tbuckley/cabot-search huggingface dataset:
Comparative effectiveness of preoperative, postoperative and perioperative treatments for resectable gastric cancer: A network meta-analysis for the literature of past 20 years
Authors: Z. Cai, Y. Yin, C. Shen, B. Zhang
Journal: Annals of Oncology (2018)

Introduction: Different preoperative, postoperative or perioperative treatment strategies including chemotherapy or chemoradiotherapy are available for patients with gastric cancer, but conventional meta-analyses assessing two alternative treatments were not powered to compare differences in overall survival. Thus, we did a network meta-analysis to identify the best treatment strategy. Methods: We systematically searched and assessed studies for eligibility, extracted data. We then pooled the data and conducted a bayesian network meta-analysis to combine direct comparisons with indirect evidence. Node-splitting method was used to assess the inconsistency. Rank probabilities were assessed by probability of treatments rankings. Results: 33 eligible randomized controlled trials were included in the network meta-analysis. Four treatments which were shown to have a significantly improved prognosis compared with surgery only were postoperative chemotherapy [HR = 0.80 with 95% CrI: (0.73, 0.88)], postoperative chemoradiotherapy [HR = 0.73 with 95% CrI: (0.61, 0.87)], preoperative chemoradiotherapy [HR = 0.77 with 95% CrI: (0.62, 0.98)] and perioperative chemotherapy [HR = 0.69 with 95% CrI: (0.55, 0.84)]. Preoperative chemotherapy however, showed no survival benefits when compared with surgery alone [HR = 0.94 with 95% CrI: (0.71, 1.2)]. There was no statistically significant difference between postoperative chemotherapy, postoperative chemoradiotherapy, preoperative chemoradiotherapy and perioperative chemotherapy in term of overall survival. Chemoradiotherapy after D2 lymphadenectomy did not significantly improve OS as compared with postoperative chemotherapy. [HR = 0.95 with 95% CrI: (0.73, 1.3)]. Conclusion: Among patients with operable gastric cancer the perioperative chemotherapy had the highest probability of being the best treatment. Further clinical resources may be required to assess the efficacy and safety of the perioperative chemotherapy for patients with gastric cancer.
MBRS-51. SINGLE CELL TRANSCRIPTOMIC ANALYSIS DEFINES DISCRETE SUBPOPULATIONS IN SHH-DRIVEN MEDULLOBLASTOMAS THAT ARE DIFFERENTIALLY AFFECTED BY VISMODEGIB
Authors: Jennifer Ocasio, Benjamin Babcock, Alejandro Colaneri, Michael Taylor, Kirk Wilhelmsen, Timothy Gershon
Journal: Neuro-Oncology (2018)

The use of SMO inhibitors for SHH-subtype medulloblastoma has been both promising and problematic. The SMO inhibitor vismodegib met safety and efficacy criteria to be FDA-approved for the treatment of basal cell carcinoma. In medulloblastoma, however, vismodegib therapy has been complicated by the emergence of resistance during treatment. We hypothesized that resistance is driven by a subset of cells with medulloblastomas that remain proliferative despite SMO inhibition and eventually drive recurrence. To test this hypothesis, we modeled vismodegib therapy in transgenic mice engineered to develop SHH-subtype medulloblastomas, driven by a constitutively active allele of Smo. We found that vismodegib induced an initial response, as in humans, but that tumors invariably progressed. We then used high-throughput single cell transcriptomic analysis (Drop-seq) to investigate how individual cells responded to vismodegib. Briefly, we paired individual dissociated cells with single bar-coded oligo-dT-bearing beads in nanoliter-scale droplets, then synthesized and sequenced cDNA libraries and disaggregated the resulting data using the cell-specific bar codes. The resulting cell-specific expression data allowed us to analyze the transcriptomes of >30,000 cells. From these data, we identified discrete cell types within the tumors, including subsets of proliferative and differentiating tumor cells, and also non-neoplastic glia, immune and endothelial cells. Vismodegib increased the size of differentiating subpopulations and reduced the population of the proliferative cell types. However, a subset of cells in vismodegib-treated tumors remained proliferative. These data support the hypothesis that resistance emerges from diversity already present before treatment, and identify resistant cells that must be targeted to improve therapy.
ATRT-23. SMARCB1-DEPENDENCIES IN ATYPICAL TERATOID/RHABDOID TUMOURS: A STRATEGY FOR PRE-CLINICAL THERAPEUTIC TARGET IDENTIFICATION IN THE ABSENCE OF ACTIONABLE MUTATIONS
Authors: Martina Anna Finetti, Matthew p Selby, Alicia del-Carpio Pons, Sarah Batting, James A Wood, James M Barker, Amanda Smith, Stephen Crosier, Matthew Bashton, Jessica C Pickles, Amy R Fairchild, Aimee Avery, Patricia O’Hare, Barry Pizer, Bernadette Brennan, Stephen Lowis, Darren Hargrave, Thomas S Jacques, Simon Bailey, Steven C Clifford, Daniel Williamson
Journal: Neuro-Oncology (2018)

