David J. Cote

African-American Ethnicity, Socioeconomic Status, and Breast Cancer Survival A Meta-Analysis of 14 Studies Involving Over 10,000 African-American and 40,000 White American Patients with Carcinoma of the Breast

African‐American women are at increased risk for breast cancer mortality compared with white American women, and the extent to which socioeconomic factors account for this outcome disparity is unclear.

Development of venous thromboembolism (VTE) in patients undergoing surgery for brain tumors: Results from a single center over a 10 year period

Patients who undergo craniotomy for brain neoplasms have a high risk of developing venous thromboembolism (VTE), including deep vein thromboses (DVT) and pulmonary emboli (PE). The reasons for this correlation are not fully understood. This retrospective, single-center review aimed to determine the risk factors for VTE in patients who underwent neurosurgical resection of brain tumors at Northwestern University from 1999 to 2010. Our cohort included 1148 patients, 158 (13.7%) of whom were diagnosed with DVT and 38 (3.3%) of whom were diagnosed with PE. A variety of clinical factors were studied to determine predictors of VTE, including sex, ethnicity, medical co-morbidities, surgical positioning, length of hospital stay, tumor location, and tumor histology. Use of post-operative anticoagulants and hemorrhagic complications were also investigated. A prior history of VTE was found to be highly predictive of post-operative DVT (odds ratio [OR]=7.6, p=0.01), as was the patients sex (OR=14.2, p<0.001), ethnicity (OR=0.5, p=0.04), post-operative intensive care unit days (OR=0.2, p=0.003), and tumor histology (OR=-0.16, p=0.01). Contrary to reports in the literature, the data collected did not indicate that the administration of post-operative medical prophylaxis for VTE was significant in preventing their formation (OR=-0.14, p=0.76). Hemorrhagic complications were low (2.2%) and resultant neurologic deficit was lower still (0.7%). The study indicates that patients with high-grade primary brain tumors and metastatic lesions should receive aggressive preventative measures in the post-operative period.

Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results

BackgroundFluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In this paper, we systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.MethodsWe searched the PubMed and Embase databases for all potentially relevant studies through March 2016. We assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression-free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.ResultsThe search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5-aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.Conclusions5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives.

Comparison of the Efficacy and Safety of Endovascular Coiling Versus Microsurgical Clipping for Unruptured Middle Cerebral Artery Aneurysms: A Systematic Review and Meta-Analysis.

OBJECTIVEnMiddle cerebral artery aneurysms (MCAAs) are regularly treated by both microsurgical clipping and endovascular coiling. We performed a systematic meta-analysis to compare the safety and efficacy of these 2 methods.nnnMETHODSnLiterature was reviewed for all studies reporting angiographic occlusion and/or functional outcomes in adults with unruptured MCAA treated by endovascular coiling or microsurgical clipping. All studies in English that reported results for adults (≥18 years) with unruptured MCAAs, from 1990 to 2011 were considered for inclusion.nnnRESULTSnTwenty-six studies involving 2295 aneurysms treated with clipping or coiling for unruptured MCAAs were included for analysis. There were 1530 aneurysms that were treated with clipping and 765 aneurysms treated with coiling. Pooled analysis revealed failure of aneurysmal occlusion in 3.0% (95% confidence interval [CI] 1.2%-7.4%) of clipped cases. Pooled analysis of 15 studies (606 aneurysms) involving coiling and occlusion revealed lack of occlusion rates of 47.7% (95% CI 43.6%-51.8%) with the fixed-effects model and 48.2% (95% CI 39.0%-57.4%) with the random-effects model. Thirteen studies examined neurological outcomes after clipping and were pooled for analysis. Both fixed-effect and random-effect models revealed unfavorable outcomes in 2.1% (95% CI 1.3%-3.3%) of patients. There were 17 studies evaluating potential unfavorable neurological outcomes after coiling that were pooled for analysis. Fixed-effect and random-effect models revealed unfavorable outcomes in 6.5% (95% CI 4.5%-9.3%) and 4.9% (95% CI 3.0%-8.1%) of patients, respectively.nnnCONCLUSIONSnBased on this systematic review and meta-analysis of unruptured MCAAs, after careful consideration of patient, aneurysmal, and treatment center factors, we recommend surgical clipping for unruptured MCAA.

