UW Neurological Surgery Recent PubMed Publications

Transpetrosal approach to petro-clival meningioma.

Neurosurg Focus. 2017 Oct;43(VideoSuppl2):V1

Authors: Elarjani T, Shetty R, Singh H, da Silva HB, Sekhar LN

Abstract
A 38-year-old woman had a 3-week gradual onset of right-sided weakness in the upper and lower extremities. MRI showed a large left petro-clival meningioma encasing the basilar and left superior cerebellar artery and compressing the brainstem. A posterior transpetrosal approach, with a left temporal and retrosigmoid craniotomy and mastoidectomy, was performed. The tumor was removed in a gross-total resection with questionable remnants adherent to the brainstem. Intraoperative partial iatrogenic injury to the left oculomotor nerve was repaired with fibrin glue. Postoperatively, the hemiparesis improved, and the patient was discharged to the rehabilitation center with left oculomotor and abducens palsies. A postoperative MRI scan showed complete resection of tumor with no remnants on the brainstem. A 6-month follow-up examination showed complete resolution of motor symptoms and complete recovery of cranial nerve (CN) palsies affecting CN III and CN VI. The video can be found here: https://youtu.be/vOu6YFA8uoo .

PMID: 28967311 [PubMed - indexed for MEDLINE]

Cohort profile: The Childhood Asthma Prevention Study (CAPS).

Int J Epidemiol. 2018 12 01;47(6):1736-1736k

Authors: Garden FL, Toelle BG, Mihrshahi S, Webb KL, Almqvist C, Tovey ER, Brew BK, Ayer JG, Skilton MR, Jones G, Ferreira MAR, Cowie CT, Weber-Chrysochoou C, Britton WJ, Celermajer DS, Leeder SR, Peat JK, Marks GB

PMID: 29800224 [PubMed - indexed for MEDLINE]

Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines.

Vaccine. 2018 06 27;36(28):4134-4141

Authors: Mwanza-Lisulo M, Chomba MS, Chama M, Besa EC, Funjika E, Zyambo K, Banda R, Imikendu M, Sianongo S, Hancock REW, Lee A, Chilengi R, Stagg AJ, Namangala B, Kelly PM

Abstract
All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4β7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/β signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.

PMID: 29801999 [PubMed - indexed for MEDLINE]

Autonomic alterations as a clinical manifestation of encephalopathy associated with autoimmune thyroid disease.

Endocr J. 2018 May 25;:

Authors: Tomkins M, Cavalcoli F, Stanley E, O'Rourke K, Murphy S, Lynch T, Tamagno G

Abstract
Encephalopathy associated with autoimmune thyroid disease (EAATD), also known as Hashimoto's encephalopathy, is a rare neurological condition that may occur in patients with clinical or sub-clinical autoimmune thyroid disease. The pathogenesis of EAATD has been not clearly elucidated yet. The diagnostic criteria include neurological or psychiatric symptoms, high levels of anti-thyroid antibodies, and exclusion of other possible causes of encephalopathy. In the large majority of cases, EAATD patients respond to immunosuppressant therapies, in particular to corticosteroids. We report the case of a patient with Hashimoto's thyroiditis and recurrent manifestations of encephalopathy over the previous few years responding to corticosteroid treatment. The patient presented with language and cognitive impairment, ataxia, and neurovegetative/autonomic symptoms. She was euthyroid with mildly raised anti-thyroid peroxidase antibodies. An extensive diagnostic work-up, including electroencephalogram, brain magnetic resonance, hormonal assessment, and an exhaustive panel of antibodies possibly associated with autoimmune encephalopathy, was carried out and excluded other possible etiologies of encephalopathy. The diagnosis of EAATD possibly affecting the hypothalamus and/or the neurovegetative regulatory centers was made and treatment with prednisolone was timely commenced with a dramatic and rapid improvement with progressive normalization of the symptoms. To the best of our knowledge, this is the first report of neurovegetative/autonomic alterations in the setting of EAATD.

PMID: 29806619 [PubMed - as supplied by publisher]

Editorial: Acute stroke intervention.