ATRTs have low mutation rates and few classically-actionable variants to direct molecularly targeted therapies; loss of SMARCB1 is the sole recurrent mutational event in >90% of ATRTs. We have designed and implemented a genome-scale strategy for target identification and prioritization in tumors devoid of significant actionable mutations. Re-expression of SMARCB1 causes ATRT cells to cease proliferation and differentiate; we therefore hypothesized that identifying and counteracting critical downstream SMARCB1-dependent events represents a primary route to therapeutic intervention. We identify such events using an integrated genome-wide approach encompassing genome-scale CRISPR/Cas9 functional screens (GeCKO screening; 122,411 sgRNAs) alongside expression/DNA methylation profiling of primary ATRTs and ATRT cells following SMARCB1 re-expression and/or treatment with demethylating agents. Cross-referencing these analyses, we use a rational selection algorithm, to identify critical tumorigenic genes/pathways and proceed to validate their ability to be targeted as therapeutic targets. Our strategy identifies, ranks and prioritizes multiple SMARCB1-dependent pathways/genes functionally essential to ATRT, and characteristic of the primary tumour; including those previously described (Rb/CDK4/6, SHH, MYC), those less well evidenced (mTOR, TGF-β, HGF, Stat3/Jak) and novel SMARCB1-dependent synthetic lethalities (NuA4 complex, PIM1). We also describe the repressive genome-wide effect of SMARCB1 mutation on the transcriptome, through altered SWI/SNF binding, associated histone marks and localized hypermethylation and the therapeutic possibilities implied therein. Data and web-based interactive analysis and visualization tools will be made publically available to help guide and benchmark future pre-clinical testing in ATRT. This study pinpoints SMARCB1-dependent therapeutic susceptibilities in MRTs with the capacity to inform future treatment strategies.
DIPG-10. THE ONCOGENIC ROLE OF THE SUPER ELONGATION COMPLEX IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: Nathan A Dahl, Sujatha Venkataraman, Ilango Balakrishnan, Krishna Madhavan, Susan Fosmire, Rajeev Vibhakar
Journal: Neuro-Oncology (2018)

Mutations in the histone 3 (H3) gene (H3K27M) are the eponymous driver in diffuse midline gliomas (DMGs). Emerging understanding of H3K27M biology suggests that secondary cooperating factors are required to promote oncogenesis. We have identified AFF4, a component of the super elongation complex (SEC), as critical for DMG viability. We hypothesized that AFF4 promotes DMG tumorigenesis by co-operating with the H3K27M mutation to drive a gene expression program which suppresses scheduled transcription of pro-differentiation pathways and promotes self-renewal of tumor stem cells. We initially performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in a patient-derived DMG cell line. We validated initial hits in secondary screens using multiple shRNA constructs. Live cell imaging systems were utilized to assay growth and neurosphere formation. Finally, we employed RNA-seq-based gene expression analysis to delineate downstream transcriptional changes under AFF4 regulatory control. We found that AFF4 expression is consistently elevated in DMG lines relative to normal pons, and AFF4 inhibition results in decreased rates of growth and stem cell maintenance uniquely within the context of the H3K27M mutation. Further mechanistic studies will lay the groundwork for pre-clinical validation of SEC inhibition as a novel therapeutic approach in DMG.
Canada’s parliament legalises recreational marijuana
Authors: Owen Dyer
Journal: BMJ (2018)

Canada will become the first G7 nation to legalise the recreational consumption of marijuana, after a federal government bill cleared its final legislative hurdle this week (19 June).