Current indications for the surgical treatment of prolactinomas

The purpose of this study was to examine the current indications for transsphenoidal surgery in the prolactinoma patient population, and to determine the outcomes of patients who undergo such operations. Transsphenoidal surgery may be indicated in prolactinoma patients who are resistant and/or intolerant to dopamine agonist (DA) therapy. We performed a retrospective review of the medical records of prolactinoma patients over a 6 year period (April 2008 to April 2014) at a large volume academic center. The median follow-up time was 12.0 months (range: 3-69). All patients who were included in the study (n=66) were treated with DA therapy and subsequently underwent an endonasal transsphenoidal operation. Of the 66 patients, 44 were women (mean age 34.2 years) and 22 were men (mean 41.7 years). There were 29 (43.9%) intolerant patients and 29 (43.9%) resistant patients. Postoperatively, 18 intolerant patients (66.7%) had normalized prolactin levels without the need for DA therapy, and five (17.2%) required DA to normalize their prolactin levels (p=0.02). Six patients (20.6%) had persistently elevated prolactin levels but were no longer receiving DA treatment (p<0.001). Postoperatively, 10 resistant patients (35.7%) had normal prolactin levels without DA therapy, and seven patients (25%) were treated with DA therapy to normalize their prolactin levels (p=0.22). Eight patients (28.6%) had supraphysiologic prolactin levels but were no longer taking a DA (p<0.001). Three patients (10.7%) were hyperprolactinemic, despite postoperative treatment with DA (p<0.001). After an appropriate treatment interval with multiple DA, radiographic follow-up, and careful clinical evaluation, prolactinoma patients can be offered surgery as an effective therapeutic option.

Predictors and Rates of Delayed Symptomatic Hyponatremia after Transsphenoidal Surgery: A Systemastic Review

BACKGROUNDnDelayed symptomatic hyponatremia (DSH) is a known complication of transsphenoidal surgery that can lead to prolonged hospital stay, readmission, and in rare cases, death. Many potential predictors for development of DSH have been investigated. A better understanding of DSH risk can lead to better patient outcomes. We performed a systematic review to determine the rates and predictors of DSH after both endoscopic transsphenoidal surgery and microscopic transsphenoidal surgery.nnnMETHODSnA systematic search of the literature was conducted using MEDLINE/PUBMED, EMBASE, and Cochrane databases. Inclusion criteria were 1) case series with at least 10 cases reported, 2) adult patients who underwent eTSS or mTSS for pituitary tumors, and 3) reported occurrence of DSH (defined as serum sodium level <135 mEq/L with associated symptoms) after postoperative day 3. Data were analyzed using CMA V.3 Statistical Software (2014).nnnRESULTSnTen case series satisfied the inclusion criteria for a total of 2947 patients. Various factors including age, gender, cerebrospinal fluid leak, and tumor size were investigated as potential predictors of DSH. DSH event rates for both mTSS and eTSS fell between around 4 and 12 percent and included a variety of proposed predictors.nnnCONCLUSIONSnAge, gender, tumor size, rate of decline of blood sodium, and Cushing disease are potential predictors of DSH. By identifying patients at high risk for DSH, preventative efforts can be implemented in the perioperative setting to reduce the incidence of potentially catastrophic hyponatremia following transsphenoidal surgery.

