The latest medical research on Neurosurgery

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Association of Treatment Inequity and Ancestry With Pancreatic Ductal Adenocarcinoma Survival.

JAMA Surgery

Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown.

To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity.

This cohort study used data on 278 936 patients with PDAC with database-defined race from the National Cancer Database from January 1, 2004, to December 31, 2015. The median follow-up for censored patients was 24 months. The National Cancer Database, comprising academic and community facilities, includes about 70% of new cancer diagnoses in the United States. Race-stratified receipt of therapy was the primary variable of interest. Multivariable analyses included additional demographic and clinical parameters. Data analysis was initially completed on November 30, 2018, and revised data analysis was completed on June 27, 2019.

Overall survival was the primary outcome, analyzed with Kaplan-Meier and multivariable Cox proportional hazards regression modeling.

The cohort included 278 936 patients (137 121 women and 141 815 men; mean [SD] age, 68.72 [11.57] years); after excluding patients from other racial categories, 243 820 of the 278 936 patients (87.4%) were white and 35 116 of the 278 936 patients (12.6%) were black. Unadjusted median overall survival was longer for white patients than for black patients (6.6 vs 6.0 months; P < .001). Black patients presented at younger ages than white patients (15 819 of 35 116 [45.0%] vs 83 846 of 243 820 [34.4%] younger than 65 years; P < .001) and with more advanced disease (20 853 of 31 600 [66.0%] vs 135 317 of 220 224 [61.4%] with stage III or IV disease; P < .001). Black patients received fewer surgical procedures than white patients for potentially resectable stage II disease (4226 of 8097 [52.2%] vs 39 214 of 65 124 [60.2%]; P < .001) and slightly less chemotherapy for advanced disease (2756 of 4067 [67.8%] vs 17 296 of 25 227 [68.6%] for stage III disease [P = .001]; 8208 of 16 104 [51.0%] vs 58 603 of 105 616 [55.5%] for stage IV disease [P < .001]). Decreased survival for black patients persisted in multivariable modeling controlled for sociodemographic parameters (hazard ratio, 1.04 [95% CI, 1.02-1.05]). Conversely, modeling that controlled specifically for clinical parameters such as disease stage and treatment revealed a modest survival advantage (hazard ratio, 0.94 [95% CI, 0.93-0.96]) among black patients. Resection was the factor most strongly associated with overall survival (hazard ratio, 0.39 [95% CI, 0.38-0.39]).

Black patients with PDAC present at younger ages and with more advanced disease than white patients, suggesting that differences in tumor biology may exist. Black patients receive less treatment stage for stage and fewer surgical procedures for resectable cancers than white patients; these findings may be only partly associated with socioeconomic differences. When disease stage and treatment were controlled for, black patients had no decrease in survival.

Association of High Mortality With Postoperative Myocardial Infarction After Major Vascular Surgery Despite Use of Evidence-Based Therapies.

JAMA Surgery

Patients undergoing vascular surgery are at high risk of postoperative myocardial infarction (POMI). Postoperative myocardial infarction is independently associated with significant risk of in-hospital mortality.

To examine the association of patient and procedural characteristics with the risk of POMI after vascular surgery and determine the association of evidence-based therapies with longer-term outcomes.

A retrospective cohort study of prospectively collected data within a statewide quality improvement collaborative database between January 2012 and December 2017. Patient demographics, comorbid conditions, and perioperative medications were captured. Patients were grouped according to occurrence of POMI. Univariate analysis and logistic regression were used to identify factors associated with POMI. The collaborative collects data from private and academic hospitals in Michigan. Patients undergoing major vascular surgery, defined as endovascular aortic aneurysm repair, open abdominal aortic aneurysm, peripheral bypass, carotid endarterectomy, or carotid artery stenting were included. Analysis began December 2018.

The presence of a POMI and 1-year mortality.

