Publications by authors named "Ankush Chandra"

52 Publications

Role of c-Met/β1 integrin complex in the metastatic cascade in breast cancer.

JCI Insight 2021 Jun 22;6(12). Epub 2021 Jun 22.

Department of Neurological Surgery, UCSF, San Francisco, California, USA.

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. Although individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a complex between receptor tyrosine kinase c-Met and β1 integrin in metastases. Using cell culture and in vivo assays, we found that c-Met/β1 complex induction promoted intravasation and vessel wall adhesion in triple-negative breast cancer cells, but did not increase extravasation. These effects may have been driven by the ability of the c-Met/β1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction. A β1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/β1 binding, decreased breast cancer cell invasion and mesenchymal gene expression. Bone-seeking breast cancer cells exhibited higher levels of c-Met/β1 complex than parental controls and preferentially adhered to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/β1 complex than brain metastases. Thus, the c-Met/β1 complex drove intravasation of triple-negative breast cancer cells and preferential affinity for bone-specific matrix. Pharmacological targeting of the complex may have prevented metastases, particularly osseous metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.138928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262466PMC
June 2021

Predictors of outcome in pleomorphic xanthoastrocytoma.

Neurooncol Pract 2021 Apr 20;8(2):222-229. Epub 2020 Nov 20.

Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston - McGovern Medical School, Houston, Texas.

Background: Pleomorphic xanthoastrocytomas (PXA) are circumscribed gliomas that typically have a favorable prognosis. Limited studies have revealed factors affecting survival outcomes in PXA. Here, we analyzed the largest PXA dataset in the literature and identify factors associated with outcomes.

Methods: Using the Surveillance, Epidemiology, and End Results (SEER) 18 Registries database, we identified histologically confirmed PXA patients between 1994 and 2016. Overall survival (OS) was analyzed using Kaplan-Meier survival and multivariable Cox proportional hazard models.

Results: In total, 470 patients were diagnosed with PXA (males = 53%; median age = 23 years [14-39 years]), the majority were Caucasian (n = 367; 78%). The estimated mean OS was 193 months [95% CI: 179-206]. Multivariate analysis revealed that greater age at diagnosis (≥39 years) (3.78 [2.16-6.59], < .0001), larger tumor size (≥30 mm) (1.97 [1.05-3.71], = .034), and postoperative radiotherapy (RT) (2.20 [1.31-3.69], = .003) were independent predictors of poor OS. Pediatric PXA patients had improved survival outcomes compared to their adult counterparts, in which chemotherapy (CT) was associated with worse OS. Meanwhile, in adults, females and patients with temporal lobe tumors had an improved survival; conversely, tumor size ≥30 mm and postoperative RT were associated with poor OS.

Conclusions: In PXA, older age and larger tumor size at diagnosis are risk factors for poor OS, while pediatric patients have remarkably improved survival. Postoperative RT and CT appear to be ineffective treatment strategies while achieving GTR confer an improved survival in male patients and remains the cornerstone of treatment. These findings can help optimize PXA treatment while minimizing side effects. However, further studies of PXAs with molecular characterization are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nop/npaa076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049416PMC
April 2021

Reducing Superfluous Opioid Prescribing Practices After Brain Surgery: It Is Time to Talk About Drugs.

Neurosurgery 2021 Jun;89(1):70-76

Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA.

Background: Opioids are prescribed routinely after cranial surgery despite a paucity of evidence regarding the optimal quantity needed. Overprescribing may adversely contribute to opioid abuse, chronic use, and diversion.

Objective: To evaluate the effectiveness of a system-wide campaign to reduce opioid prescribing excess while maintaining adequate analgesia.

Methods: A retrospective cohort study of patients undergoing a craniotomy for tumor resection with home disposition before and after a 2-mo educational intervention was completed. The educational initiative was composed of directed didactic seminars targeting senior staff, residents, and advanced practice providers. Opioid prescribing patterns were then assessed for patients discharged before and after the intervention period.

Results: A total of 203 patients were discharged home following a craniotomy for tumor resection during the study period: 98 who underwent surgery prior to the educational interventions compared to 105 patients treated post-intervention. Following a 2-mo educational period, the quantity of opioids prescribed decreased by 52% (median morphine milligram equivalent per day [interquartile range], 32.1 [16.1, 64.3] vs 15.4 [0, 32.9], P < .001). Refill requests also decreased by 56% (17% vs 8%, P = .027) despite both groups having similar baseline characteristics. There was no increase in pain scores at outpatient follow-up (1.23 vs 0.85, P = .105).

