tbuckley/cabot-search huggingface dataset:
LGG-28. NEUROCOGNITIVE SEQUELAE IN PEDIATRIC LOW GRADE GLIOMA PATIENTS UNDER OBSERVATION - NEUROPSYCHOLOGICAL RESULTS FROM THE SIOP-LGG-2004 STUDY &amp; LGG-REGISTER
Authors: Thomas Traunwieser, Daniela Kandels, Astrid Gnekow
Journal: Neuro-Oncology (2018)

Neuropsychological late-effects for pediatric low-grade-glioma (LGG) patients under observation following complete or subtotal tumor resection (CR), or biopsy or radiological diagnosis only, are poorly defined. We report results of the German “neuropsychological basic diagnostic” tool (NBD) in LGG-patients without neurofibromatosis NF1 under observation from the German and Swiss SIOP-LGG-2004 & LGG-Register cohort. LGG-patients ≥4 years of age from 32 oncology centers were examined 2 (T1) and 5 years (T2) after diagnosis with the NBD measuring primary cognitive abilities with age-appropriate tests: fluid intelligence (FI), verbal short-term-memory (SM), visual-motoric integration (VMI), vocabulary (VB), fine-motor skills (FM) and processing speed (PS). 42 CR-patients were assessed at T1 and 52 at T2; tumor sites were infratentorial only. 20 patients observed following biopsy or radiological diagnosis were assessed at T1 and 14 at T2. Tumor sites were supratentorial-hemispheric (18%), supratentorial-midline (62%), infratentorial (20%). Because of extended overall neurocognitive impairment in previous analysis, NF1-patients were excluded. At T1, CR-patients displayed statistically noticeable deficits compared to expected population score in VMI, FM and PS (p<.001-.004; r=.47-.88). This was unchanged in the same dimensions at T2 (p<.001-.007; r=.45-.82). Biopsy and no-treatment patients showed statistically noticeable impairments at T1 in FM and PS (p<.001-.013; r=.65-.84), and additionally in VMI at T2 (p=.002-.041; r=.59-.90). Previous reports implied neuropsychological sequelae for the entire LGG-cohort “under observation”. This more detailed analysis underscores, that deficits occur in all subgroups, and that impairments, especially in motoric and in information processing tasks, of mostly high effect sizes even persist over time.
ATRT-15. SPINAL CORD ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT) IN CHILDREN: RESULTS OF A EUROPEAN RETROSPECTIVE ANALYSIS UNDER THE AUSPICES OF THE EU-RHAB STUDY GROUP
Authors: Martin Benesch, Petra Neumayer, Karolina Nemes, Torsten Pietsch, Beate Timmermann, Brigitte Bison, Monika Warmuth-Metz, Pablo Hernáiz Driever, Georg Ebetsberger-Dachs, Franck Bourdeaut, Christelle Dufour, Fanny Fouyssac, Martin Hasselblatt, Veronica Biassoni, Andrés Morales La Madrid, Natacha Entz-Werle, Véronique Laithier, Franz Quehenberger, Michael C Frühwald
Journal: Neuro-Oncology (2018)

A retrospective European survey was conducted to collect data sets on treatment and outcome of children with intramedullary spinal cord AT/RT. Twelve patients (male, n=4; median age 32 [range, 0.7–97] months) were identified. Lumbar (n=9) and thoracic segments (n=9) were most commonly involved, followed by sacral (n=3) and cervical segments (n=2). In 8 patients more than one spinal cord region was affected. Half of the patients presented with metastatic disease. Primary tumor resection was partial in 6 and gross total in 2 patients. In 4 patients tumors were biopsied only. Central pathology review was performed in 10 patients. Systemic postoperative chemotherapy was administered to all patients. Three patients only received intrathecal therapy and five were irradiated (craniospinal, n=3; local, n=2). Median observation time of the entire cohort was 6 (range, 1–71) months. Three patients, treated according to the EU-RHAB guidelines are alive in complete remission 58, 60, and 71 months after diagnosis. One patient died of intracerebral haemorrhage prior to response evaluation. Five patients progressed early and died within 1–3 months following diagnosis. Three patients died after 7–22 months due to disease progression after having achieved a partial remission (n=1) or disease stabilization (n=2). Event-free and overall survival rates at 1 and (2 years) were 38.9 ± 14.7% (29.2 ± 13.9%) and 41.7 ± 14.2% (25 ± 12.5%), respectively. Spinal cord AT/RT carry a rather grave prognosis. Long-term survival in selected patients is achievable using aggressive multimodality treatment.
Head of GP partnership review dismisses Darzi’s call for salaried profession
Authors: Abi Rimmer
Journal: BMJ (2018)

The GP leading a government commissioned review into the partnership model has said that he disagrees with calls for all GPs to be offered salaried NHS employment.

