tbuckley/cabot-search huggingface dataset:
MODL-17. SHP2 INHIBITORS SHOW ACTIVITY AGAINST NF1-DEFICIENT GLIOMAS AND ENHANCE MAPK PATHWAY INHIBITION IN BRAF-V600E MUTANT GLIOMAS
Authors: Daniel Muldoon, Guisheng Zhao, Carly Batt, Mallika Singh, Theodore Nicolaides
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Activation of the RAS-MAPK signaling cascade is common in pediatric gliomas. Based on the role of SHP2 in RAS pathway signaling, we hypothesized that NF1-deficient pediatric glioma models would respond to SHP2 inhibitor monotherapy whereas BRAF-V600E gliomas would not. However, we postulated that the latter would exhibit increased sensitivity to a BRAF inhibitor (BRAFi) in combination with SHP2i. Here we demonstrate that the SHP2 inhibitors SHP099 and RMC-4550 (SHP2i) show significant single-agent activity in vitro against NF1-deficient glioma cells and that the combination of RMC-4550 with BRAFi shows increased activity in BRAF-V600E glioma cells relative to the single-agents. METHODS Using a panel of NF1 mutant/deficient and BRAF-V600E mutant glioma cell lines we examined effects on cell viability and protein expression levels of total and phosphorylated MEK, ERK, and AKT. RESULTS LN229 and U87 NF1-deficient glioma cells are sensitive to SHP2i alone but not A375 cells (melanoma, BRAF-V600E). Additionally, we show that in multiple BRAF-V600E glioma cell lines BRAFi sensitivity increases when combined with a SHP2i. Immunoblots show decreased expression of pERK and pMEK in LN229 cells following SHP2i exposure, while A375 cells maintain MAPK pathway signaling. A sustained decrease in the expression of pERK after 24 hours was observed in BRAF-V600E glioma cells with BRAFi in combination with SHP2i, consistent with relief of feedback inhibition. In vivo studies using orthotopic xenograft models are underway. CONCLUSION SHP2i shows preclinical activity in vitro against NF1-deficient pediatric glioma cell lines as a single-agent and against BRAF-V600E gliomas in combination with BRAFi.
PATH-24. MOLECULAR CLASSIFICATION OF HIGH RISK INFANT EMBRYONAL BRAIN TUMORS ENROLLED IN THE ACNS0334 TRIAL: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Bryan K Li, Peter Burger, Alexander R Judkins, Ben L B Ho, Guolian Kang, Jeffrey Gossett, Sarah Leary, Ian Pollack, Amar Gajjar, Maryam Fouladi, Stewart J Kellie, Claire Mazewski, Annie Huang
Journal: Neuro-Oncology (2020)

Abstract Young children with embryonal brain tumors including medulloblastoma (MB), supratentorial primitive neuro-ectodermal tumor, or pineoblastoma have historically been considered high-risk patients with poor outcomes despite the use of intensive radiation-sparing treatment. In the ACNS0334 phase III trial, 91 consented children &amp;lt;36 months old with the above diagnoses were randomized to intensive induction chemotherapy with or without methotrexate followed by consolidation with stem cell rescue. Here we present the results of a centralized integrated molecular analysis including global methylation profiling (65/91), and whole exome sequencing of tumor (46/91) and germline (35/91) DNA. Unsupervised clustering analyses of methylation profiles using multiple orthogonal methods against a reference dataset of 1200 pediatric brain tumors, revealed known and new molecular entities. For tumors diagnosed as MB on central pathology review, 7.3% (3/41) had a non-MB molecular diagnosis (2 embryonal tumor with multiple rosettes/ETMR, 1 group MYC pineoblastoma), with the remainder as MB Group SHH (11/41), Group3 (25/41), and Group4 (2/41). Among histologic non-MBs, 3/24 (12.5%) were molecular entities not intended for trial inclusion (1 each for ATRT, pleomorphic xanthoastrocytoma, and high-grade glioma). ETMR, historically considered a rare entity, was molecularly identified in a significant proportion (14/65; 21.5%) of samples. Among MB-SHH, we detected deleterious PTCH1 mutations in 6/9 tumors but none among 5 germline samples tested; a germline SUFU frameshift mutation with tumor LOH was also observed in MB-SHH. Correlation of these and other molecular features to the parallel clinical analysis will yield important markers of risk stratification and predictors of treatment response.
