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Or Cohen-Inbar, Han-Hsun Shih, Zhiyuan Xu, David Schlesinger and Jason P. Sheehan

OBJECTIVE

Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with Stage IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. The authors report on a cohort of patients treated for brain metastases with immunotherapy and evaluate the effect of SRS timing on the intracranial response.

METHODS

All consecutively treated melanoma patients receiving ipilimumab and SRS for treatment of brain metastases at the University of Virginia between 2009 and 2014 were included in this retrospective analysis; data from 46 patients harboring 232 brain metastases were reviewed. The median duration of clinical follow-up was 7.9 months (range 3–42.6 months). The median age of the patients was 63 years (range 24.3–83.6 years). Thirty-two patients received SRS before or during ipilimumab cycles (Group A), whereas 14 patients received SRS after ipilimumab treatment (Group B). Radiographic and clinical responses were assessed at approximately 3-month intervals after SRS.

RESULTS

The 2 cohorts were comparable in pertinent baseline characteristics with the exception of SRS timing relative to ipilimumab. Local recurrence–free duration (LRFD) was significantly longer in Group A (median 19.6 months, range 1.1–34.7 months) than in Group B patients (median 3 months, range 0.4–20.4 months) (p = 0.002). Post-SRS perilesional edema was more significant in Group A.

CONCLUSIONS

The effect of SRS and ipilimumab on LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may affect LRFD and postradiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

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Hsiu-Mei Wu, David Hung-Chi Pan, Wen-Yuh Chung, Wan-Yuo Guo, Kang-Du Liu, Cheng-Ying Shiau, Ling-Wei Wang and Shih-Jen Chen

Object

The purpose of this study was to assess the efficacy and safety of Gamma Knife surgery (GKS) for the treatment of cavernous sinus dural arteriovenous fistulas (CSDAVFs) and other intracranial dural arteriovenous fistulas (ODAVFs).

Methods

Among the 238 GKS procedures performed for intracranial DAVFs in the authors' institute, 227 cases (146 CSDAVFs and 81 OIDAVFs) with clinical follow up formed the database from which the authors determined clinical outcome and the incidence of untoward events. One hundred ninety-five cases (118 CSDAVFs and 77 ODAVFs) with imaging follow up formed the database from which the authors determined the imaging results.

Older age, female sex, higher incidence of diabetes, and shorter duration of symptoms were noted more in cases of CSDAVF than in ODAVFs. Most patients had symptomatic improvement after GKS. A symptomatic cure was observed in one patient with CSDAVFs as early as 6 weeks. The cumulative cure rate based on follow-up angiography of CSDAVFs approached 75% at 24 months, which was much better than that of ODAVFs (approximately 50% at 24 months). A neuroimaging-based cure lagged behind that of the clinical symptoms. Overall, there were only two nonfatal intracerebral hemorrhages during the follow-up period, both occurring less than 1 week after GKS and both being Cognard Type IIa+b with initial aggressive symptoms. Transient deterioration of neurological status without hemorrhage was noted in six patients with ODAVFs. Thrombosis of the superior ophthalmic vein occurred in 11 patients with CSDAVFs, in two of whom there were unilateral visual impairments. There were three cranial nerve neuropathies: transient in one CSDAVF and one ODAVF involving the jugular foramen, and another one was a CSDAVF previously treated by conventional radiotherapy.

Conclusions

Gamma Knife surgery provides a safe and effective option for treatment of intracranial DAVFs with a low risk of complications. In cases of DAVFs with benign clinical presentation, GKS can serve as a primary treatment. In some cases of aggressive DAVFs in which there is extensive retrograde cortical vein drainage, combined treatment with embolization or surgery is suggested.

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Stephen M. Wilson, Daniel Lam, Miranda C. Babiak, David W. Perry, Tina Shih, Christopher P. Hess, Mitchel S. Berger and Edward F. Chang

OBJECT

Transient aphasias are often observed in the first few days after a patient has undergone resection in the language-dominant hemisphere. The aims of this prospective study were to characterize the incidence and nature of these aphasias and to determine whether there are relationships between location of the surgical site and deficits in specific language domains.