Speaking at the Next Generation GP conference in London on 20 June, Nigel Watson, chair of the review and chief executive of Wessex local medical committee, said, “I think the NHS needs [GP] partnerships, and it needs us to work together.”

In a …
MBRS-42. GMYC: A NOVEL INDUCIBLE TRANSGENIC MODEL OF GROUP 3 MEDULLOBLASTOMA
Authors: Holger Weishaupt, Oliver Mainwaring, Sonja Hutter, Antonia Kalushkova, Helena Jernberg-Wiklund, Gabriela Rosén, Fredrik J Swartling
Journal: Neuro-Oncology (2018)

Group 3 medulloblastoma (MB) carry the worst prognosis of all MB. The transcription factors MYC and MYCN have been suggested as drivers for a subset of these tumors, with MYC amplifications (17-20%) representing the most common genetic alteration in Group 3 tumors, while MYCN amplifications (4-6%) are less frequent. In order to study MYC/MYCN-driven Group 3 MB and improve current treatment options for these patients, it is of crucial importance to decipher differential features of MYCN- and MYC-driven tumors and to establish accurate animal models for both groups of patients. Driving MYC from the hindbrain-specific Glutamate transporter 1 (Glt1) promoter using a Tet-OFF system we have established a novel murine model of spontaneous MYC-driven MB (GMYC), which accurately recapitulates aggressive Group 3 MB. GMYC tumours develop with ~70% penetrance and tumor-prone GMYC mice can be cured by MYC-depletion through dox treatment. Comparison of transcriptional profiles between GMYC and our MYCN-driven GTML tumors revealed that both models accurately represent Group 3 MB, while showing differential expression of key features of MYC- or MYCN-driven tumours. CDKN2A was identified as one of the top upregulated genes in our GTML model as compared to our GMYC model. CDKN2A encodes the tumor suppressors p16INK4A and p14ARF, which act as key regulators of cell cycle progression and activation/stabilization of p53. Similar enhancement of this gene was observed in MYCN-amplified as compared to MYC-amplified Group 3/4 patients. Ongoing analyses will explore the effects on tumour formation/progression following partial or complete knockout of CDKN2A in both mouse models.
Gastrointestinal stromal tumours: Retrospective review of an institution
Authors: A. Silva, H. Magalhães, C. Vieira, A. Ferreira, J. Dinis, M. Soares
Journal: Annals of Oncology (2018)

Introduction: Gastrointestinal stromal tumours (GIST) are rare tumours, accounting 1-3% of all gastrointestinal (GI) cancers. Our purpose was to review the experience of a single institution in advanced GIST, aiming on demographics, treatment and outcomes. Methods: Retrospective analysis of patients with unresectable e/or metastatic GIST between January 2003 and December 2016 in our institution. Descriptive analysis and survival evaluation was determined by Kaplan-Meier method. Evaluation of differences between survival curves was calculated by log rank test. Results: From the 62 patients included, 34 (54.8%) were male, and the median age was 62,5 years (range: 37-79). The majority of patients had an ECOG PS 0-1 at diagnosis of advanced disease (n = 47, 75.8%). The most common presenting symptoms were abdominal pain (n = 14; 22.6%) and GI bleeding (n = 9; 14.5%). Primary tumour site was predominantly in the stomach (50%) and small intestine (32.3%). At time of diagnosis, 42 patients (67.8%) presented with locally advanced or metastatic disease. The most common metastatic sites were liver (n = 34; 54.8%) and peritoneum (n = 35; 56.5%). Mutation in KIT exon 11 was present in 26 patients (41.9%). Surgery was performed in 51 patients (82.2%). First line treatment with imatinib had an overall response rate (ORR) of 53.2%; median time of treatment was 26.5 months (range 1-146). Adverse events happened in 45 patients (72.6%), the most common were oedema (41.9%), followed by diarrhea, nausea and abdominal pain. One patient discontinued treatment for persistent grade (G) 2 GI toxicity. Twenty patients (32.3%) received second line treatment with imatinib 800mg/d, with toxicity of any grade in 10 patients, mainly G1; one patient had oedema G3, warranting dose reduction. ORR was 15%. Seventeen patients (27.4%) were treated with sunitinib, with 17.6% of ORR. Almost all patients (82.3%) had adverse events; 4 patients (23.5%) had toxicity G ≥ 3. Four patients received regorafenib (6.5%), with ORR of 25%. Two patients had hand-foot syndrome demanding dose reduction. Median overall survival was 108.1 months (95% CI 47.7-168.4). Conclusion: The results obtained in our sample are in agreement with the existing literature. All patients should be managed by a multidisciplinary team in a reference centre.
Neutrophil-to-lymphocyte ratio as a predictive or prognostic factor for gastric cancer treated with nivolumab: A retrospective study
Authors: T. Ogata, H. Satake, M. Ogata, Y. Hatachi, H. Yasui
Journal: Annals of Oncology (2018)

