In 1955, Vincent du Vigneaud (1901–1978), the chairman of the Department of Biochemistry at Cornell University Medical College, was awarded the Nobel Prize for Chemistry for his research on insulin and for the first synthesis of the posterior pituitary hormones—oxytocin and vasopressin. His tremendous contribution to organic chemistry, which began as an interest in sulfur-containing compounds, paved the way for a better understanding of the pituitary gland and for the development of diagnostic and therapeutic tools for diseases of the pituitary. His seminal research continues to impact neurologists, endocrinologists, and neurosurgeons, and enables them to treat patients who had no alternatives prior to du Vigneaud’s breakthroughs in peptide structure and synthesis. The ability of neurosurgeons to aggressively operate on parasellar pathology was directly impacted and related to the ability to replace these hormones after surgery. The authors review the life and career of Vincent du Vigneaud, his groundbreaking discoveries, and his legacy of the understanding and treatment of the pituitary gland in health and disease.
Malte Ottenhausen, Imithri Bodhinayake, Matei A. Banu, Philip E. Stieg, and Theodore H. Schwartz
Alexander M. Stessin, Allie Schwartz, Grigorij Judanin, Susan C. Pannullo, John A. Boockvar, Theodore H. Schwartz, Philip E. Stieg, and A. Gabriella Wernicke
The aim of this study was to examine the effect of postoperative external-beam radiation therapy (EBRT) on disease-specific survival in patients with nonbenign meningiomas.
The Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2007 was queried for cases of resected Grades II (atypical) and III (malignant) meningioma. Disease-specific survival outcomes were determined using Kaplan-Meier survival analysis and Cox proportional hazards models. Logistic regression analysis was used to determine the likelihood of receiving EBRT for Grade II versus Grade III. Because atypical and malignant meningiomas underwent WHO reclassification in 2000, the authors carried out an additional analysis of outcomes of these tumors from 2000 to 2008.
There were 657 patients included in the analysis; of these, 244 received adjuvant radiation. Compared with patients with Grade II meningioma, patients with Grade III disease were 41.9% more likely to receive EBRT after gross-total resection and 36.7% more likely to receive it after subtotal resection (95% CI 0.58–3.26). Controlling for grade, extent of resection, size and anatomical location of the tumor, year of diagnosis, race, age, and sex, adjuvant EBRT did not impart a survival benefit (HR 1.492; 95% CI 0.827–2.692). There was also no survival advantage to EBRT in an analysis of cases diagnosed after the WHO 2000 reclassification of meningiomas (HR 0.828; 95% CI 0.350–1.961).
The results of this population-based retrospective analysis demonstrate that the role of radiation remains unclear. They underscore the need for randomized prospective clinical trials to assess the usefulness of adjuvant EBRT in Grades II and III meningioma so as to define more precisely the subset of patients who may benefit from the addition of adjuvant radiation.
Oszkar Szentirmai, Yuan Hong, Lino Mascarenhas, Al Amin Salek, Philip E. Stieg, Vijay K. Anand, Aaron A. Cohen-Gadol, and Theodore H. Schwartz
The expansion of endovascular procedures for obliteration of cerebral aneurysms highlights one of the drawbacks of clip ligation through the transcranial route, namely brain retraction or brain transgression. Sporadic case reports have emerged over the past 10 years describing endonasal endoscopic clip ligation of cerebral aneurysms. The authors present a detailed anatomical study to evaluate the feasibility of an endoscopic endonasal approach for application of aneurysm clips.
Nine human cadaveric head specimens were used to evaluate operative exposures for clip ligation of aneurysms in feasible anterior and posterior circulation locations. Measurements of trajectories were completed using a navigation system to calculate skull base craniectomy size, corridor space, and the surgeon's ability to gain proximal and distal control of parent vessels.
In each of the 9 cadaveric heads, excellent exposure of the target vessels was achieved. The transplanum, transtuberculum, and transcavernous approaches were used to explore the feasibility of anterior circulation access. Application of aneurysm clips was readily possible to the ophthalmic artery, A1 and A2 segments of the anterior cerebral artery, anterior communicating artery complex, and the paraclinoid and paraclival internal carotid artery. The transclival approach was explored, and clips were successfully deployed along the proximal branches of the vertebrobasilar system and basilar trunk and bifurcation. The median sizes of skull base craniectomy necessary for exposure of the anterior communicating artery complex and basilar tip were 3.24 cm2 and 4.62 cm2, respectively. The mean angles of surgical corridors to the anterior communicating artery complex and basilar tip were 11.4° and 14°, respectively. Although clip placement was feasible on the basilar artery and its branches, the associated perforating arteries were difficult to visualize, posing unexpected difficulty for safe clip application, with the exception of ventrolateral-pointing aneurysms.
