UW Neurological Surgery Recent PubMed Publications

Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study).

Clin Cancer Res. 2019 Sep 15;25(18):5493-5502

Authors: Le DT, Picozzi VJ, Ko AH, Wainberg ZA, Kindler H, Wang-Gillam A, Oberstein P, Morse MA, Zeh HJ, Weekes C, Reid T, Borazanci E, Crocenzi T, LoConte NK, Musher B, Laheru D, Murphy A, Whiting C, Nair N, Enstrom A, Ferber S, Brockstedt DG, Jaffee EM

Abstract
PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial.
PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses.
RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9-5.3), 5.4 (4.2-6.4), and 4.6 (4.2-5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred.
CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)See related commentary by Salas-Benito et al., p. 5435.

PMID: 31126960 [PubMed - indexed for MEDLINE]

Neurophysiological evidence for early modulation of amygdala activity by emotional reappraisal.

Biol Psychol. 2019 07;145:211-223

Authors: Guex R, Hofstetter C, Domínguez-Borràs J, Méndez-Bértolo C, Sterpenich V, Spinelli L, Seeck M, Vuilleumier P

Abstract
How emotions unfold through time in the brain, and how fast they can be regulated by voluntary control, remain unresolved. Psychological accounts of emotion regulation posit cognitive reappraisal mechanisms may alter early emotion generative processes directly, whereas suppression impacts only later processing stages, after emotion has arisen. However, to date, there is no neurophysiological data concerning the precise latency of emotion regulation effects on the amygdala, a major emotion processing relay in the brain. Here we record amygdala activity from six patients undergoing surgery for pharmaco-resistant epilepsy during both reappraisal and suppression. We find that emotion reappraisal strategy, but not suppression, modulates early neural responses to emotional scenes during an extended period of time, starting 130 ms post-stimulus onset. Further, reappraisal produced earlier impact on amygdala responses to positive compared to negative scenes. Our results provide the first neurophysiological support for theoretical accounts of emotion regulation that postulate an early modulation of emotion generative processes by reappraisal.

PMID: 31129312 [PubMed - indexed for MEDLINE]

Promoting physical activity in regional and remote cancer survivors (PPARCS) using wearables and health coaching: randomised controlled trial protocol.

BMJ Open. 2019 05 24;9(5):e028369

Authors: Hardcastle SJ, Hince D, Jiménez-Castuera R, Boyle T, Cavalheri V, Makin G, Tan P, Salfinger S, Tan J, Mohan GR, Levitt M, Cohen PA, Saunders C, Platell C

Abstract
INTRODUCTION: Physically active cancer survivors have substantially less cancer recurrence and improved survival compared with those who are inactive. However, the majority of survivors (70%-90%) are not meeting the physical activity (PA) guidelines. There are also significant geographic inequalities in cancer survival with poorer survival rates for the third of Australians who live in non-metropolitan areas compared with those living in major cities. The primary objective of the trial is to increase moderate-to-vigorous PA (MVPA) among cancer survivors living in regional and remote Western Australia. Secondary objectives are to reduce sedentary behaviour and in conjunction with increased PA, improve quality of life (QoL) in non-metropolitan survivors. Tertiary objectives are to assess the effectiveness of the health action process approach (HAPA) model variables, on which the intervention is based, to predict change in MVPA.
METHODS AND ANALYSIS: Eighty-six cancer survivors will be randomised into either the intervention or control group. Intervention group participants will receive a Fitbit and up to six telephone health-coaching sessions. MVPA (using Actigraph), QoL and psychological variables (based on the HAPA model via questionnaire) will be assessed at baseline, 12 weeks (end of intervention) and 24 weeks (end of follow-up). A general linear mixed model will be used to assess the effectiveness of the intervention.
ETHICS AND DISSEMINATION: Ethics approval has been obtained from St John of God Hospital Subiaco (HREC/#1201). We plan to submit a manuscript of the results to a peer-reviewed journal. Results will be presented at conferences, community and consumer forums and hospital research conferences.
TRIAL REGISTRATION NUMBER: ACTRN12618001743257; pre-results, U1111-1222-5698.

