tbuckley/cabot-search huggingface dataset:
Dialectical Behavior Therapy—A Highly Effective Treatment for Some Adolescents Who Self-harm
Authors: Paul Oliver Wilkinson
Journal: JAMA Psychiatry (2018)

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EPEN-03. PEDIATRIC INTRACRANIAL EPENDYMOMA: CORRELATION OF SYMPTOMS AND SIGNS AT RECURRENCE WITH OUTCOME IN THE SECOND PROSPECTIVE AIEOP PROTOCOL FOLLOW-UP
Authors: Maura Massimino, Francesco Barretta, Felice Giangaspero, Luisa Chiapparini, Alessandra Erbetta, Luna Boschetti, Piergiorgio Modena, Manila Antonelli, Paolo Ferroli, Daniele Bertin, Emilia Pecori, Veronica Biassoni, Maria Luisa Garrè, Elisabetta Schiavello, Iacopo Sardi, Elisabetta Viscardi, Giovanni Scarzello, Maurizio Mascarin, Lucia Quaglietta, Giuseppe Cinalli, Lorenzo Genitori, Paola Peretta, Anna Mussano, Salvina Barra, Angela Mastronuzzi, Carlo Giussani, Carlo Efisio Marras, Rita Balter, Patrizia Bertolini, Assunta Tornesello, Milena La Spina, Francesca Romana Buttarelli, Antonio Ruggiero, Massimo Caldarelli, Geraldina Poggi, Lorenza Gandola
Journal: Neuro-Oncology (2018)

Aims of patient follow-up are: discovering relapse to apply second-line therapy for possible cure, accruing patients in phase 1/2 protocols if second-line therapy is not standardized/curative, evaluating/treating iatrogenic effects. To lessen the patient/family emotional and social economic burdens, we should ideally understand if scheduled radiological follow-up has a better rationale/outcome than the symptomatic relapse. We analyzed the Italian series of 2016 (doi:10.1093/neuonc/now108) comprehending 160 newly diagnosed pediatric/adolescent patients with intracranial ependymoma (EPD) according to relapse status (recurrence at scheduled exam [RECPT]/sign-symptomatic recurring [SYMPPT]). RECPT and SYMPPT were assessed in Cox model as time-dependent variables for overall survival (OS). Differences in characteristics between RECPT and SYMPPT subgroups were assessed by Wilcoxon-Mann-Whitney or Fisher Exact tests. Kaplan-Meier curves depicted event-free survival (EFS) and OS after recurrence according to signs/symptoms. There were 16 SYMPPT /34 RECPT, at a median follow-up of 55 months. No significant differences were found between SYMPPT/RECPT for gender, age, tumor grade/site, shunt, residual disease, radiation boost, type of relapse (local/distant/combined). Time-to-relapse (median:19 months, range 5–104) and treatment adoption did not differ between SYMPPT/RECPT while signs/symptoms depicted an unfavorable factor for OS after relapse (5-year OS: 8% vs 37%). Adjusted model in multivariate analysis confirmed that presence of signs/symptoms was prognostically unfavorable. In order to improve the OS in symptomatic patients, their early identification-in the first two/three years after diagnosis- would be desirable. Perhaps, this could be obtained paying attention to “heuristically detected” subgroup of patients, not just describing general prognostic variables but discovering possible biology differences according to signs/symptoms.
EAPH-10. SUCCESSFUL TREATMENT OF A SECONDARY PEDIATRIC HIGH GRADE GLIOMA WITH A NOVEL BEND4-NTRK2 FUSION WITH ENTRECTINIB, A TRK INHIBITOR
Authors: James Felker, Bryan Philbrook, Matthew Schneiderjan, Joshua Chern, Claire Mazewski, Bree Eaton, Edna Chow-Maneval, Tobey MacDonald, Dolly Aguilera
Journal: Neuro-Oncology (2018)