Complications after transsphenoidal surgery for patients with Cushing's disease and silent corticotroph adenomas

OBJECT The purpose of this study was to describe complications associated with the endonasal, transsphenoidal approach for the treatment of adrenocorticotropic hormone (ACTH)-positive staining tumors (Cushings disease [CD] and silent corticotroph adenomas [SCAs]) performed by 1 surgeon at a high-volume academic medical center. METHODS Medical records from Brigham and Womens Hospital were retrospectively reviewed. Selected for study were 82 patients with CD who during April 2008-April 2014 had consecutively undergone transsphenoidal resection or who had subsequent pathological confirmation of ACTH-positive tumor staining. In addition to demographic, patient, tumor, and surgery characteristics, complications were evaluated. Complications of interest included syndrome of inappropriate antidiuretic hormone secretion, diabetes insipidus (DI), CSF leakage, carotid artery injury, epistaxis, meningitis, and vision changes. RESULTS Of the 82 patients, 68 (82.9%) had CD and 14 (17.1%) had SCAs; 55 patients were female and 27 were male. Most common (n = 62 patients, 82.7%) were microadenomas, followed by macroadenomas (n = 13, 14.7%). A total of 31 (37.8%) patients underwent reoperation. Median follow-up time was 12.0 months (range 3-69 months). The most common diagnosis was ACTH-secreting (n = 68, 82.9%), followed by silent tumors/adenomas (n = 14, 17.1%). ACTH hyperplasia was found in 8 patients (9.8%). Of the 74 patients who had verified tumors, 12 (16.2%) had tumors with atypical features. The overall (CD and SCA) rate of minor complications was 35.4%; the rate of major complications was 8.5% (n = 7). All permanent morbidity was associated with DI (n = 5, 6.1%). In 16 CD patients (23.5%), transient DI developed. Transient DI was more likely to develop in CD patients who had undergone a second operation (37.9%) than in those who had undergone a first operation only (12.8%, p < 0.05). Permanent DI developed in 4 CD patients (5.9%) and 1 SCA patient (7.1%). For 1 CD patient, intraoperative carotid artery injury required endovascular sacrifice of the injured artery, but the patient remained neurologically intact. For another CD patient, aseptic meningitis developed and was treated effectively with corticosteroids. One CD patient experienced major postoperative epistaxis requiring another operative procedure to achieve hemostasis. For 2 CD patients, development of sinus mucoceles was managed conservatively. For 1 SCA patient, an abdominal wound dehisced at the fat graft site. No patients experienced postoperative CSF leakage, visual impairment, or deep vein thrombosis. CONCLUSIONS Transsphenoidal surgery is the treatment of choice for patients with CD and other ACTH-positive staining tumors. Recent advances in endoscopic technology and increasing surgeon comfort with this technology are making transsphenoidal procedures safer, faster, and more effective. Serious complications are uncommon and can be managed successfully.

Readmission and Other Adverse Events after Transsphenoidal Surgery: Prevalence, Timing, and Predictive Factors

BACKGROUNDnTranssphenoidal surgery is a common neurosurgical procedure for accessing the pituitary and anterior skull base, yet few multicenter analyses have evaluated outcomes after this procedure.nnnSTUDY DESIGNnPatients undergoing transsphenoidal surgery from 2006 to 2015 were extracted from the American College of Surgeons NSQIP database. Logistic regression was used to identify predictors of 30-day complications.nnnRESULTSnOf 1,240 patients included in this analysis, 6.9% experienced a major complication, and 9.4% experienced any complication within 30 days. Other adverse events included death in 0.7% and nonroutine hospital discharge in 5.3%. Most adverse events occurred within the first 2 weeks postoperatively; 82.9% of patients experienced their first complication during the initial hospital stay. Multivariable analysis demonstrated that predictors of hospital stay longer than 4 days included American Society of Anesthesiologists classification III to V (pxa0= 0.015), insulin-dependent diabetes mellitus (p < 0.001), and operative time in the third and fourth quartiles (both p < 0.001). American Society of Anesthesiologists classification III to V and operative time in the fourth quartile were also predictors of any adverse event (pxa0= 0.01 and pxa0= 0.005, respectively). Among these patients, 3.7% underwent reoperation, the most common reason for which was postoperative cerebrospinal fluid leak (63.6%). Readmission occurred after 8.5% of cases at a median of 11.0 days post-discharge. The most common cause of readmission was hyponatremia (29.5%), followed by delayed postoperative cerebrospinal fluid leak (16.0%).nnnCONCLUSIONSnOverall rates of adverse events in patients undergoing transsphenoidal surgery are relatively low, and most occur before discharge from the hospital. Post-discharge complications associated with transsphenoidal surgery include deep vein thrombosis, pulmonary embolism, and urinary tract infection. Delayed postoperative cerebrospinal fluid leak is the major cause of reoperation, and hyponatremia is the major cause of readmission.