PMID: 31129600 [PubMed - indexed for MEDLINE]

Consensus statement from the International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury : Consensus statement.

Acta Neurochir (Wien). 2019 07;161(7):1261-1274

Authors: Hutchinson PJ, Kolias AG, Tajsic T, Adeleye A, Aklilu AT, Apriawan T, Bajamal AH, Barthélemy EJ, Devi BI, Bhat D, Bulters D, Chesnut R, Citerio G, Cooper DJ, Czosnyka M, Edem I, El-Ghandour NMF, Figaji A, Fountas KN, Gallagher C, Hawryluk GWJ, Iaccarino C, Joseph M, Khan T, Laeke T, Levchenko O, Liu B, Liu W, Maas A, Manley GT, Manson P, Mazzeo AT, Menon DK, Michael DB, Muehlschlegel S, Okonkwo DO, Park KB, Rosenfeld JV, Rosseau G, Rubiano AM, Shabani HK, Stocchetti N, Timmons SD, Timofeev I, Uff C, Ullman JS, Valadka A, Waran V, Wells A, Wilson MH, Servadei F

Abstract
BACKGROUND: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach.
METHODS: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries.
RESULTS: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval.
CONCLUSIONS: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction.

PMID: 31134383 [PubMed - indexed for MEDLINE]

The Cost of Inflammatory Bowel Disease: An Initiative From the Crohn's & Colitis Foundation.

Inflamm Bowel Dis. 2020 01 01;26(1):1-10

Authors: Park KT, Ehrlich OG, Allen JI, Meadows P, Szigethy EM, Henrichsen K, Kim SC, Lawton RC, Murphy SM, Regueiro M, Rubin DT, Engel-Nitz NM, Heller CA

Abstract
BACKGROUND: The Crohn's & Colitis Foundation's Cost of Inflammatory Bowel Disease (IBD) Care Initiative seeks to quantify the wide-ranging health care costs affecting patients living with IBD. We aimed to (1) describe the annualized direct and indirect costs of care for patients with Crohn's disease (CD) or ulcerative colitis (UC), (2) determine the longitudinal drivers of these costs, and (3) characterize the cost of care for newly diagnosed patients.
METHODS: We analyzed the Optum Research Database from the years 2007 to 2016, representing commercially insured and Medicare Advantage-insured patients in the United States. Inclusion for the study was limited to those who had continuous enrollment with medical and pharmacy benefit coverage for at least 24 months (12 months before through 12 months after the index date of diagnosis). The value of patient time spent on health care was calculated as number of workplace hours lost due to health care encounters multiplied by the patients' estimated average wage derived from the Bureau of Labor Statistics. Comparisons between IBD patients and non-IBD patients were analyzed based on demographics, health plan type, and length of follow-up. We used generalized linear models to estimate the association between total annual costs and various patient variables.
RESULTS: There were 52,782 IBD patients (29,062 UC; 23,720 CD) included in the analysis (54.1% females). On a per-annual basis, patients with IBD incurred a greater than 3-fold higher direct cost of care compared with non-IBD controls ($22,987 vs $6956 per-member per-year paid claims) and more than twice the out-of-pocket costs ($2213 vs $979 per-year reported costs), with all-cause IBD costs rising after 2013. Patients with IBD also experienced significantly higher costs associated with time spent on health care as compared with controls. The burden of costs was most notable in the first year after initial IBD diagnosis (mean = $26,555). The study identified several key drivers of cost for IBD patients: treatment with specific therapeutics (biologics, opioids, or steroids); ED use; and health care services associated with relapsing disease, anemia, or mental health comorbidity.
CONCLUSION: The costs of care for IBD have increased in the last 5 years and are driven by specific therapeutics and disease features. In addition, compared with non-IBD controls, IBD patients are increasingly incurring higher costs associated with health care utilization, out-of-pocket expenditures, and workplace productivity losses. There is a pressing need for cost-effective strategies to address these burdens on patients and families affected by IBD.

