UW Neurological Surgery Recent PubMed Publications

Timing of Ossification of the Anterior Skull Base in Syndromic Synostosis.

J Craniofac Surg. 2020 Jul-Aug;31(5):1256-1260

Authors: Nassar AH, Mercan E, Massenburg BB, Lee A, Brown J, Skladman R, Guo Y, Hopper RA

Abstract
The anterior skull base undergoes a progressive ossification after birth. This has implications on the epidural dissection of early trans-craniofacial osteotomy procedures such as monobloc advancements. Our purpose was to determine the rate of ossification in syndromic synostosis patients relative to a normal cohort to establish when maturation of the anterior skull base is complete. The authors analyzed CT scans from 35 patients with Crouzon, Apert or Pfeiffer syndrome, and 84 patients without any craniofacial anomaly between the ages of 0 and 6 years. The non-ossified anterior skull base area was measured using 3D Slicer. The authors compared the sizes of the defects at different ages between the three syndromes and with the control group using Mann-Whitney test. Significance was set at P < 0.05. All patients less than 12 months of age had a measurable defect anterior to the cribriform whereas patients greater than five years of age had full ossification of the anterior skull base with no evidence of defect. The relationship of defect size and age at scan was non-linear, with most defects closing rapidly in the first six months. The temporal closure pattern of the defect was similar between the three syndromes and the control group with no significant difference. Our findings indicate that syndromic children undergo skull base maturation at the same rate as non-syndromic cases, with the majority ossified by three years of age. Anterior skull base surgeries performed before three years should optimize visualization of this area during dissection.

PMID: 32282683 [PubMed - indexed for MEDLINE]

The Cognitive Effects of Statins are Modified by Age.

Sci Rep. 2020 04 10;10(1):6187

Authors: Alsehli AM, Olivo G, Clemensson LE, Williams MJ, Schiöth HB

Abstract
To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5-10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1-4 years, 5-10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.

PMID: 32277109 [PubMed - indexed for MEDLINE]

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-mesothelin (CRS-207) With or Without Nivolumab in Patients with Pancreatic Cancer.

Clin Cancer Res. 2020 Apr 09;:

Authors: Tsujikawa T, Crocenzi T, Durham JN, Sugar EA, Wu AA, Onners B, Nauroth JM, Anders RA, Fertig EJ, Laheru DA, Reiss K, Vonderheide RH, Ko AH, Tempero MA, Fisher GA, Considine M, Danilova L, Brockstedt DG, Coussens LM, Jaffee EM, Le DT

Abstract
PURPOSE: Two studies in previously-treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).
EXPERIMENTAL DESIGN: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses and immunologic correlates.
RESULTS: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 (95% CI, 4.7, 8.6) and 6.1 (95% CI, 3.5, 7.0) months, respectively, with a hazard ratio 0.86 (95% CI, 0.55, 1.34). Objective responses were seen in three patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The <underline>><underline> grade 3 related adverse event rate while higher in Arm A (35.3% vs 11.9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only.
CONCLUSIONS: While the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable to standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.

PMID: 32273276 [PubMed - as supplied by publisher]

High frequency nonlinear Doppler contrast-enhanced ultrasound imaging of blood flow.

IEEE Trans Ultrason Ferroelectr Freq Control. 2020 Apr 08;:

Authors: Bruce M, Hannah A, Hammond R, Khaing ZZ, Tremblay-Darveau C, Burns PN, Hofstetter CP

Abstract
Current methods for in-vivo microvascular imaging (<1mm) are limited by trade-offs between depth of penetration, resolution and acquisition time. Ultrasound Doppler approaches combined at elevated frequencies (>7.5MHz) are able to visualize smaller vasculature, however are still limited in the segmentation of lower velocity blood flow from moving tissue. Contrast enhanced ultrasound (CEUS) has been successful in visualizing changes in microvascular flow at conventional diagnostic ultrasound imaging frequencies (<7.5MHz). However, conventional CEUS approaches at elevated frequencies have met with limited success, due inpart to the diminishing microbubble response with frequency. We apply a plane-wave acquisition combined with non-linear Doppler processing of ultrasound contrast agents at 15MHz to improve resolution of microvascular blood flow, while compensating for reduced microbubble response. This planewave Doppler approach of imaging ultrasound contrast agents also enables simultaneous detection and separation of blood flow in the microcirculation and higher velocity flow in the larger vasculature. We apply singular value decomposition filtering on the non-linear Doppler signal to orthogonally separate the more stationary lower velocity flow in the microcirculation and higher velocity flow in the larger vasculature. This orthogonal separation was also utilized to improve time intensity curve analysis of the microcirculation, by removing higher velocity flow corrupting bolus kinetics. We demonstrate the utility of this imaging approach in a rat spinal cord injury model, requiring sub-millimeter resolution.

