UW Neurological Surgery Recent PubMed Publications

Operationalization of the Transition to Comfort Measures Only in the Neurocritical Care Unit: A Quality Improvement Project.

Am J Hosp Palliat Care. 2019 Jan;36(1):38-44

Authors: Lele A, Cheever C, Healey L, Hurley K, Kim LJ, Creutzfeldt CJ

Abstract
INTRODUCTION:: Transition to comfort measures only (CMO) is common in the neurocritical care unit, and close communication between interdisciplinary health-care teams is vital to a smooth transition. We developed and implemented a CMO huddle in an effort to reduce inconsistencies during the process of CMO transition.
METHODS:: The CMO huddle was a multiphase quality improvement project in a neurocritical care unit of a level-1 trauma and comprehensive stroke center. Interdisciplinary critical care clinicians engaged in a huddle during CMO processes and participated in a pre- and postimplementation survey to examine the impact of CMO huddle on communication, missed opportunities, and improvement in knowledge.
RESULTS:: Since the CMO implementation, a total of 131 patients underwent CMO transitions. After implementation of an interdisciplinary CMO huddle, 64.3% of neurocritical care nurses reported that they felt included and involved in CMO process compared to 28% before implementation ( P = .003); 87.9% of all neurocritical care clinicians reported that they felt comfortable participating in CMO discussions compared to 69.8% before ( P < .001); 57.4% of all neurocritical care clinicians reported that the CMO huddle improved communication among neurocritical care clinicians, 51.9% reported reduction in missed opportunities during CMO process, and 21.7% reported witnessing less-than-ideal CMO process compared to 80% before ( P < .001).
CONCLUSIONS:: Implementation of a multidisciplinary huddle in the neuro-intensive care unit before transition to CMO may improve clinician's experience of the end-of-life process through enhanced nursing inclusion and involvement and organized communication with the neurocritical care team.

PMID: 30041532 [PubMed - indexed for MEDLINE]

Editorial: A new definition of postconcussive syndrome.

J Neurosurg. 2016 11;125(5):1204-1205

Authors: Connolly ES, Ellenbogen RG

PMID: 26918480 [PubMed - indexed for MEDLINE]

Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor.

Oncotarget. 2018 Jul 03;9(51):29698-29714

Authors: Bakewell SJ, Rangel DF, Ha DP, Sethuraman J, Crouse R, Hadley E, Costich TL, Zhou X, Nichols P, Lee AS

Abstract
In many cancers, combination therapy regimens are successfully improving response and survival rates, but the challenges of toxicity remain. GRP78, the master regulator of the unfolded protein response, is emerging as a target that is upregulated in tumors, specifically following treatment, and one that impacts tumor cell survival and disease recurrence. Here, we show IT-139, an antitumor small molecule inhibitor, suppresses induction of GRP78 from different types of endoplasmic reticulum (ER) stress in a variety of cancer cell lines, including those that have acquired therapeutic resistance, but not in the non-cancer cells being tested. We further determined that IT-139 treatment exacerbates ER stress while at the same time suppresses GRP78 induction at the transcriptional level. Our studies revealed a differential effect of IT-139 on chaperone protein family expression at multiple levels in different cancer cell lines. In xenograft studies, IT-139 decreased BRAF inhibitor upregulation of GRP78 expression in the tumor, while having minimal effect on GRP78 expression in the adjacent normal cells. The preferential decrease in GRP78 levels in tumor cells over normal cells, supported by the manageable safety profile seen in the Phase 1 clinical trial, reinforce the value IT-139 brings to combination therapies as it continues its clinical development.

