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Ultrasmall theranostic gadolinium-based nanoparticles improve high-grade rat glioma survival

Dufort, Sandrine; Appelboom, Geoffrey; Verry, Camille; Barbier, Emmanuel L; Lux, François; Bräuer-Krisch, Elke; Sancey, Lucie; Chang, Steven D; Zhang, Michael; Roux, Stéphane; Tillement, Olivier; Le Duc, Géraldine
We formulated an ultra-small, gadolinium-based nanoparticle (AGuIX) with theranostic properties to simultaneously enhance MRI tumor delineation and radiosensitization in a glioma model. The 9L glioma cells were orthotopically implanted in 10-week-old Fischer rats. The intra-tumoral accumulation of AGuIX was quantified using MRI T1-maps. Rats randomized to intervention cohorts were subsequently treated with daily temozolomide for five consecutive days before radiotherapy treatment. Collectively, a series of 32 rats were divided into untreated (n = 7), temozolomide-only (n = 7), temozolomide and MRT (n = 9), AGuIX and MRT (n = 7), and triple therapy (temozolomide, AGuIX NPs, and MRT; n = 9) cohorts. AGuIX nanoparticles achieved a maximum intra-tumoral concentration (expressed as concentration of Gd3+) at 1 h after intravenous injection, reaching a mean of 227.9 ± 60 μM. This was compared to concentrations of 10.5 ± 9.2 μM and 62.9 ± 24.7 μM in the contralateral hemisphere and cheek, respectively. There was a slower washout in the intra-tumor region, with sustained tumor-to-contralateral ratio of AGuIX, up to 14-fold, for each time point. The combination of AGuIX or temozolomide with MRT improved the median survival time (40 days) compared to the MeST of control rats (25 days) (p < 0.002). There was a trend towards further increased survival when the three treatments were combined (MeST of 46 days). This study demonstrated the selective accumulation of AGuIX in high grade glioma, as well as the potential survival benefits when combined with chemoradiation.
PMID: 31281087
ISSN: 1532-2653
CID: 4622502

Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: a meta-analytic study

Kumar, Kevin K; Appelboom, Geoffrey; Lamsam, Layton; Caplan, Arthur L; Williams, Nolan R; Bhati, Mahendra T; Stein, Sherman C; Halpern, Casey H
BACKGROUND:The safety and efficacy of neuroablation (ABL) and deep brain stimulation (DBS) for treatment refractory obsessive-compulsive disorder (OCD) has not been examined. This study sought to generate a definitive comparative effectiveness model of these therapies. METHODS:A EMBASE/PubMed search of English-language, peer-reviewed articles reporting ABL and DBS for OCD was performed in January 2018. Change in quality of life (QOL) was quantified based on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the impact of complications on QOL was assessed. Mean response of Y-BOCS was determined using random-effects, inverse-variance weighted meta-analysis of observational data. FINDINGS/RESULTS:Across 56 studies, totalling 681 cases (367 ABL; 314 DBS), ABL exhibited greater overall utility than DBS. Pooled ability to reduce Y-BOCS scores was 50.4% (±22.7%) for ABL and was 40.9% (±13.7%) for DBS. Meta-regression revealed no significant change in per cent improvement in Y-BOCS scores over the length of follow-up for either ABL or DBS. Adverse events occurred in 43.6% (±4.2%) of ABL cases and 64.6% (±4.1%) of DBS cases (p<0.001). Complications reduced ABL utility by 72.6% (±4.0%) and DBS utility by 71.7% (±4.3%). ABL utility (0.189±0.03) was superior to DBS (0.167±0.04) (p<0.001). INTERPRETATION/CONCLUSIONS:Overall, ABL utility was greater than DBS, with ABL showing a greater per cent improvement in Y-BOCS than DBS. These findings help guide success thresholds in future clinical trials for treatment refractory OCD.
PMID: 30679237
ISSN: 1468-330x
CID: 3683132

Response to the Letter to the Editor from Gustavo Cartaxo Patriota, M.D., M.Sc., on "Clinical Grading Scales in Intracerebral Hemorrhage" [Letter]

Hwang, Brian Y; Appelboom, Geoffrey; Kellner, Christopher P; Connolly, E Sander
PMID: 20811961
ISSN: 1556-0961
CID: 4622202

Brainstem Dose Constraints in Nonisometric Radiosurgical Treatment Planning of Trigeminal Neuralgia: A Single-Institution Experience