The Expanding Spectrum of Disease Treated by the Transnasal, Transsphenoidal Microscopic and Endoscopic Anterior Skull Base Approach: A Single-Center Experience 2008–2015

INTRODUCTIONnThe transsphenoidal approach was initially developed in neurosurgical practice as an operative approach to the pituitary gland. The introduction of the operating endoscope has improved the versatility of the transsphenoidal approach, broadening the spectrum of lesions that can be treated effectively with this operative strategy.nnnMETHODSnWe performed a retrospective review of all patients who underwent transnasal, transsphenoidal operations at Brigham and Womens Hospital from April 2008 to February 2015 and categorized each case by pathologic diagnosis.nnnRESULTSnA total of 792 transnasal, transsphenoidal operations (512 endoscopic) were performed by 9 neurosurgeons for 33 pathologies over a 7-year period. Pituitary adenomas (535, 67.55%) were the most common impetus for a transsphenoidal operation. Others included Rathke cleft cysts (86, 10.86%), craniopharyngiomas (25, 3.16%), lympocytic hypophysitis/pituitary inflammation (21, 2.65%), arachnoid cysts (8, 1.01%), spindle cell oncocytoma (4, 0.51%), colloid cysts (4, 0.51%), and pituicytoma (2, 0.25%). Pituitary hyperplasia was treated in 9 cases (1.14%) and pituitary apoplexy in 7 (0.88%). Nineteen operations were undertaken for postoperative repairs (2.40%) and 3 for abscesses (0.38%). Other diseases treated transsphenoidally included chordomas (12, 1.52%), metastases (9, 1.14%), meningiomas (5, 0.63%), clival lesions (4, 0.51%), germinomas (3, 0.38%), granulomas (2, 0.25%), dermoid tumors (2, 0.25%), and 1 (0.13%) each of esthesioneuroblastoma, granular cell tumor, Wegener granulomatosis, olfactory neuroblastoma, glioneuronal tumor, chondromyxoid fibroma, epidermoid, meningoencephalocele, aneurysm, neuroendocrine carcinoma, chondrosarcoma, and lymphoma.nnnCONCLUSIONSnAlthough initially devised in neurosurgical practice for tumors of the pituitary gland, developments in technology now make the transsphenoidal approach an effective operative strategy for a wide range of anterior skull base lesions.

Ethical clinical translation of stem cell interventions for neurologic disease

The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven—they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk. In some cases, patients undergoing such operations are not included in a clinical trial, and do not provide genuinely informed consent. For these reasons and others, some current stem cell interventions for neurologic diseases are ethically dubious and could jeopardize progress in the field. We provide discussion points for the evaluation of new stem cell interventions for neurologic disease, based primarily on the new Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research in May 2016. Important considerations in the ethical translation of stem cells to clinical practice include regulatory oversight, conflicts of interest, data sharing, the nature of investigation (e.g., within vs outside of a clinical trial), informed consent, risk-benefit ratios, the therapeutic misconception, and patient vulnerability. To help guide the translation of stem cells from the laboratory into the neurosurgical clinic in an ethically sound manner, we present an ethical discussion of these major issues at stake in the field of stem cell clinical research for neurologic disease.