Steadily Straining Toward Clinical Utility: Real-Time Quantitative CMR of Myocardial Deformation During Stress⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Christopher M. Kramer, W. Gregory Hundley
Journal: JACC. Cardiovascular imaging (2010)
Implementing Group-Based Pelvic Floor Muscle Training in Clinical Practice
Authors: Satoshi Funada, Yan Luo
Journal: JAMA Internal Medicine (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Residual Shunt After Patent Foramen Ovale Closure and Long-Term Stroke Recurrence
Authors: Wenjun Deng, Shanye Yin, David McMullin, Ignacio Inglessis-Azuaje, Sammy Elmariah, Judy Hung, Eng H. Lo, Igor F. Palacios, Ferdinando S. Buonanno, MingMing Ning
Journal: Annals of Internal Medicine (2020)

Residual shunt is observed in up to 25% of patients after patent foramen ovale (PFO) closure, but its long-term influence on stroke recurrence currently is unknown.To investigate the association of residual shunt after PFO closure with the incidence of recurrent stroke and transient ischemic attack (TIA).Prospective cohort study comparing stroke or TIA recurrence in patients with and without residual shunt after PFO closure.Single hospital center.1078 consecutive patients (mean age, 49.3 years) with PFO-attributable cryptogenic stroke who were undergoing percutaneous PFO closure were followed for up to 11 years.Residual shunt was evaluated by transthoracic echocardiography with saline contrast. Primary outcome was a composite of the first recurrent ischemic stroke or TIA after PFO closure.Compared with complete closure, the presence of residual shunt after PFO closure was associated with an increased incidence of recurrent stroke or TIA: 2.32 versus 0.75 events per 100 patient-years (hazard ratio [HR], 3.05 [95% CI, 1.65 to 5.62]; P < 0.001). This result remained robust after adjustment for important covariates, namely age; study period; device; presence of atrial septal aneurysm, hypertension, hyperlipidemia, diabetes, hypercoagulability, or hypermobile septum; and medication use (HR, 3.01 [CI, 1.59 to 5.69]; P < 0.001). Further stratification based on shunt size revealed that moderate or large residual shunts were associated with a higher risk for stroke or TIA recurrence (HR, 4.50 [CI, 2.20 to 9.20]; P < 0.001); the result for small residual shunts was indeterminate (HR, 2.02 [CI, 0.87 to 4.69]; P = 0.102).Nonrandomized study with potential unmeasured confounding.Among patients undergoing PFO closure to prevent future stroke, the presence of residual shunt, particularly a moderate or large residual shunt, was associated with an increased risk for stroke or TIA recurrence.National Institutes of Health.
RADT-26. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: POOLED ANALYSES OF AVAILABLE LITERATURE
Authors: Amanda Munoz Casabella, Masum Rahman, Mohammed Alvi, Desmond Brown
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Laser Interstitial Thermal Therapy (LITT) is a novel treatment modality that has been used for an array of intracranial pathology. In the current manuscript, we sought to conduct a systematic review and meta-analysis to summarize all available literature to date, on outcomes of patients with recurrent GBM (r-GBM) undergoing LITT, pooling together quantitatively the overall survival and progression-free survival data. METHODS A comprehensive literature search was performed to retrieve all studies investigating overall survival, post-procedure survival, and progression-free survival outcomes of patients with r-GBM undergoing LITT. All statistics were pooled together by the meta-analysis of the mean using a weighted random-effects (RE) or fixed-effect (FE) model. RESULTS Eleven studies were included in the final cohort, representing a total of 134 patients with rGBM. The pooled mean age of the cohort at the time of recurrence diagnosis was found to be 56.7 ± 4.56 while 41% of the cohort were females. For the delivery of LITT, two studies utilized neodymium-yttrium aluminum-garnet laser (Neodp-YAG Laser), three studies utilized the Visualase system, five studies utilized the Neuroblate system, and one study used both the Neuroblate and the Visualase system. A total of eight studies with 107 patients had available data for overall median survival. The pooled overall survival was found to be 18.6 months (95%CI 16.2-21.1). A total of six studies with 93 patients had available data for post-LITT survival. The pooled post-LITT survival was found to be 10.1 months (95%CI 8.8-11.6). A total of eight studies with 119 patients had available data for progression-free survival. The pooled progression-free survival was found to be 6 months (95%CI 5.3-6.7). CONCLUSION LITT is a novel minimally invasive procedure which, when used with optimal adjuvant therapy, may confer survival benefit for patients with r-GBM.
