UW Neurological Surgery Recent PubMed Publications

Rehabilitation Trajectories and Outcomes in Individuals With Mild Traumatic Brain Injury and Psychiatric Histories: A TRACK-TBI Pilot Study.

J Head Trauma Rehabil. 2019 Jan/Feb;34(1):36-44

Authors: Bertisch H, Satris G, Temkin N, Barber J, Manley GT, Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Investigators

Abstract
OBJECTIVE: To determine differences in rehabilitation trajectories and return to work (RTW) and social outcomes in individuals with mild traumatic brain injury (mTBI) with and without significant psychiatric histories at index hospitalization.
SETTING: Three level 1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) consortium.
PARTICIPANTS: A total of 305 individuals with index mTBI enrolled in the TRACK-TBI pilot project.
DESIGN: Secondary analysis of data from the TRACK-TBI pilot study.
MAIN MEASURES: Chart review and patient/family interview at emergency department (ED) admission, ED clinical data, ED discharge plan, functional interview data at 3- and 6-month outcomes, Trail Making Tests, the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index, the California Verbal Learning Test, Second Edition, and the Craig Handicap Assessment and Reporting Technique.
RESULTS: Controlling for neurological history and CT lesion at ED admission, participants with and without psychiatric histories did not differ in terms of treatment, return to work, or reported social function. Individuals with psychiatric histories demonstrated lower processing speed and reported reduced satisfaction with occupational function at outcome.
CONCLUSIONS: Individuals with mTBI and psychiatric histories may require specialized rehabilitation planning to address increased risk for cognitive difficulties and occupational dissatisfaction at outcome. CT lesion may independently influence outcomes.

PMID: 29863617 [PubMed - indexed for MEDLINE]

Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma.

Nanomedicine. 2017 Oct;13(7):2131-2139

Authors: Kievit FM, Wang K, Ozawa T, Tarudji AW, Silber JR, Holland EC, Ellenbogen RG, Zhang M

Abstract
Glioblastoma (GBM) remains incurable, and recurrent tumors rarely respond to standard-of-care radiation and chemo-therapies. Therefore, strategies that enhance the effects of these therapies should provide significant benefits to GBM patients. We have developed a nanoparticle delivery vehicle that can stably bind and protect nucleic acids for specific delivery into brain tumor cells. These nanoparticles can deliver therapeutic siRNAs to sensitize GBM cells to radiotherapy and improve GBM treatment via systemic administration. We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM. Specific knockdown of Ape1 activity by 30% in brain tumor tissue doubled the extended survival achieved with radiotherapy alone. Ape1 is a promising target for increasing the effectiveness of radiotherapy, and nanoparticle-mediated delivery of siRNA is a promising strategy for tumor specific knockdown of Ape1.

PMID: 28614736 [PubMed - indexed for MEDLINE]

Reduction of the molecular chaperone binding immunoglobulin protein (BiP) accentuates the effect of aging on sleep-wake behavior.

Neurobiol Aging. 2018 09;69:10-25

Authors: Naidoo N, Zhu J, Galante RJ, Lian J, Strus E, Lee A, Keenan BT, Pack AI

Abstract
Sleep and wake quality, quantity, and architecture become modified with aging. Sleep and wake quality decline coinciding with increased fragmentation of both states across aging. We have previously shown that this age-related decline in sleep-wake quality is associated with increased endoplasmic reticular (ER) stress and decreased expression of the major ER chaperone binding immunoglobulin protein (BiP). BiP, also known as glucose-regulated protein 78, plays a key role in controlling the cellular response to ER stress, acting as a regulator of a protein homeostatic signaling pathway known as the unfolded protein response. Induction of BiP during cellular stress is part of an adaptive prosurvival mechanism. Here, using mice heterozygous for BiP, we investigated the effect of reduced BiP expression on sleep-wake behavior across aging; complete knockdown of BiP is embryonic lethal. We report that BiP heterozygosity accentuates the aging sleep-wake phenotype. Sleep and wake fragmentation was more pronounced in the BiP heterozygotes across the 3 ages examined. In mice lacking 1 functional copy of BiP, we observed an age-related significant reduction in wake bout duration and increase in wake bout numbers during the active period, as well as an increase in non rapid eye movement and rapid eye movement bout numbers accompanied by reduced bout durations of both non rapid eye movement and rapid eye movement during the sleep period. In addition, we observed increased ER stress in orexin neurons and occurrence of aggregates immunopositive for orexin at the terminals and projections of orexin neurons in the middle-aged BiP heterozygotes. Taken together, our data indicate that a reduction in the molecular chaperone BiP impacts sleep architecture across aging and that orexin processing is likely to be affected.