Neurosurg Focus. 2017 04;42(4):E9

Authors: Kim LJ

PMID: 28366061 [PubMed - indexed for MEDLINE]

Introduction: New techniques and technologies in the management of ischemic stroke.

Neurosurg Focus. 2017 04;42(4):E1

Authors: Mack WJ, Kim LJ, Lopes DK, Mocco J

PMID: 28366068 [PubMed - indexed for MEDLINE]

Different roles for inhibition in the rhythm-generating respiratory network.

J Neurophysiol. 2017 Oct 01;118(4):2070-2088

Authors: Harris KD, Dashevskiy T, Mendoza J, Garcia AJ, Ramirez JM, Shea-Brown E

Abstract
Unraveling the interplay of excitation and inhibition within rhythm-generating networks remains a fundamental issue in neuroscience. We use a biophysical model to investigate the different roles of local and long-range inhibition in the respiratory network, a key component of which is the pre-Bötzinger complex inspiratory microcircuit. Increasing inhibition within the microcircuit results in a limited number of out-of-phase neurons before rhythmicity and synchrony degenerate. Thus unstructured local inhibition is destabilizing and cannot support the generation of more than one rhythm. A two-phase rhythm requires restructuring the network into two microcircuits coupled by long-range inhibition in the manner of a half-center. In this context, inhibition leads to greater stability of the two out-of-phase rhythms. We support our computational results with in vitro recordings from mouse pre-Bötzinger complex. Partial excitation block leads to increased rhythmic variability, but this recovers after blockade of inhibition. Our results support the idea that local inhibition in the pre-Bötzinger complex is present to allow for descending control of synchrony or robustness to adverse conditions like hypoxia. We conclude that the balance of inhibition and excitation determines the stability of rhythmogenesis, but with opposite roles within and between areas. These different inhibitory roles may apply to a variety of rhythmic behaviors that emerge in widespread pattern-generating circuits of the nervous system.NEW & NOTEWORTHY The roles of inhibition within the pre-Bötzinger complex (preBötC) are a matter of debate. Using a combination of modeling and experiment, we demonstrate that inhibition affects synchrony, period variability, and overall frequency of the preBötC and coupled rhythmogenic networks. This work expands our understanding of ubiquitous motor and cognitive oscillatory networks.

PMID: 28615332 [PubMed - indexed for MEDLINE]

Outcomes of the house advancement flap for pilonidal sinus.

ANZ J Surg. 2017 Sep;87(9):692-694

Authors: Mackowski A, Levitt M

Abstract
BACKGROUND: Many surgical techniques have been described for the treatment of pilonidal sinus, yet rates of recurrence and prolonged wound healing remain high and consensus on the optimal technique is lacking. This retrospective study evaluates outcomes of the use of the house advancement flap in the treatment of pilonidal sinus including time to wound healing, sinus recurrence, wound infection and flap necrosis.
METHOD: Thirty-three consecutive patients who underwent excision and house advancement flap for pilonidal sinus, of whom seven patients (21%) had recurrent pilonidal sinus disease following previous surgical intervention, were reviewed retrospectively. Follow-up ranged from 4 to 59 months (mean 28 months).
RESULTS: All 33 patients completed a follow-up survey. Age at time of operation ranged from 14 to 44 years with a mean of 25 years. No patients developed wound infection or flap necrosis. Four patients (12%) failed to achieve primary wound healing; mean time to wound healing for the remaining 29 patients was 62 days. Recurrence of pilonidal sinus occurred in eight patients (24%), at a mean time of 22 months post-operatively.
CONCLUSION: The house advancement flap achieves primary wound closure in almost 90% of cases with few acute post-operative complications. However delayed wound healing and sinus recurrence remain issues with this technique and it appears to have little advantage over other primary closure techniques.

PMID: 25787062 [PubMed - indexed for MEDLINE]

Clinical utility and psychometric properties of the Disability Rating Scale with individuals with traumatic brain injury.