Introduction: The ATTRACTION-2 study showed that nivolumab is an effective treatment for advanced gastric cancer (AGC). Many studies have examined the effectiveness of predictive factors, such as programmed death ligand-1, mismatch repaired deficiency, and mutation burden. Several studies have demonstrated that the neutrophil-to-lymphocyte ratio (NLR) is effective as a predictive or prognostic factor for lung cancer treated with nivolumab. The objective of this study was to determine the effectiveness of NLR for AGC treated with nivolumab monotherapy. Methods: This study was a retrospective study in a single center and we collected data on patients with AGC treated with nivolumab from June 2017 to December 2017. The NLRs were calculated before the first cycle (NLR pre) and two weeks after the first cycle (NLR post) of nivolumab. The parameters were tested for their association with progression-free survival (PFS) and overall survival (OS). Results: Twenty-two patients (pts) were enrolled, and the median age was 64 years. Fifteen pts were male, and seven pts were female. Regarding the Eastern Cooperative Oncology Group performance status, twenty pts had a scores of 1 and two pts had scores of 2. The overall response rate was 13.6% (complete response, one pt; partial response, two pts), and the disease control rate was 40.9% (stable disease, six pts). With a median follow-up period of 140 days, the median PFS was 52 days (range, 11–265) and the median OS was not reached. The median NLR pre and NLR post were 2.42 (range, 1.00–17.4) and 2.84 (range, 1.27–12.3), respectively. Stratified with high NLR (≥5) and low NLR (<5), the median PFS was shorter in the high NLR pre arm (57 days vs. 45 days; p = 0.161) and significantly shorter in the high NLR post arm (67 days vs. 21 days; p = 0.015). The median OS was also shorter in the high NLR pre arm (not reached vs. 175 days; p = 0.068) and significantly shorter in the high NLR post arm (not reached vs. 111 days; p = 0.012). Conclusion: NLR, especially NLR post, might be effective as a predictive or prognostic factor in gastric cancer treated with nivolumab monotherapy. Further study is warranted to develop this finding to detect progression cases as early as possible.
G-quadruplex DNA targeting alters class-switch recombination in B cells and attenuates allergic inflammation
Authors: Zeinab Dalloul, Pauline Chenuet, Iman Dalloul, François Boyer, Jean-Claude Aldigier, Brice Laffleur, Yolla El Makhour, Bernhard Ryffel, Valerie F.J. Quesniaux, Dieudonnée Togbé, Jean-Louis Mergny, Jeanne Cook-Moreau, Michel Cogné
Journal: Journal of Allergy and Clinical Immunology (2018)
The Human Placenta in Diabetes and Obesity: Friend or Foe? The 2017 Norbert Freinkel Award Lecture
Authors: Gernot Desoye
Journal: Diabetes Care (2018)