PMID: 30038714 [PubMed]

SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future

Book. 2018 05

Authors: Duncan JR, Byard RW

Abstract
The identification of risk factors associated with sudden infant death syndrome (SIDS) has led to significant advances in the prevention of this tragic outcome. The discovery of the prone sleeping position and smoking as two of the major risk factors (1-5) led to worldwide awareness campaigns, such as, for example, the “Back to Sleep” campaign launched in the United States in 1996, and various smoking cessation campaigns (6, 7). These initiatives resulted in a dramatic reduction in the number of children succumbing to SIDS (5, 8). Unfortunately, SIDS still remains the number-one cause of death in infants under 1 year of age in many countries, despite epidemiological and pathological studies that continue to identify additional risk factors, such as hearing deficiencies, or various genetic alterations associated with SIDS (9-11, 12, 13). To parents and families, as well as some health professionals and researchers, the sheer number of suggested risk factors and gene mutations can also be bewildering. The Triple Risk hypothesis by Dr Hannah Kinney and collaborators (14) can partly resolve this confusion. This hypothesis states that SIDS is caused by an incident in which not just one but three risk factors come together to bring an infant into a situation that leads to the sudden death. Specifically, it was proposed that those factors include [1] a vulnerable infant; [2] a critical period of development in homeostatic control; and [3] an exogenous stressor (14, 15). In other words, in the presence of two risk factors, namely being a vulnerable infant in a critical period of development, a third risk factor (e.g. an exogenous stressor) can become the ultimate cause that triggers an irreversible cascade of events leading to the sudden death. The Triple Risk hypothesis also has important practical implications. The awareness campaigns have shown that it is possible to significantly reduce the risk of an infant being exposed to exogenous stressors. A potentially more challenging task is to identify the infant who is particularly vulnerable, which is clearly one of the major tasks for research. A better understanding of the characteristics of a vulnerable infant would facilitate the development of strategies that target a specific vulnerability. Similarly, it will be important for research to identify and recognize the specific developmental conditions that characterize the critical period for SIDS, especially if they are dysregulated, or to target the important developmental and homeostatic mechanisms to prevent the death. This chapter will describe how different risk factors can contribute to the sudden death, the failure to arouse, the specific conditions associated with sleep, and the neuronal networks controlling cardiorespiratory functions and how they contribute to the events leading to sudden death. In this context we will review the physiology and pathophysiology of important brainstem mechanisms that are critical for survival, but that can sometimes fail. Understanding how these brainstem mechanisms interact with endogenous and exogenous mechanisms can also facilitate understanding of the significance of a variety of risk factors known to contribute to SIDS.

PMID: 30035952

Estimates of health utility scores in chronic kidney disease.

Int Urol Nephrol. 2017 Nov;49(11):2043-2049

Authors: Sekercioglu N, Curtis B, Murphy S, Blackhouse G, Barrett B

Abstract
INTRODUCTION: Coverage decisions in publicly funded healthcare systems require a formal, systematic and transparent assessment process for policies related to distribution of resources. The process is complex and employs multiple types of information, such as clinical effectiveness, costs and health utility scores which are used to produce quality-adjusted life years. The purpose of this study was to create health utility scores for CKD patients within the Canadian population.
METHODS: This is a cross-sectional study of CKD patients. We administered the Short-Form 36 Quality of Life Questions to all participants and employed the Short-Form 6 Dimension index to create health utility scores which were created using a set of parametric preference weights, nonparametric preference weights and ordinal health state valuation techniques obtained from a sample of the general population.
RESULTS: Utility values in the dialysis group were lower than in the non-dialysis group. There was a significant relationship between age and health utility scores: As age increases, health utility scores decrease. Diabetes was associated with lower health utility scores in dialysis patients, whereas other covariates did not reach levels of statistical significance in our stepwise regression models. The parametric Bayesian model and standard gamble approach yielded the same results, while the correlation between the nonparametric and parametric methods was above 0.9.
CONCLUSION: Health utility scores were low relative to the general population norm in our study cohort. Longitudinal assessment of CKD patients to capture possible fluctuations in health utility scores may add useful information.