Conclusion: A dramatic reduction in opioids prescribed was achieved without affecting refill requests, patient satisfaction, or perceived analgesia. The use of targeted didactic education to safely improve opioid prescribing following intracranial surgery uniquely highlights the ability of simple, evidence-based interventions to impact clinical decision making, lessen potential patient harm, and address national public health concerns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyab061DOI Listing
June 2021

Commentary: The Ki-67 Proliferation Index as a Marker of Time to Recurrence in Intracranial Meningioma.

Neurosurgery 2021 Jun;89(1):E66-E67

Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyab100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203418PMC
June 2021

Detrimental and Beneficial Effect of Autophagy and a Potential Therapeutic Target after Ischemic Stroke.

Evid Based Complement Alternat Med 2020 23;2020:8372647. Epub 2020 Sep 23.

Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.

Autophagy, a physiologic mechanism that promotes energy recycling and orderly degradation through self-regulated disassembly of cellular components, helps maintain homeostasis. A series of evidences suggest that autophagy is activated as a response to ischemia and has been well-characterized as a therapeutic target. However, the role of autophagy after ischemia remains controversial. Activated-autophagy can remove necrotic substances against ischemic injury to promote cell survival. On the contrary, activation of autophagy may further aggravate ischemic injury, causing cell death. Therefore, the present review will examine the current understanding of the precise mechanism and role of autophagy in ischemia and recent neuroprotective therapies on autophagy, drug therapies, and nondrug therapies, including electroacupuncture (EA).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8372647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924073PMC
September 2020

Extent of resection and survival outcomes of geriatric patients with glioblastoma: Is there benefit from aggressive surgery?

Clin Neurol Neurosurg 2021 Mar 6;202:106474. Epub 2021 Jan 6.

Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX, USA; Memorial Hermann Hospital-TMC, Houston, TX, USA; Center for Precision Health, School of Biomedical Informatics, the University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Objective: We examine the impact of age and extent of resection (EOR) on overall survival (OS) in geriatric patients with Glioblastoma (GBM).

Methods: The SEER 18 Registries was used to identify patients aged 65 and above with GBM from 2000-2016. Patients were categorized into 4 groups based on EOR: Biopsy/Local Excision (B/LE), Subtotal Resection (STR), Gross Total Resection (GTR), and Supratotal Resection (SpTR). Primary endpoint was OS, which was calculated using the Kaplan-Meier method and analyzed by the Log-rank and Wilcoxon-Breslow-Gehan test. Multivariable Cox proportional hazards regression model was utilized to identify factors associated with OS. Likelihood of undergoing SpTR was explored using a multivariable logistic regression model. Results are given as median [IQR] and HR [95 % CI].

Results: Among 17,820 geriatric patients with GBM, median age was 73 years [68-78], 44 % were female, 91 % White, and 8% Hispanic. SpTR was performed in 2907 (16 %), GTR was performed in 2451 (14 %) patients, STR in 4879 (28 %), and B/LE in 7396 (42 %). There was a decline in the proportion of patients treated with SpTR with advancing age (65-69 years, 17 % vs 95+ years, 0%; p < 0.0001), and older age corresponded with a decrease in the odds of undergoing SpTR. In survival analysis, GTR (HR 0.61 [0.58-0.65]) and SpTR (HR 0.65 [0.62-0.68]) were associated with improved survival, even in octogenarian patients.

Conclusions: These findings suggest that aggressive surgical resection is associated with improvement in OS in geriatric patients. These results emphasize that age should not influence surgical strategy, as there is a survival benefit from maximal resection in geriatric patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clineuro.2021.106474DOI Listing
March 2021

Hamartin: An Endogenous Neuroprotective Molecule Induced by Hypoxic Preconditioning.

Front Genet 2020 30;11:582368. Epub 2020 Sep 30.

Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.