Of 26 231 patients identified, 16 989 (65.8%) were men and the overall mean (SD) age was 69.35 (9.89) years. A total of 410 individuals (1.6%) experienced a POMI. Factors associated with higher rates of POMI were age (odds ratio [OR], 1.032 [95% CI, 1.019-1.045]; P < .001), diabetes (OR, 1.514 [95% CI, 1.201-1.907]; P < .001), congestive heart failure (OR, 1.519 [95% CI, 1.163-1.983]; P = .002), valvular disease (OR, 1.447 [95% CI, 1.024-2.046]; P = .04), coronary artery disease (OR, 1.381 [95% CI, 1.058-1.803]; P = .02), and preoperative P2Y12 antagonist use (OR, 1.37 [95% CI, 1.08-1.725]; P = .009). Procedurally, open abdominal aortic aneurysm (OR, 4.53 [95% CI, 2.73-7.517]; P < .001) and peripheral bypass (OR, 2.375 [95% CI, 1.818-3.102]; P < .001) were associated with the highest risk of POMI. After POMI, patients were discharged and received evidence-based therapy with high fidelity, including β-blockade (296 [82.7%]) and antiplatelet therapy (336 [95.7%]). A high portion of patients with POMI were dead at 1 year compared with patients without POMI (113 [37.42%] vs 993 [5.05%]; χ2 = 589.3; P < .001).

Despite high rates of discharge with evidence-based therapies, the long-term burden of POMI is substantial, with a high mortality rate in the following year. Patients with diabetes mellitus, coronary artery disease, congestive heart failure, and valvular disease warrant additional consideration in the preoperative period. Further, aggressive strategies to treat patients who experience a POMI are needed to reduce the risk of postoperative mortality.

Stereotactic Radiosurgery for Non-Functioning Pituitary Adenomas: Meta-Analysis and International Society of Stereotactic Radiosurgery (ISRS) Practice Opinion.


This systematic review reports on outcomes and toxicities following stereotactic radiosurgery (SRS) for non-functioning pituitary adenomas (NFAs) and presents consensus opinions regarding appropriate patient management.

Using the PRISMA guidelines, a systematic review was performed from articles of ≥10 patients with NFAs published prior to May 2018 from the Medline database using the key words: "radiosurgery" and "pituitary" and/or "adenoma." Weighted random effects models were used to calculate pooled outcome estimates.

Of the 678 abstracts reviewed, 35 full-text articles were included describing the outcomes of 2671 patients treated between 1971-2017 with either single fraction SRS or hypofractionated stereotactic radiotherapy (HSRT). All studies were retrospective (level IV evidence). SRS was used in 27 studies (median dose: 15 Gy, Range: 5-35 Gy) and HSRT in 8 studies (median total dose: 21 Gy, range: 12-25 Gy, delivered in 3-5 fractions). The 5-year random effects local control estimate after SRS was 94% (95% CI: 93.0-96.0%) and 97.0% (95% CI: 93.0-98.0%) after HSRT. The 10-year local control random effects estimate after SRS was 83.0% (95% CI, 77.0%-88.0%). Post-SRS hypopituitarism was the most common treatment-related toxicity observed, with a random effects estimate of 21.0% (95% CI: 15.0%-27.0%), whereas visual dysfunction or other cranial nerve injuries were uncommon (range: 0-7%).

SRS is an effective and safe treatment for patients with NFAs. Encouraging short-term data support HSRT for select patients, and mature outcomes are needed before definitive recommendations can be made. Clinical practice opinions were developed on behalf of the International Stereotactic Radiosurgery Society (ISRS).

Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma.


Most glioblastoma recurrences occur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an 'abscopal effect', whereby un-irradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-PD-L1 demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remains unknown.

We modified an immune-competent, genetically-driven mouse glioma model (forced PDGF expression + PTEN loss) where a portion of the tumor burden is irradiated (PDGF) and another un-irradiated luciferase expressing tumor (PDGF+Luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of EGFRvIII (PDGF+EGFRvIII). Statistical tests were two-sided.

Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the un-irradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF+Luciferase, n=8), the abscopal response occurred via anti-PD-L1-driven, ERK-mediated, bone marrow-derived macrophage phagocytosis of adjacent un-irradiated tumor cells, with modest survival implications (median survival 41 days vs. radiation alone 37.5 days, P=.03). In PDGF-driven gliomas with tumor neoepitope (PDGF+EGFRvIII, n=8), anti-PD-L1-enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs. radiation alone 28 days, P=.001).

