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.
Arman Jahangiri, Aaron T. Chin, Patrick M. Flanigan, Rebecca Chen, Krystof Bankiewicz, and Manish K. Aghi
Arman Jahangiri, Kathleen R. Lamborn, Lewis Blevins, Sandeep Kunwar, and Manish K. Aghi
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.
The authors retrospectively reviewed NFAs resected at their institution between 2004 and 2010 for duration of visual symptoms, postoperative improvement, and associated factors.
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).
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.
Jonathan Rick, Arman Jahangiri, Patrick M. Flanigan, Ankush Chandra, Sandeep Kunwar, Lewis Blevins, and Manish K. Aghi
Acromegaly results in disfiguring growth and numerous medical complications. This disease is typically caused by growth hormone (GH)–secreting pituitary adenomas, which are treated first by resection, followed by radiation and/or medical therapy if needed. A subset of acromegalics have dual-staining pituitary adenomas (DSPAs), which stain for GH and prolactin. Presentations and treatment outcomes for acromegalics with DSPAs are not well understood.
The authors retrospectively reviewed the records of more than 5 years of pituitary adenomas resected at their institution. Data were collected on variables related to clinical presentation, tumor pathology, radiological size, and disease recurrence. The Fisher’s exact test, ANOVA, Student t-test, chi-square test, and Cox proportional hazards and multiple logistic regression were used to measure statistical significance.
Of 593 patients with pituitary adenoma, 91 presented with acromegaly. Of these 91 patients, 69 (76%) had tumors that stained for GH only (single-staining somatotrophic adenomas [SSAs]), while 22 (24%) had tumors that stained for GH and prolactin (DSPAs). Patients with DSPAs were more likely to present with decreased libido (p = 0.012), signs of acromegalic growth (p = 0.0001), hyperhidrosis (p = 0.0001), and headaches (p = 0.043) than patients with SSAs. DSPAs presented with significantly higher serum prolactin (60.7 vs 10.0 µg/L, p = 0.0002) and insulin-like growth factor-1 (IGF-1) (803.6 vs 480.0 ng/ml, p = 0.0001), and were more likely to have IGF-1 levels > 650 ng/ml (n = 13 [81.3%] vs n = 6 [21.4%], p = 0.0001) than patients with SSAs despite similar sizes (1.8 vs 1.7 cm, p = 0.5). Patients with DSPAs under 35 years of age were more likely to have a recurrence (n = 4 [50.0%] vs n = 3 [11.1%], p = 0.01) than patients with SSAs under the age of 35. DSPA patients were less likely to achieve remission with surgery than SSA patients (n = 2 [20%] vs n = 19 [68%], p = 0.01). Univariate analysis identified single-staining tumors (p = 0.02), gross-total resection (p = 0.02), and tumor diameter (p = 0.05) as predictors of surgical remission. Multiple logistic regression demonstrated that SSAs (p = 0.04) were independently associated with surgical remission of acromegaly. Kaplan-Meier analysis revealed that DSPAs had more time until disease remission (p = 0.033).
Acromegalics with tumors that stain for prolactin and GH, which represented almost a quarter of acromegalics in this cohort, had more aggressive clinical presentations and postoperative outcomes than SSAs. Prolactin staining provides useful information for acromegalics undergoing pituitary surgery.
Arman Jahangiri, Jeffrey Wagner, Mai T. Tran, Liane M. Miller, Maxwell W. Tom, Sandeep Kunwar, Lewis Blevins Jr., and Manish K. Aghi
Syndrome of inappropriate antidiuretic hormone secretion–induced hyponatremia is a common morbidity after pituitary surgery that can be profoundly symptomatic and cause costly readmissions. The authors calculated the frequency of postoperative hyponatremia after 1045 consecutive operations and determined the efficacy of interventions correcting hyponatremia.
The authors performed a retrospective review of 1045 consecutive pituitary surgeries in the first 946 patients treated since forming a dedicated pituitary center 5 years ago. Patients underwent preoperative and daily inpatient sodium checks, with outpatient checks as needed.