Hypoxic/ischemic preconditioning (HPC/IPC) is an innate neuroprotective mechanism in which a number of endogenous molecules are known to be involved. Tuberous sclerosis complex 1 (TSC1), also known as hamartin, is thought to be one such molecule. It is also known that hamartin is involved as a target in the rapamycin (mTOR) signaling pathway, which functions to integrate a variety of environmental triggers in order to exert control over cellular metabolism and homeostasis. Understanding the role of hamartin in ischemic/hypoxic neuroprotection will provide a novel target for the treatment of hypoxic-ischemic disease. Therefore, the proposed molecular mechanisms of this neuroprotective role and its preconditions are reviewed in this paper, with emphases on the mTOR pathway and the relationship between the expression of hamartin and DNA methylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.582368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556298PMC
September 2020

Comparative Analysis of Survival Outcomes and Prognostic Factors of Supratentorial versus Cerebellar Glioblastoma in the Elderly: Does Location Really Matter?

World Neurosurg 2021 02 7;146:e755-e767. Epub 2020 Nov 7.

Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address:

Background: Cerebellar glioblastomas (cGBMs) are rare tumors that are uncommon in the elderly. In this study, we compare survival outcomes and identify prognostic factors of cGBM compared with the supratentorial (stGBM) counterpart in the elderly.

Methods: Data from the SEER 18 registries were used to identify patients with a glioblastoma (GBM) diagnosis between 2000 and 2016. The log-rank method and a multivariable Cox proportional hazards regression model were used for analysis.

Results: Among 110 elderly patients with cGBM, the median age was 74 years (interquartile range [IQR], 69-79 years), 39% were female and 83% were white. Of these patients, 32% underwent gross total resection, 73% radiotherapy, and 39% chemotherapy. Multivariable analysis of the unmatched and matched cohort showed that tumor location was not associated with survival; in the unmatched cohort, insurance status (hazard ratio [HR], 0.11; IQR, 0.02-0.49; P = 0.004), gross total resection (HR, 0.53; IQR, 0.30-0.91; P = 0.022), and radiotherapy (HR, 0.33; IQR, 0.18-0.61; P < 0.0001) were associated with better survival. Patients with cGBM and stGBM undergoing radiotherapy (7 months vs. 2 months; P < 0.001) and chemotherapy (10 months vs. 3 months; P < 0.0001) had improved survival. Long-term mortality was lower for cGBM in the elderly at 24 months compared with the stGBM cohort (P = 0.007).

Conclusions: In our study, elderly patients with cGBM and stGBM have similar outcomes in overall survival, and those undergoing maximal resection with adjuvant therapies, independent of tumor location, have improved outcomes. Thus, aggressive treatment should be encouraged for cGBM in geriatric patients to confer the same survival benefits seen in stGBM. Single-institutional and multi-institutional studies to identify patient-level prognostic factors are warranted to triage the best surgical candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.11.003DOI Listing
February 2021

In Reply to the Letter to the Editor "Regarding the Path to U.S. Neurosurgical Residency for Foreign Medical Graduates: Trends from a Decade 2007-2017".

World Neurosurg 2020 11;143:625

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.08.107DOI Listing
November 2020

Treatment trends and overall survival in patients with grade II/III ependymoma: The role of tumor grade and location.

Clin Neurol Neurosurg 2020 12 6;199:106282. Epub 2020 Oct 6.

Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX, USA; Memorial Hermann Hospital-Texas Medical Center, Houston, TX, USA; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Background: Treatment of ependymoma (EPN) is guided by associated tumor features, such as grade and location. However, the relationship between these features with treatments and overall survival in EPN patients remains uncharacterized. Here, we describe the change over time in treatment strategies and identify tumor characteristics that influence treatment and survival in EPN.

Methods And Materials: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 Registries (1973-2016) database, we identified patients with EPN microscopically confirmed to be grade II (EPN-GII) or III (EPN-GIII) tumors between 2004-2016. Overall survival (OS) was analyzed using Kaplan-Meier survival estimates and multivariable Cox proportional hazard models. A sub-analysis was performed by tumor location (supratentorial, posterior fossa, and spine). Change over time in rates of gross total resection (GTR), radiotherapy (RT), and chemotherapy (CS) were analyzed using linear regression, and predictors of treatment were identified using multivariable logistic regression models.

Results: Between 2004-2016, 1,671 patients were diagnosed with EPN, of which 1,234 (74 %) were EPN-GII and 437 (26 %) EPN-GIII. Over the study period, EPN-GII patients underwent a less aggressive treatment (48 % vs 27 %, GTR; 60 % vs 30 %, RT; 22 % vs 2%, CS; 2004 vs 2016; p < 0.01 for all). Age, tumor size, location, and grade were positive predictors of undergoing treatment. Univariate analysis revealed that tumor grade and location were significantly associated with OS (p < 0.0001 for both). In multivariable Cox regression, tumor grade was an independent predictor of OS among patients in the cohort (grade III, HR 3.89 [2.84-5.33]; p < 0.0001), with this finding remaining significant across all tumor locations.