PMID: 32275589 [PubMed - as supplied by publisher]

Sustained release of stromal cell-derived factor-1 alpha from silk fibroin microfiber promotes urethral reconstruction in rabbits.

J Biomed Mater Res A. 2020 Apr 10;:

Authors: Liu Y, Huang L, Yuan W, Zhang D, Gu Y, Huang J, Murphy S, Ali M, Zhang Y, Song L

Abstract
We developed a stromal cell-derived factor-1 alpha (SDF-1α)-aligned silk fibroin (SF)/three-dimensional porous bladder acellular matrix graft (3D-BAMG) composite scaffold for long-section ventral urethral regeneration and repair in vivo. SDF-1α-aligned SF microfiber/3D-BAMG, aligned SF microfiber/3D-BAMG, and nonaligned SF microfiber/3D-BAMG scaffolds were prepared using electrostatic spinning and wet processing. Adipose-derived stem cell (ADSC) and bone marrow stromal cell (BMSC) migration was assessed in the SDF-1α-loaded scaffolds. Sustained SDF-1α release in vitro and vivo was analyzed using enzyme-linked immunosorbent assay (ELISA) and western blotting, respectively. The scaffolds were used to repair a 1.5 × 1 cm2 ventral urethral defect in male rabbits in vivo. General observation and retrograde urinary tract contrast assessment were used to examine urethral lumen patency and continuity at 1 month and 3 months post-surgery. Postoperative rehabilitation was evaluated using histological detection. The composite scaffolds sustained SDF-1α release for over 16 days in vitro. SDF-1α-aligned SF nanofiber promoted regeneration of urethral mucosa, submucosal smooth muscles, and microvasculature, increased cellular proliferation, and reduced collagen deposition. SDF-1α expression was increased in reconstructed urethra at 3 months post-surgery in SDF-1α-aligned SF group. SDF-1α-aligned SF microfiber/3D-BAMG scaffolds may be used to repair and reconstruct long urethral defects because they accelerate urethral regeneration.

PMID: 32276293 [PubMed - as supplied by publisher]

Ghost Aneurysms in Acute Subdural Hematomas: A Report of Two Cases.

World Neurosurg. 2020 07;139:e159-e165

Authors: Abecassis ZA, Nistal DA, Abecassis IJ, Sen RD, Levitt MR

Abstract
OBJECTIVE: Acute subdural hematoma (aSDH) is a common pathology encountered in neurosurgery. Although most cases are associated with trauma and injuries to draining veins, traumatic aSDH from injury to arteries or spontaneous aSDH because of a ruptured intracranial aneurysm can occur. For some patients without a clear clinical history, it can be difficult to distinguish between these etiologies purely based on radiography. The objective of this research was to describe a case series in which imaging was suggestive of the presence of distal cortical intracranial aneurysm associated with aSDH, but operative management demonstrated no evidence of aneurysm.
METHODS: We retrospectively reviewed 2 patients known to have aSDH with suspicion for associated aneurysm between May 2019 and September 2019 at our institution. Data collected included demographic, clinical, and operative course, including age, gender, past medical history, presenting symptoms, and pre and postoperative imaging.
RESULTS: In 2 patients presenting with aSDH with preoperative radiographic imaging suggesting distal middle cerebral artery aneurysms, surgical exploration revealed no aneurysm. In both cases, noniatrogenic active arterial bleeding from an injured cortical middle cerebral artery branch was identified.
CONCLUSIONS: Although there are prior reports of arterial aSDH, to our knowledge, this is the first to describe the radiographic "ghost aneurysm" sign. It is important for clinicians to be aware of this potential misleading radiographic sign, which indicates active extravasation into a spherical cast of clot.