Thirty-two patients presented with hyponatremia; 41% of these patients were symptomatic. Postoperative hyponatremia occurred after 165 operations (16%) a mean of 4 days after surgery (range 0–28 days); 19% of operations leading to postoperative hyponatremia were associated with postoperative symptoms (38% involved dizziness and 29% involved nausea/vomiting) and 15% involved readmission for a mean of 5 days (range 1–20 days). In a multivariate analysis including lesion size, age, sex, number of prior pituitary surgeries, surgical approach, pathology, lesion location, and preoperative hypopituitarism, only preoperative hypopituitarism predicted postoperative hyponatremia (p = 0.006). Of patients with preoperative hyponatremia, 59% underwent medical correction preoperatively and 56% had persistent postoperative hyponatremia. The mean correction rates were 0.4 mEq/L/hr (no treatment; n = 112), 0.5 mEq/L/hr (free water restriction; n = 24), 0.7 mEq/L/hr (salt tablets; n = 14), 0.3 mEq/L/hr (3% saline; n = 20), 0.7 mEq/L/hr (intravenous vasopressin receptor antagonist Vaprisol; n = 22), and 1.2 mEq/L/hr (oral vasopressin receptor antagonist tolvaptan; n = 9) (p = 0.002, ANOVA). While some patients received more than 1 treatment, correction rates were only recorded when a treatment was given alone.
After 1045 pituitary operations, postoperative hyponatremia was associated exclusively with preoperative hypopituitarism and was most efficiently managed with oral tolvaptan, with several interventions insignificantly different from no treatment. Promptly identifying hyponatremia in high-risk patients and management with agents like tolvaptan can improve safety and decrease readmission. For readmitted patients with severely symptomatic hyponatremia, the intravenous vasopressin receptor antagonist Vaprisol is another treatment option.
Arman Jahangiri, Patrick M. Flanigan, Maxine Arnush, Ankush Chandra, Jonathan W. Rick, Sarah Choi, Alvin Chou, Mitchel S. Berger, and Manish K. Aghi
Neurosurgeons play an important role in advancing medicine through research, the funding of which is historically linked to the National Institutes of Health (NIH). The authors defined variables associated with neurosurgical NIH funding, prevalence of funded topics by neurosurgical subspecialty, and temporal trends in NIH neurosurgical funding.
The authors conducted a retrospective review of NIH-funded American Association of Neurological Surgeons members using NIH RePORTER (http://report.nih.gov/) for the years 1991–2015.
The authors followed 6515 neurosurgeons from 1991 to 2015, including 6107 (94%) non–MD-PhD physicians and 408 (6%) MD-PhDs. NIH grants were awarded to 393 (6%) neurosurgeons, with 23.2% of all first-time grants awarded to the top 5 funded institutions. The average total funded grant-years per funded neurosurgeon was 12.5 (range 1–85 grant-years). A higher percentage of MD-PhDs were NIH funded than MDs (22% [n = 91] vs 5% [n = 297], p < 0.0001). The most common grants awarded were R01 (128, 33%), K08 (69, 18%), F32 (60, 15%), M01 (50, 13%), and R21 (39, 10%). F32 and K08 recipients were 9-fold (18% vs 2%, p < 0.001) and 19-fold (38% vs 2%, p < 0.001) more likely to procure an R01 and procured R01 funding earlier in their careers (F32: 7 vs 12 years after residency, p = 0.03; K08: 9 vs 12 years, p = 0.01). Each year, the number of neurosurgeons with active grants linearly increased by 2.2 (R2 = 0.81, p < 0.001), whereas the number of total active grants run by neurosurgeons increased at nearly twice the rate (4.0 grants/year) (R2 = 0.91, p < 0.001). Of NIH-funded neurosurgical grants, 33 (9%) transitioned to funded clinical trial(s). Funded neurosurgical subspecialties included neuro-oncology (33%), functional/epilepsy (32%), cerebrovascular (17%), trauma (10%), and spine (6%). Finally, the authors modeled trends in the number of active training grants and found a linear increase in active R01s (R2 = 0.95, p < 0.001); however, both F32 (R2 = 0.36, p = 0.01) and K08 (R2 = 0.67, p < 0.001) funding had a significant parabolic rise and fall centered around 2003.
