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Martin J. Rutkowski, Sandeep Kunwar, Lewis Blevins and Manish K. Aghi

OBJECTIVE

Pituitary apoplexy is a clinical syndrome consisting of neurological and endocrine abnormalities secondary to hemorrhage or ischemia of an underlying pituitary adenoma. The authors investigated whether there was a significant difference in neurological, endocrine, and nonneuroendocrine outcomes for patients with pituitary apoplexy, based on the time between symptom onset and surgical intervention.

METHODS

The authors retrospectively analyzed the medical records of 32 patients who had presented to their institution with acute pituitary apoplexy and subsequently undergone endonasal transsphenoidal resection in the period from 2003 to 2014. All patients had undergone preoperative MRI demonstrating evidence of apoplexy in the form of intratumoral hemorrhage, ischemia, and necrosis. Neurological deficits, partial or complete endocrinopathy, and nonneuroendocrine abnormalities were analyzed both pre- and postoperatively.

RESULTS

Preoperatively, neurological deficits including visual loss and cranial nerve palsies were found in 31 (97%) of the 32 patients, endocrinopathy in the form of partial or panhypopituitarism was seen in 28 patients (88%), and nonneuroendocrine signs and symptoms were seen in 32 patients (100%). Thirteen patients (41%) underwent surgery within 72 hours of symptom onset (“early”), whereas 19 patients (59%) underwent surgery more than 72 hours from symptom onset (“delayed”). Early versus delayed resection did not appear to significantly improve visual deficits, total visual loss, resolution of oculomotor palsy, recovery from hypopituitarism, or nonneuroendocrine signs and symptoms such as headache and encephalopathy. Overall, visual improvement was seen in 77% of patients, complete restoration of normal vision in 38% of patients, and resolution of preoperative oculomotor palsies in 81% of patients. Only 6 (21%) of 28 patients showed evidence of partial hormone recovery following preoperative hypopituitarism. An absence of benefit for early surgery held true even when considering time to surgery from symptom onset as a continuous variable.

CONCLUSIONS

Neurological deficits such as visual loss and cranial neuropathies show moderate improvement following surgical decompression, as does preoperative hypopituitarism. The timing of surgical intervention relative to the onset of symptoms does not appear to significantly affect the resolution of neurological or endocrinological deficits.

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Michael C. Oh and Manish K. Aghi

The authors' object in this paper was to review the definition, epidemiology, biology, resistance mechanisms, and treatment options for dopamine agonist–resistant prolactinomas (DARPs).

Prolactinomas are relatively unique among primary brain tumors in that medical treatment alone using dopamine agonists carries a high probability of disease control or even radiographic and endocrine remission, and thus has replaced surgery as the first line of therapy. Unfortunately, slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy. A literature review underscores that in male patients these DARPs are more likely to be invasive macroadenomas than dopamine agonist–responsive prolactinomas and that they are also more angiogenic, more proliferative, and more likely to exhibit cellular atypia. Estrogen receptor antagonists and temozolomide are the most commonly applied medical therapies in cases in which resection and radiosurgery have not induced remission of the hyperprolactinemia.

Dopamine agonist–resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions.

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Nathan C. Rowland and Manish K. Aghi

The high morbidity and mortality associated with acromegaly can be addressed with multiple treatment modalities, including surgery, medicines, and radiation therapy. Radiation was initially delivered through conventional fractionated radiotherapy, which targets a wide area over many treatment sessions and has been shown to induce remission in 50%–60% of patients with acromegaly. However, conventional fractionated radiotherapy takes several years to achieve remission in patients with acromegaly and carries a risk of hypopituitarism that may limit its use. Stereotactic radiosurgery, of which there are several forms, including Gamma Knife surgery, CyberKnife therapy, and proton beam therapy, offers slightly attenuated efficacy but achieves remission in less time and provides more precise targeting of the adenoma with better control of the dose of radiation received by adjacent structures such as the pituitary stalk, pituitary gland, optic chiasm, and cranial nerves in the cavernous sinus. Of the forms of stereotactic radiosurgery, Gamma Knife surgery is the most widely used and, because of its long-term follow-up in clinical studies, is the most likely to compete with medical therapy for first-line adjuvant use after resection. In this review, the authors outline the major modes of radiation therapies in clinical use today, and they critically assess the feasibility of these modalities for acromegaly treatment. Acromegaly is a multisystem disorder that demands highly specialized treatment protocols including neurosurgical and endocrinological intervention. As more efficient forms of pituitary radiation develop, acromegaly treatment options may continue to change with radiation therapies playing a more prominent role.

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Darryl Lau, Caleb Rutledge and Manish K. Aghi

OBJECT

Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD.

METHODS

A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase “(name of agent) and Cushing's” was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review.

RESULTS

A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%–100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth.

CONCLUSIONS

Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.