Association of Programmed Cell Death 1 Inhibitor With Circumorificial Plasmacytosis
Authors: Abraham M. Korman, Kelley Zyniewicz, Gabriel Tinoco, Carl M. Allen, Ashleigh Briody
Journal: JAMA Dermatology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
CTIM-16. INTERSTITIAL PHOTODYNAMIC THERAPY WITH 5-ALA FOR MALIGNANT GLIOMA RECURRENCES
Authors: Stefanie Lietke, Michael Schmutzer, Christoph Schwartz, Jonathan Weller, Maximilian Aumiller, Christian Heckl, Robert Forbrig, Maximilian Niyazi, Herbert Stepp, Ronald Sroka, Joerg-Christian Tonn, Adrian Rühm, Niklas Thon
Journal: Neuro-Oncology (2020)

Abstract Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a cytotoxic photosensitizer has been shown to be a feasible treatment option for malignant gliomas. We present outcome measures and a risk profile analysis of salvage iPDT in a large monocentric cohort with local tumor recurrence following standard therapy. This study included consecutive adult patients undergoing salvage iPDT for small, circumscribed, biopsy-proven malignant glioma recurrences not deemed eligible for safe complete resection of contrast enhancing tumor. A modified 3-D treatment-planning software was used to calculate the treatment-volume and the position of the stereotactic light diffusers within the lesion. Outcome measurements included estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and the risk profile of iPDT. Prognostic factors were obtained from logistic regression models. The institutional review board approved the study. A total of 44 patients (median age: 49.4 years, range 33.4–87.0 years, 17 female) were included. Recurrent tumors included 37/44 glioblastomas WHO grade IV and 7/44 anaplastic astrocytomas WHO grade III. Thirty (68.2%) tumors were MGMT methylated. Median treatment volume was 3.3 ccm (range, 0.5–22.8 ccm). A median number of 4 (range: 3–8) laser fibers were used. Median illumination time was 60min (range: 60–167 min). Symptomatic edema (8/44) or intratumoral hemorrhagic imbibition (7/44) did not result in any permanent morbidity. Median TTF was 7.1 months and median PRS was 13.0 months. The 2- and 5-years PRS rates were 25.0% and 4.5%. Treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. In conclusion, iPDT was associated with promising outcome measurements in local malignant glioma recurrences in highly selected patients. Transient neurologic deterioration did not lead to any permanent morbidity. The procedure deserves further prospective evaluation particularly to identify mechanisms of favorable treatment response and prognostic factors associated with long-term survival.