A 2 month old child with a large hemispheric tumor; after subtotal resection, pathology showed pilomyxoid astrocytoma with BRAFV600E mutation by immunohistochemistry and pyrosequencing. He had multiple episodes of radiographic and clinical progression. Over the course of 5 years, therapy included carboplatin, TPCV, velban, and immunotherapy. Vemurafenib and dabrafenib were administered with no response. MRI showed rapid tumor progression in the brain with spinal dissemination and significant clinical deterioration. Patient underwent tumor debulking and pathology confirmed a high grade astrocytoma, without BRAF V600E mutation, but with a novel BEND4-NTRK2 fusion by molecular genetic testing. He underwent whole brain radiation of 33 Gy in 16 fractions and boost to primary tumor bed to a total dose of 43 Gy. No radiation was given to the spine. One month later, patient started compassionate treatment with entrectinib, a novel, CNS-active, TRK inhibitor, at 400 mg/m2/day. MRI obtained after 28 days on treatment demonstrated significant radiographic regression, with rapid improvement in clinical symptoms. His dose was then increased to 550 mg/m2/day. After 2 additional cycles, the tumor continues to decrease in size in the brain and a spine MRI demonstrated complete response despite no radiation to the spine. Toxicities included Grade 1 ALT, cholesterol and peripheral edema. In summary, we report the case of a refractory BRAF V600E mutated low grade glioma transformed into a high grade with a novel BEND4-NTRK2 fusion, and profound radiographic and clinical response to entrectinib.
MBRS-29. IN-VIVO METABOLITE PROFILES FOR THE NON-INVASIVE AND RAPID IDENTIFICATION OF MOLECULAR SUBGROUP IN MEDULLOBLASTOMA
Authors: Sarah E Kohe, Ben Babourina-Brooks, Fatma Scerif, Debbie Hicks, Ed C Schwalbe, Stephen Crosier, Janet Lindsey, Magretta Adiamah, Lisa C D Storer, Anbarasu Lourdusamy, Simrandip K Gill, Christopher D Bennett, Martin Wilson, Shivaram Avula, Dipayan Mitra, Rob Dineen, Simon Bailey, Daniel Williamson, Richard G Grundy, Steven C Clifford, Andrew C Peet
Journal: Neuro-Oncology (2018)

Molecular subgroup is now influencing risk stratification and disease management in medulloblastoma. Tissue metabolite profiles have shown promise in identifying the four consensus subgroups. A smaller number of metabolites can be measured non-invasively in patients using magnetic resonance spectroscopy (MRS). We investigated if a classifier constructed from tissue metabolites could be applied to in-vivo metabolite profiles to accurately predict subgroup non-invasively. Machine learning was used to construct a classifier with tissue concentrations from 10 metabolites reliably detected in-vivo. Retrospectively acquired diagnostic in-vivo MRS was available for 37 cases from four treatment centres. Although we identified WNT tumours by the presence of GABA with 100% accuracy in tissue, GABA was not reliability quantified in this in-vivo dataset. Therefore the classifier was developed using tissue profiles of known molecular subgroup (determined using DNA methylation array) from group 3(n=20), group 4(n=34) and SHH(n=23). The cross-validated accuracy of the tissue classifier was 86%. When applied to in-vivo metabolite profiles, subgroup was predicted non-invasively with an overall accuracy of 76%. Group 3 had the highest proportion of incorrectly classified cases (4/11), followed by SHH (2/10), and group 4 (3/16), largely due to differences in measuring lipids, glutamate, glutamine and hypotaurine in-vivo. We have established the feasibility of non-invasive metabolite profiling to identify medulloblastoma subgroups. With the ongoing optimization of MRS to target specific metabolites including GABA, we can further improve accuracy. Rapid, non-invasive preoperative diagnosis of subgroup will offer opportunities to stratify early therapeutic intervention especially surgery, avoiding long-term sequalae and improving quality of survival.
RETRACTION: Improved Bone Safety of Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate Over 2 Years in Patients with Chronic HBV Infection
Authors: Wai-Kay Seto, Yasuhiro Asahina, Todd T. Brown, Cheng-Yuan Peng, Carol Stanciu, Dzhamal Abdurakhmanov, Fehmi Tabak, Tuan T. Nguyen, Wan-Long Chuang, Tetsuro Inokuma, Fusao Ikeda, Teresa Antonia Santantonio, François Habersetzer, Alnoor Ramji, Audrey H. Lau, Vithika Suri, John F. Flaherty, Hongyuan Wang, Anuj Gaggar, G. Mani Subramanian, Shrikant Mukewar, Maurizia R. Brunetto, Scott Fung, Henry Lik-Yuen Chan
Journal: Clinical Gastroenterology and Hepatology (2018)
The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway
Authors: Mylène Tajan, Romain Paccoud, Sophie Branka, Thomas Edouard, Armelle Yart
Journal: Endocrine Reviews (2018)