Conclusions: In EPN, tumor grade and location are predictors of treatment and overall survival. These findings support the importance of histologic WHO grade and location in the decision-making for treatment and their role in individualizing treatment for different patient populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clineuro.2020.106282DOI Listing
December 2020

Letter to the Editor Regarding "Global Diversity and Academic Success of Foreign-Trained Academic Neurosurgeons in the United States".

World Neurosurg 2020 07;139:704-705

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.04.144DOI Listing
July 2020

Sarcopenia as a Prognostic Factor for 90-Day and Overall Mortality in Patients Undergoing Spine Surgery for Metastatic Tumors: A Multicenter Retrospective Cohort Study.

Neurosurgery 2020 10;87(5):1025-1036

Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan.

Background: Novel methods in predicting survival in patients with spinal metastases may help guide clinical decision-making and stratify treatments regarding surgery vs palliative care.

Objective: To evaluate whether the frailty/sarcopenia paradigm is predictive of survival and morbidity in patients undergoing surgery for spinal metastasis.

Methods: A total of 271 patients from 4 tertiary care centers who had undergone surgery for spinal metastasis were identified. Frailty/sarcopenia was defined by psoas muscle size. Survival hazard ratios were calculated using multivariate analysis, with variables from demographic, functional, oncological, and surgical factors. Secondary outcomes included improvement of neurological function and postoperative morbidity.

Results: Patients in the smallest psoas tertile had shorter overall survival compared to the middle and largest tertile. Psoas size (PS) predicted overall mortality more strongly than Tokuhashi score, Tomita score, and Karnofsky Performance Status (KPS). PS predicted 90-d mortality more strongly than Tokuhashi score, Tomita score, and KPS. Patients with a larger PS were more likely to have an improvement in deficit compared to the middle tertile. PS was not predictive of 30-d morbidity.

Conclusion: In patients undergoing surgery for spine metastases, PS as a surrogate for frailty/sarcopenia predicts 90-d and overall mortality, independent of demographic, functional, oncological, and surgical characteristics. The frailty/sarcopenia paradigm is a stronger predictor of survival at these time points than other standards. PS can be used in clinical decision-making to select which patients with metastatic spine tumors are appropriate surgical candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyaa245DOI Listing
October 2020

In Reply to the Letter to the Editor Regarding "The Path to U.S. Neurosurgical Residency for Foreign Medical Graduates: Trends from a Decade 2007-2017".

World Neurosurg 2020 06;138:594

Department of Neurological Surgery, University of California, San Francisco, California, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.04.036DOI Listing
June 2020

Letter to the Editor Regarding "Geographic Distribution of International Medical Graduate Residents in U.S. Neurosurgery Training Programs".

World Neurosurg 2020 06;138:591

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.03.059DOI Listing
June 2020

Strategies to Address Projected Challenges Facing Foreign Applicants in the U.S. Neurosurgery Match.

World Neurosurg 2020 06;138:553-555

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.03.180DOI Listing
June 2020

Sideline Concussion Assessment: The Current State of the Art.

Neurosurgery 2020 09;87(3):466-475

Department of Neurological Surgery, University of California, San Francisco, California.

More than 200 million American adults and children participate in organized physical activity. Growing awareness has highlighted that concussion, especially when repeated, may be associated with prolonged neurological, cognitive, and/or neuropsychiatric sequelae. Objective diagnosis of concussion remains challenging. Although some concussion symptoms may be apparent even to nonmedical observers, diagnosis and removal from play for evaluation depend on validated assessment tools and trained, vigilant healthcare personnel. Over the past 2 decades, sideline concussion measures have undergone significant revision and augmentation to become more comprehensive batteries in order to detect a wide spectrum of symptomatology, eg, neurocognitive function, postconcussive symptoms, gait/balance, and saccadic eye movements. This review summarizes the current state-of-the-art concussion evaluation instruments, ranging from the Sports Concussion Assessment Tool (SCAT) and tools that may enhance concussion detection, to near-term blood-based biomarkers and emerging technology (eg, head impact sensors, vestibulo-ocular/eye-tracking, and mobile applications). Special focus is directed at feasibility, utility, generalizability, and challenges to implementation of each measure on-field and on the sidelines. This review finds that few instruments beyond the SCAT provide guidance for removal from play, and establishing thresholds for concussion detection and removal from play in qualification/validation of future instruments is of high importance. Integration of emerging sideline concussion evaluation tools should be supported by resources and education to athletes, caregivers, athletic staff, and medical professionals for standardized administration as well as triage, referral, and prevention strategies. It should be noted that concussion evaluation instruments are used to assist the clinician in sideline diagnosis, and no single test can diagnose concussion as a standalone investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyaa022DOI Listing
September 2020