Our results indicate that anti-PD-L1 immunotherapy enhances a radiation induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.

Outcomes of Transcatheter Aortic Valve Replacement in Patients with Severe Aortic Stenosis: A Review of a Disruptive Technology in Aortic Valve Surgery.

JAMA Surgery

Medically treated symptomatic severe aortic stenosis has poor outcomes, and in the past 6 decades, it has successfully been treated with surgical aortic valve replacement (SAVR). However, one-third of patients with indications for SAVR are not offered surgery because of the high risk of complications. Transcatheter aortic valve replacement (TAVR), initially developed as a less invasive treatment for inoperable patients, has successfully been used in healthier patient cohorts. In 2017, TAVR became the most common approach for aortic valve replacement in the United States.

During the past decade, the Placement of Aortic Transcatheter Valve (PARTNER) trials (for balloon-expandable valves) and the CoreValve trials (for self-expandable valves) investigated the performance of TAVR in progressively lower-risk patient cohorts. The initial trials demonstrated TAVR to be superior (PARTNER B) and noninferior (CoreValve Extreme Risk) to optimal medical therapy in inoperable patients. Subsequent trials showed both balloon-expandable and self-expandable valves to have good results in high-risk, medium-risk, and low-risk surgical patients when compared with SAVR. However, owing to the fundamentally different nature of the procedure, some complications have been more prevalent with TAVR, most notably moderate or severe paravalvular leak, conduction abnormalities necessitating permanent pacemaker placement, and vascular complications. When present, these complications have been associated with worse outcomes.

The results of the groundbreaking TAVR trials from the past decade have led to a revolution in the treatment of aortic stenosis. There are now 3 US Food and Drug Administration-approved TAVR devices, and with the encouraging results from the latest low-risk trials, TAVR is likely going to become the dominant treatment for symptomatic severe aortic stenosis. New devices on the horizon are looking to improve the complication rates of TAVR, and ongoing trials are looking to further expand the indications of TAVR and answer 1 of the main remaining questions, ie, long-term durability of percutaneously placed devices.

Effect of Cognitive Aids on Adherence to Best Practice in the Treatment of Deteriorating Surgical Patients: A Randomized Clinical Trial in a Simulation Setting.

JAMA Surgery

Failure to rescue causes significant morbidity and mortality in the surgical population. Human error is often the underlying cause of failure to rescue. Human error can be reduced by the use of cognitive aids.

To test the effectiveness of cognitive aids on adherence to best practice in the management of deteriorating postoperative surgical ward patients.

Randomized clinical trial in a simulation setting. Surgical teams consisted of 1 surgeon and 2 nurses from a surgical ward from 4 different hospitals in Amsterdam, the Netherlands. Data were analyzed between February 2, 2017, and December 18, 2018.

The teams were randomized to manage 3 simulated deteriorating patient scenarios with or without the use of cognitive aids.

The primary outcome of the study was failure to adhere to best practice, expressed as the percentage of omitted critical management steps. The secondary outcome of the study was the perceived usability of the cognitive aids.

Of the total participants, 93 were women and 51 were men. Twenty-five surgical teams performed 75 patient scenarios with cognitive aids, and 25 teams performed 75 patient scenarios without cognitive aids. Using the cognitive aids resulted in a reduction of omitted critical management steps from 33% to 10%, which is a 70% (P < .001) reduction. This effect remained significant (odds ratio, 0.63; 95% CI, -0.228 to -0.061; P = .001) in a multivariate analysis. Overall usability (scale of 0-10) of the cognitive aids was scored at a median of 8.7 (interquartile range, 8-9).

Failure to comply with best practice management of postoperative complications is associated with worse outcomes. In this simulation study, adherence to best practice in the management of postoperative complications improves significantly by the use of cognitive aids. Cognitive aids for deteriorating surgical patients therefore have the potential to reduce failure to rescue and improve patient outcome. identifier: NCT03812861.

INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFRamplified glioblastoma.


Depatux-M is a tumor-specific antibody-drug-conjugate consisting of an antibody (ABT-806) directed against the activated Epithelial Growth Factor Receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma.

Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150-200 mg/m2 day 1-5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival.

260 patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 months) the hazard ratio (HR) for the combination arm compared to the control arm was 0.71, 95% CI [0.50, 1.02]; p = 0.062. The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR =1.04, 95%CI [0.73, 1.48]; p = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grade 3-4 in 25-30% of patients. In the long-term follow-up analysis with median follow-up of 28,7 months the HR for the comparison of the combination arm versus the control arm was 0.66 (95%CI [0.48, 0.93].

This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406).

ΔNp73/ETS2 complex drives glioblastoma pathogenesis- targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma.


Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM.

ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model.

ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma.

Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.

Long-term Functional, Psychological, Emotional, and Social Outcomes in Survivors of Firearm Injuries.

JAMA Surgery

The outcomes of firearm injuries in the United States are devastating. Although firearm mortality and costs have been investigated, the long-term outcomes after surviving a gunshot wound (GSW) remain unstudied.

To determine the long-term functional, psychological, emotional, and social outcomes among survivors of firearm injuries.

This prospective cohort study assessed patient-reported outcomes among GSW survivors from January 1, 2008, through December 31, 2017, at a single urban level I trauma center. Attempts were made to contact all adult patients (aged ≥18 years) discharged alive during the study period. A total of 3088 patients were identified; 516 (16.7%) who died during hospitalization and 45 (1.5%) who died after discharge were excluded. Telephone contact was made with 263 (10.4%) of the remaining patients, and 80 (30.4%) declined study participation. The final study sample consisted of 183 participants. Data were analyzed from June 1, 2018, through June 20, 2019.

A GSW sustained from January 1, 2008, through December 31, 2017.

Scores on 8 Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (Global Physical Health, Global Mental Health, Physical Function, Emotional Support, Ability to Participate in Social Roles and Activities, Pain Intensity, Alcohol Use, and Severity of Substance Use) and the Primary Care PTSD (posttraumatic stress disorder) Screen for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

Of the 263 patients who survived a GSW and were contacted, 183 (69.6%) participated. Participants were more likely to be admitted to the hospital compared with those who declined (150 [82.0%] vs 54 [67.5%]; P = .01). Participants had a median time from GSW of 5.9 years (range, 4.7-8.1 years) and were primarily young (median age, 27 years [range, 21-36 years]), black (168 [91.8%]), male (169 [92.3%]), and employed before GSW (pre-GSW, 139 [76.0%]; post-GSW, 113 [62.1%]; decrease, 14.3%; P = .004). Combined alcohol and substance use increased by 13.2% (pre-GSW use, 56 [30.8%]; post-GSW use, 80 [44.0%]). Participants had mean (SD) scores below population norms (50 [10]) for Global Physical Health (45 [11]; P < .001), Global Mental Health (48 [11]; P = .03), and Physical Function (45 [12]; P < .001) PROMIS metrics. Eighty-nine participants (48.6%) had a positive screen for probable PTSD. Patients who required intensive care unit admission (n = 64) had worse mean (SD) Physical Function scores (42 [13] vs 46 [11]; P = .045) than those not requiring the intensive care unit. Survivors no more than 5 years after injury had greater PTSD risk (38 of 63 [60.3%] vs 51 of 119 [42.9%]; P = .03) but better mean (SD) Global Physical Health scores (47 [11] vs 43 [11]; P = .04) than those more than 5 years after injury.

This study's results suggest that the lasting effects of firearm injury reach far beyond mortality and economic burden. Survivors of GSWs may have negative outcomes for years after injury. These findings suggest that early identification and initiation of long-term longitudinal care is paramount.

Simulated management of inferior vena cava injury during robotic paraaortic lymphadenectomy utilizing the porcine model.

Journal of Robotic Surgery

Injury of the inferior vena cava is an infrequent but serious complication of paraaortic lymphadenectomy. Training in the management of this injury...