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Brandyn A. Castro and Manish K. Aghi

Initial enthusiasm after promising Phase II trials for treating recurrent glioblastomas with the antiangiogenic drug bevacizumab—a neutralizing antibody targeting vascular endothelial growth factor—was tempered by recent Phase III trials showing no efficacy for treating newly diagnosed glioblastomas. As a result, there is uncertainty about the appropriate indications for the use of bevacizumab in glioblastoma treatment. There are also concerns about the effects of bevacizumab on wound healing that neurosurgeons must be aware of. In addition, biochemical evidence suggests a percentage of tumors treated with bevacizumab for an extended period of time will undergo transformation into a more biologically aggressive and invasive phenotype with a particularly poor prognosis. Despite these concerns, there remain numerous examples of radiological and clinical improvement after bevacizumab treatment, particularly in patients with recurrent glioblastoma with limited therapeutic options. In this paper, the authors review clinical results with bevacizumab for glioblastoma treatment to date, ongoing trials designed to address unanswered questions, current clinical indications based on existing data, neurosurgical implications of bevacizumab use in patients with glioblastoma, the current scientific understanding of the tumor response to short- and long-term bevacizumab treatment, and future studies that will need to be undertaken to enable this treatment to fulfill its therapeutic promise for glioblastoma.

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Martin J. Rutkowski, Patrick M. Flanigan and Manish K. Aghi

After transsphenoidal surgery, Cushing's disease (CD) shows excellent long-term remission rates, but it may recur and pose a therapeutic challenge. Findings in recent published reports on the treatment of recurrent adrenocorticotropic hormone (ACTH)–secreting tumors suggest that repeat resection, radiation-based therapies such as Gamma Knife surgery and proton-beam radiosurgery, pharmacotherapy, and bilateral adrenalectomy all have important roles in the treatment of recurrent CD. Each of these interventions has inherent risks and benefits that should be presented to the patient during counseling on retreatment options. Radiation-based therapies increasingly appear to have efficacies similar to those of repeat resection in achieving biochemical remission and tumor control. In addition, an expanding retinue of medication-based therapies, several of which are currently being evaluated in clinical trials, has shown some promise as tertiary adjunctive therapies. Lastly, bilateral adrenalectomy may offer durable control of refractory recurrent CD. An increasing number of published studies with long-term patient outcomes highlight the evolving treatment patterns in the management of recurrent CD.

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Darryl Lau, Stephen T. Magill and Manish K. Aghi

Object

Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma.

Methods

A systematic search was performed with the phrase “(name of particular agent) and glioblastoma” as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies.

Results

A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10–15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%–20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%–20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied.

Conclusions

Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials.

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Stephen T. Magill, Jacob S. Young, Ricky Chae, Manish K. Aghi, Philip V. Theodosopoulos and Michael W. McDermott

OBJECTIVE

Prior studies have investigated preoperative risk factors for meningioma; however, no association has been shown between meningioma tumor size and tumor grade. The objective of this study was to investigate the relationship between tumor size and grade in a large single-center study of patients undergoing meningioma resection.

METHODS

A retrospective chart review of patients undergoing meningioma resection at the University of California, San Francisco, between 1985 and 2015 was performed. Patients with incomplete information, spinal meningiomas, multiple meningiomas, or WHO grade III meningiomas were excluded. The largest tumor dimension was used as a surrogate for tumor size. Univariate and multivariate logistic regression models were used to investigate the relationship between tumor grade and tumor size. A recursive partitioning analysis was performed to identify groups at higher risk for atypical (WHO grade II) meningioma.

RESULTS

Of the 1113 patients identified, 905 (81%) had a WHO grade I tumor and in 208 (19%) the tumors were WHO grade II. The median largest tumor dimension was 3.6 cm (range 0.2–13 cm). Tumors were distributed as follows: skull base (n = 573, 51%), convexity/falx/parasagittal (n = 431, 39%), and other (n = 109, 10%). On univariate regression, larger tumor size (p < 0.001), convexity/falx/parasagittal location (p < 0.001), and male sex (p < 0.001) were significant predictors of WHO grade II pathology. After controlling for interactions, multivariate regression found male sex (OR 1.74, 95% CI 1.25–2.43), size 3–6 cm (OR 1.69, 95% CI 1.08–2.66), size > 6 cm (OR 3.01, 95% CI 1.53–5.94), and convexity/falx/parasagittal location (OR 1.83, 95% CI 1.19–2.82) to be significantly associated with WHO grade II. Recursive partitioning analysis identified male patients with tumors > 3 cm as a high-risk group (32%) for WHO grade II meningioma.

CONCLUSIONS

Larger tumor size is associated with a greater likelihood of a meningioma being WHO grade II, independent of tumor location and male sex, which are known risk factors.

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Lauren E. Rotman, T. Brooks Vaughan, James R. Hackney and Kristen O. Riley

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Arman Jahangiri, Aaron T. Chin, Patrick M. Flanigan, Rebecca Chen, Krystof Bankiewicz and Manish K. Aghi

Glioblastoma is the most common malignant brain tumor, and it carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the blood-brain barrier prevents many drugs from reaching tumors cells. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. A number of alternative methods of delivery have been developed, one of which is convection-enhanced delivery (CED), the focus of this review. The authors describe CED as a therapeutic measure and review preclinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. The utilization of this technique for the delivery of a variety of agents is covered, and its shortcomings and challenges are discussed in detail.