Abstract Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.
Nimotuzumab bi-weekly/low dose combined to chemotherapy in advanced pancreatic cancer: A clinical study
Authors: M. Lima, V. Jennifer, C. Dominguez, G. Robin, M. Dunia, O. Alexander, G. Giselle, M. Amparo, R. Ivan, B. Noyde, J. Soriano
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer is the fourth most common cause of death by an oncological disease worldwide and treatment for advanced stages has not shown satisfactory results in terms of survival. The primary end points were overall survival and the frequency and severity of adverse events. Methods: Outcomes of advanced and/or metastatic pancreatic cancer, treated with nimotuzumab (between January 2012 and December 2015) were retrospectively analyzed (n = 63). Patients were treated with nimotuzumab (dose:200 mg q2w) in combination with standard chemotherapy, according with Cuban Clinical Practice Guidelines. Once chemotherapy was discontinued, nimotuzumab was continued, at the same dose, until symptomatic disease progression or death of patients. Univariate survival analysis was performed by Kaplan-Meier curves, as compared by the Log-rank and/or Breslow test, considering p<.05 statistically significant. Results: Median age was 59 years old. Patients were mostly man (63.5%) with comorbidities (60.3%), ECOG= 1 (54%) and ECOG= 2 (33%). Tumors were mostly differentiated (69.8%) with metastasis (60.3%). Treatment combinations were mainly with gemcitabine (73.0%). Achieved median OS was 9.6 months (CI 95%: 5.7; 13.1). Survival rate at 6 and 12 months were 73.2% and 42.5%, respectively. Patients with ECOG=0 and ECOG=1 achieved median OS of 14.1 months (6.9; 21.3) p=.03 and 11.1 months (5.9; 16.3) p=.01, respectively. Patients who achieved stable disease, showed an OS of 39.5 months (29.3; 49.6) p=.00. KRAS status was determined in 33% of the patients. Despite that median OS of KRAS wild-type patients (45%) was 2.2 months higher compared with patients with muted KRAS, this was not significant [11.6 vs 9,4 months (p=.66)]. Toxicity was detected in twenty six patients. Six patients developed increase of transaminases (grade 1-2). Five patients presented diarrhea (grade 1-2) and 1 patient presented diarrhea grade 3. Only one patient developed neuropathy grade 3 and other three developed neuropathy grade 1-2. 36.5% of the patients required adjustment of the gemcitabine or the oxaliplatin, according to the chemotherapy regimen. These adjustments generated delays in the following dose administration. No allergy or skin rashes were observed. Conclusion: Survivals obtained with the use of lose doses of nimotuzumab, in combination with chemotherapy, was similar to the one observed in other groups with a higher dose and a lower toxicity. The addition of nimotuzumab to standard chemotherapy does not increase toxicity and it is well tolerated. Other trials must be developed in order to confirm obtained results.
HGG-05. miR-379-5p REGULATES PROLIFERATION, MIGRATION AND INVASION IN BRAF MUTANT-GLIOBLASTOMA
Authors: Rui-qi Zhang, Kay Ka-Wai Li, Ho-Keung Ng
Journal: Neuro-Oncology (2018)