The Path to U.S. Neurosurgical Residency for Foreign Medical Graduates: Trends from a Decade 2007-2017.

World Neurosurg 2020 05 19;137:e584-e596. Epub 2020 Feb 19.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. Electronic address:

Objective: The increasing competitiveness of the neurosurgical residency match has made it progressively difficult for foreign medical graduates (FMGs) to match in neurosurgery. We compared FMG to U.S. medical graduate (USMG) match rates in neurosurgery and identified factors associated with match outcomes for FMGs in neurosurgery.

Methods: Retrospective review of American Association of Neurological Surgeons membership data and Association of American Medical Colleges Charting the Outcomes match reports (2007-2017).

Results: Across 1857 neurosurgical residents (USMG: 91.1%, FMG: 8.9%), average FMG match rates were 24% (range, 15%-35%) versus 83% (range, 75%-94%; P < 0.001) for USMG. FMGs were more male (89.5% vs. 82.0%, P = 0.016), older (33.9 vs. 31.8 years, P = 0.008), and more likely to take research year(s) before matching (95.8% vs. 78.5%, P < 0.001). FMGs had greater publications (5 vs. 2, P < 0.001) and H-indices (3 vs. 1, P < 0.001). The number of matched USMGs increased by 3.3 annually, whereas that of matched FMGs remained unchanged (β = 0.07). Compared with USMGs, FMGs were less likely to match to National Institutes of Health (NIH) Top 40 (32.7% vs. 47.5%, P < 0.001) and Doximity Top 20 (20.0% vs. 29.0%, P = 0.014) programs. FMGs with prior U.S. neurosurgery program affiliation were more likely to match at NIH and Doximity Top 20 programs (P < 0.05). For NIH programs, FMGs were older (35.3 vs. 32.0, P = 0.011), had higher H-indices (5 vs. 2, P < 0.001), publications (7 vs. 2, P < 0.001), and were more likely to take research year(s) (94.4% vs. 76.0%, P = 0.002) than USMGs. FMGs had similar patterns for matching into Doximity Top 20 programs.

Conclusions: Although FMGs have lower match rates into U.S. neurosurgery residencies than USMGs, several demographic, professional, and academic factors could increase the chances of successful FMG neurosurgical match.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.02.069DOI Listing
May 2020

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Cancer Res 2020 04 10;80(7):1498-1511. Epub 2020 Feb 10.

Department of Neurosurgery, University of California San Francisco, San Francisco, California.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-1305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236890PMC
April 2020

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.

JAMA Oncol 2020 04;6(4):495-503

Department of Neurological Surgery, University of California, San Francisco.

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood.

Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery.

Design, Setting, And Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019.

Main Outcomes And Measures: Overall survival.

Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase.

Conclusions And Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2019.6143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042822PMC
April 2020

Postoperative intracranial migration of a C2 odontoid screw: A case report and literature review.

Surg Neurol Int 2019 10;10:173. Epub 2019 Sep 10.

Department of Neurological Surgery, Detroit Medical Center, Wayne State University, United States.

Background: Intracranial migration of odontoid screws is a rare but serious complication of anterior odontoid screw fixation not often reported in literature by neurosurgeons. Here, we describe the second case in literature of intracranial migration of an odontoid screw.

Case Description: A 64-year-old neurologically intact patient with a type II odontoid fracture secondary to trauma underwent anterior odontoid screw fixation without any intraoperative complications. He tolerated the procedure well, and postoperative imaging demonstrated near anatomic correction of the fracture with satisfactory placement of the lag screw. Unfortunately, the patient was subsequently lost to follow up and he presented 7 months later for a routine outpatient computed tomography (CT) of the cervical spine, which demonstrated upward migration of the screw into the intracranial cavity abutting the medulla, with CT angiography of the neck also confirming the screw lying between the two vertebral arteries. Magnetic resonance imaging of the cervical spine also demonstrated the odontoid screw lying within close proximity to the ventral cervicomedullary junction, marginating the left vertebral artery. Subsequently, the patient was managed with removal of the odontoid screw and posterior cervical arthrodesis and instrumented fusion.