The Senate voted in favour of the legislation by 52 votes to 29, with two abstentions. Canada’s third biggest party, the New Democrats, voted with the Liberal government. It will allow over 18s to carry and share a maximum of 30 g of legal marijuana in public. Consumers will be expected to buy marijuana from retailers regulated by provinces, territories, or federally licensed producers, and the drug will not be sold …
“I will survive”: A tale of bacteriophage-bacteria coevolution in the gut
Authors: Luisa De Sordi, Marta Lourenço, Laurent Debarbieux
Journal: Gut Microbes (2018)

Viruses that infect bacteria, or bacteriophages, are among the most abundant entities in the gut microbiome. However, their role and the mechanisms by which they infect bacteria in the intestinal tract remain poorly understood. We recently reported that intestinal bacteria are an evolutionary force, driving the expansion of the bacteriophage host range by boosting the genetic variability of these viruses. Here, we expand these observations by studying antagonistic bacteriophage-bacteria coevolution dynamics and revealing that bacterial genetic variability is also increased under the pressure of bacteriophage predation. We propose a model showing how the expansion of bacteriophage-bacteria infection networks is relative to the opportunities for coevolution encountered in the intestinal tract. Our data suggest that predator-prey dynamics are perpetuated and differentiated in parallel, to generate and maintain intestinal microbial diversity and equilibrium.
The effect of surgical weight loss on obstructive sleep apnoea: A systematic review and meta-analysis
Authors: Ai-Ming Wong, Hayley N. Barnes, Simon A. Joosten, Shane A. Landry, Eli Dabscheck, Darren R. Mansfield, Shyamali C. Dharmage, Chamara V. Senaratna, Bradley A. Edwards, Garun S. Hamilton
Journal: Sleep Medicine Reviews (2018)
RONC-05. NEUROLOGIC COMPROMISE AND OUTCOME AFTER PROTON BEAM THERAPY (PBT) FOR POSTERIOR FOSSA TUMORS (PFTs) OF CHILDHOOD
Authors: Aimee Sato, Jonathan Murnick, Matthew Ladra, Elizabeth Wells, Lindsay Kilburn, Eugene Hwang, Roger Packer
Journal: Neuro-Oncology (2018)

The outcomes and neurologic status of patients after PBT have been incompletely characterized, although radiographic changes have been described. The neurologic status of 29 consecutive children treated with PBT (a median of 44 months of age, range 17mo-13yrs) with PFTs (16 embryonal, 9 ependymoma, and 4 gliomas) was retrospectively assessed, and correlated to neuroradiographic findings. Median RT dose was 54GyRBE (range, 50.4-59.4GyRBE). Twenty-five of 29 patients (86%) had evidence of PBT-associated neuroradiographic change. At initial detection of neuroradiographic change, which occurred at a median of 4 months after PBT (range 1-12mo), 10 patients were symptomatic, including new or worsening ataxia (n=6), hemiparesis (n=4), and/or lower brainstem dysfunction (n=7). Four asymptomatic patients became symptomatic over the ensuing 6 months, including 2 who developed severe lower brainstem dysfunction and ataxia/hemiparesis. Eight of 15 symptomatic patients worsened during the year following initial radiographic change, including 3 who died of radiation-induced autopsy-proven brainstem injury; 4 patients improved but remained impaired, 1 was stable, and 2 returned to baseline. MR changes of all patients were scored by a neuroradiologist blinded to clinical status, on a novel neuroradiographic- damage scale (0 to 27) based on extent and location of signal abnormality, diffusion restriction, enhancement, and hemorrhage. Radiation change ranged between 0 and 18, with higher scores associated with poorer neurological outcome. Neurologic changes can occur after PBT for PFTs, dysfunction may occur early, can be progressive and fatal, and may result in ongoing neurologic dysfunction at least 1 year after initial radiographic detection.
Mitochondrial Supercomplexes Do Not Enhance Catalysis by Quinone Channeling
Authors: Justin G. Fedor, Judy Hirst
Journal: Cell Metabolism (2018)