Glioblastoma can be found in teenagers and young adults and our previous study identified a subgroup of such glioblastomas characterized by BRAFV600E mutation and they are clinically and molecularly different from those IDH- or H3F3-mutated glioblastomas (Zhang R et al. Oncotarget 2015). MicroRNAs (miRNAs) are short, non-coding RNAs of about 22bp that acts as post-transcriptional regulators of gene expression. MiRNAs affect diverse physiological processes, and have been implicated in malignancies. By miRNA expression profiling, we detected down-regulation of miR-379-5p from our previous cohort. Quantitative reverse transcription (RT)-PCR-based miRNA assays confirmed significant reduction of miR-379-5p in 18/28 (64.3%) of young adult GBM. The effects of miR-379-5p in cell growth, invasion and metastasis were then investigated in two BRAF mutant-GBM cell lines. We showed ectopic expression of miR-379-5p resulted in dramatic inhibition of cell proliferation of AM-38 and DBTRG-05MG cells by 47.0% and 32.1% respectively (p=0.014; p<0.0005). In vitro assay revealed cell migration and invasion were markedly suppressed in BRAF mutant-GBM cell lines transfected with miR-379-5p. By computational algorithms, we identified the proto-oncogenes PDGFRA and MDM2 as potential target genes of miR-379-5p. Our findings suggest miR-379-5p controls tumor biology of BRAF-mutated GBM.
Venous Leg Ulcers (Japanese Version)
Authors: Alejandra Vivas, Hadar Lev-Tov, Robert S. Kirsner
Journal: Annals of Internal Medicine (2016)

In the Clinic2 August 2016Venous Leg Ulcers (Japanese Version)Correction(s) for this article:CorrectionsNov 2022Correction: Japanese Translations of In the ClinicFREEAlejandra Vivas, MD, Hadar Lev-Tov, MD, and Robert S. Kirsner, MD, PhDAlejandra Vivas, MDSearch for more papers by this author, Hadar Lev-Tov, MDSearch for more papers by this author, and Robert S. Kirsner, MD, PhDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/IsTranslatedFrom_AITC201608020_Japanese SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Editors' Note: This article (available in PDF format) is the translated Japanese version of In the Clinic: Venous Leg Ulcers (Vivas A, Lev-Tov H, Kirsner RS. Venous Leg Ulcers. Ann Intern Med. 2016;165:ITC17-ITC32. doi:10.7326/AITC201608020). Author, Article, and Disclosure InformationAffiliations: Correction: This article was updated on 1 November 2022 to remove the glossary of terms, which was not present on the original publication, and to indicate the translators of the article.Funding Source: American College of Physicians.Disclosures: Drs. Vivas and Lev-Tov, ACP Contributing Authors, have nothing to disclose. Dr. Kirsner, ACP Contributing Author, reports personal fees from Organogenesis and 3M outside the submitted work. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0831.With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians.In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoVenous Leg Ulcers Alejandra Vivas , Hadar Lev-Tov , and Robert S. Kirsner Correction: Japanese Translations of In the Clinic Metrics Cited byCorrection: Japanese Translations of In the Clinic 2 August 2016Volume 165, Issue 3Page: JITC17-JITC32 ePublished: 19 June 2018 Issue Published: 2 August 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
TBIO-26. INTEGRATED REPORTING FOR PEDIATRIC NEURO-ONCOLOGY: THE CHLA EXPERIENCE
Authors: Jennifer A Cotter, Joanna C Green, Matthew C Hiemenz, Jianling Ji, Jaclyn A Biegel, Alexander R Judkins
Journal: Neuro-Oncology (2018)

In keeping with the WHO 2016 revision of the classification of CNS tumors, we designed a new vehicle for reporting all tissue-based molecular tests within the body of a single surgical pathology report. This Integrated Report for CNS tumors required a novel clinical informatics pipeline to allow faculty members to edit and release component reports into the corresponding surgical pathology report. The Integrated Report is a collaborative document shared among pathology faculty, and final interpretation is issued by the surgical pathologist after consultation with co-authors. A new Integrated Diagnosis portion of the report is generated above the histologic diagnosis, at the top of the original surgical pathology report. Key informatics tools include safeguards against release of partial reports and creation of a digital workspace for collaborative editing. To date 23 integrated reports have been issued for CNS tumors at CHLA, with followup germline testing recommended for three patients. Common alterations identified include KIAA1549-BRAF fusion, TP53 mutation, CDKN2A/B deletion, and MYC amplification. A key component of the success of the Integrated Report was a molecular pathology/histopathology working conference, at which cases are discussed in a round-table format with neuro-oncologists. Inclusion of molecular findings in the report has allowed neuro-oncologists to more readily identify patients eligible for specific clinical trials. Implementation of an Integrated Reporting method requires collaboration within a pathology department and interdisciplinary cooperation from clinical stakeholders. At CHLA the Integrated Report has enhanced diagnostic accuracy and has had a positive impact on patient care.
First-line doublet or triplet chemotherapy for advanced esophagogastric cancer: A systematic review and meta-analysis.
Authors: Nadia Haj Mohammad, Emil ter Veer, Lok Lam Ngai, Rosa Mali, Martijn G.H. van Oijen, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2015)