Conclusion: Our case demonstrates the rare but serious complication of intracranial odontoid screw migration, which we bring to the attention of the neurosurgical community. The recognition of risk factors for this complication and optimized management of this rare occurrence is important for surgeons to recognize.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.25259/SNI_245_2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763670PMC
September 2019

Fibronectin in malignancy: Cancer-specific alterations, protumoral effects, and therapeutic implications.

Semin Oncol 2019 06 27;46(3):284-290. Epub 2019 Aug 27.

Department of Neurosurgery, University of California at San Francisco (UCSF), San Francisco, California. Electronic address:

Initial studies on cancer primarily focused on malignant cells themselves. The overarching narrative of cancer revolved around unchecked and rapidly proliferating cells. Special attention was given to the molecular, genetic, and metabolic profiles of isolated cancer cells in hopes of elucidating a critical factor in malignancy. However, the scope of cancer research has broadened over the past few decades to include the local environment around cancer. It has become increasingly apparent that the immune cells, vascular networks, and the extracellular matrix all have a part in cancer progression. The impact of the extracellular matrix is particularly fascinating and key stromal changes have been identified in various cancers. Pioneering work studying laminin and hyaluronate has shown that these molecules have vital roles in cancer progression. More recently, fibronectin has been included as an extracellular driver of malignancy. Fibronectin is thought to play a considerable, albeit poorly understood, role in cancer pathogenesis. In this review, we present fundamental studies that have investigated the impact of fibronectin in cancer. As an abundant component of the extracellular matrix, understanding the effect of this molecule has the potential to elucidate cancer biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.seminoncol.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801036PMC
June 2019

Autophagy as a mechanism for anti-angiogenic therapy resistance.

Semin Cancer Biol 2020 11 28;66:75-88. Epub 2019 Aug 28.

Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, United States of America (USA). Electronic address:

Autophagy is a lysosomal-dependent degradation process that is highly conserved and maintains cellular homeostasis by sequestering cytosolic material for degradation either non-specifically by non-selective autophagy, or targeting specific proteins aggregates by selective autophagy. Autophagy serves as a protective mechanism defending the cell from stressors and also plays an important role in enabling tumor cells to overcome harsh conditions arising in their microenvironment during growth as well as oxidative and non-oxidative injuries secondary to therapeutic stressors. Recently, autophagy has been implicated to cause tumor resistance to anti-angiogenic therapy, joining an existing literature implicating autophagy in cancer resistance to conventional DNA damaging chemotherapy and ionizing radiation. In this review, we discuss the role of angiogenesis in malignancy, mechanisms of resistance to anti-angiogenic therapy in general, the role of autophagy in driving malignancy, and the current literature in autophagy-mediated anti-angiogenic therapy resistance. Finally, we provide future insight into the current challenges of using autophagy inhibitors in the clinic and provides tips for future studies to focus on to effectively target autophagy in overcoming resistance to anti-angiogenic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2019.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047534PMC
November 2020

From bench to bedside: trends in National Institutes of Health funding for neurosurgeons from 1991 to 2015.

J Neurosurg 2019 Aug 30:1-10. Epub 2019 Aug 30.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2019.1.JNS181531DOI Listing
August 2019

Neuroprotection by mesenchymal stem cell (MSC) administration is enhanced by local cooling infusion (LCI) in ischemia.

Brain Res 2019 12 24;1724:146406. Epub 2019 Aug 24.

Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA; Department of Research & Development Center, John D. Dingell VA Medical Center, Detroit, MI, USA.

Objective: The present study aimed to determine if hypothermia augments the neuroprotection conferred by MSC administration by providing a conducive micro-environment.

Methods: Sprague-Dawley rats were subjected to 1.5 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion for molecular analyses, as well as 1, 14 and 28 days for brain infarction or functional outcomes. Rats were treated with either MSC (1 × 10), LCI (cold saline, 0.6 ml/min, 5 min) or both. Brain damage was determined by Infarct volume and neurological deficits. Long-term functional outcomes were evaluated using foot-fault and Rota-rod testing. Human neural SHSY5Y cells were investigated in vitro using 2 h oxygen-glucose deprivation (OGD) followed by MSC with or without hypothermia (HT) (34 °C, 4 h). Mitochondrial transfer was assessed by confocal microscope, and cell damage was determined by cell viability, ATP, and ROS level. Protein levels of IL-1β, BAX, Bcl-2, VEGF and Miro1 were measured by Western blot following 6 h and 24 h of reperfusion and reoxygenation.