PMID: 32272269 [PubMed - indexed for MEDLINE]

Patterns of Failure After Stereotactic Radiosurgery for Recurrent High-Grade Glioma: A Single Institution Experience of 10 Years.

Neurosurgery. 2019 08 01;85(2):E322-E331

Authors: Ene CI, Macomber MW, Barber JK, Ferreira MJ, Ellenbogen RG, Holland EC, Rockhill JK, Silbergeld DL, Halasz LM

Abstract
BACKGROUND: Stereotactic radiosurgery (SRS) is a treatment modality that is frequently used as salvage therapy for small nodular recurrent high-grade gliomas (HGG). Due to the infiltrative nature of HGG, it is unclear if this highly focused technique provides a durable local control benefit.
OBJECTIVE: To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas.
METHODS: We retrospectively reviewed clinical, radiographic, and follow-up information for 47 consecutive patients receiving SRS for recurrent HGG at our institution between June 2006 and July 2016. All patients initially presented with an HGG (WHO grade III and IV). Following SRS for recurrence, all patients experienced treatment failure, and we evaluated patterns of local, regional, and distant failure in relation to the SRS 50% isodose line.
RESULTS: Most patients with recurrent HGG developed "in-field" treatment failure following SRS (n = 40; 85%). Higher SRS doses were associated with longer time to failure (hazards ratio = 0.80 per 1 Gy increase; 95% confidence interval 0.67-0.96; P = .016). There was a statistically significant increase in distant versus in-field failure among older patients (P = .035). This effect was independent of bevacizumab use (odds ratio = 0.54, P = 1.0).
CONCLUSION: Based on our experience, the majority of treatment failures after SRS for recurrent HGG were "in-field." Older patients, however, presented with more distant failures. Our results indicate that higher SRS doses delivered to a larger area as fractioned or unfractioned regimen may prolong time to failure, especially in the older population.

PMID: 30576476 [PubMed - indexed for MEDLINE]

Both Dietary Ratio of n-6 to n-3 Fatty Acids and Total Dietary Lipid Are Positively Associated with Adiposity and Reproductive Health in Zebrafish.

Curr Dev Nutr. 2020 Apr;4(4):nzaa034

Authors: Fowler LA, Dennis-Cornelius LN, Dawson JA, Barry RJ, Davis JL, Powell ML, Yuan Y, Williams MB, Makowsky R, D'Abramo LR, Watts SA

Abstract
Background: Controversial findings have been reported in human and animal studies regarding the influence of n-6 (ω-6) to n-3 (ω-3) fatty acid ratios on obesity and health. Two confounding factors may be related to interactions with other dietary lipid components or sex-specific differences in fatty acid metabolism.
Objective: This study investigated main and interactive effects of total dietary lipid, ratio of n-6 to n-3 fatty acids, and sex on growth, adiposity, and reproductive health in wild-type zebrafish.
Methods: Male and female zebrafish (3 wk old) were fed 9 diets consisting of 3 ratios of n-6 to n-3 fatty acids (1.4:1, 5:1, and 9.5:1) varied within 3 total lipid amounts (80, 110, and 140 g/kg) for 16 wk. Data were then collected on growth, body composition (determined by chemical carcass analysis), and female reproductive success (n = 32 breeding events/diet over 4 wk). Main and interactive effects of dietary lipid and sex were evaluated with regression methods. Significant differences within each dietary lipid component were relative to the intercept/reference group (80 g/kg and 1.4:1 ratio).
Results: Dietary lipid and sex interacted in their effects on body weight (P = 0.015), total body length (P = 0.003), and total lipid mass (P = 0.029); thus, these analyses were stratified by sex. Female spawning success decreased as dietary total lipid and fatty acid ratio increased (P = 0.030 and P = 0.026, respectively). While total egg production was not associated with either dietary lipid component, females fed the 5:1 ratio produced higher proportions of viable embryos compared with the 1.4:1 ratio [median (95% CI): 0.915 (0.863, 0.956) vs 0.819 (0.716, 0.876); P < 0.001].
Conclusions: Further characterization of dietary lipid requirements will help define healthy balances of dietary lipid, while the sex-specific responses to dietary lipid identified in this study may partially explain sex disparities in the development of obesity and its comorbidities.