PMID: 31112238 [PubMed - indexed for MEDLINE]

Effects of surgical targeting in laser interstitial thermal therapy for mesial temporal lobe epilepsy: A multicenter study of 234 patients.

Epilepsia. 2019 06;60(6):1171-1183

Authors: Wu C, Jermakowicz WJ, Chakravorti S, Cajigas I, Sharan AD, Jagid JR, Matias CM, Sperling MR, Buckley R, Ko A, Ojemann JG, Miller JW, Youngerman B, Sheth SA, McKhann GM, Laxton AW, Couture DE, Popli GS, Smith A, Mehta AD, Ho AL, Halpern CH, Englot DJ, Neimat JS, Konrad PE, Neal E, Vale FL, Holloway KL, Air EL, Schwalb J, Dawant BM, D'Haese PF

Abstract
OBJECTIVE: Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) has reported seizure freedom rates between 36% and 78% with at least 1 year of follow-up. Unfortunately, the lack of robust methods capable of incorporating the inherent variability of patient anatomy, the variability of the ablated volumes, and clinical outcomes have limited three-dimensional quantitative analysis of surgical targeting and its impact on seizure outcomes. We therefore aimed to leverage a novel image-based methodology for normalizing surgical therapies across a large multicenter cohort to quantify the effects of surgical targeting on seizure outcomes in LITT for mTLE.
METHODS: This multicenter, retrospective cohort study included 234 patients from 11 centers who underwent LITT for mTLE. To investigate therapy location, all ablation cavities were manually traced on postoperative magnetic resonance imaging (MRI), which were subsequently nonlinearly normalized to a common atlas space. The association of clinical variables and ablation location to seizure outcome was calculated using multivariate regression and Bayesian models, respectively.
RESULTS: Ablations including more anterior, medial, and inferior temporal lobe structures, which involved greater amygdalar volume, were more likely to be associated with Engel class I outcomes. At both 1 and 2 years after LITT, 58.0% achieved Engel I outcomes. A history of bilateral tonic-clonic seizures decreased chances of Engel I outcome. Radiographic hippocampal sclerosis was not associated with seizure outcome.
SIGNIFICANCE: LITT is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center. Consideration of surgical factors is imperative to the complete assessment of LITT. Based on our model, ablations must prioritize the amygdala and also include the hippocampal head, parahippocampal gyrus, and rhinal cortices to maximize chances of seizure freedom. Extending the ablation posteriorly has diminishing returns. Further work is necessary to refine this analysis and define the minimal zone of ablation necessary for seizure control.

PMID: 31112302 [PubMed - indexed for MEDLINE]

The authors reply.

Crit Care Med. 2017 11;45(11):e1194-e1195

Authors: Krishnamoorthy V, Rowhani-Rahbar A, Gibbons EF, Rivara FP, Temkin NR, Chaikittisilpa N, Luk K, Vavilala MS

PMID: 29028720 [PubMed - indexed for MEDLINE]

Medical marijuana laws are associated with increases in substance use treatment admissions by pregnant women.