Mitochondrial respiratory supercomplexes, comprising complexes I, III, and IV, are the minimal functional units of the electron transport chain. Assembling the individual complexes into supercomplexes may stabilize them, provide greater spatiotemporal control of respiration, or, controversially, confer kinetic advantages through the sequestration of local quinone and cytochrome c pools (substrate channeling). Here, we have incorporated an alternative quinol oxidase (AOX) into mammalian heart mitochondrial membranes to introduce a competing pathway for quinol oxidation and test for channeling. AOX substantially increases the rate of NADH oxidation by O2 without affecting the membrane integrity, the supercomplexes, or NADH-linked oxidative phosphorylation. Therefore, the quinol generated in supercomplexes by complex I is reoxidized more rapidly outside the supercomplex by AOX than inside the supercomplex by complex III. Our results demonstrate that quinone and quinol diffuse freely in and out of supercomplexes: substrate channeling does not occur and is not required to support respiration.
Muscular weakness in adolescence is associated with disability 30 years later: a population-based cohort study of 1.2 million men
Authors: Hanna Henriksson, Pontus Henriksson, Per Tynelius, Francisco B Ortega
Journal: British Journal of Sports Medicine (2018)

Objective To investigate the associations of muscular strength in adolescence with later disability pension (DP), across different body mass index (BMI) categories and in combination with aerobic fitness. Method This prospective cohort study consisted of males aged 16–19 years, recruited from the Swedish military conscription register between 1969 and 1994. A total of 1 212 503 adolescents met all the inclusion criteria and were therefore included in the analyses. Knee extension, handgrip and elbow flexion strength and aerobic fitness (bicycle ergometer test) were measured during conscription. Causes of DP were retrieved from the Social Insurance Office between years 1971 and 2012 (average follow-up time: 29.6 years). Results Knee extension strength in adolescence was inversely associated with men’s risk of obtaining DP due to all causes (HR 1.40, 95% CI 1.36 to 1.44 for lowest vs highest strength quintile). Thus, muscular weakness was associated with DP. The risk associated with low muscular strength differed between specific causes of DP and the strongest associations were found for psychiatric, nervous system and other causes (HRs between 1.47 and 1.90 for lowest vs highest quintile). Being strong was associated with lower DP risk across BMI categories and being unfit, weak and obese was associated with the highest DP risk (HR 3.70, 95% CI 2.99 to 4.58). Conclusion There was a strong association between muscular weakness and disability. A combination of muscular weakness and low aerobic fitness was an especially important risk factor for disability. This adds weight to call for muscular strength and fitness enhancing exercise for adolescents in all BMI categories.
Исследование трофологической недостаточности у больных хроническим панкреатитом в возрастном аспекте
Authors: L.S. Babinets, N.A. Shevchenko
Journal: GASTROENTEROLOGY (2018)

Актуальность. Хронический панкреатит (ХП) — это заболевание с тяжелым течением, приводящее со временем к нарушению всех видов обмена и прогрессированию трофологической недостаточности с увеличением возраста пациентов. Цель. Лабораторное исследование ряда показателей витаминного и минерального обмена в крови пациентов с ХП в зависимости от их биологического возраста. Материалы и методы. Обследование 218 больных ХП в возрастном аспекте на основании количественного исследования некоторых показателей витаминного и минерального обмена в крови. Результаты. Исследование трофологической недостаточности пациентов с ХП в зависимости от их биологического возраста свидетельствует о том, что возраст больных является предиктором витаминной и минеральной недостаточности, а также накопления токсических минералов в сыворотке крови обследуемых пациентов. Выводы. Полученные данные свидетельствуют о том, что возраст больных ХП является предиктором витаминной и минеральной недостаточности, накопления токсических минералов, что необходимо учитывать при формировании комплексного лечения данной категории пациентов.
Safety and antitumor activity of pembrolizumab in patients with advanced microsatellite instability–high (MSI-H) colorectal cancer: KEYNOTE-164
Authors: D. Le, P. Kavan, T. Kim, M. Burge, E. Van Cutsem, H. Hara, P. Boland, J. Van Laethem, R. Geva, H. Taniguchi, T. Crocenzi, M. Sharma, C. Atreya, L. Diaz, L. Liang, P. Marinello, T. Dai, B. O’Neill
Journal: Annals of Oncology (2018)