The authors characterize the feasibility of endonasal endoscopic clip ligation of aneurysms involving the paraclinoid, anterior communicating, and basilar arteries and proximal control of the paraclival internal carotid artery. The endoscopic approach should be initially considered for nonruptured aneurysms involving the paraclinoid and anterior communicating arteries, as well as ventrolateral basilar trunk aneurysms. Clinical experience will be mandatory to determine the applicability of this approach in practice.
Swathi Chidambaram, Susan C. Pannullo, Michelle Roytman, David J. Pisapia, Benjamin Liechty, Rajiv S. Magge, Rohan Ramakrishna, Philip E. Stieg, Theodore H. Schwartz, and Jana Ivanidze
There is a need for advanced imaging biomarkers to improve radiation treatment planning and response assessment. T1-weighted dynamic contrast-enhanced perfusion MRI (DCE MRI) allows quantitative assessment of tissue perfusion and blood-brain barrier dysfunction and has entered clinical practice in the management of primary and secondary brain neoplasms. The authors sought to retrospectively investigate DCE MRI parameters in meningiomas treated with resection and adjuvant radiation therapy using volumetric segmentation.
A retrospective review of more than 300 patients with meningiomas resected between January 2015 and December 2018 identified 14 eligible patients with 18 meningiomas who underwent resection and adjuvant radiotherapy. Patients were excluded if they did not undergo adjuvant radiation therapy or DCE MRI. Demographic and clinical characteristics were obtained and compared to DCE perfusion metrics, including mean plasma volume (v p), extracellular volume (v e), volume transfer constant (K trans), rate constant (k ep), and wash-in rate of contrast into the tissue, which were derived from volumetric analysis of the enhancing volumes of interest.
The mean patient age was 64 years (range 49–86 years), and 50% of patients (7/14) were female. The average tumor volume was 8.07 cm3 (range 0.21–27.89 cm3). The median Ki-67 in the cohort was 15%. When stratified by median Ki-67, patients with Ki-67 greater than 15% had lower median v p (0.02 vs 0.10, p = 0.002), and lower median wash-in rate (1.27 vs 4.08 sec−1, p = 0.04) than patients with Ki-67 of 15% or below. Logistic regression analysis demonstrated a statistically significant, moderate positive correlation between v e and time to progression (r = 0.49, p < 0.05). Furthermore, there was a moderate positive correlation between K trans and time to progression, which approached, but did not reach, statistical significance (r = 0.48, p = 0.05).
This study demonstrates a potential role for DCE MRI in the preoperative characterization and stratification of meningiomas, laying the foundation for future prospective studies incorporating DCE as a biomarker in meningioma diagnosis and treatment planning.
A. Gabriella Wernicke, Andrew W. Smith, Shoshana Taube, Menachem Z. Yondorf, Bhupesh Parashar, Samuel Trichter, Lucy Nedialkova, Albert Sabbas, Paul Christos, Rohan Ramakrishna, Susan C. Pannullo, Philip E. Stieg, and Theodore H. Schwartz
Managing patients whose intraparenchymal brain metastases recur after radiotherapy remains a challenge. Intraoperative cesium-131 (Cs-131) brachytherapy performed at the time of neurosurgical resection may represent an excellent salvage treatment option. The authors evaluated the outcomes of this novel treatment with permanent intraoperative Cs-131 brachytherapy.
Thirteen patients with 15 metastases to the brain that recurred after stereotactic radiosurgery and/or whole brain radiotherapy were treated between 2010 and 2015. Stranded Cs-131 seeds were placed as a permanent volume implant. Prescription dose was 80 Gy at 5-mm depth from the resection cavity surface. The primary end point was resection cavity freedom from progression (FFP). Resection cavity freedom from progression (FFP), regional FFP, distant FFP, median survival, overall survival (OS), and toxicity were assessed.
The median duration of follow-up after salvage treatment was 5 months (range 0.5–18 months). The patients' median age was 64 years (range 51–74 years). The median resected tumor diameter was 2.9 cm (range 1.0–5.6 cm). The median number of seeds implanted was 19 (range 10–40), with a median activity per seed of 2.25 U (range 1.98–3.01 U) and median total activity of 39.6 U (range 20.0–95.2 U). The 1-year actuarial local FFP was 83.3%. The median OS was 7 months, and 1-year OS was 24.7%. Complications included infection (3), pseudomeningocele (1), seizure (1), and asymptomatic radionecrosis (RN) (1).