The authors observed an upward trend in R01s awarded to neurosurgeons during the last quarter century. However, their findings of decreased K08 and F32 training grant funding to neurosurgeons and the impact of these training grants on the ultimate success and time to success for neurosurgeons seeking R01 funding suggests that this upward trend in R01 funding for neurosurgeons will be difficult to maintain. The authors’ work underscores the importance of continued selection and mentorship of neurosurgeons capable of impacting patient care through research, including the MD-PhDs, who are noted to be more represented among NIH-funded neurosurgeons.
Patrick M. Flanigan, Arman Jahangiri, Joshua L. Golubovsky, Jaret M. Karnuta, Francis J. May, Mitchel S. Berger, and Manish K. Aghi
The position of neurosurgery department chair undergoes constant evolution as the health care landscape changes. The authors’ aim in this paper was to characterize career attributes of neurosurgery department chairs in order to define temporal trends in qualities being sought in neurosurgical leaders. Specifically, they investigated the hypothesis that increased qualifications in the form of additional advanced degrees and research acumen are becoming more common in recently hired chairs, possibly related to the increased complexity of their role.
The authors performed a retrospective study in which they collected data on 105 neurosurgeons who were neurosurgery department chairs as of December 31, 2016, at accredited academic institutions with a neurosurgery residency program in the United States. Descriptive data on the career of neurosurgery chairs, such as the residency program attended, primary subspecialty focus, and age at which they accepted their position as chair, were collected.
The median age and number of years in practice postresidency of neurosurgery chairs on acceptance of the position were 47 years (range 36–63 years) and 14 years (range 6–33 years), respectively, and 87% (n = 91) were first-time chairs. The median duration that chairs had been holding their positions as of December 31, 2016, was 10 years (range 1–34 years). The most common subspecialties were vascular (35%) and tumor/skull base (27%), although the tendency to hire from these specialties diminished over time (p = 0.02). More recently hired chairs were more likely to be older (p = 0.02), have more publications (p = 0.007), and have higher h-indices (p < 0.001) at the time of hire. Prior to being named chair, 13% (n = 14) had a PhD, 4% (n = 4) had an MBA, and 23% (n = 24) were awarded a National Institutes of Health R01 grant, tendencies that were stable over time (p = 0.09–0.23), although when additional degrees were analyzed as a binary variable, chairs hired in 2010 or after were more likely to have an MBA and/or PhD versus those hired before 2010 (26% vs 10%, p = 0.04). The 3 most common residency programs attended by the neurosurgery chairs were Massachusetts General Hospital (n = 8, 8%), University of California, San Francisco (n = 8, 8%), and University of Michigan (n = 6, 6%). Most chairs (n = 63, 61%) attended residency at the institution and/or were staff at the institution before they were named chair, a tendency that persisted over time (p = 0.86).
Most neurosurgery department chairs matriculated into the position before the age of 50 years and, despite selection processes usually involving a national search, most chairs had a previous affiliation with the department, a phenomenon that has been relatively stable over time. In recent years, a large increase has occurred in the proportion of chairs with additional advanced degrees and more extensive research experience, underscoring how neurosurgical leadership has come to require scientific skills and the ability to procure grants, as well as the financial skills needed to navigate the ever-changing financial health care landscape.
Disparities in care
John H. Sampson, Carlos A. Bagley, and Benjamin S. Carson Sr.
Arman Jahangiri, Aaron J. Clark, Seunggu J. Han, Sandeep Kunwar, Lewis S. Blevins Jr., and Manish K. Aghi
Pituitary apoplexy is associated with worse outcomes than are pituitary adenomas detected without acute clinical deterioration. The association between pituitary apoplexy and socioeconomic factors that may limit access to health care has not been examined in prior studies.
This study involved retrospectively evaluating data obtained in all patients who underwent surgery for nonfunctioning pituitary adenoma causing visual symptoms between January 2003 and July 2012 at the University of California, San Francisco. Patients were grouped into those who presented with apoplexy and those who did not (“no apoplexy”). The 2 groups were compared with respect to annual household income, employment status, health insurance status, and whether or not the patient had a primary health care provider. Associations between categorical variables were analyzed by chi-square test and continuous variables by Student t-test. Multivariate logistic regression was also performed.