NFB-17. MEK INHIBITOR BINIMETINIB SHOWS CLINICAL ACTIVITY IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1- ASSOCIATED PLEXIFORM NEUROFIBROMAS: A REPORT FROM PNOC AND THE NF CLINICAL TRIALS CONSORTIUM
Authors: Sabine Mueller, Alyssa T Reddy, Eva Dombi, Jeffrey Allen, Roger Packer, Wade Clapp, Stewart Goldman, Elizabeth Schorry, James Tonsgard, Jaishri Blakeley, Nicole J Ullrich, Andrea Gross, Karin Walsh, Coretta Thomas, Lloyd Edwards, Michael Prados, Bruce Korf, Michael J Fisher
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Plexiform neurofibromas (PNs) can cause significant morbidity. In this phase 2 study, we assessed imaging and functional outcomes to the MEK-inhibitor Binimetinib in pediatric patients with PNs. METHODS Children (age 1–17 years) with PN that were progressive or causing significant morbidity were eligible. Binimetinib is dosed twice-daily (starting dose of 32mg/m2) for maximum of 24 four-week courses. Participants with partial response (PR; &amp;gt;20% decrease in PN volume on central MRI review) at cycle 12 may stay on therapy. Participants undergo MRI and functional assessments at baseline and after courses 4, 8, 12, 18 and 24. Functional assessments are based on PN location. RESULTS Here we present 1-year response data. Twenty participants (55% male) with median age 12 years (range 2–16 years) enrolled; 19 are evaluable for response. Median baseline tumor volume was 326 ml (range, 8-6661 ml). Fourteen participants (74%) met criteria for PR, with 11 achieving PR by course 5. Median maximal PN volume reduction was 25.5% (range, 9–54%). As of August 2020, 14 participants received at least 12 cycles of Binimetinib; 10 remain on therapy. Off study reasons include treatment associated toxicities (n=2), subject withdrawal (n=2), non-compliance (n=2), prolonged treatment delay (n=1), and lack of response (n=3). Thirteen participants underwent dose reduction. Institution-reported related grade 3 toxicities included dry skin, weight gain, muscle weakness, rash, paronychia, cellulitis, diarrhea, gastric hemorrhage and CPK increase. CONCLUSIONS Binimetinib appears reasonably well-tolerated and shows promising activity in children with NF1-associated PNs. Outcomes on functional improvement will be reported at the meeting.
CTNI-44. INTERIM RESULTS OF PHASE 2 STUDY TO EVALUATE PI3K/mTOR INHIBITOR PAXALISIB (GDC-0084) GIVEN TO NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER
Authors: Patrick Wen, John de Groot, James Battiste, Samuel Goldlust, Denise Damek, James Garner, Jeremy Simpson, Alan Olivero, Timothy Cloughesy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Paxalisib (GDC-0084) is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). Paxalisib crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. An MTD of 60mg per day has been identified in newly diagnosed glioblastoma (GBM) patient with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. Paxalisib has shown encouraging indications of clinical activity. METHODS This study has a 2-part design: an open-label, dose-escalation phase (Stage 1) to define MTD, followed by an expansion cohort (Stage 2) at the MTD and patients are randomized to take paxalisib, in fed or fasted states. Pharmacokinetic data will be analysed and compared by dose and fed/fasted status. RESULTS Stage 2 (expansion cohort) is fully enrolled and patients are in follow-up. Adverse event profile seems broadly consistent with prior clinical experience and with other PI3K-targeting agents. With analysis including all patients, a sustained PFS signal of 8.5 months is seen and this compares favourably with historical controls. CONCLUSION Paxalisib displays a safety profile consistent with previous data and promising efficacy signals in newly diagnosed GBM. A pivotal study in GBM is planned to commence recruitment later this year.
DDEL-16. UNDERSTANDING OPTIMAL CONVECTION-ENHANCED DELIVERY PHYSICO-CHEMICAL INFUSION PARAMETERS: THE ROLE OF BBB EFFLUX PUMPS IN DRUG DISTRIBUTION AND CLEARANCE
Authors: Erica Power, Liang Zhang, David Daniels
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse midline gliomas harboring the H3K27M mutation are aggressive and universally fatal brain tumors that primarily occur in children. The blood-brain barrier (BBB) prevents many drugs from reaching the tumor at cytotoxic concentrations and efflux pumps found on the epithelial cells of the BBB rapidly pump drugs out of the brain. Convection enhanced delivery (CED) is a drug delivery technique that bypasses the BBB by directly injecting the drug into the tumor site under a pressure gradient. Further clinical implementation of CED requires understanding drug distribution, as optimal drug physico-chemical properties have never been evaluated. METHODS Sprague Dawley rats underwent a single injection of drug by CED to the brainstem with and without an efflux pump inhibitor. Animals were euthanized at 0, 2, 4, 8, 12 and 24 hours. Their brain drug concentration/distribution was analyzed by MALDI-MSI and plasma drug concentration was measured by LC-MS/MS. RESULTS Drug distribution and brainstem concentration were increased following BBB efflux pump inhibition compared to no pump inhibition controls. Additionally, efflux pump inhibition resulted in slower drug clearance for those drugs that are known pump substrates. CONCLUSIONS BBB efflux pump inhibition resulted in a larger volume of distribution, increased drug concentration and slower drug clearance following CED to the brainstem of known efflux substrates.