After failure of prior irradiation of brain metastases, re-irradiation with intraoperative Cs-131 brachytherapy implants provides durable local control and limits the risk of RN. The authors' initial experience demonstrates that this treatment approach is well tolerated and safe for patients with previously irradiated tumors after failure of more than 1 radiotherapy regimen and that it results in excellent response rates and minimal toxicity.
Sacit Bulent Omay, Yu-Ning Chen, Joao Paulo Almeida, Armando Saul Ruiz-Treviño, John A. Boockvar, Philip E. Stieg, Jeffrey P. Greenfield, Mark M. Souweidane, Ashutosh Kacker, David J. Pisapia, Vijay K. Anand, and Theodore H. Schwartz
Exome sequencing studies have recently demonstrated that papillary craniopharyngiomas (PCPs) and adamantinomatous craniopharyngiomas (ACPs) have distinct genetic origins, each primarily driven by mutually exclusive alterations: either BRAF (V600E), observed in 95% of PCPs, or CTNNB1, observed in 75%–96% of ACPs. How the presence of these molecular signatures, or their absence, correlates with clinical, radiographic, and outcome variables is unknown.
The pathology records for patients who underwent surgery for craniopharyngiomas between May 2000 and March 2015 at Weill Cornell Medical College were reviewed. Craniopharyngiomas were identified and classified as PCP or ACP. Patients were placed into 1 of 3 groups based on their genomic mutations: BRAF mutation only, CTNNB1 mutation only, and tumors with neither of these mutations detected (not detected [ND]). Demographic, radiological, and clinical variables were collected, and their correlation with each genomic group was tested.
Histology correlated strongly with mutation group. All BRAF tumors with mutations were PCPs, and all CTNNB1 with mutations and ND tumors were ACPs. Preoperative and postoperative clinical symptoms and radiographic features did not correlate with any mutation group. There was a statistically significant relationship (p = 0.0323) between the age group (pediatric vs adult) and the mutation groups. The ND group tumors were more likely to involve the sella (p = 0.0065).
The mutation signature in craniopharyngioma is highly predictive of histology. The subgroup of tumors in which these 2 mutations are not detected is more likely to occur in children, be located in the sella, and be of ACP histology.
A. Gabriella Wernicke, Menachem Z. Yondorf, Luke Peng, Samuel Trichter, Lucy Nedialkova, Albert Sabbas, Fridon Kulidzhanov, Bhupesh Parashar, Dattatreyudu Nori, K. S. Clifford Chao, Paul Christos, Ilhami Kovanlikaya, Susan Pannullo, John A. Boockvar, Philip E. Stieg, and Theodore H. Schwartz
Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole-brain radiotherapy (WBRT) remains the standard of care with a local control rate > 90%. However, WBRT is delivered over 10–15 days, which can delay other therapy and is associated with acute and long-term toxicities. Permanent cesium-131 (131Cs) implants can be used at the time of metastatic resection, thereby avoiding the need for any additional therapy. The authors evaluated the safety, feasibility, and efficacy of a novel therapeutic approach with permanent 131Cs brachytherapy at the resection for brain metastases.
After institutional review board approval was obtained, 24 patients with a newly diagnosed metastasis to the brain were accrued to a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung cancer (16), breast cancer (2), kidney cancer (2), melanoma (2), colon cancer (1), and cervical cancer (1). Stranded 131Cs seeds were placed as permanent volume implants. The prescription dose was 80 Gy at a 5-mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. The primary end point was local (resection cavity) freedom from progression (FFP). Secondary end points included regional FFP, distant FFP, median survival, overall survival (OS), and toxicity.
The median follow-up was 19.3 months (range 12.89–29.57 months). The median age was 65 years (range 45–84 years). The median size of resected tumor was 2.7 cm (range 1.5–5.5 cm), and the median volume of resected tumor was 10.31 cm3 (range 1.77–87.11 cm3). The median number of seeds used was 12 (range 4–35), with a median activity of 3.82 mCi per seed (range 3.31–4.83 mCi) and total activity of 46.91 mCi (range 15.31–130.70 mCi). Local FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI 63.2%–99.1%). One-year distant FFP was 48.4% (95% CI 26.3%–67.4%). Median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated) and 1-year OS was 50.0% (95% CI 29.1%–67.8%). Complications included CSF leak (1), seizure (1), and infection (1). There was no radiation necrosis.
The use of postresection permanent 131Cs brachytherapy implants resulted in no local recurrences and no radiation necrosis. This treatment was safe, well tolerated, and convenient for patients, resulting in a short radiation treatment course, high response rate, and minimal toxicity. These findings merit further study with a multicenter trial.