e15090 Background: Gastric and esophageal cancer are the second and the sixth most common cause of cancer related deaths worldwide. Most patients present with advanced disease. Palliative chemotherapy improves survival as compared to best supportive care. There is debate whether doublet (DO) or triplet (TRI) chemotherapy should be used as first-line treatment. A previous meta-analysis demonstrated a significant benefit for TRI chemotherapy. Since the publication in 2010 new combination regimens have been developed. We conducted a meta-analysis to assess the efficacy of DO versus TRI chemotherapy with the inclusion of the most recently published data. Methods: We searched Medline, Embase and CENTRAL between 1980 and November 2014, and abstracts of major cancer meetings from 1990 to 2014 for randomized controlled phase II and III trials comparing a DO with a TRI. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and toxicity. Hazard ratios (HR) with confidence intervals (CI) were estimated with a fixed-effects model based on limited heterogeneity of included studies using RevMan 5.3. We performed a sensitivity analysis, excluding trials that were conducted in Asia, because of the differences in treatment and prognosis compared to non-Asian countries. Results: Fourteen studies with in total 1917 participants were included. A significant improvement in OS (HR 0.78 95% CI 0.70-0.87) and PFS (HR 0.76 95% CI 0.61-0.96) was observed in favor of a TRI. In addition, the use of a TRI was associated with better ORR (risk ratio = 1.44 95% CI 1.26-1.64) compared to a DO. The risks of grade 3-4 thrombocytopenia (7.2% vs 3.7%), infection (13.0% vs 7.0%) and mucositis (10.7% vs 2.7%) were increased with a TRI compared to a DO. A sensitivity analysis excluding those trials that were conducted in Asia had no impact on the HR (0.79 95% CI 0.70-0.89) for OS. Conclusions: Our results show that first-line triplet therapy is superior to doublet therapy in patients with advanced esophagogastric cancer in terms of OS, PFS and ORR, although the HRs are not below 0.7 and the risks of grade 3-4 thrombocytopenia, infection and mucositis are increased.
Caspase-3 Is a Pivotal Regulator of Microvascular Rarefaction and Renal Fibrosis after Ischemia-Reperfusion Injury
Authors: Bing Yang, Shanshan Lan, Mélanie Dieudé, Jean-Paul Sabo-Vatasescu, Annie Karakeussian-Rimbaud, Julie Turgeon, Shijie Qi, Lakshman Gunaratnam, Natalie Patey, Marie-Josée Hébert
Journal: Journal of the American Society of Nephrology (2018)

Background Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis.Methods We performed unilateral renal artery clamping for 30 minutes and contralateral nephrectomy in wild-type mice (C57BL/6) or caspase-3-/- mice.Results Compared with their wild-type counterparts, caspase-3-/- mice in the early stage of AKI had high urine cystatin C levels, tubular injury scores, and serum creatinine levels. Electron microscopy revealed evidence of tubular epithelial cell necrosis in caspase-3-/- mice, and immunohistochemistry showed upregulation of the necroptosis marker receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in renal cortical sections. Western blot analysis further demonstrated enhanced levels of phosphorylated RIPK3 in the kidneys of caspase-3-/- mice. In contrast, caspase-3-/- mice had less microvascular congestion and activation in the early and extension phases of AKI. In the long term (3 weeks after IRI), caspase-3-/- mice had reduced microvascular rarefaction and renal fibrosis, as well as decreased expression of α-smooth muscle actin and reduced collagen deposition within peritubular capillaries. Moreover, caspase-3-/- mice exhibited signs of reduced tubular ischemia, including lower tubular expression of hypoxia-inducible factor-1α and improved tubular injury scores.Conclusions These results establish the pivotal importance of caspase-3 in regulating microvascular endothelial cell apoptosis and renal fibrosis after IRI. These findings also demonstrate the predominant role of microvascular over tubular injury as a driver of progressive renal damage and fibrosis after IRI.