PMID: 28733768 [PubMed - indexed for MEDLINE]

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Oncologist. 2017 12;22(12):1427-e129

Authors: Ko AH, Murphy PB, Peyton JD, Shipley DL, Al-Hazzouri A, Rodriguez FA, Womack MS, Xiong HQ, Waterhouse DM, Tempero MA, Guo S, Lane CM, Earwood C, DeBusk LM, Bendell JC

Abstract
LESSONS LEARNED: The addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.
BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.
METHODS: Patients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).
RESULTS: One hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.
CONCLUSION: Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.

PMID: 28935773 [PubMed - indexed for MEDLINE]

Estimated Glomerular Filtration Rate is not Associated with Alzheimer's Disease in a Northern Ireland Cohort.

J Alzheimers Dis. 2017;60(4):1379-1385

Authors: Paterson EN, Williams MA, Passmore P, Silvestri G, MacGillivray TJ, Maxwell AP, McKay GJ

Abstract
BACKGROUND: Alzheimer's disease (AD) prevalence is increasing globally and typically progresses for several years prior to clinical presentation of dementia. Renal dysfunction and vascular disease have been reported in association with dementia in several cross-sectional and longitudinal studies, and may contribute to AD risk. Experimental and observational studies suggest amyloid-β (Aβ) clearance may be impaired in chronic kidney disease (CKD) indicating a mechanism for increased AD risk.
OBJECTIVE: The objective of this study was to compare estimated glomerular filtration rate (eGFR) between individuals with AD and cognitively intact controls, controlling for potential confounding factors.
METHODS: A cross-sectional, case-control study was carried out in 317 cognitively normal participants and 253 cases with a clinical diagnosis of AD in a UK tertiary care dementia clinic. Associations were considered using logistic regression adjusting for confounding variables (age, APOEɛ4 genotype, systolic blood pressure, education (left school at 14), and smoking status).
RESULTS: AD cases were older than cognitively intact controls, had lower MMSE scores, were more likely to have at least one APOEɛ4 allele, had higher rates of smoking, were more likely to be taking aspirin and/or clopidogrel, and had lower blood pressure. We found no significant association between eGFR and AD both before and following adjustment for appropriate confounders.
CONCLUSION: This study failed to find an association between eGFR and AD in a cross-sectional sample study of elderly white individuals.

PMID: 29036821 [PubMed - indexed for MEDLINE]

Retroperitoneal necrotizing soft tissue infection post perforated diverticulitis: a rare case reiterating the need for caution in patients with delayed presentation.

ANZ J Surg. 2018 Jul 22;:

Authors: Ranasinghe S, Williams M, Cohen B, Perera S, Carroll J, Walker D, Lisec C, Brown J

PMID: 30033603 [PubMed - as supplied by publisher]

Rethinking Regenerative Medicine From a Transplant Perspective (and Vice Versa).

Transplantation. 2019 02;103(2):237-249

Authors: Orlando G, Murphy SV, Bussolati B, Clancy M, Cravedi P, Migliaccio G, Murray P

Abstract
No field in health sciences has more interest than organ transplantation in fostering progress in regenerative medicine (RM) because the future of no other field more than the future of organ transplantation will be forged by progress occurring in RM. In fact, the most urgent needs of modern transplant medicine, namely, more organs to satisfy the skyrocketing demand and immunosuppression-free transplantation, cannot be met in full with current technologies and are at risk of remaining elusive goals. Instead, in the past few decades, groundbreaking progress in RM is suggesting a different approach to the problem. New, RM-inspired technologies among which decellularization, 3-dimensional printing and interspecies blastocyst complementation, promise organoids manufactured from the patients' own cells and bear potential to render the use of currently used allografts obsolete. Transplantation, a field that has traditionally been immunology-based, is therefore destined to become a RM-based discipline. However, the contours of RM remain unclear, mainly due to the lack of a universally accepted definition, the lack of clarity of its potential modalities of application and the unjustified and misleading hype that often follows the reports of clinical application of RM technologies. All this generates excessive and unmet expectations and an erroneous perception of what RM really is and can offer. In this article, we will (1) discuss these aspects of RM and transplant medicine, (2) propose a definition of RM, and (3) illustrate the state of the art of the most promising RM-based technologies of transplant interest.