Addiction. 2019 09;114(9):1593-1601

Authors: Meinhofer A, Witman A, Murphy SM, Bao Y

Abstract
BACKGROUND AND AIMS: Between 2002 and 2014, past-month marijuana use among pregnant women in the United States increased 62%, nearly twice the growth of the general population. This growth coincides with the proliferation of state medical marijuana laws (MMLs) authorizing physicians to recommend marijuana for approved conditions. We estimated the association between MMLs and substance use treatment utilization among pregnant and non-pregnant women of reproductive age. We also examined whether the association varied across MML provisions, age groups and treatment referral sources to clarify potential pathways.
DESIGN: Nation-wide administrative data from the 2002-14 Treatment Episodes Data Set Admissions, and a difference-in-differences design that exploited the staggered implementation of MMLs to compare changes in outcomes before and after implementation between MML and non-MML states.
SETTING: Twenty-one MML and 27 non-MML US states.
PARTICIPANTS: Pregnant and non-pregnant women aged 12-49 admitted to publicly funded specialty substance use treatment facilities.
MEASUREMENTS: The primary outcome variable was the number of treatment admissions per 100 000 women aged 12-49, aggregated at the state-year level (n = 606). Admissions for marijuana, alcohol, cocaine and opioids were considered. The primary independent variable was an indicator of MML implementation in a state.
FINDINGS: Among pregnant women, the rate of marijuana treatment admissions increased by 4.69 [95% confidence interval (CI) = 1.32, 8.06] in MML states relative to non-MML states. This growth was accompanied by increases in treatment admissions involving alcohol (β = 3.19; 95% CI = 0.97, 5.410 and cocaine (β = 2.56; 95% CI = 0.34, 4.79), was specific to adults (β = 5.50; 95% CI = 1.52, 9.47) and was largest in states granting legal protection for marijuana dispensaries (β = 6.37; 95% CI = -0.97, 13.70). There was no statistically significant association between MMLs and treatment admissions by non-pregnant women.
CONCLUSIONS: Medical marijuana law implementation in US states has been associated with greater substance use treatment utilization by pregnant adult women, especially in states with legally protected dispensaries.

PMID: 31106499 [PubMed - indexed for MEDLINE]

Engagement in rehabilitation therapy and functional outcomes among individuals with acquired brain injuries ‡.

Disabil Rehabil. 2019 May 17;:1-9

Authors: Williams MW, Rapport LJ, Hanks RA, Parker HA

Abstract
PURPOSE: The purpose was to examine the role of therapy engagement as a potential mediator for the relationship between neuropsychological performance and functional outcomes.
MATERIALS AND METHOD: Participants were 94 adults with medically documented ABI recruited from three outpatient rehabilitation clinics at the start of occupational therapy. Participants (57% men) ranged from 18 to 82 in age, with the majority (81%) having completed 12 or more years of education. They completed a comprehensive neuropsychological assessment at baseline. Separately, occupational therapists (OTs) assessed functional independence and disability at baseline and follow up. The OTs also rated the participants' therapy engagement.
RESULTS: Therapy engagement predicted functional outcomes and mediated the relationship between neuropsychological performance and outcomes. Moreover, therapy engagement accounted for unique variance in functional outcome, even after accounting for education, comorbid health conditions, emotional distress, apathy, and baseline functional ability.
CONCLUSIONS: Engagement in therapy is a crucial patient characteristic in successful rehabilitation outcome. Cognitive deficits associated with ABI undermine full engagement in rehabilitation therapy, which in turn diminishes potential gains made in therapy and functional recovery. Neuropsychological assessment can enhance rehabilitation outcomes by identifying characteristics that underlie therapy engagement, which can ultimately be used to maximize the effectiveness of individualized treatment plans. Implications for rehabilitation Neuropsychological assessment can identify cognitive abilities that are strongly related to functional outcomes during occupational therapy for acquired brain injury. Therapy engagement is an important pathway by which neuropsychological impairment predicts functional outcomes after acquired brain injuries.

PMID: 31099267 [PubMed - as supplied by publisher]

Vascular.

Oper Neurosurg (Hagerstown). 2019 Aug 01;17(Suppl 2):S76-S118

Authors: Arthur AS, Abecassis IJ, Abi-Aad KR, Albuquerque FC, Almefty RO, Aoun RJN, Barrow DL, Bederson J, Bendok BR, Ducruet AF, Fanous AA, Fennell VS, Flores BC, Griessenauer CJ, Kim LJ, Levitt MR, Mack WJ, Mascitelli J, Min E, Mocco J, Morr S, Nerva JD, Richards AE, Schirmer CM, See AP, Snyder KV, Tian F, Walcott BP, Welz ME

PMID: 31099843 [PubMed - indexed for MEDLINE]

Cost-effectiveness of Hepatitis C Virus Treatment Models for People Who Inject Drugs in Opioid Agonist Treatment Programs.

