), were evaluated at a median follow-up of 71 months.

RESULTS

Patients who were treated with a medium ID had superior pain relief either with or without medications (p = 0.006). In the medium ID group, the rates of complete pain relief without medications at 1, 3, and 6 years after SRS were 67%, 54%, and 33%, respectively, while the rates in the rest of the cohort were 55%, 36%, and 19%, respectively. Patients given a high ID had a higher rate of post-SRS trigeminal sensory deterioration (p < 0.0001). At 1, 3, and 6 years after SRS, the high ID group had an estimated rate for developing sensory dysfunction of 35%, 45%, and 50%, respectively, while the rates in patients receiving low and medium IDs were 3%, 4%, and 9%, respectively. The optimal clinical outcome (maximum pain relief and minimal trigeminal sensory dysfunction) was obtained in patients who had received a medium ID.

CONCLUSIONS

With current dose selection methods, nerve volume affects long-term clinical outcomes in patients with TN who have undergone SRS. This study suggests that the prescribed SRS dose should be customized for each TN patient based on the nerve volume.