PMID: 30028414 [PubMed - indexed for MEDLINE]

Neuronal susceptibility to beta-amyloid toxicity and ischemic injury involves histone deacetylase-2 regulation of endophilin-B1.

Brain Pathol. 2019 03;29(2):164-175

Authors: Wang DB, Kinoshita C, Kinoshita Y, Sopher BL, Uo T, Lee RJ, Kim JK, Murphy SP, Dirk Keene C, Garden GA, Morrison RS

Abstract
Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.

PMID: 30028551 [PubMed - indexed for MEDLINE]

Onyx embolization prior to stereotactic radiosurgery for brain arteriovenous malformations: a single-center treatment algorithm.

J Neurointerv Surg. 2018 Mar;10(3):258-267

Authors: Nerva JD, Barber J, Levitt MR, Rockhill JK, Hallam DK, Ghodke BV, Sekhar LN, Kim LJ

Abstract
BACKGROUND: Embolization before stereotactic radiosurgery (SRS) for brain arteriovenous malformations (BAVMs) is controversial.
OBJECTIVE: To compare clinical and radiographic outcomes in patients undergoing pre-SRS embolization with ethylene copolymer (Onyx) with outcomes in patients undergoing SRS alone.
METHODS: Seventy consecutive patients with BAVMs who underwent SRS were retrospectively reviewed. Univariate and multivariate analyses were performed to assess the factors associated with radiographic obliteration and complication.
RESULTS: Forty-one (59%) patients presented without BAVM rupture and 29 (41%) patients presented with rupture. Pre-SRS embolization was used in 20 patients (28.6%; 7 unruptured and 13 ruptured). Twenty-five of 70 (36%) patients sustained a complication from treatment, including 6 (9%) patients with a post-SRS latency period hemorrhage. Ten (14%) patients had persistent neurological deficits after treatment. Functional outcome (as modified Rankin Scale), complication rate, and radiographic obliteration at last follow-up were not significantly different between embolized and non-embolized groups in both unruptured and ruptured BAVMs. For unruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 23% and 73% for non-embolized patients and 20% and 60% for embolized patients, respectively. For ruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 45% and 72% for non-embolized patients and 53% and 82% for embolized patients, respectively.
CONCLUSION: Pre-SRS embolization with Onyx was not associated with worse clinical or radiographic outcomes than SRS treatment without embolization. Pre-SRS embolization has a low complication rate and can safely be used to target high-risk BAVM features in carefully selected patients destined for SRS.

PMID: 28710086 [PubMed - indexed for MEDLINE]

Frequency of Cannabis Use Among Primary Care Patients in Washington State.

J Am Board Fam Med. 2017 Nov-Dec;30(6):795-805

Authors: Lapham GT, Lee AK, Caldeiro RM, McCarty D, Browne KC, Walker DD, Kivlahan DR, Bradley KA

Abstract
INTRODUCTION: Over 12% of US adults report past-year cannabis use, and among those who use daily, 25% or more have a cannabis use disorder. Use is increasing as legal access expands. Yet, cannabis use is not routinely assessed in primary care, and little is known about use among primary care patients and relevant demographic and behavioral health subgroups. This study describes the prevalence and frequency of past-year cannabis use among primary care patients assessed for use during a primary care visit.
METHODS: This observational cohort study included adults who made a visit to primary care clinics with annual behavioral health screening, including a single-item question about frequency past-year cannabis use (March 2015 to February 2016; n = 29,857). Depression, alcohol and other drug use were also assessed by behavioral health screening. Screening results, tobacco use, and diagnoses for past-year behavioral health conditions (e.g., mental health and substance use disorders) were obtained from EHRs.
RESULTS: Among patients who completed the cannabis use question (n = 22,095; 74% of eligible patients), 15.3% (14.8% to 15.8%) reported any past-year use: 12.2% (11.8% to 12.6%) less than daily, and 3.1% (2.9%-3.3%) daily. Among 2228 patients age 18 to 29 years, 36.0% (34.0% to 38.0%) reported any cannabis use and 8.1% (7.0% to 9.3%) daily use. Daily cannabis use was common among men age 18 to 29 years who used tobacco or screened positive for depression or used tobacco: 25.5% (18.8% to 32.1%) and 31.7% (23.3% to 40.0%), respectively.
CONCLUSIONS: Cannabis use was common in adult primary care patients, especially among younger patients and those with behavioral health conditions. Results highlight the need for primary care approaches to address cannabis use.