Clin Infect Dis. 2020 03 17;70(7):1397-1405

Authors: Gutkind S, Schackman BR, Morgan JR, Leff JA, Agyemang L, Murphy SM, Akiyama MJ, Norton BL, Litwin AH, Linas BP

Abstract
BACKGROUND: Many people who inject drugs in the United States have chronic hepatitis C virus (HCV). On-site treatment in opiate agonist treatment (OAT) programs addresses HCV treatment barriers, but few evidence-based models exist.
METHODS: We evaluated the cost-effectiveness of HCV treatment models for OAT patients using data from a randomized trial conducted in Bronx, New York. We used a decision analytic model to compare self-administered individual treatment (SIT), group treatment (GT), directly observed therapy (DOT), and no intervention for a simulated cohort with the same demographic characteristics of trial participants. We projected long-term outcomes using an established model of HCV disease progression and treatment (hepatitis C cost-effectiveness model: HEP-CE). Incremental cost-effectiveness ratios (ICERs) are reported in 2016 US$/quality-adjusted life years (QALY), discounted 3% annually, from the healthcare sector and societal perspectives.
RESULTS: For those assigned to SIT, we projected 89% would ever achieve a sustained viral response (SVR), with 7.21 QALYs and a $245 500 lifetime cost, compared to 22% achieving SVR, with 5.49 QALYs and a $161 300 lifetime cost, with no intervention. GT was more efficient than SIT, resulting in 0.33 additional QALYs and a $14 100 lower lifetime cost per person, with an ICER of $34 300/QALY, compared to no intervention. DOT was slightly more effective and costly than GT, with an ICER > $100 000/QALY, compared to GT. In probabilistic sensitivity analyses, GT and DOT were preferred in 91% of simulations at a threshold of <$100 000/QALY; conclusions were similar from the societal perspective.
CONCLUSIONS: All models were associated with high rates of achieving SVR, compared to standard care. GT and DOT treatment models should be considered as cost-effective alternatives to SIT.

PMID: 31095683 [PubMed - indexed for MEDLINE]

Effects of Preweaning Manganese in Combination with Adult Striatal Dopamine Lesions on Monoamines, BDNF, TrkB, and Cognitive Function in Sprague-Dawley Rats.

Neurotox Res. 2019 Apr;35(3):606-620

Authors: Bailey RA, Gutierrez A, Kyser TL, Hemmerle AM, Hufgard JR, Seroogy KB, Vorhees CV, Williams MT

Abstract
Manganese (Mn) is an essential nutrient especially during development, but Mn overexposure (MnOE) produces long-term cognitive deficits. Evidence of long-term changes in dopamine in the neostriatum was found in rats from developmental MnOE previously. To examine the relationship between MnOE and dopamine, we tested whether the effects of developmental MnOE would be exaggerated by dopamine reductions induced by 6-hydroxydopamine (6-OHDA) neostriatal infusion when the rats were adults. The experiment consisted of four groups of females and males: Vehicle/Sham, MnOE/Sham, Vehicle/6-OHDA, and MnOE/6-OHDA. Both MnOE/Sham and Vehicle/6-OHDA groups displayed egocentric and allocentric memory deficits, whereas MnOE+6-OHDA had additive effects on spatial memory in the Morris water maze and egocentric learning in the Cincinnati water maze. 6-OHDA reduced dopamine in the neostriatum and nucleus accumbens, reduced norepinephrine in the hippocampus, reduced TH+ cells and TrkB and TH expression in the substantia nigra pars compacta (SNpc), but increased TrkB in the neostriatum. MnOE alone had no effect on monoamines or TrkB in the neostriatum or hippocampus but reduced BDNF in the hippocampus. A number of sex differences were noted; however, only a few significant interactions were found for MnOE and/or 6-OHDA exposure. These data further implicate dopamine and BDNF in the cognitive deficits arising from developmental MnOE.

PMID: 30612279 [PubMed - indexed for MEDLINE]

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis.