The placenta plays a key role in sustaining fetal growth and development. Due to its position between mother and fetus, it is exposed to changes in the intrauterine environment in both circulations. The relative influence of changes in those circulations depends on the period of gestation. Early in pregnancy, maternal influences prevail and may affect the complex biological processes characteristic for this pregnancy period, such as placentation, early cell differentiation, and spiral artery remodeling. It is still unclear whether the placenta early in pregnancy is a friend or foe for the fetus. Later in pregnancy, when the fetal circulation is gradually establishing, fetal signals gain importance in regulating placental structure and function. Many of the placental alterations seen at term of pregnancy are the result of fetoplacental interactions often driven by fetal signals associated with maternal diabetes or obesity. These alterations, such as hypervascularization or enhanced cholesterol removal from placental endothelial cells, can be regarded as adaptations to maintain homeostasis at the fetoplacental interface and, thus, to protect the fetus. However, extreme conditions such as poorly controlled diabetes or pronounced obesity may exceed placental homeostatic capacity, with potentially adverse consequences for the fetus. Thus, in late pregnancy, the placenta acts mostly as a friend as long as the environmental perturbations do not exceed placental capacity for mounting adaptive responses.
Neurovascular Stent Caution
Authors: Rebecca Voelker
Journal: JAMA (2018)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
NFM-06. NF106: PHASE 2 TRIAL OF THE MEK INHIBITOR PD-0325901 IN ADOLESCENTS AND ADULTS WITH NF1-RELATED PLEXIFORM NEUROFIBROMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY
Authors: Brian Weiss, Scott Plotkin, Brigitte Widemann, James Tonsgard, Jaishri Blakeley, Jeffrey Allen, Elizabeth Schorry, Bruce Korf, Tena Rosser, Stewart Goldman, Alexander Vinks, Gary Cutter, Eva Dombi, Nancy Ratner, Roger Packer, Michael Fisher
Journal: Neuro-Oncology (2018)

Plexiform neurofibromas (PNs) can cause significant disfigurement, compression of vital structures, neurologic dysfunction, and pain. MEK pathway inhibition results in significant PN shrinkage in neurofibromatosis type 1 (NF1) mouse models of PN. We evaluated the efficacy of the MEK inhibitor, PD0325901, in adolescents (≥ 16 years of age) and adults with symptomatic or growing NF1-PN in a phase II open label study. The primary aim was to assess tumor response by cycle 12 using centrally read MRI, defined as at least 20% decrease in tumor volume from baseline. Subjects received PD-0325901 by mouth twice daily at 2 mg/m2/dose (maximum dose 4 mg bid). Each course was 4 weeks, and subjects received drug on a 3 week on / 1 week off schedule. NF106 enrolled 19 subjects (7M;12F) in two stages with a median age of 24 years (range 16-39 years). The mean PN volume was 797.8 mL. Eight subjects (42.1%; 95% CI: 20%, 67%) had a response. PD0325901 was well tolerated, with the most common dose limiting toxicity being acneiform rash in 3/19 patients (16%). Five subjects (26.3%) developed Grade 3 toxicities, mostly pain (4/19; 21%). No subjects developed Grade 4 or higher toxicities. Five subjects (26.3%) had a dose reduction for toxicity: one for Grade 3 abdominal and back pain, the others for intolerable Grade 1-2 nausea, rash, or fatigue. This study demonstrated that PD0325901 is well tolerated and results in PN shrinkage in 42% of adolescent and adult subjects with NF1-PN. Supported by DOD Award W81XWH-12-1-0155.
De novo variants in neurodevelopmental disorders with epilepsy
Authors: Henrike O. Heyne, Tarjinder Singh, Hannah Stamberger, Rami Abou Jamra, Hande Caglayan, Dana Craiu, Peter De Jonghe, Renzo Guerrini, Katherine L. Helbig, Bobby P. C. Koeleman, Jack A. Kosmicki, Tarja Linnankivi, Patrick May, Hiltrud Muhle, Rikke S. Møller, Bernd A. Neubauer, Aarno Palotie, Manuela Pendziwiat, Pasquale Striano, Sha Tang, Sitao Wu, Annapurna Poduri, Yvonne G. Weber, Sarah Weckhuysen, Sanjay M. Sisodiya, Mark J. Daly, Ingo Helbig, Dennis Lal, Johannes R. Lemke
Journal: Nature Genetics (2018)
EMBR-01. MOLECULAR AND CLINICAL HETEROGENEITY IN HISTOLOGICALLY-DIAGNOSED CNS-PNET PATIENTS PROSPECTIVELY TREATED AS A SINGLE ENTITY: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP ACNS0332 TRIAL
Authors: Eugene Hwang, Marcel Kool, Peter Burger, David Capper, Lukas Chavez, Sebastian Brabetz, Chris Williams-Hughes, Catherine Billups, Linda Heier, Alok Jaju, Jeff Michalski, Yimei Li, Sarah Leary, Tianni Zhou, Andreas vonDiemling, David TWJones, Maryam Fouladi, Ian Pollack, Amar Gajjar, Roger Packer, Stefan Pfister, James Olson
Journal: Neuro-Oncology (2018)