PMID: 29180554 [PubMed - indexed for MEDLINE]

Clinical Management: Metastatic Disease.

Cancer J. 2017 Nov/Dec;23(6):355-361

Authors: Ko AH

Abstract
Most patients with pancreatic cancer either present with or eventually develop metastatic disease during the course of their illness. For such individuals, systemic therapy, namely, cytotoxic therapy, represents the mainstay of treatment and is administered with noncurative intent. Of the various chemotherapy options now available for treating metastatic pancreatic cancer, 2 combination regimens, FOLFIRINOX (infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the doublet of gemcitabine and albumin-bound paclitaxel, have emerged as frontline standards of care, based on phase III studies demonstrating a significant survival benefit compared with single-agent gemcitabine. More patients are also now able to be sequenced through 2 or more lines of treatment, with newer regimens such as nanoliposomal irinotecan plus infusional 5-fluorouracil and leucovorin receiving US Food and Drug Administration approval specifically for use in this second-line setting. Selection of therapies remains primarily guided by clinical considerations, particularly performance status, as well as age, comorbid medical conditions, and organ and bone marrow function. In contrast, molecular predictors of efficacy and toxicity have not yet been validated in this disease context. Areas of novel therapeutic development include targeting the stromal microenvironment, exploring combinations of immunotherapeutic agents, and identifying molecular subsets of metastatic pancreatic cancer that may uniquely susceptible to specific strategies, such as hampering DNA damage repair.

PMID: 29189332 [PubMed - indexed for MEDLINE]

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet. 2018 08;50(8):1072-1080

Authors: Waage J, Standl M, Curtin JA, Jessen LE, Thorsen J, Tian C, Schoettler N, 23andMe Research Team, AAGC collaborators, Flores C, Abdellaoui A, Ahluwalia TS, Alves AC, Amaral AFS, Antó JM, Arnold A, Barreto-Luis A, Baurecht H, van Beijsterveldt CEM, Bleecker ER, Bonàs-Guarch S, Boomsma DI, Brix S, Bunyavanich S, Burchard EG, Chen Z, Curjuric I, Custovic A, den Dekker HT, Dharmage SC, Dmitrieva J, Duijts L, Ege MJ, Gauderman WJ, Georges M, Gieger C, Gilliland F, Granell R, Gui H, Hansen T, Heinrich J, Henderson J, Hernandez-Pacheco N, Holt P, Imboden M, Jaddoe VWV, Jarvelin MR, Jarvis DL, Jensen KK, Jónsdóttir I, Kabesch M, Kaprio J, Kumar A, Lee YA, Levin AM, Li X, Lorenzo-Diaz F, Melén E, Mercader JM, Meyers DA, Myers R, Nicolae DL, Nohr EA, Palviainen T, Paternoster L, Pennell CE, Pershagen G, Pino-Yanes M, Probst-Hensch NM, Rüschendorf F, Simpson A, Stefansson K, Sunyer J, Sveinbjornsson G, Thiering E, Thompson PJ, Torrent M, Torrents D, Tung JY, Wang CA, Weidinger S, Weiss S, Willemsen G, Williams LK, Ober C, Hinds DA, Ferreira MA, Bisgaard H, Strachan DP, Bønnelykke K

Abstract
Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

PMID: 30013184 [PubMed - indexed for MEDLINE]

The successful use of tocilizumab as third-line biologic therapy in a case of refractory anti-synthetase syndrome.