Results: MSC, LCI, and LCI + MSC significantly reduced infarct volume and deficit scores. Combination therapy of LCI + MSC precipitated better long-term functional outcomes than monotherapy. Upregulation of Miro1 in the combination group increased mitochondrial transfer and lead to a greater increase in neuronal cell viability and ATP, as well as a decrease in ROS. Further, combination therapy significantly decreased expression of IL-1β and BAX while increasing Bcl-2 and VEGF expression.

Conclusion: Therapeutic hypothermia upregulated Miro1 and enhanced MSC mitochondrial transfer-mediated neuroprotection in ischemic stroke. Combination of LCI with MSC therapy may facilitate clinical translation of this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2019.146406DOI Listing
December 2019

Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study.

Lancet Neurol 2019 10 23;18(10):953-961. Epub 2019 Aug 23.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA. Electronic address:

Background: After traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on CT scan. Some patients with suspected TBI with normal CT findings show pathology on MRI. We assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings.

Methods: TRACK-TBI is a prospective cohort study that enrolled patients with TBI who had a clinically indicated head CT scan within 24 h of injury at 18 level 1 trauma centres in the USA. For this analysis, we included patients with normal CT findings (Glasgow Coma Scale score 13-15) who consented to venepuncture within 24 h post injury and who had an MRI scan 7-18 days post injury. We compared MRI findings in these patients with those of orthopaedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform. We used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 h (time between injury and venepuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings within 24 h of injury. The Dunn Kruskal-Wallis test was used to compare GFAP concentrations between MRI lesion types with Benjamini-Hochberg correction for multiple comparisons. This study is registered with ClinicalTrials.gov, number NCT02119182.

Findings: Between Feb 26, 2014, and June 15, 2018, we recruited 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopaedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 (95% CI 0·726-0·829) over 24 h. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414·4 pg/mL, 25-75th percentile 139·3-813·4), followed by patients with CT-negative and MRI-negative findings (74·0 pg/mL, 17·5-214·4), orthopaedic trauma controls (13·1 pg/mL, 6·9-20·0), and healthy controls (8·0 pg/mL, 3·0-14·0; all comparisons between patients with CT-negative MRI-positive findings and other groups p<0·0001).

Interpretation: Analysis of blood GFAP concentrations using prototype assays on a point-of-care platform within 24 h of injury might improve detection of TBI and identify patients who might need subsequent MRI and follow-up.

Funding: National Institute of Neurological Disorders and Stroke and US Department of Defense.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(19)30282-0DOI Listing
October 2019

Systemic therapy for brain metastases.

Crit Rev Oncol Hematol 2019 Oct 22;142:44-50. Epub 2019 Jul 22.

Department of Neurosurgery, University of California at San Francisco (UCSF), United States. Electronic address:

Metastases from cells outside of the central nervous system are the most common cancer found in the brain and are commonly associated with poor prognosis. Although cancer treatment is improving overall, central nervous system metastases are becoming more prevalent and require finesse to properly treat. Physicians must consider the biology of the primary tumor and the complex neurological environment that the metastasis resides in. This can be further complicated by the fact that the practice of cancer management is constantly evolving and therapy that works outside of the blood-brain barrier may not be effective inside of it. Therefore, this review seeks to update the reader on recent advancements made on the three most common sources of brain metastases: lung cancer, breast cancer, and melanoma. Each of these malignancies has been the subject of intriguing and novel avenues of therapy which are reviewed here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746616PMC
October 2019

Sarcopenia Predicts Overall Survival in Patients with Lung, Breast, Prostate, or Myeloma Spine Metastases Undergoing Stereotactic Body Radiation Therapy (SBRT), Independent of Histology.

Neurosurgery 2020 05;86(5):705-716

Department of Neurosurgery, Neuroscience Institute, Henry Ford Hospital, Detroit, Michigan.

Background: Predicting survival of patients with spinal metastases would help stratify treatments from aggressive to palliation.

Objective: To evaluate whether sarcopenia predicts survival in patients with lung, breast, prostate, or multiple myeloma spinal metastases.