Rehabil Psychol. 2017 Aug;62(3):407-408

Authors: Williams MW, Smith EL

Abstract
This Rehabilitation Measures Database summary provides a review of the psychometric properties of the Disability Rating Scale (DRS) which is an observer-rated instrument designed to measure general functional disability in individuals with traumatic brain injury. A full review of the DRS as well as reviews of over 300 other instruments can be found at www.rehabmeasures.org. (PsycINFO Database Record

PMID: 28836811 [PubMed - indexed for MEDLINE]

The Biological Basis of Chronic Traumatic Encephalopathy following Blast Injury: A Literature Review.

J Neurotrauma. 2017 Sep;34(S1):S26-S43

Authors: Aldag M, Armstrong RC, Bandak F, Bellgowan PSF, Bentley T, Biggerstaff S, Caravelli K, Cmarik J, Crowder A, DeGraba TJ, Dittmer TA, Ellenbogen RG, Greene C, Gupta RK, Hicks R, Hoffman S, Latta RC, Leggieri MJ, Marion D, Mazzoli R, McCrea M, O'Donnell J, Packer M, Petro JB, Rasmussen TE, Sammons-Jackson W, Shoge R, Tepe V, Tremaine LA, Zheng J

Abstract
The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.

PMID: 28937953 [PubMed - indexed for MEDLINE]

Microsurgical Resection of Ruptured Large Left Temporo-Occipital Arteriovenous Malformation: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 May 18;:

Authors: Cheng CY, Shetty R, Sekhar LN

Abstract
A 59-yr-old man presented with intraventricular hemorrhage and was found to have a large temporo-occipital arteriovenous malformation (AVM), Spetzler-Martin grade 4. The preoperative intra-arterial digital subtraction angiography (IADSA) showed the AVM was 4 × 4 cm2, had superficial and deep venous drainage, and was fed by multiple branches of the posterior cerebral artery and middle cerebral artery. Preoperative embolization was done in 4 stages. He underwent a left temporo-occipital craniotomy, mastoidectomy, and retrosigmoid craniotomy with a posterior temporal approach. Intraoperatively, there was a large draining vein draining into the sigmoid sinus in the location of the vein of Labbe, and multiple other feeding arteries and draining veins, including periventricular vessels. Circumferential dissection of the AVM was done from posteriorly, superiorly, anteriorly, and then inferiorly. The technique of temporary clipping and cauterizing the perforating arteries, and then sectioning them after flow arrest is shown in the video. Large arterial feeders were cauterized and divided. Three permanent aneurysm clips were left to control bleeding from the vessels of the trigone of the lateral ventricle. After the large draining vein into the sigmoid sinus was occluded, the AVM was completely removed. The patient had acute nonfluent aphasia postoperatively but improved after speech therapy. The postoperative IADSA demonstrated total resection. At 3-mo follow-up, he had recovered completely (mRS0). This 3-D video shows the technical nuances of microsurgical resection of a complex large AVM. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 29788334 [PubMed - as supplied by publisher]

A Randomized Controlled Trial of a Citywide Emergency Department Care-Coordination Program to Reduce Prescription Opioid-Related Visits: An Economic Evaluation.

J Emerg Med. 2017 Aug;53(2):186-194

Authors: Murphy SM, Howell D, McPherson S, Grohs R, Roll J, Neven D

Abstract
BACKGROUND: Care provided in the emergency department (ED) can cost up to five times as much as care received for comparable diagnoses in alternative settings. Small groups of patients, many of whom suffer from an opioid use disorder, often account for a large proportion of total ED visits. We recently conducted, and demonstrated the effectiveness of, the first randomized controlled trial of a citywide ED care-coordination program intending to reduce prescription-opioid-related ED visits. All EDs in the metropolitan study area were connected to a Web-based information exchange system.
OBJECTIVE: The objective of this article was to perform an economic evaluation of the 12-month trial from a third-party-payer perspective.
METHODS: We modeled the person-period monthly for the 12-month observation period, and estimated total treatment costs and return on investment (ROI) with regard to cost offsets, over time, for all visits where the patient was admitted to and discharged from the ED.
RESULTS: By the end of month 4, the mean cumulative cost differential was significantly lower for intervention relative to treatment-as-usual participants (-$1370; p = 0.03); this figure climbed to -$3200 (p = 0.02) by the end of month 12. The ROI trended upward throughout the observation period, but failed to reach statistical significance by the end of month 12 (ROI = 3.39, p = 0.07).
CONCLUSION: The intervention produced significant cost offsets by the end of month 4, which continued to accumulate throughout the trial; however, ROI was not significant. Because the per-patient administrative costs of the program are incurred at the time of enrollment, our results highlight the importance of future studies that are able to follow participants for a period beyond 12 months to more accurately estimate the program's ROI.