COVD-26. TELEPHONE CONSULTATIONS IN NEURO-ONCOLOGY DURING THE COVID-19 PANDEMIC: LEVELS OF PATIENT SATISFACTION AND COMPARISON WITH TRADITIONAL FACE-TO-FACE CONSULTATIONS
Authors: Emma Toman, Claire Goddard, Frederick Berki, William Garratt, Teresa Scott, Zenab Sher, Andrew Stevens, Vladimir Petrik, Ismail Ughratdar, Anwen White, Athanasios Zisakis, Colin Watts, Victoria Wykes
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Controversy exists as to whether telephone clinics are appropriate in neurosurgical-oncology. The COVID-19 pandemic forced neuro-oncology services worldwide to re-design and at the University Hospitals Birmingham UK, telephone clinics were quickly implemented in select patients to limit numbers of patients attending hospital. It was important to determine how these changes were perceived by patients. METHODS A 20-question patient satisfaction questionnaire was distributed to patients who attended neuro-oncology clinic in person (“face-to-face”), or via the telephone. Fisher’s exact test was used to determine significance, which was set at p&amp;lt; 0.05. RESULTS Eighty questionnaires were distributed between June 2020 and August 2020. Overall, 50% (n=40) of patients returned the questionnaire, 50% (n=23) of face-to-face and 50% (n=17) telephone patients. Of those who received telephone consultations, 88% (n=15) felt the consultation was convenient, 88% (n=15) were satisfied with their consultation and 18% (n=3) felt they would have preferred to have a face-to-face appointment. Of those who attended clinic in person, 96% (n=22) felt their consultation was convenient, 100% (n=23) were satisfied with their consultation and 13% (n=3) would have preferred a telephone consultation. Within the face-to-face clinic attendees, only 13% (n=3) were concerned regarding the COVID risk associated with attending hospital. There was no significant difference in patient convenience or satisfaction (p=0.565 and p=0.174 respectively) between face-to-face and telephone clinics. There was no significant difference in whether patients would’ve preferred the alternative method of consultation (p &amp;gt; 0.999). CONCLUSION Our study suggests that careful patient selection for neuro-oncology telephone clinic is not inferior to face-to-face clinic. Telephone clinic during COVID-19 pandemic proved to be convenient, safe and effective. This global health crisis has transformed telephone neuro-oncology consultations from an experimental innovation into established practice and should be continued beyond the pandemic in select cases.
Covid-19: Test and trace system must improve its below par performance, NAO concludes
Authors: Jacqui Wise
Journal: BMJ (2020)

Covid-19: Test and trace system must improve its below par performance, NAO concludes Jacqui WiseEngland's test and trace service must improve its performance because laboratories are working well below capacity, the public spending watchdog has said, as only 38% of tests are turned around within 24 hours and just two thirds of contacts of infected people are reached and told to self-isolate.
AMP-activated protein kinase (AMPK) signaling in GnRH neurons links energy status and reproduction
Authors: D. Franssen, A. Barroso, F. Ruiz-Pino, M.J. Vázquez, D. García-Galiano, J.M. Castellano, R. Onieva, M. Ruiz-Cruz, M. Poutanen, F. Gaytán, C. Diéguez, L. Pinilla, M. Lopez, J. Roa, M. Tena-Sempere
Journal: Metabolism (2020)