Methods: Psoas muscle measurements in patients with spinal metastasis were taken from computed tomography scans at 2 time points: at first episode of stereotactic body radiation therapy (SBRT) and from the most recent scan available. Overall survival and hazard ratios were calculated with multivariate cox proportional hazards regression analyses.

Results: In 417 patients with spinal metastases, 40% had lung cancer, 27% breast, 21% prostate, and 11% myeloma. Overall survival was not associated with age, sex, ethnicity, levels treated, or SBRT volume. Multivariate analysis showed patients in the lowest psoas tertile had shorter survival (222 d, 95% CI = 185-323 d) as compared to the largest tertile (579 d, 95% CI = 405-815 d), (HR1.54, P = .005). Median psoas size as a cutoff value was also strongly predictive for survival (HR1.48, P = .002). Survival was independent of tumor histology. The psoas/vertebral body ratio was also successful in predicting overall survival independent of tumor histology and gender (HR1.52, P < .01). Kaplan-Meier survival curves visually represent survival (P = .0005).

Conclusion: In patients with spine metastases, psoas muscle size as a hallmark of frailty/sarcopenia is an objective, simple, and effective way to identify patients who are at risk for shorter survival, regardless of tumor histology. This information can be used to help with surgical decision making in patients with advanced cancer, as patients with small psoas sizes are at higher risk of death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyz216DOI Listing
May 2020

Insurance type impacts the economic burden and survival of patients with newly diagnosed glioblastoma.

J Neurosurg 2019 Jun 21:1-11. Epub 2019 Jun 21.

Objective: Glioblastoma (GBM) carries a high economic burden for patients and caregivers, much of which is associated with initial surgery. The authors investigated the impact of insurance status on the inpatient hospital costs of surgery for patients with GBM.

Methods: The authors conducted a retrospective review of patients with GBM (2010-2015) undergoing their first resection at the University of California, San Francisco, and corresponding inpatient hospital costs.

Results: Of 227 patients with GBM (median age 62 years, 37.9% females), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher overall hospital costs for surgery compared to non-Medicaid patients ($50,285 vs $38,779, p = 0.01). Medicaid patients had higher intensive care unit (ICU; p < 0.01), operating room (p < 0.03), imaging (p < 0.001), room and board (p < 0001), and pharmacy (p < 0.02) costs versus non-Medicaid patients. Medicaid patients had significantly longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured patients (3.9 and 1.8 days, p < 0.01). Medicaid patients had similar comorbidity rates to Medicare patients (67.8% vs 68.1%), and both groups had higher comorbidity rates than privately insured patients (37.3%, p < 0.0001). Only 67.7% of Medicaid patients had primary care providers (PCPs) versus 91.5% of Medicare and 86.3% of privately insured patients (p = 0.009) at the time of presentation. Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm, p = 0.03). Preoperative (70 vs 90, p = 0.02) and postoperative (80 vs 90, p = 0.03) Karnofsky Performance Scale (KPS) scores were lowest for Medicaid versus non-Medicaid patients, while in subgroup analysis, postoperative KPS score was lowest for Medicaid patients (80, vs 90 for Medicare and 90 for private insurance; p = 0.03). Medicaid patients had significantly shorter median overall survival (10.7 months vs 12.8 months for Medicare and 15.8 months for private insurance; p = 0.02). Quality-adjusted life year (QALY) scores were 0.66 and 1.05 for Medicaid and non-Medicaid patients, respectively (p = 0.036). The incremental cost per QALY was $29,963 lower for the non-Medicaid cohort.

Conclusions: Patients with GBMs and Medicaid have higher surgical costs, longer lengths of stay, poorer survival, and lower QALY scores. This study indicates that these patients lack PCPs, have more comorbidities, and present later in the disease course with larger tumors; these factors may drive the poorer postoperative function and greater consumption of hospital resources that were identified. Given limited resources and rising healthcare costs, factors such as access to PCPs, equitable adjuvant therapy, and early screening/diagnosis of disease need to be improved in order to improve prognosis and reduce hospital costs for patients with GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2019.3.JNS182629DOI Listing
June 2019

Low dose concomitant treatment with chlorpromazine and promethazine is safe in acute ischemic stroke.

J Neurosurg Sci 2019 Jun;63(3):265-269

Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.

Background: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS.

Methods: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status.

Results: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group.

Conclusions: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S0390-5616.19.04665-4DOI Listing
June 2019
-->