PMID: 28410960 [PubMed - indexed for MEDLINE]

A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS.

Oncologist. 2017 Sep;22(9):1024-e89

Authors: Lieu CH, Hidalgo M, Berlin JD, Ko AH, Cervantes A, LoRusso P, Gerber DE, Eder JP, Eckhardt SG, Kapp AV, Tsuhako A, McCall B, Pirzkall A, Uyei A, Tabernero J

Abstract
LESSONS LEARNED: Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents.The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested.
BACKGROUND: KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit.
METHODS: Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination.
RESULTS: Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease.
CONCLUSION: Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment.

PMID: 28592615 [PubMed - indexed for MEDLINE]

Rapid Intraoperative in Situ Synthetic Cranioplasty.

World Neurosurg. 2018 Apr;112:161-165

Authors: Young CC, Hanak BW, Patel AP, Sekhar LN

Abstract
Craniectomy is a frequently performed neurosurgical procedure, and coverage of the cranial defect is necessary for protection of the underlying brain, cosmesis, and patient satisfaction. We report a new technique for intraoperative in situ synthetic cranioplasty that provides one-step resection of skull osteomas and reconstruction of cranial defects. Strategies of intraoperative cranioplasty are reviewed. A 48-year-old man who presented with a suspected benign osteoma over his forehead was offered surgical excision and primary cranioplasty in a one-step procedure using hydroxyapatite bone cement, a dural prosthetic, and a resorbable plate. Following craniectomy around the lesion, there was evidence of dural and bone involvement. The craniectomy was enlarged, and the involved dura was resected. SYNTHECEL dura repair was used to repair the dural defect and at the same time fashioned to form a receptacle for the cranioplasty by fixation of the dural substrate to the cut vertical bone edges. DirectInject hydroxyapatite bone cement was used to fill the receptacle and contoured to the curvature of the adjacent skull. A Delta resorbable plate was then placed over the bone cement and fixed to the skull. This technique provided a satisfactory cosmetic outcome following craniectomy for benign skull tumor excision. When possible, one-step surgery with primary cranioplasty should be considered.

PMID: 29409926 [PubMed - indexed for MEDLINE]

Atypical Presentation of Giant Aneurysm in Pediatric Patient with Duane Syndrome.

World Neurosurg. 2018 Aug;116:25-28

Authors: Kuo CH, McGrath LB, Carnevale JA, Marupudi NI, Ojemann JG, Ellenbogen RG, Wang AC

Abstract
BACKGROUND: Duane syndrome is a congenital eye movement disorder characterized by congenital malformation of the abducens nucleus. Thrombogenic conditions during development may lead to vascular anomalies in Duane syndrome; however, the presence of a giant aneurysm in this patient population is a rarely documented phenomenon.
CASE DESCRIPTION: We reported a case of a large cerebral aneurysm in a pediatric patient with Duane syndrome and performed a review of the literature to identify other potential cases and associations. The pathophysiologic hallmarks of Duane syndrome that lead to alterations in the fetal cerebral vasculature and that may form the basis for a potential mechanism for aneurysm formation were reviewed in this study. The patient was an 11-year-old female with Duane syndrome who presented with seizures. Computed tomography and magnetic resonance imaging demonstrated a large, heterogeneously enhancing right temporal mass. Intraoperatively, the mass was revealed to be a partially thrombosed giant middle cerebral artery aneurysm. After surgery, the patient had an uneventful postoperative course without residual aneurysm presented on postoperative angiogram. No clinical or radiographic appearance of recurrent aneurysm was evident at her 6-month follow-up.
CONCLUSIONS: The pathophysiology of vascular anomalies with Duane syndrome may be related to thrombogenic conditions during development leading to alterations in cerebral fetal vasculature. Strong consideration for vascular anomaly should be given when evaluating cerebral masses in patients with Duane syndrome.