One hundred thirty-five patients were identified, 18 of whom presented with apoplexy. There were significantly more unmarried patients and emergency room presentations in the apoplexy group than in the “no apoplexy” group. There was a nonsignificant trend toward lower mean household income in the apoplexy group. Lack of health insurance and lack of a primary health care provider were both highly significantly associated with apoplexy. In a multivariate analysis including marital status, emergency room presentation, income, insurance status, and primary health care provider status as variables, lack of insurance remained associated with apoplexy (OR 11.6; 95% CI 1.9–70.3; p = 0.008).
The data suggest that patients with limited access to health care may be more likely to present with pituitary apoplexy than those with adequate access.
Arman Jahangiri, Jeffrey R. Wagner, Sung Won Han, Mai T. Tran, Liane M. Miller, Rebecca Chen, Maxwell W. Tom, Lauren R. Ostling, Sandeep Kunwar, Lewis Blevins, and Manish K. Aghi
The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery.
Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed.
Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm3 vs 0.43 cm3, respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05).
After NFA resection, endocrine normalization rates in this study varied with the hormonal axis and were greater than the incidence of new endocrine deficits. Low preoperative gland volume precluded recovery. Patient age and the severity of the deficiency influenced the recovery of the thyroid and male reproductive axes, the most commonly impaired axes and most likely to normalize postoperatively. This information can be of use in counseling patients with hypopituitarism who undergo NFA surgery.
Martin J. Rutkowski, Ryan M. Alward, Rebecca Chen, Jeffrey Wagner, Arman Jahangiri, Derek G. Southwell, Sandeep Kunwar, Lewis Blevins, Han Lee, and Manish K. Aghi
In 2004, the WHO classified atypical pituitary adenoma as a distinct adenoma subtype. However, the clinical significance of this distinction remains undetermined. The authors sought to define patient characteristics, tumor features, and treatment outcomes associated with atypical pituitary adenoma.
The authors reviewed records of patients who underwent resection of pituitary adenoma at the University of California, San Francisco, between 2007 and 2014. Per institutional protocol, adenomas exhibiting mitotic activity underwent evaluation for all 3 markers of atypicality (mitotic index, extensive p53 staining, and MIB-1 index ≥ 3%). Statistical analyses were performed using χ2, Fisher’s exact test, t-test, log-rank, and logistic regression.
Between 2007 and 2014, 701 patients underwent resection for pituitary adenoma. Among these patients, 122 adenomas exhibited mitotic activity and therefore were evaluated for all 3 markers of atypicality, with 36 tumors (5%) proving to be atypical. There were 21 female patients (58%) and 15 male patients (42%) in the atypical cohort, and 313 female patients (47%) and 352 male patients (53%) in the nonatypical cohort (p = 0.231). The mean age of patients in the atypical cohort was 37 years (range 10–65 years), which was significantly lower than the mean age of 49 years (range 10–93 years) for patients in the nonatypical cohort (p < 0.001). The most common presenting symptoms for patients with atypical adenomas were headaches (42%) and visual changes (33%). Atypical adenomas were more likely to be functional (78%) than nonatypical adenomas (42%; p < 0.001). Functional atypical adenomas were significantly larger than functional nonatypical adenomas (mean diameter 2.2 vs 1.4 cm; p = 0.009), as were nonfunctional atypical adenomas compared with nonfunctional nonatypical adenomas (mean diameter 3.3 vs 2.3 cm; p = 0.01). Among the entire adenoma cohort, larger presenting tumor size was associated with cavernous sinus invasion (p < 0.001), and subtotal resection was associated with cavernous sinus invasion (p < 0.001) and larger size (p < 0.001) on binomial multivariate regression. The median time until recurrence was 56 months for atypical adenomas, 129 months for functional nonatypical adenomas, and 204 months for nonfunctional nonatypical adenomas (p < 0.001). Functional atypical adenomas recurred more frequently and significantly earlier than functional nonatypical adenomas (p < 0.001). When accounting for extent of resection, cavernous sinus invasion, size, age, sex, and functional subtype, atypicality remained a significant predictor of earlier recurrence among functional adenomas (p = 0.002).
When compared with nonatypical pituitary adenomas, atypical adenomas are more likely to present in younger patients at a larger size, are more often hormonally hypersecretory, and are associated with earlier recurrence. These features lend credence to atypical pituitary adenomas being a distinct clinical entity in addition to a discrete pathological diagnosis.