Children with high-risk medulloblastoma, supratentorial primitive neuroectodermal tumor (CNS-PNET) and pineoblastoma (PBLs) have poor survival and were enrolled in this prospective trial. However, subsequent molecular profiling uncovered diagnostic discrepancies not detectable at protocol inception. Outcomes for patients with CNS-PNET/PBL are reported here. In this phase 3 trial, children aged 3–22 years with newly-diagnosed CNS-PNET/PBL were randomly assigned to receive carboplatin during radiation and/or adjuvant isotretinoin after standard intensive therapy. DNA methylation profiling was retrospectively completed in patients with sufficient tissue. Out of eighty-five participants with institutionally-diagnosed CNS-PNETs/PBLs, 60 patients underwent molecular analysis. 31/60 were non-pineal in location, of which 22 (71%) represented tumors not intended for trial inclusion, including 18 high-grade gliomas (HGG), two atypical teratoid rhabdoid tumors, and two ependymomas. Retrospective central review was more consistent with molecular diagnosis, but maintained the discrepancy in some cases. Outcomes across tumor types were strikingly different. Patients with supratentorial embryonal tumors/PBLs exhibited 5-year event-free (EFS) and overall survival (OS) of 62.8% (95%CI,43.4%-82.2%) and 78.5% (95%CI,62.2–94.8%), respectively, while patients with molecularly-classified HGG had EFS/OS of 5.6% (95%CI,0%-13.0%) and 12.0% (95%CI,0%-24.7%), respectively. Neither carboplatin nor isotretinoin significantly altered outcomes. Survival for patients with HGG was similar to historic studies without craniospinal irradiation or intensive chemotherapy. For patients with CNS-PNETs/PBLs, prognosis is considerably better than previously assumed when molecularly-confirmed HGG are removed. Identification of HGG may spare children from unhelpful intensive treatment. This trial highlights the challenges of histology-based diagnosis and indicates that molecular profiling should become a standard component of initial diagnosis.
Novel HDAC inhibitor, LBH589, potently blocks growth of Ph-negative acute lymphoblastic leukemia (ALL) cells and induces expression of DNA damage response genes
Authors: Anna Scuto, Mark Kirschbaum, Agnes Juhasz, Leo Kretzner, Stephen Forman, Yun Yen, Richard Jove
Journal: Cancer Research (2007)

698  Histone deacetylases (HDACs) catalyze deacetylation of both histones and non-histone proteins, thereby regulating gene expression and protein function. Aberrant recruitment of HDACs has been shown to have an important role in leukemogenesis, and HDAC inhibitors are being studied widely for potential cancer therapy. In this study we evaluated the antitumor efficacy and mechanism of action of LBH589, an HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). Because relapsed ALL remains common, treatment of ALL cells with an HDAC inhibitor offers an appealing strategy, potentially promoting reactivation of genes that suppress the growth of tumor cells. Two model human Ph- ALL cell lines (T-cell MOLT-4, and non-T non-B cell Rhe) were treated with LBH589 and evaluated in terms of biological and gene expression responses. Our results show that low concentrations (10 nM) of LBH589 induced potent cell cycle arrest and apoptosis in a time- and dose-dependent manner in both cell lines. Western blot analyses revealed that the antitumor activities of LBH589 correlate with induction of histone (H3 and H4) hyperacetylation, elevation of p21 and p27, and suppression of c-Myc in the two cell lines treated. Using gene expression arrays, we determined the effects of LBH589 on the expression of proliferation, apoptosis and DNA damage response genes. Our data show that LBH589 treatment induced significant increases in mRNA levels of pro-apoptotic, growth arrest and DNA repair genes, some of which were previously reported to be epigenetically down-regulated in human malignancies. With quantitative real time PCR, we confirmed that LBH589 induces expression of FANCG, FOXO3A, GADD45A, GADD45B and GADD45G genes. Significantly, GADD45G, which induces growth arrest in response to DNA damage, was the most dramatically expressed gene after treatment with LBH589. Finally, chromatin immunoprecipitation (ChIP) assay results showed increased histone acetylation at the GADD45G promoter following treatment with LBH589. In sum, LBH589 possesses potent antitumor activity against Ph- ALL cells that correlates with induction of histone hyperacetylation and expression of genes critical for cell cycle arrest, apoptosis and DNA repair. Therefore, LBH589 represents a potential new therapeutic option for Ph- ALL treatment, which may result in higher complete remission rates in combination with conventional therapies.