METHODS

One hundred ten patients undergoing resection to the language-dominant hemisphere participated in the study. Language was evaluated prior to surgery and 2–3 days and 1 month postsurgery using the Western Aphasia Battery and the Boston Naming Test. Voxel-based lesion-symptom mapping was used to identify relationships between the surgical site location assessed on MRI and deficits in fluency, information content, comprehension, repetition, and naming.

RESULTS

Seventy-one percent of patients were classified as aphasic based on the Western Aphasia Battery 2–3 days postsurgery, with deficits observed in each of the language domains examined. Fluency deficits were associated with resection of the precentral gyrus and adjacent inferior frontal cortex. Reduced information content of spoken output was associated with resection of the ventral precentral gyrus and posterior inferior frontal gyrus (pars opercularis). Repetition deficits were associated with resection of the posterior superior temporal gyrus. Naming deficits were associated with resection of the ventral temporal cortex, with midtemporal and posterior temporal damage more predictive of naming deficits than anterior temporal damage. By 1 month postsurgery, nearly all language deficits were resolved, and no language measure except for naming differed significantly from its presurgical level.

CONCLUSIONS

These findings show that transient aphasias are very common after left hemisphere resective surgery and that the precise nature of the aphasia depends on the specific location of the surgical site. The patient cohort in this study provides a unique window into the neural basis of language because resections are discrete, their locations are not limited by vascular distribution or patterns of neurodegeneration, and language can be studied prior to substantial reorganization.

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Cheng-Chia Lee, David Hung-Chi Pan, Wen-Yuh Chung, Kang-Du Liu, Huai-Che Yang, Hsiu-Mei Wu, Wan-Yuo Guo and Yang-Hsin Shih

Object

The authors retrospectively reviewed the efficacy and safety of Gamma Knife surgery (GKS) in patients with brainstem cavernous malformations (CMs). The CMs had bled repeatedly and placed the patients at high risk with respect to surgical intervention.

Methods

Between 1993 and 2010, 49 patients with symptomatic CMs were treated by GKS. The mean age in these patients was 37.8 years, and the predominant sex was female (59.2%). All 49 patients experienced at least 2 instances of repeated bleeding before GKS; these hemorrhages caused neurological deficits including cranial nerve deficits, hemiparesis, hemisensory deficits, spasticity, chorea or athetosis, and consciousness disturbance.

Results

The mean size of the CMs at the time of GKS was 3.2 cm3 (range 0.1–14.6 cm3). The mean radiation dose directed to the lesion was 11 Gy with an isodose level at 60.0%. The mean clinical and imaging follow-up time was 40.6 months (range 1.0–150.7 months). Forty-five patients participated in regularly scheduled follow-up. Twenty-nine patients (59.2%) were followed up for > 2 years, and 16 (32.7%) were followed up for < 2 years. The pre-GKS annual hemorrhage rate was 31.3% (69 symptomatic hemorrhages during a total of 220.3 patient-years). After GKS, 3 episodes of symptomatic hemorrhage were observed within the first 2 years of follow-up (4.29% annual hemorrhage rate), and 3 episodes of symptomatic hemorrhage were observed after the first 2 years of follow-up (3.64% annual hemorrhage rate). In this study of 49 patients, symptomatic radiation-induced complications developed in only 2 patients (4.1%; cyst formation in 1 patient and perifocal edema with neurological deficits in the other patient). There were no deaths in this group.

Conclusions

Gamma Knife surgery is effective in reducing the rate of recurrent hemorrhage. In the authors' experience, it was possible to control bleeding using a low-dose treatment. In addition, there were few symptomatic radiation-induced complications. As a result, the authors believe that GKS is a good alternative treatment for brainstem CMs.