PMID: 32258992 [PubMed]

Alzheimer's disease beyond amyloid: Can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery?

Biochem Pharmacol. 2020 07;177:113945

Authors: Mullane K, Williams M

Abstract
Alzheimer's Disease (AD) therapeutics based on the amyloid hypothesis have repeatedly failed in clinical trials. Together with numerous reports that amyloid is present in brains from aged individuals without cognitive dysfunction, this suggests that the association of amyloid with AD is collateral rather than causal. However, the preeminence of the amyloid hypothesis has resulted in the 'systematic …thwart[ing of] alternative approaches' to AD/dementia driven by a 'cabal' of amyloid acolytes who have effectively controlled the ideas funded and published, which startups received venture investment and which programs were advanced in biopharmaceutical companies where they consulted. As a result, dementia research is estimated to be 15-30 years behind where it could be with conflicting data ignored in favor of the amyloid dogma and clinical trial failures being ascribed to faulty design or inadequacies in the compound selection process including flawed animal models. Major concerns regarding the precise diagnosis of AD/dementia and conflicting views on the validated status of fluid biomarker assays have resulted in trials that included patients with unknown amyloid pathologies. With the failure of the amyloid approach, emerging data on the role(s) of vascular, mitochondrial and synaptic network dysfunction, infection, diabetes, sleep, hearing loss, the gut microbiome and neuroinflammation/ innate immune function as dementia targets are driving research in new directions bolstered by recent findings on the genetic, omics and systems biology associated with AD/dementia. In moving forward, lessons learnt from the amyloid debacle should be used to enhance the objective identification of AD/dementia therapeutics as a multifactorial disease syndrome.

PMID: 32247851 [PubMed - indexed for MEDLINE]

Feasibility and safety of transradial access for pediatric neurointerventions.

J Neurointerv Surg. 2020 Sep;12(9):893-896

Authors: Srinivasan VM, Hadley CC, Prablek M, LoPresti M, Chen SH, Peterson EC, Sweid A, Jabbour P, Young C, Levitt M, Osbun JW, Burkhardt JK, Johnson J, Kan P

Abstract
BACKGROUND: Diagnostic cerebral angiograms are increasingly being performed by transradial access (TRA) in adults, following data from the coronary literature supporting fewer access-site complications. Despite this ongoing trend in neuroangiography, there has been no discussion of its use in the pediatric population. Pediatric TRA has scarcely been described even for coronary or other applications. This is the first dedicated large study of transradial access for neuroangiography in pediatric patients.
METHODS: A multi-institutional series of consecutively performed pediatric transradial angiograms and interventions was collected. This included demographic, procedural, outcomes, and safety data. Data was prospectively recorded and retrospectively analyzed.
RESULTS: Thirty-seven diagnostic angiograms and 24 interventions were performed in 47 pediatric patients. Mean age, height, and weight was 14.1 years, 158.6 cm, and 57.1 kg, respectively. The radial artery measured 2.09+/-0.54 mm distally, and 2.09+/-0.44 mm proximally. Proximal and distal angiography were performed for both diagnostic and interventional application (17 distal angiograms, two distal interventions). Clinically significant vasospasm occurred in eight patients (13.1%). Re-access was successfully performed 11 times in seven patients. Conversion to femoral access occurred in five cases (8.2%). The only access-related complication was a small asymptomatic wrist hematoma after TR band removal.
CONCLUSIONS: Transradial access in pediatric patients is safe and feasible. It can be performed successfully in many cases but carries some unique challenges compared with the adult population. Despite the challenge of higher rates of vasospasm and conversion to femoral access, it is worth exploring further, given the potential benefits.

PMID: 32241922 [PubMed - indexed for MEDLINE]

Pediatric functional hemispherectomy: operative techniques and complication avoidance.