Rheumatology (Oxford). 2016 Dec;55(12):2277-2278

Authors: Murphy SM, Lilleker JB, Helliwell P, Chinoy H

PMID: 27550295 [PubMed - indexed for MEDLINE]

Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents.

Clin Cancer Res. 2017 Dec 01;23(23):7158-7164

Authors: Wages NA, Portell CA, Williams ME, Conaway MR, Petroni GR

Abstract
In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158-64. ©2017 AACR.

PMID: 28733439 [PubMed - indexed for MEDLINE]

Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations.

Mol Cancer Res. 2018 10;16(10):1491-1498

Authors: Wang AC, Jones DTW, Abecassis IJ, Cole BL, Leary SES, Lockwood CM, Chavez L, Capper D, Korshunov A, Fallah A, Wang S, Ene C, Olson JM, Geyer JR, Holland EC, Lee A, Ellenbogen RG, Ojemann JG

Abstract
Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4-ALK fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations.Implications: DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAF V600E or BRAF V600D mutations. Mol Cancer Res; 16(10); 1491-8. ©2018 AACR.

PMID: 30006355 [PubMed - indexed for MEDLINE]

The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca2+ - ATPase activity by influencing calcium homoeostasis.

Exp Dermatol. 2017 Sep;26(9):792-797

Authors: Sato E, Williams MR, Sanford JA, Sen GL, Nakama T, Imafuku S, Gallo RL

Abstract
Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum (ER) Ca2+ - ATPase (SERCA2). Mutations of this gene result in alterations of calcium homoeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, was then applied to this ATP2A2-silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+ ]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the ER, the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene-silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin 10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signalling and may be used as a potential strategy for improving aspects of DD.

PMID: 28094886 [PubMed - indexed for MEDLINE]

Prevalence of Abnormal Magnetic Resonance Imaging Findings in Children with Persistent Symptoms after Pediatric Sports-Related Concussion.

J Neurotrauma. 2017 Oct 01;34(19):2706-2712

Authors: Bonow RH, Friedman SD, Perez FA, Ellenbogen RG, Browd SR, Mac Donald CL, Vavilala MS, Rivara FP

Abstract
A subset of patients experience persistent symptoms after pediatric concussion, and magnetic resonance imaging (MRI) is commonly used to evaluate for pathology. The utility of this practice is unclear. We conducted a retrospective cohort study to describe the MRI findings in children with concussion. A registry of all patients seen at our institution from January 2010 through March 2016 with pediatric sports-related concussion was cross-referenced with a database of radiographical studies. Radiology reports were reviewed for abnormal findings. Patients with abnormal computed tomographies or MRI scans ordered for reasons other than concussion were excluded. Among 3338 children identified with concussion, 427 underwent MRI. Only 2 (0.5%) had findings compatible with traumatic injury, consisting in both of microhemorrhage. Sixty-one patients (14.3%) had abnormal findings unrelated to trauma, including 24 nonspecific T2 changes, 15 pineal cysts, eight Chiari I malformations, and five arachnoid cysts. One child underwent craniotomy for a cerebellar hemangioblastoma after presenting with ataxia; another had cortical dysplasia resected after seizure. The 2 patients with microhemorrhage each had three previous concussions, significantly more than patients whose scans were normal (median, 1) or abnormal without injury (median, 1.5; p = 0.048). MRI rarely revealed intracranial injuries in children post-concussion, and the clinical relevance of these uncommon findings remains unclear. Abnormalities unrelated to trauma are usually benign. However, MRI should be thoughtfully considered in children who present with concerning or atypical symptoms.

PMID: 28490224 [PubMed - indexed for MEDLINE]

Prevalence of Behavioral Health Conditions Across Frequency of Cannabis Use Among Adult Primary Care Patients in Washington State.

J Gen Intern Med. 2018 11;33(11):1833-1835

Authors: Lapham GT, Lee AK, Caldeiro RM, Glass JE, Carrell DS, Richards JE, Bradley KA

Abstract

PMID: 29992423 [PubMed - indexed for MEDLINE]