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Zhiyuan Xu, Cheng-Chia Lee, Arjun Ramesh, Adam C. Mueller, David Schlesinger, Or Cohen-Inbar, Han-Hsun Shih and Jason P. Sheehan

OBJECTIVE

Recent advancements in molecular biology have identified the BRAF mutation as a common mutation in melanoma. The wide use of BRAF kinase inhibitor (BRAFi) in patients with metastatic melanoma has been established. The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with stereotactic radiosurgery (SRS).

METHODS

This was a single-center retrospective study. Patient's charts and electronic records were reviewed for date of diagnosis of primary malignancy, BRAF mutation status, chemotherapies used, date of the diagnosis of CNS metastases, date of SRS, survival, local tumor control after SRS, and adverse events. Patients were divided into 3 groups: Group A, those with mutant BRAF without BRAFi treatment (13 patients); Group B, those with mutant BRAF with BRAFi treatment (17 patients); and Group C, those with wild-type BRAF (35 patients). Within a cohort of 65 patients with the known BRAF mutation status and treated with SRS between 2010 and 2014, 436 individual brain metastases (BMs) were identified. Kaplan-Meier methodology was then used to compare survival based on each binary parameter.

RESULTS

Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (Group B) compared with the patients with wild-type BRAF (Group C, 23 vs 8 months and 13 vs 5 months, respectively; p < 0.01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (Group B) compared with patients with wild-type (Group C) or with BRAF mutation but no BRAFi (Group A) as an adjunct treatment for BMs.

CONCLUSIONS

BRAF mutation status appears to play an important role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile.

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Andrew A. Kanner, Susan M. Staugaitis, Elias A. Castilla, Olga Chernova, Richard A. Prayson, Michael A. Vogelbaum, Glen Stevens, David Peereboom, John Suh, Shih-Yuan Lee, Raymond R. Tubbs and Gene H. Barnett

Object

Oligodendrogliomas are rare primary brain tumors. They comprise approximately 5 to 33% of all glial tumors but differ from astrocytomas by being associated with a more favorable prognosis, making their correct identification important. Allelic loss of chromosome arms 1p and 19q is found in a substantial subpopulation of tumors with an oligodendroglioma phenotype. Anaplastic oligodendrogliomas with allelic loss of 1p have been associated with chemosensitivity and a longer patient survival period.

Methods

Oligodendroglial neoplasms were studied using fluorescence in situ hybridization of formalin-fixed, paraffin-embedded tissue specimens; reference and target probe sets were used to map the telomeric regions of 1p and 19q. The results were correlated with the clinical characteristics of patients treated at our institution between 1993 and 2003.

Data obtained in 96 patients were analyzed. This included 63 patients (65.6%) with World Health Organization (WHO) Grade II oligodendroglioma, 22 (23%) with Grade III oligodendroglioma, and 11 (11.4%) with mixed oligoastrocytoma. Analysis of 1p in patients with pure oligodendroglioma revealed a loss of 1p in 42 patients (49.4%). In 46 of these patients 19q was lost and in 70 (82.3%) there was concordance for combined loss or retention of both 1p and 19q (p < 0.0001). Patients with oligodendroglioma in whom a loss of 1p was present fared significantly better, and this outcome was unrelated to the treatment modality or WHO grade, compared with patients in whom 1p was intact (p < 0.05).

Conclusions

To the authors’ knowledge, this study includes the largest published series of WHO Grade II oligodendroglioma and 1p analysis. The results suggest that the association between long-term survival and 1p loss in oligodendroglioma is unrelated to treatment. The authors of further prospective studies may better determine the true value of the allelic loss of 1p and its implication for clinical decision making.

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Wen-Yuh Chung, David Hung-Chi Pan, Cheng-Chia Lee, Hsiu-Mei Wu, Kang-Du Liu, Yu-Shu Yen, Wan-Yuo Guo, Cheng-Ying Shiau and Yang-Hsin Shih

Object

Although radiosurgery has been well accepted as a treatment for small- to medium-sized vestibular schwannomas (VSs), its application in the treatment of large VSs remains controversial because of unfavorable effects such as tumor swelling and potential compression of the brainstem. The authors present a retrospective study spanning 17 years, during which 21 patients underwent Gamma Knife surgery (GKS) for large VSs. Long-term outcomes are reported, and possible factors affecting tumor responses to GKS are analyzed.