Neurosurg Focus. 2020 Apr 01;48(4):E9

Authors: Young CC, Williams JR, Feroze AH, McGrath M, Ravanpay AC, Ellenbogen RG, Ojemann JG, Hauptman JS

Abstract
Functional hemispherectomy/hemispherotomy is a disconnection procedure for severe medically refractory epilepsy where the seizure foci diffusely localize to one hemisphere. It is an improvement on anatomical hemispherectomy and was first performed by Rasmussen in 1974. Less invasive surgical approaches and refinements have been made to improve seizure freedom and minimize surgical morbidity and complications. Key anatomical structures that are disconnected include the 1) internal capsule and corona radiata, 2) mesial temporal structures, 3) insula, 4) corpus callosum, 5) parietooccipital connection, and 6) frontobasal connection. A stepwise approach is indicated to ensure adequate disconnection and prevent seizure persistence or recurrence. In young pediatric patients, careful patient selection and modern surgical techniques have resulted in > 80% seizure freedom and very good functional outcome. In this report, the authors summarize the history of hemispherectomy and its development and present a graphical guide for this anatomically challenging procedure. The use of the osteoplastic flap to improve outcome and the management of hydrocephalus are discussed.

PMID: 32234987 [PubMed - in process]

DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels.

Epigenetics. 2020 Apr 01;:1-10

Authors: Jones GT, Marsman J, Bhat B, Phillips VL, Chatterjee A, Rodger EJ, Williams MJA, van Rij AM, McCormick SPA

Abstract
Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF <0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study.

PMID: 32237968 [PubMed - as supplied by publisher]

WHO malaria nucleic acid amplification test external quality assessment scheme: results of distribution programmes one to three.

Malar J. 2020 Mar 30;19(1):129

Authors: Cunningham JA, Thomson RM, Murphy SC, de la Paz Ade M, Ding XC, Incardona S, Legrand E, Lucchi NW, Menard D, Nsobya SL, Saez AC, Chiodini PL, Shrivastava J

Abstract
BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria. In recent years, there has been surge in the use of various kinds of nucleic-acid amplification based tests (NAATs) for detection and identification of Plasmodium spp. to support clinical care in high-resource settings and clinical and epidemiological research worldwide. However, these tests are not without challenges, including lack (or limited use) of standards and lack of reproducibility, due in part to variation in protocols amongst laboratories. Therefore, there is a need for rigorous quality control, including a robust external quality assessment (EQA) scheme targeted towards malaria NAATs. To this effect, the WHO Global Malaria Programme worked with the UK National External Quality Assessment Scheme (UK NEQAS) Parasitology and with technical experts to launch a global NAAT EQA scheme in January 2017.
METHODS: Panels of NAAT EQA specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were tested and validated by six expert referee laboratories prior to distribution. Between 37 and 45 laboratories participated in each distribution and submitted results using the online submission portal of UK NEQAS. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers.
RESULTS: Analysis of the first three distributions revealed that the factors that most significantly affected performance were sample format (DBS vs LB), species and parasite density, while laboratory location and the reported methodology used (type of nucleic acid extraction, amplification, or DNA vs RNA target) did not significantly affect performance. Referee laboratories performed better than non-referee laboratories.
CONCLUSIONS: Globally, malaria NAAT assays now inform a range of clinical, epidemiological and research investigations. EQA schemes offer a way for laboratories to assess and improve their performance, which is critical to safeguarding the reliability of data and diagnoses especially in situations where various NAAT methodologies and protocols are in use.

PMID: 32228615 [PubMed - indexed for MEDLINE]

Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy.

Oncoimmunology. 2020;9(1):1730538

Authors: Georganaki M, Ramachandran M, Tuit S, Núñez NG, Karampatzakis A, Fotaki G, van Hooren L, Huang H, Lugano R, Ulas T, Kaunisto A, Holland EC, Ellmark P, Mangsbo SM, Schultze J, Essand M, Tugues S, Dimberg A

Abstract
CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed in endothelial cells within the tumor microenvironment, and its expression in tumor endothelium was positively correlated to T-cell infiltration and to increased intratumoral expression of IFNγ. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.

PMID: 32231867 [PubMed]

Exploring Ethical Concerns About Human Challenge Studies: A Qualitative Study of Controlled Human Malaria Infection Study Participants' Motivations and Attitudes.

J Empir Res Hum Res Ethics. 2019 02;14(1):49-60

Authors: Kraft SA, Duenas DM, Kublin JG, Shipman KJ, Murphy SC, Shah SK

Abstract
Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants' understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.