Zhang, Michael; Lamsam, Layton A; Schoen, Matthew K; Mehta, Swapnil S; Appelboom, Geoffrey; Adler, John K; Soltys, Scott G; Chang, Steven D
BACKGROUND:CyberKnife stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) administers nonisometric, conformational high-dose radiation to the trigeminal nerve with risk of subsequent hypoesthesia. METHODS:We performed a retrospective, single-institution review of 66 patients with TGN treated with CyberKnife SRS to compare outcomes from 2 distinct treatment periods: standard dosing (n = 38) and reduced dosing (n = 28). Standard and reduced dosing permitted a maximum brainstem dose of 45 Gy and 25 Gy, respectively, each with a prescription dose of 60 Gy. Primary and secondary outcomes were Barrow Neurologic Institute pain and numbness scores. Maximum brainstem dose, prepontine nerve length, and treatment history were recorded for their predictive contributions by logistic regression. RESULTS:After matching, patients in the standard dosing and reduced dosing groups were followed for a median of 25 months and 19.5 months, respectively. Mean trigeminal nerve length was 8.55 mm in the standard dosing group and 9.46 mm in the reduced dosing group. Baseline rates of poorly controlled pain were 97% and 88%, respectively, which improved to 23.4% and 8.3%, respectively (P < 0.001 for both). The baseline rates of bothersome numbness were null in both groups, and increased to 25% in the standard group (P = 0.006) and to 21% in the reduced group (P = 0.07). Regression analyses suggested that reduced brainstem exposure (P = 0.01), as well as a longer trigeminal nerve (P = 0.01), were predictive of durable pain control. CONCLUSIONS:These outcomes demonstrate that a lower maximum brainstem dose can provide excellent pain control without affecting facial numbness. Longer nerves may achieve better long-term outcomes and help optimize individual plans.
PMID: 29454124
ISSN: 1878-8769
CID: 4622492

Causes and Timing of Unplanned Early Readmission After Neurosurgery

Taylor, Blake E S; Youngerman, Brett E; Goldstein, Hannah; Kabat, Daniel H; Appelboom, Geoffrey; Gold, William E; Connolly, Edward Sander
BACKGROUND:Reducing the rate of 30-day hospital readmission has become a priority in healthcare quality improvement policy, with a focus on better characterizing the reasons for unplanned readmission. In neurosurgery, however, peer-reviewed analyses describing the patterns of readmission have been limited in their number and generalizability. OBJECTIVE:To determine the incidence, timing, and causes of 30-day readmission after neurosurgical procedures. METHODS:We conducted a retrospective longitudinal study from 2009 to 2012 using the Statewide Planning And Research Cooperative System, which collects patient-level details for all admissions and discharges within New York. We identified patients readmitted within 30 days of initial discharge. The rate of, reasons for, and time to readmission were determined overall and within 4 subgroups: craniotomies, cranial surgery without craniotomy, spine, and neuroendovascular procedures. RESULTS:There were 163 743 index admissions, of whom 14 791 (9.03%) were readmitted. The most common reasons for unplanned readmission were infection (29.52%) and medical complications (19.22%). Median time to readmission was 11 days, with hemorrhagic strokes and seizures occurring earlier, and medical complications and infections occurring later. Readmission rates were highest among patients undergoing cerebrospinal fluid shunt revision and malignant tumor resection (15.57%-22.60%). Spinal decompressions, however, accounted for the largest volume of readmissions (33.13%). CONCLUSION:Many readmissions may be preventable and occur at predictable time intervals. The causes and timing of readmission vary significantly across neurosurgical subgroups. Future studies should focus on detecting specific complications in select cohorts at predefined time points, which may allow for interventions to lower costs and reduce patient morbidity. ABBREVIATIONS:CSF, cerebrospinal fluidIQR, interquartile rangeSPARCS, Statewide Planning And Research Cooperative System.
PMID: 26562821
ISSN: 1524-4040
CID: 4622462

Preoperative chemotherapy and corticosteroids: independent predictors of cranial surgical-site infections