PMID: 29843048 [PubMed - indexed for MEDLINE]

Asleep Deep Brain Stimulation Reduces Incidence of Intracranial Air during Electrode Implantation.

Stereotact Funct Neurosurg. 2018;96(2):83-90

Authors: Ko AL, Magown P, Ozpinar A, Hamzaoglu V, Burchiel KJ

Abstract
BACKGROUND: Asleep deep brain stimulation (aDBS) implantation replaces microelectrode recording for image-guided implantation, shortening the operative time and reducing cerebrospinal fluid egress. This may decrease pneumocephalus, thus decreasing brain shift during implantation.
OBJECTIVE: To compare the incidence and volume of pneumocephalus during awake (wkDBS) and aDBS procedures.
METHODS: A retrospective review of bilateral DBS cases performed at Oregon Health & Science University from 2009 to 2017 was undertaken. Postimplantation imaging was reviewed to determine the presence and volume of intracranial air and measure cortical brain shift.
RESULTS: Among 371 patients, pneumocephalus was noted in 66% of wkDBS and 15.6% of aDBS. The average volume of air was significantly higher in wkDBS than aDBS (8.0 vs. 1.8 mL). Volumes of air greater than 7 mL, which have previously been linked to brain shift, occurred significantly more frequently in wkDBS than aDBS (34 vs 5.6%). wkDBS resulted in significantly larger cortical brain shifts (5.8 vs. 1.2 mm).
CONCLUSIONS: We show that aDBS reduces the incidence of intracranial air, larger air volumes, and cortical brain shift. Large volumes of intracranial air have been correlated to shifting of brain structures during DBS procedures, a variable that could impact accuracy of electrode placement.

PMID: 29847829 [PubMed - indexed for MEDLINE]

A robust ex vivo experimental platform for molecular-genetic dissection of adult human neocortical cell types and circuits.

Sci Rep. 2018 05 30;8(1):8407

Authors: Ting JT, Kalmbach B, Chong P, de Frates R, Keene CD, Gwinn RP, Cobbs C, Ko AL, Ojemann JG, Ellenbogen RG, Koch C, Lein E

Abstract
The powerful suite of available genetic tools is driving tremendous progress in understanding mouse brain cell types and circuits. However, the degree of conservation in human remains largely unknown in large part due to the lack of such tools and healthy tissue preparations. To close this gap, we describe a robust and stable adult human neurosurgically-derived ex vivo acute and cultured neocortical brain slice system optimized for rapid molecular-genetic manipulation. Surprisingly, acute human brain slices exhibited exceptional viability, and neuronal intrinsic membrane properties could be assayed for at least three days. Maintaining adult human slices in culture under sterile conditions further enabled the application of viral tools to drive rapid expression of exogenous transgenes. Widespread neuron-specific labeling was achieved as early as two days post infection with HSV-1 vectors, with virally-transduced neurons exhibiting membrane properties largely comparable to uninfected neurons over this short timeframe. Finally, we demonstrate the suitability of this culture paradigm for optical manipulation and monitoring of neuronal activity using genetically encoded probes, opening a path for applying modern molecular-genetic tools to study human brain circuit function.

PMID: 29849137 [PubMed - indexed for MEDLINE]

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]