PMID: 30585505 [PubMed - indexed for MEDLINE]

Economic evaluation in the National Drug Abuse Treatment Clinical Trials Network: Past, present, and future.

J Subst Abuse Treat. 2020 Mar;112S:18-27

Authors: Jalali A, Ryan DA, McCollister KE, Marsch LA, Schackman BR, Murphy SM

Abstract
Economic evaluations provide evidence that informs stakeholders on how to efficiently allocate real and financial healthcare resources. The purpose of this study was to review and discuss the integration of economic evaluations into the National Drug Abuse Treatment Clinical Trials Network (CTN) since its inception, as well as expectations for the future of this relationship. A systematic review was performed on published and planned CTN economic evaluations in the CTN dissemination library and PubMed. The well-established Drummond checklist was used to evaluate the comprehensiveness and methodological rigor of published articles. One hundred thirty-eight ancillary, follow-up, or original protocols were reviewed, and 78 potentially relevant published articles were identified. A total number of 14 protocols included an economic evaluation. Of these, 6 protocols were completed, 2 were reported as active, and 6 were reported as in-development at the time of this review. Of the 78 published articles, 9 met the inclusion criteria. As gauged by the Drummond checklist, the quality of CTN published economic evaluations were found to improve over time, and recent published articles were identified as guides to cutting-edge economic research. As the CTN continues to grow and mature, it is imperative that high-quality economic evaluations are incorporated alongside trials in order to maximize the public health impact of the CTN.

PMID: 32220406 [PubMed - in process]

Percutaneous cervical cordotomy for cancer-related pain: national data.

BMJ Support Palliat Care. 2020 Mar 27;:

Authors: Poolman M, Makin M, Briggs J, Scofield K, Campkin N, Williams M, Sharma ML, Laird B, Mayland CR, INPIC Group

Abstract
OBJECTIVES: Percutaneous cervical cordotomy (PCC) is an interventional ablative procedure in the armamentarium for cancer pain treatment, but there is limited evidence to support its use. This study aimed to assess the effectiveness and safety of PCC.
METHODS: Analysis was undertaken of the first national (UK) prospective data repository of adult patients with cancer undergoing PCC for pain treatment. The relationship between pain and other outcomes before and after PCC was examined using appropriate statistical methods.
RESULTS: Data on 159 patients' PCCs (performed from 1 January 2012 to 6 June 2017 in three centres) were assessed: median (IQR) age was 66 (58-71) years, 47 (30%) were female. Mesothelioma was the most common primary malignancy (57%). The median (IQR) time from cancer diagnosis to PCC assessment was 13.3 (6.2-23.2) months; PCC to follow-up was 9 (8-25) days; and survival after PCC was 1.3 (0.6-2.8) months. The mean (SD) for 'average pain' using a numerical rating scale was 6 (2) before PCC and 2 (2) at follow-up, and for 'worst pain' 9 (1) and 3 (3), respectively. The median (IQR) reduction in strong opioid dose at follow-up was 50% (34-50). With the exception of 'activity', all health-related quality of life scores (5-level version of EuroQol-5 Dimension) either improved or were stable after PCC. Six patients (4%) had PCC-related adverse events.
CONCLUSIONS: PCC is an effective treatment for cancer pain; however, findings in this study suggest PCC referrals tended to be late in patients' disease trajectories. Further study into earlier treatment and seeking international consensus on PCC outcomes will further enhance opportunities to improve patient care.

PMID: 32220943 [PubMed - as supplied by publisher]

Bilateral Squamosal Suture Craniosynostosis Presenting with Abducens Nerve Palsy and Severe Papilledema.

World Neurosurg. 2020 06;138:344-348

Authors: Cho DY, Evans KN, Weed MC, Lee A, Susarla SM

Abstract
BACKGROUND: Patients with single-suture or minor suture craniosynostosis are typically asymptomatic at early presentation; intervention is aimed at reducing the risk of elevated intracranial pressure and associated developmental sequelae. Patients may be symptomatic in cases of major multisuture syndromic synostoses or delayed diagnosis. Clinical presentation in this context may include headaches, papilledema, cognitive delay, or behavioral issues. Cranial nerve palsies are atypical symptoms of intracranial hypertension in this patient population.
CASE DESCRIPTION: An 11-month-old, otherwise healthy girl presented with bilateral severe papilledema and left abducens nerve palsy owing to nonsyndromic near-complete bilateral squamosal suture synostosis with associated incomplete sagittal and right lambdoid synostoses. The patient underwent urgent open cranial expansion, with resolution of her papilledema and improvement in eye position and motility.
CONCLUSIONS: Cranial nerve palsies may be presenting symptoms of intracranial hypertension in patients with craniosynostosis. Multidisciplinary evaluation and treatment is paramount for appropriate management.

