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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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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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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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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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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.

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Editorial

Disparities in care

John H. Sampson, Carlos A. Bagley and Benjamin S. Carson Sr.

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Arman Jahangiri, Kathleen R. Lamborn, Lewis Blevins, Sandeep Kunwar and Manish K. Aghi

Object

The duration of visual symptoms associated with a nonfunctioning pituitary adenoma (NFA) is a predictive factor for chances of visual improvement. The authors investigated factors associated with increased duration of visual symptoms in patients with NFAs.

Methods

The authors retrospectively reviewed NFAs resected at their institution between 2004 and 2010 for duration of visual symptoms, postoperative improvement, and associated factors.

Results

Seventy-five patients underwent NFA resection with a median visual symptom duration of 6.5 months (range 1 week–15 years). A multivariate logistic regression showed that duration of symptoms (p = 0.04), but not age at surgery (p = 0.2), predicted postoperative normalization of vision. Univariate nonparametric analyses investigating age at symptom onset, sex, race, insurance type, ophthalmological conditions, income, marital status, emergency department admission, language, and medical provider found that age was the only variable significantly prolonging symptom duration (p = 0.04), a finding confirmed by a multivariate regression analysis. Patients 20–39, 40–59, and 60–79 years old had median durations of symptoms of 4, 7, and 9 months, respectively. Seven older patients had symptoms attributed to preexisting ophthalmological conditions for a median of 18 months before NFA diagnosis. Among age and race subgroups, the largest difference in median symptom duration was between white patients in the 60–79-year age range (duration of 5 months) and nonwhite patients in the 60–79-year age range (duration of 24 months) (p = 0.04).

Conclusions

The authors found that older age was associated with delayed NFA diagnosis in visually impaired patients. Contributing factors were the attributing of visual symptoms from NFAs to other ophthalmological conditions in these patients, and delayed presentation in elderly nonwhite patients. These findings highlight challenges associated with timely NFA diagnosis in visually impaired patients, a key factor for chances of improvement.

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Michael M. Safaee, Ramin A. Morshed, Jordan Spatz, Sujatha Sankaran, Mitchel S. Berger and Manish K. Aghi

OBJECTIVE

Interfacility neurosurgical transfers to tertiary care centers are driven by a number of variables, including lack of on-site coverage, limited available technology, insurance factors, and patient preference. The authors sought to assess the timing and necessity of surgery and compared transfers to their institution from emergency departments (ED) and inpatient units at other hospitals.

METHODS

Adult neurosurgical patients who were transferred to a single tertiary care center were analyzed over 12 months. Patients with traumatic injuries or those referred from skilled nursing facilities or rehabilitation centers were excluded.

RESULTS

A total of 504 transferred patients were included, with mean age 55 years (range 19–92 years); 53% of patients were women. Points of origin were ED in 54% cases and inpatient hospital unit in 46%, with a mean distance traveled for most patients of 119 miles. Broad diagnosis categories included brain tumors (n = 142, 28%), vascular lesions, including spontaneous and hypertensive intracerebral hemorrhage (n = 143, 28%), spinal lesions (n = 126, 25%), hydrocephalus (n = 45, 9%), wound complications (n = 29, 6%), and others (n = 19, 4%). Patients transferred from inpatient units had higher rates of surgical intervention (75% vs 57%, p < 0.001), whereas patients transferred from the ED had higher rates of urgent surgery (20% vs 8%, p < 0.001) and shorter mean time to surgery (3 vs 5 days, p < 0.001). Misdiagnosis rates were higher among ED referrals (11% vs 4%, p = 0.008). Across the same timeframe, patients undergoing elective admission (n = 1986) or admission from the authors’ own ED (n = 248) had significantly shorter lengths of stay (p < 0.001) and ICU days (p < 0.001) than transferred patients, as well as a significantly lower total cost ($44,412, $46,163, and $72,175, respectively; p < 0.001).

CONCLUSIONS

The authors present their 12-month experience from a single tertiary care center without Level I trauma designation. In this cohort, 65% of patients required surgery, but the rates were higher among inpatient referrals, and misdiagnosis rates were higher among ED transfers. These data suggest that admitting nonemergency patients to local hospitals may improve diagnostic accuracy of patients requiring urgent care, more precisely identify patients in need of transfer, and reduce costs. Referring facilities may lack necessary resources or expertise, and the Emergency Medical Treatment and Active Labor Act (EMTALA) obligates tertiary care centers to accept these patients under those circumstances. Telemedicine and integration of electronic medical records may help guide referring hospitals to pursue additional workup, which may eliminate the need for unnecessary transfer and provide additional cost savings.