Lieber, Bryan A; Appelboom, Geoffrey; Taylor, Blake E; Lowy, Franklin D; Bruce, Eliza M; Sonabend, Adam M; Kellner, Christopher; Connolly, E Sander; Bruce, Jeffrey N
OBJECT Preoperative corticosteroids and chemotherapy are frequently prescribed for patients undergoing cranial neurosurgery but may pose a risk of postoperative infection. Postoperative surgical-site infections (SSIs) have significant morbidity and mortality, dramatically increase the length and cost of hospitalization, and are a major cause of 30-day readmission. In patients undergoing cranial neurosurgery, there is a lack of data on the role of patient-specific risk factors in the development of SSIs. The authors of this study sought to determine whether chemotherapy and prolonged steroid use before surgery increase the risk of an SSI at postoperative Day 30. METHODS Using the national prospectively collected American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for 2006-2012, the authors calculated the rates of superficial, deep-incisional, and organ-space SSIs at postoperative Day 30 for neurosurgery patients who had undergone chemotherapy or had significant steroid use within 30 days before undergoing cranial surgery. Trauma patients, patients younger than 18 years, and patients with a preoperative infection were excluded. Univariate analysis was performed for 25 variables considered risk factors for superficial and organ-space SSIs. To identify independent predictors of SSIs, the authors then conducted a multivariate analysis in which they controlled for duration of operation, wound class, white blood cell count, and other potential confounders that were significant on the univariate analysis. RESULTS A total of 8215 patients who had undergone cranial surgery were identified. There were 158 SSIs at 30 days (frequency 1.92%), of which 52 were superficial, 27 were deep-incisional, and 79 were organ-space infections. Preoperative chemotherapy was an independent predictor of organ-space SSIs in the multivariate model (OR 5.20, 95% CI 2.33-11.62, p < 0.0001), as was corticosteroid use (OR 1.86, 95% CI 1.03-3.37, p = 0.04), but neither was a predictor of superficial or deep-incisional SSIs. Other independent predictors of organ-space SSIs were longer duration of operation (OR 1.16), wound class of ≥ 2 (clean-contaminated and further contaminated) (OR 3.17), and morbid obesity (body mass index ≥ 40 kg/m(2)) (OR 3.05). Among superficial SSIs, wound class of 3 (contaminated) (OR 6.89), operative duration (OR 1.13), and infratentorial surgical approach (OR 2.20) were predictors. CONCLUSIONS Preoperative chemotherapy and corticosteroid use are independent predictors of organ-space SSIs, even when data are controlled for leukopenia. This indicates that the disease process in organ-space SSIs may differ from that in superficial SSIs. In effect, this study provides one of the largest analyses of risk factors for SSIs after cranial surgery. The results suggest that, in certain circumstances, modulation of preoperative chemotherapy or steroid regimens may reduce the risk of organ-space SSIs and should be considered in the preoperative care of this population. Future studies are needed to determine optimal timing and dosing of these medications.
PMID: 26544775
ISSN: 1933-0693
CID: 4622452

Assessment of the "July Effect": outcomes after early resident transition in adult neurosurgery

Lieber, Bryan A; Appelboom, Geoffrey; Taylor, Blake E S; Malone, Hani; Agarwal, Nitin; Connolly, E Sander
OBJECT Each July, 4th-year medical students become 1st-year resident physicians and have much greater responsibility in making management decisions. In addition, incumbent residents and fellows advance to their next postgraduate year and face greater challenges. It has been suggested that among patients who have resident physicians as members of their neurosurgical team, this transition may be associated with increased rates of morbidity and mortality, a phenomenon known as the "July Effect." In this study, the authors compared morbidity and mortality rates between the initial and later months of the academic year to determine whether there is truly a July Effect that has an impact on this patient population. METHODS The authors compared 30-day postoperative outcomes of neurosurgery performed by surgical teams that included resident physicians in training during the first academic quarter (Q1, July through September) with outcomes of neurosurgery performed with resident participation during the final academic quarter (Q4, April through June), using 2006-2012 data from the prospectively collected American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Regression analyses were performed on outcome data that included mortality, surgical complications, and medical complications, which were graded as mild or severe. To determine whether a July Effect was present in subgroups, secondary analyses were performed to analyze the association of outcomes with each major neurosurgical subspecialty, the postgraduate year of the operating resident, and the academic quarter during which the surgery was performed. To control for possible seasonal trends in certain diseases, the authors compared patient outcomes at academic medical centers to those at community-based hospitals, where procedures were not performed by residents. In addition, the efficiency of academic centers was compared to that of community centers in terms of operative duration and total length of hospital stay. RESULTS Overall, there were no statistically significant differences in mortality, morbidity, or efficiency between the earlier and later quarters of the academic year, a finding that also held true among neurosurgical subspecialties and among postgraduate levels of training. There was, however, a slight increase in intraoperative transfusions associated with the transitional period in July (6.41% of procedures in Q4 compared to 7.99% in Q1 of the prior calendar year; p = 0.0005), which primarily occurred in cases involving junior (2nd- to 4th-year) residents. In addition, there was an increased rate of reoperation (1.73% in Q4 to 2.19% in Q1; p < 0.0001) observed mainly among senior (5th- to 7th-year) residents in the early academic months and not paralleled in our community cohort. CONCLUSIONS There is minimal evidence for a significant July Effect in adult neurosurgery. Our results suggest that, overall, the current resident training system provides enough guidance and support during this challenging transition period.
PMID: 26666349
ISSN: 1933-0693
CID: 4622472

Association of Steroid Use with Deep Venous Thrombosis and Pulmonary Embolism in Neurosurgical Patients: A National Database Analysis