PMID: 32217173 [PubMed - indexed for MEDLINE]

Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access.

J Neurointerv Surg. 2020 Nov;12(11):1122-1126

Authors: Almallouhi E, Al Kasab S, Sattur MG, Lena J, Jabbour PM, Sweid A, Chalouhi N, Gooch MR, Starke RM, Peterson EC, Yavagal DR, Chen SH, Li Y, Gross BA, Tonetti DA, Zussman BM, Stone JG, Jadhav AP, Jankowitz BT, Young CC, Lim DH, Levitt MR, Osbun JW, Spiotta AM

Abstract
BACKGROUND: The transradial approach (TRA) has gained increasing popularity for neuroendovascular procedures. However, the experience with TRA in neuroangiography is still in early stages in most centers, and the safety and feasibility of this approach have not been well established. The purpose of this study is to report the safety and feasibility of TRA for neuroendovascular procedures.
METHODS: We reviewed charts from six institutions in the USA to include consecutive patients who underwent diagnostic or interventional neuroendovascular procedures through TRA from July 2018 to July 2019. Collected data included baseline characteristics, procedural variables, complications, and whether there was a crossover to transfemoral access.
RESULTS: A total of 2203 patients were included in the study (age 56.1±15.2, 60.8% women). Of these, 1697 (77%) patients underwent diagnostic procedures and 506 (23%) underwent interventional procedures. Successfully completed procedures included aneurysm coiling (n=97), flow diversion (n=89), stent-assisted coiling (n=57), balloon-assisted coiling (n=19), and stroke thrombectomy (n=76). Crossover to femoral access was required in 114 (5.2%). There were no major complications related to the radial access site. Minor complications related to access site were seen in 14 (0.6%) patients.
CONCLUSION: In this early stage of transforming to the 'radial-first' approach for neuroendovascular procedures, TRA was safe with low complication rates for both diagnostic and interventional procedures. A wide range of procedures were completed successfully using TRA.

PMID: 32217626 [PubMed - indexed for MEDLINE]

Cytotoxic Effects of Zoom® Whitening Product in Human Fibroblasts.

Materials (Basel). 2020 Mar 25;13(7):

Authors: Marto CM, Laranjo M, Paula A, Coelho AS, Abrantes AM, Casalta-Lopes J, Gonçalves AC, Sarmento-Ribeiro AB, Ferreira MM, Cabrita A, Botelho MF, Carrilho E

Abstract
Tooth whitening procedures are increasing; however, side effects can occur, such as damage to pulp cells, by the whitening products. This study aims to assess the cellular effects promoted by a whitening product, namely, the oxidative stress fostered by the active agent hydrogen peroxide, with and without photoactivation. Additionally, if cellular recovery occurred, we intended to determine the time point where cells recover from the tooth whitening induced damage. Human fibroblasts were exposed to hydrogen peroxide, Zoom®, Zoom® + irradiation, and irradiation alone. The following analysis was performed: metabolic activity evaluation by the MTT assay; cell viability, mitochondrial membrane potential, peroxides production, superoxide radical production, and reduced glutathione expression by flow cytometry. We determined the IC50 value for all groups, and a dose-dependent cytotoxic effect was verified. At the times analyzed, hydrogen peroxide groups showed no metabolic activity recovery while a cell recovery was observed after 24 h (Zoom®) and 48 h (Zoom® + irradiation). Cell death was seen in hydrogen peroxide and Zoom® + irradiation groups, mainly by apoptosis, and the irradiation had a cytotoxic effect per se. This in vitro study supports that whitening products with moderate hydrogen peroxide (HP) concentration have a temporary effect on cells, allowing a cellular recovery.

PMID: 32218276 [PubMed - as supplied by publisher]