J Natl Cancer Inst. 2019 08 01;111(8):782-794

Authors: Janssen QP, Buettner S, Suker M, Beumer BR, Addeo P, Bachellier P, Bahary N, Bekaii-Saab T, Bali MA, Besselink MG, Boone BA, Chau I, Clarke S, Dillhoff M, El-Rayes BF, Frakes JM, Grose D, Hosein PJ, Jamieson NB, Javed AA, Khan K, Kim KP, Kim SC, Kim SS, Ko AH, Lacy J, Margonis GA, McCarter MD, McKay CJ, Mellon EA, Moorcraft SY, Okada KI, Paniccia A, Parikh PJ, Peters NA, Rabl H, Samra J, Tinchon C, van Tienhoven G, van Veldhuisen E, Wang-Gillam A, Weiss MJ, Wilmink JW, Yamaue H, Homs MYV, van Eijck CHJ, Katz MHG, Groot Koerkamp B

Abstract
BACKGROUND: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.
METHODS: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.
RESULTS: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX.
CONCLUSIONS: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

PMID: 31086963 [PubMed - indexed for MEDLINE]

Unsupervised determination of protein crystal structures.

Proc Natl Acad Sci U S A. 2019 05 28;116(22):10813-10818

Authors: Ufimtsev IS, Levitt M

Abstract
We present a method for automatic solution of protein crystal structures. The method proceeds with a single initial model obtained, for instance, by molecular replacement (MR). If a good-quality search model is not available, as often is the case with MR of distant homologs, our method first can automatically screen a large pool of poorly placed models and single out promising candidates for further processing if there are any. We demonstrate its utility by solving a set of synthetic cases in the 2.9- to 3.45-Å resolution.

PMID: 31088963 [PubMed - indexed for MEDLINE]

Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination.

Proc Natl Acad Sci U S A. 2019 05 28;116(22):10819-10823

Authors: Ufimtsev IS, Almagor L, Weis WI, Levitt M

Abstract
In the companion paper by Ufimtsev and Levitt [Ufimtsev IS, Levitt M (2019) Proc Natl Acad Sci USA, 10.1073/pnas.1821512116], we presented a method for unsupervised solution of protein crystal structures and demonstrated its utility by solving several test cases of known structure in the 2.9- to 3.45-Å resolution range. Here we apply this method to solve the crystal structure of a 966-amino acid construct of human lethal giant larvae protein (Lgl2) that resisted years of structure determination efforts, at 3.2-Å resolution. The structure was determined starting with a molecular replacement (MR) model identified by unsupervised refinement of a pool of 50 candidate MR models. This initial model had 2.8-Å RMSD from the solution. The solved structure was validated by comparison with a model subsequently derived from an alternative crystal form diffracting to higher resolution. This model could phase an anomalous difference Fourier map from an Hg derivative, and a single-wavelength anomalous dispersion phased density map made from these sites aligned with the refined structure.

PMID: 31088964 [PubMed - indexed for MEDLINE]

Long-term outcomes of surgical management of rectal prolapse.

ANZ J Surg. 2019 May 13;:

Authors: Ng ZQ, Levitt M, Tan P, Makin G, Platell C

Abstract
BACKGROUND: Various surgical options for rectal prolapse are available but none have been shown to be clearly superior. The aims of this study were to investigate the long-term recurrence rate of a variety of surgical approaches, their associated morbidities and the types of reoperation used to treat recurrence.
METHODS: A retrospective analysis was performed of all cases of rectal prolapse surgery within one colorectal surgical unit between January 2000 and June 2017. Abdominal approaches consisted of rectopexy (RP) and resection rectopexy (RRP); perineal approaches included perineal rectosigmoidectomy (PR) and Delorme's repair (DR). Complications were graded according to the Clavien-Dindo classification. The median follow-up was 4.5 years (interquartile range 1.5-10.1, maximum 16.5). Statistical analysis was performed using Kaplan-Meier to determine recurrence rates.
RESULTS: A total of 157 patients were included in the study. The numbers for each procedure were: DR (n = 55), RRP (n = 44), RP (n = 38) and PR (n = 20). The majority were females (94%). The perineal group were significantly older than the abdominal group (80 versus 67 years, P = 0.0001). At 5 years, the recurrence rates were 52%, 30%, 5% and 3% for DR, PR, RP and RRP, respectively. Morbidity was highest in PR (20%) followed by RRP (18%), RP (16%) and DR (7%) (n.s.). The overall morbidity rates for perineal group and abdominal group were 10.7% and 17.1%, respectively (n.s.).
CONCLUSION: Abdominal approaches have a significantly lower recurrence rate at 5 years but tend to be associated with higher morbidity.