PMID: 29777883 [PubMed - indexed for MEDLINE]

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats.

Int J Dev Neurosci. 2017 Oct;61:92-111

Authors: Sprowles JLN, Hufgard JR, Gutierrez A, Bailey RA, Jablonski SA, Williams MT, Vorhees CV

Abstract
Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6h apart) with 5mg/kg CIT, 5mg/kg FLX, 15mg/kg BUP, or saline (SAL) from embryonic day (E) 6-21, and directly to the pups from postnatal day (P) 1-20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted.

PMID: 28655626 [PubMed - indexed for MEDLINE]

The Outcome of Severe Traumatic Brain Injury in Latin America.

World Neurosurg. 2018 Mar;111:e82-e90

Authors: Bonow RH, Barber J, Temkin NR, Videtta W, Rondina C, Petroni G, Lujan S, Alanis V, La Fuente G, Lavadenz A, Merida R, Jibaja M, Gonzáles L, Falcao A, Romero R, Dikmen S, Pridgeon J, Chesnut RM, Global Neurotrauma Research Group

Abstract
BACKGROUND: Traumatic brain injury (TBI) disproportionately affects lower- and middle-income countries (LMIC). The factors influencing outcomes in LMIC have not been examined as rigorously as in higher-income countries.
METHODS: This study was conducted to examine clinical and demographic factors influencing TBI outcomes in Latin American LMIC. Data were prospectively collected during a randomized trial of intracranial pressure monitoring in severe TBI and a companion observational study. Participants were aged ≥13 years and admitted to study hospitals with Glasgow Coma Scale score ≤8. The primary outcome was Glasgow Outcome Scale, Extended (GOS-E) score at 6 months. Predictors were analyzed using a multivariable proportional odds model created by forward stepwise selection.
RESULTS: A total of 550 patients were identified. Six-month outcomes were available for 88%, of whom 37% had died and 44% had achieved a GOS-E score of 5-8. In multivariable proportional odds modeling, higher Glasgow Coma Scale motor score (odds ratio [OR], 1.41 per point; 95% confidence interval [CI], 1.23-1.61) and epidural hematoma (OR, 1.83; 95% CI, 1.17-2.86) were significant predictors of higher GOS-E score, whereas advanced age (OR, 0.65 per 10 years; 95% CI, 0.57-0.73) and cisternal effacement (P < 0.001) were associated with lower GOS-E score. Study site (P < 0.001) and race (P = 0.004) significantly predicted outcome, outweighing clinical variables such as hypotension and pupillary examination.
CONCLUSIONS: Mortality from severe TBI is high in Latin American LMIC, although the rate of favorable recovery is similar to that of high-income countries. Demographic factors such as race and study site played an outsized role in predicting outcome; further research is required to understand these associations.

PMID: 29229352 [PubMed - indexed for MEDLINE]

What is the current role of bypass surgery in the management of cerebral aneurysms?

Neurol India. 2018 May-Jun;66(3):661-663

Authors: Sekhar LN, Cheng CY, Da Silva HB, Qazi Z

PMID: 29766916 [PubMed - indexed for MEDLINE]

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras-driven pancreatic tumorigenesis in mice.

Proc Natl Acad Sci U S A. 2017 05 16;114(20):E4020-E4029

Authors: Shen J, Ha DP, Zhu G, Rangel DF, Kobielak A, Gill PS, Groshen S, Dubeau L, Lee AS

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;KrasG12D/+;p53f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78f/+ allele (PKC78f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78f/+ and c78f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.

PMID: 28461470 [PubMed - indexed for MEDLINE]

Nanoparticles That Reshape the Tumor Milieu Create a Therapeutic Window for Effective T-cell Therapy in Solid Malignancies.

Cancer Res. 2018 07 01;78(13):3718-3730

Authors: Zhang F, Stephan SB, Ene CI, Smith TT, Holland EC, Stephan MT

Abstract
A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an α-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T-cell therapy, vaccines, and BITE platforms.Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors. Cancer Res; 78(13); 3718-30. ©2018 AACR.

PMID: 29760047 [PubMed - indexed for MEDLINE]