Methods

Five hundred thirteen patients harboring VSs underwent GKS between March 1993 and October 2009. A large VS was defined as a tumor whose diameter was > 3 cm. This paper focuses on 21 patients who harbored large VSs ranging in volume from 12.7 to 25.2 cm3 (mean 17.3 cm3) and were treated by GKS. Fourteen of these patients had undergone 1 or more craniotomies previously to remove the tumor. Seven patients underwent GKS alone because of patient preference or a poor clinical condition that precluded microsurgery with general anesthesia. The mean radiation dose directed to the tumor ranged from 15 to 17.5 Gy. The mean radiation dose prescribed to the tumor margin was 11.9 Gy (range 11–14 Gy). The mean follow-up period was 66 months (range 12–155 months), and the median follow-up period was 53 months.

Results

The tumor control rate was 90.5% (19 of 21 lesions). No deterioration in facial nerve or trigeminal nerve function was noted. Disturbances in balance (some temporary) occurred in 5 patients. Three of the 21 patients developed initial tumor swelling, which required minor surgical interventions, including aspiration using an Ommaya reservoir or placement of a ventriculoperitoneal shunt. All 3 patients recovered satisfactorily after aspiration of an enlarging cyst or ventriculoperitoneal shunt placement. There was no significant correlation between tumor control and the following factors: patient age or sex, tumor volume, radiation dose, previous operation, presence of brainstem compression, petrous bone invasion, T2 signal ratio between tumor and brainstem, and presence of a cyst. However, there was a significant correlation between the T2 signal ratio between tumor and brainstem and the duration of tumor swelling (p = 0.003).

Conclusions

Treatment of large VSs remains a challenge to neurosurgeons regardless of whether they perform microsurgery or radiosurgery. Control of tumor growth and preservation of neurological function are the main goals of treatment. Although delayed microsurgery was required in 2 patients (9.5%), the satisfactory tumor control rate and excellent preservation of facial and trigeminal nerve function are the great advantages of radiosurgery. Radiosurgery is not only a practical treatment for patients with small- to medium-sized VSs, but it is also an excellent tool for treating larger tumors up to 25 cm3. In selected cases, radiosurgery plays an important role in treating large VSs with satisfactory results.

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Sameer Agnihotri, Isabel Gugel, Marc Remke, Antje Bornemann, Georgios Pantazis, Stephen C. Mack, David Shih, Sanjay K. Singh, Nesrin Sabha, Michael D. Taylor, Marcos Tatagiba, Gelareh Zadeh and Boris Krischek

Object

Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown.

Methods

In this study the authors performed gene-expression profiling of 49 schwannomas and 7 normal control vestibular nerves to identify tumor-specific gene-expression patterns. They also interrogated whether schwannomas comprise several molecular subtypes using several transcription-based clustering strategies. The authors also performed in vitro experiments testing therapeutic inhibitors of over-activated pathways in a schwannoma cell line, namely the PI3K/AKT/mTOR pathway.

Results

The authors identified over 4000 differentially expressed genes between controls and schwannomas with network analysis, uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, they could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2–associated schwannomas, suggesting that they are highly similar entities. The authors identified overexpression of PI3K/AKT/mTOR signaling networks in their geneexpression study and evaluated this pathway for therapeutic targeting. Testing the compounds BEZ235 and PKI-587, both novel dual inhibitors of PI3K and mTOR, attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that pharmacological inhibition of the PI3K/AKT/mTOR pathway with next-generation compounds led to decreased cell viability and increased cell death.

Conclusions

These findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in VS and suggest inhibition of this pathway as a potential treatment strategy.