PMID: 31083789 [PubMed - as supplied by publisher]

Differentiation of epileptic regions from voluntary high-gamma activation via interictal cross-frequency windowed power-power correlation.

J Neurosurg. 2019 May 10;:1-11

Authors: Kogan M, Caldwell DJ, Hakimian S, Weaver KE, Ko AL, Ojemann JG

Abstract
OBJECTIVEElectrocorticography is an indispensable tool in identifying the epileptogenic zone in the presurgical evaluation of many epilepsy patients. Traditional electrocorticographic features (spikes, ictal onset changes, and recently high-frequency oscillations [HFOs]) rely on the presence of transient features that occur within or near epileptogenic cortex. Here the authors report on a novel corticography feature of epileptogenic cortex-covariation of high-gamma and beta frequency band power profiles. Band-limited power was measured from each recording site based on native physiological signal differences without relying on clinical ictal or interictal epileptogenic features. In this preliminary analysis, frequency windowed power correlation appears to be a specific marker of the epileptogenic zone. The authors' overall aim was to validate this observation with the location of the eventual resection and outcome.METHODSThe authors conducted a retrospective analysis of 13 adult patients who had undergone electrocorticography for surgical planning at their center. They quantified the correlation of high-gamma (70-200 Hz) and beta (12-18 Hz) band frequency power per electrode site during a cognitive task. They used a sliding window method to correlate the power of smoothed, Hilbert-transformed high-gamma and beta bands. They then compared positive and negative correlations between power in the high-gamma and beta bands in the setting of a hand versus a tongue motor task as well as within the resting state. Significant positive correlations were compared to surgically resected areas and outcomes based on reviewed records.RESULTSPositive high-gamma and beta correlations appeared to predict the area of eventual resection and, preliminarily, surgical outcome independent of spike detection. In general, patients with the best outcomes had well-localized positive correlations (high-gamma and beta activities) to areas of eventual resection, while those with poorer outcomes displayed more diffuse patterns.CONCLUSIONSData in this study suggest that positive high-gamma and beta correlations independent of any behavioral metric may have clinical applicability in surgical decision-making. Further studies are needed to evaluate the clinical potential of this methodology. Additional work is also needed to relate these results to other methods, such as HFO detection or connectivity with other cortical areas.

PMID: 31075773 [PubMed - as supplied by publisher]

Implementation facilitation to promote emergency department-initiated buprenorphine for opioid use disorder: protocol for a hybrid type III effectiveness-implementation study (Project ED HEALTH).

Implement Sci. 2019 05 07;14(1):48

Authors: D'Onofrio G, Edelman EJ, Hawk KF, Pantalon MV, Chawarski MC, Owens PH, Martel SH, VanVeldhuisen P, Oden N, Murphy SM, Huntley K, O'Connor PG, Fiellin DA