Association of Preoperative Patient Frailty and Operative Stress With Postoperative Mortality.

JAMA Surgery

Patients with frailty have higher risk for postoperative mortality and complications; however, most research has focused on small groups of high-risk procedures. The associations among frailty, operative stress, and mortality are poorly understood.

To assess the association between frailty and mortality at varying levels of operative stress as measured by the Operative Stress Score, a novel measure created for this study.

This retrospective cohort study included veterans in the Veterans Administration Surgical Quality Improvement Program from April 1, 2010, through March 31, 2014, who underwent a noncardiac surgical procedure at Veterans Health Administration Hospitals and had information available on vital status (whether the patient was alive or deceased) at 1 year postoperatively. A Delphi consensus method was used to stratify surgical procedures into 5 categories of physiologic stress.

Frailty as measured by the Risk Analysis Index and operative stress as measured by the Operative Stress Score.

Postoperative mortality at 30, 90, and 180 days.

Of 432 828 unique patients (401 453 males [92.8%]; mean (SD) age, 61.0 [12.9] years), 36 579 (8.5%) were frail and 9113 (2.1%) were very frail. The 30-day mortality rate among patients who were frail and underwent the lowest-stress surgical procedures (eg, cystoscopy) was 1.55% (95% CI, 1.20%-1.97%) and among patients with frailty who underwent the moderate-stress surgical procedures (eg, laparoscopic cholecystectomy) was 5.13% (95% CI, 4.79%-5.48%); these rates exceeded the 1% mortality rate often used to define high-risk surgery. Among patients who were very frail, 30-day mortality rates were higher after the lowest-stress surgical procedures (10.34%; 95% CI, 7.73%-13.48%) and after the moderate-stress surgical procedures (18.74%; 95% CI, 17.72%-19.80%). For patients who were frail and very frail, mortality continued to increase at 90 and 180 days, reaching 43.00% (95% CI, 41.69%-44.32%) for very frail patients at 180 days after moderate-stress surgical procedures.

We developed a novel operative stress score to quantify physiologic stress for surgical procedures. Patients who were frail and very frail had high rates of postoperative mortality across all levels of the Operative Stress Score. These findings suggest that frailty screening should be applied universally because low- and moderate-stress procedures may be high risk among patients who are frail.

A Consensus Framework for the Humanitarian Surgical Response to Armed Conflict in 21st Century Warfare.

JAMA Surgery

Armed conflict in the 21st century poses new challenges to a humanitarian surgical response, including changing security requirements, access to patients, and communities in need, limited deployable surgical assets, resource constraints, and the requirement to address both traumatic injuries as well as emergency surgical needs of the population. At the same time, recent improvements in trauma care and systems have reduced injury-related mortality. This combination of new challenges and medical capabilities warrants reconsideration of long-standing humanitarian surgery protocols.

To describe a consensus framework for surgical care designed to respond to this emerging need.

An international group of 35 representatives from humanitarian agencies, US military, and academic trauma programs was invited to the Stanford Humanitarian Surgical Response in Conflict Working Group to engage in a structured process to review extant trauma protocols and make recommendations for revision.

The working group's method adapted core elements of a modified Delphi process combined with consensus development conference from August 3 to August 5, 2018.

Lessons from civilian and military trauma systems as well as recent battlefield experiences in humanitarian settings were integrated into a tiered continuum of response from point of injury through rehabilitation. The framework addresses the security and medical requirements as well as ethical and legal principles that guide humanitarian action. The consensus framework includes trained, lay first responders; far-forward resuscitation/stabilization centers; rapid damage control surgical access; and definitive care facilities. The system also includes nontrauma surgical care, injury prevention, quality improvement, data collection, and predeployment training requirements.

Evidence suggests that modern trauma systems save lives. However, the requirements of providing this standard of care in insecure conflict settings places new burdens on humanitarian systems that must provide both emergency and trauma surgical care. This consensus framework integrates advances in trauma care and surgical systems in response to a changing security environment. It is possible to reduce disparities and improve the standard of care in these settings.