Lieber, Bryan A; Han, James; Appelboom, Geoffrey; Taylor, Blake E S; Han, ByoungJun; Agarwal, Nitin; Connolly, E Sander
OBJECTIVE:Venous thromboembolism (VTE) is a major preventable cause of morbidity and mortality in hospitalized patients and is a widely accepted measure for quality of care. Prolonged corticosteroid therapy, which is common in neurosurgical patients, has been associated with VTE. Using a national database, we sought to determine whether corticosteroid use for >10 days was an independent risk factor for deep venous thrombosis (DVT) and pulmonary embolism (PE). METHODS:The well-validated American College of Surgeons National Surgical Quality Improvement Program database was queried to evaluate the rates of VTE during the period 2006-2013 in patients undergoing neurosurgical procedures. A multivariate regression model was constructed to assess the effect of prolonged corticosteroid use on the occurrence of PE and DVT by postoperative day 30. RESULTS:Of 94,620 patients identified, 565 (0.60%) developed PE and 1057 (1.12%) developed DVT within 30 days after surgery. In the multivariate model, patients receiving corticosteroids were significantly more likely to have PE (odds ratio = 1.47, 95% confidence interval = 1.13-1.90, P = 0.004) and DVT (odds ratio = 1.55, 95% confidence interval = 1.28-1.87, P < 0.001). Other factors independently associated with development of PE and DVT included the presence of malignancy, longer hospitalization, certain infections (including pneumonia and urinary tract infections), and stroke with a neurologic deficit. CONCLUSIONS:In the neurosurgical population, prolonged courses of corticosteroids are associated with an increased risk of developing postoperative DVT and PE, even when controlling for potential confounders.
PMID: 26805689
ISSN: 1878-8769
CID: 4622482

Impact of Hyponatremia on Morbidity, Mortality, and Complications After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review

Mapa, Ben; Taylor, Blake E S; Appelboom, Geoffrey; Bruce, Eliza M; Claassen, Jan; Connolly, E Sander
BACKGROUND:Hyponatremia is a common metabolic disturbance after aneurysmal subarachnoid hemorrhage (SAH), and it may worsen outcomes. This review aims to characterize the effect of hyponatremia on morbidity and mortality after SAH. OBJECTIVES/OBJECTIVE:We sought to determine the prevalence of hyponatremia after SAH, including in subgroups, as well as its effect on mortality and certain outcome measures, including degree of disability and duration of hospitalization. METHODS:A search of terms "hyponatremia" and "subarachnoid hemorrhage" was performed on PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Studies were included if they reported prevalence of hyponatremia and if they discussed outcomes such as mortality, duration of stay, functional outcomes (e.g., Glasgow Outcomes Scale), or incidence of complications in patients with aneurysmal SAH. Two independent researchers assessed the titles and abstracts and reviewed articles for inclusion. RESULTS:Thirteen studies met inclusion criteria. The prevalence of at least mild hyponatremia was 859 of 2387 (36%) of patients. Hyponatremia was associated with vasospasm and duration of hospitalization, but it did not influence mortality. CONCLUSION/CONCLUSIONS:Hyponatremia is common after SAH, and there is evidence that it is associated with certain poorer outcomes. Larger, prospective studies are needed to assess these findings and provide further evidence.
PMID: 26361321
ISSN: 1878-8769
CID: 4622442

Unilateral Craniofacial Microsomia: Unrecognized Cause of Pediatric Obstructive Sleep Apnea

Szpalski, Caroline; Vandegrift, Meredith; Patel, Parit A; Appelboom, Geoffrey; Fisher, Mark; Marcus, Jeffrey; McCarthy, Joseph G; Shetye, Pradip R; Warren, Stephen M
Bilateral craniofacial microsomia causes obstructive sleep apnea (OSA). We hypothesize that unilateral craniofacial microsomia (UCFM) is an underappreciated cause of OSA. The records of all pediatric UCFM patients from 1990 to 2010 were reviewed; only complete records were included in the study. UCFM patients with OSA (apnea hypopnea index >1/hr) were compared to UCFM patients without OSA. Univariate and multivariate Fisher and chi tests were performed. Of the 62 UCFM patients, 7 (11.3%) had OSA. All OSA patients had Pruzansky IIB or III mandibles. OSA patients presented with snoring (71.4%), failure to thrive (FTT) (57.1%), and chronic respiratory infections (42.8%). Snoring (P < 0.001), Goldenhar syndrome (P = 0.001), and FTT (P = 0.004) were significantly associated with OSA, but race, obesity, clefts, respiratory anomalies, adenotonsillar hypertrophy, and laterality were not. The prevalence of OSA in UCFM patients is up to 10 times greater than in the general population. Snoring, Goldenhar syndrome, and FTT are significantly associated with the presence of OSA.
PMID: 26080175
ISSN: 1536-3732
CID: 1704042