Abstract
BACKGROUND: Patients with opioid use disorder (OUD) frequently present to the emergency department (ED) after overdose, or seeking treatment for general medical conditions, their addiction, withdrawal symptoms, or complications of injection drug use, such as soft tissue infections. ED-initiated buprenorphine has been shown to be effective in increasing patient engagement in treatment compared with brief intervention with a facilitated referral or referral alone. However, adoption into practice has lagged behind need. To address this implementation challenge, we are evaluating the impact of implementation facilitation (IF) on the adoption of ED-initiated buprenorphine for OUD into practice.
METHODS: This protocol describes a study that is being conducted through the National Institute on Drug Abuse's Center for the Clinical Trials Network. A hybrid type III effectiveness-implementation study design is used to evaluate the effectiveness of a standard educational dissemination strategy versus IF on implementation (primary) and effectiveness (secondary) outcomes in four urban, academic EDs. Sites start with a standard 60-min "Grand Rounds" educational intervention describing the prevalence of ED patients with OUD, the evidence for opioid agonist treatment and for innovative interventions with ED-initiated buprenorphine; followed by a 1-year baseline evaluation period. Using a modified stepped wedge design, sites are randomly assigned to the IF intervention which is guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework to assess evidence, context, and facilitation-related factors impacting the adoption of ED-initiated buprenorphine. During the 6 months of IF through the 1-year IF evaluation period, external facilitators work with local stakeholders to tailor and refine a bundle of activities to meet the site's needs. The primary analyses compare the baseline evaluation period to the IF evaluation period (n = 120 patients with untreated OUD enrolled during each period) on (1) rates of provision of ED-initiated buprenorphine by ED providers with referral for ongoing medication (implementation outcome) and (2) rates of patient engagement in addiction treatment on the 30th day after the ED visit (effectiveness outcome). Finally, we will perform a cost-effectiveness analysis (CEA) to determine if the effectiveness benefits are worth the additional costs.
DISCUSSION: Results will generate novel information regarding the impact of IF as a strategy to promote ED-initiated buprenorphine.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03023930 first posted 1/10/2017, https://clinicaltrials.gov/ct2/show/NCT03023930?term=0069&rank=1.

PMID: 31064390 [PubMed - indexed for MEDLINE]

GPR124 regulates microtubule assembly, mitotic progression, and glioblastoma cell proliferation.

Glia. 2019 08;67(8):1558-1570

Authors: Cherry AE, Vicente JJ, Xu C, Morrison RS, Ong SE, Wordeman L, Stella N

Abstract
GPR124 is involved in embryonic development and remains expressed by select organs. The importance of GPR124 during development suggests that its aberrant expression might participate in tumor growth. Here we show that both increases and decreases in GPR124 expression in glioblastoma cells reduce cell proliferation by differentially altering the duration mitotic progression. Using mass spectrometry-based proteomics, we discovered that GPR124 interacts with ch-TOG, a known regulator of both microtubule (MT)-plus-end assembly and mitotic progression. Accordingly, changes in GPR124 expression and ch-TOG similarly affect MT assembly measured by real-time microscopy in cells. Our study describes a novel molecular interaction involving GPR124 and ch-TOG at the plasma membrane that controls glioblastoma cell proliferation by modifying MT assembly rates and controlling the progression of distinct phases of mitosis.

PMID: 31058365 [PubMed - indexed for MEDLINE]

Best Vascular Access in the Elderly: Time for Innovation?

Blood Purif. 2019;47(1-3):236-239

Authors: Asif A, Bakr MM, Levitt M, Vachharajani T

Abstract
BACKGROUND: Conflicting data continue to surround the optimal dialysis access for the elderly. Many propose that catheters are the best option for this population; others emphasize the creation of an arteriovenous fistula.
SUMMARY: While an arteriovenous access is the best available access, it has a high early failure rate, particularly in the elderly. However, significant differences exist in forearm (men ≥65 years ~70%; women ≥65 years ~80%) versus upper arm (men ≥65 years ~40%; women ≥65 years ~38%) fistula failure rates in the elderly, with upper arm having much lower failure rates. Two percutaneous innovative techniques that successfully establish fistulas at the upper arm using proximal radial/ulnar -artery as the inflow have been recently introduced. These procedures have been successfully performed in the elderly. Importantly, these techniques bypass the open surgical exploration and as such avoid the surgical manipulation of the juxta-anastomotic region (a common cause for the development of juxta-anastomotic stenosis and early fistula failure). Key Message: This article discusses the arteriovenous fistula creation in the elderly, highlights the factors necessary for successful fistula creation, and describes the 2 innovative techniques that can be used to provide a robust platform for successful fistula creation in this population.

PMID: 30517921 [PubMed - indexed for MEDLINE]