Introduction: Approval of pembrolizumab as treatment for adult and pediatric patients with unresectable or metastatic previously treated MSI-H or mismatch repair–deficient cancer, regardless of tumor type or site, was partly based on data from cohort A of the phase 2 KEYNOTE-164 (NCT02460198) study of patients with MSI-H colorectal cancer (CRC) after ≥2 prior lines of standard therapy. Data are presented herein from cohort B of KEYNOTE-164, which was conducted to evaluate pembrolizumab in patients with metastatic MSI-H CRC previously treated with ≥1 line of therapy. Methods: Cohort B of the KEYNOTE-164 study enrolled patients with metastatic CRC who had locally confirmed MSI-H status per immunohistochemistry or polymerase chain reaction and had received ≥1 prior line of therapy (irinotecan, oxaliplatin, fluoropyrimidine, or anti-vascular endothelial growth factor/endothelial growth factor receptor). Patients received pembrolizumab 200 mg every 3 weeks (Q3W) for 2 years or until progression, unacceptable toxicity, or withdrawal of consent. Tumor response was assessed per RECIST v1.1 by independent review Q9W. End points included objective response rate (ORR) (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary). Results: Sixty-three patients were enrolled; median age was 59 years (range: 23-83); 52% were male. Most patients (94%) had ≥1 prior therapy for advanced disease; median number of prior therapies was 2. As of September 12, 2017, median follow-up was 12.6 months (range: 0.1-15.4). ORR was 32% (95% CI, 21-45), with 2 complete responses and 18 partial responses. Median DOR was not reached (NR); 95% of responses were ongoing; and DOR for 75% of responders was ≥6 months. Median PFS was 4.1 months (95% CI, 2.1-NR) and median OS was NR. The 12-month PFS rate was 41% and the 12-month OS rate was 76%. Forty (64%) patients experienced treatment-related adverse events (AEs) of any grade, most commonly (≥10%) fatigue (18%), hypothyroidism (16%), and hyperthyroidism (11%). Seven (11%) patients had grade ≥3 treatment-related AEs of anemia, thrombocytopenia, diarrhea, pneumatosis intestinalis, pneumonitis, syncope, arthritis, and vasculitis (n = 1 each). There were no treatment-related deaths. Twenty (32%) patients had immune-mediated AEs of any grade. Two (3%) patients had grade ≥3 immune-mediated AEs of pneumonitis and colitis (n = 1 each). Conclusion: Pembrolizumab demonstrated durable antitumor activity with a safety profile that was manageable in cohort B of KEYNOTE-164, which was conducted to evaluate patients with MSI-H CRC whose disease progressed after ≥1 line of prior therapy.
EPEN-12. NOVEL PTCH1-INPPL1 FUSION IN A PATIENT WITH EXTRANEURAL METASTATIC EPENDYMOMA - A CASE REPORT
Authors: Gurcharanjeet Kaur, Ira Dunkel, Neerav Shukla, Ahmet Zahir, Matthias Karajannis
Journal: Neuro-Oncology (2018)

Extraneural metastatic spread of ependymoma is rare, and associated molecular genetic drivers are unknown. We report a 6 year-old male diagnosed with a right fronto-parietal tumor who underwent gross total resection in February, 2015. Pathology revealed anaplastic ependymoma and FISH was positive for RELA fusion. The patient received adjuvant proton beam radiation therapy. He developed locally recurrent disease with spinal metastasis at T8 level in May, 2016 and subsequent treatment included surgery, focal radiotherapy, everolimus and craniospinal irradiation. He received nivolumab for further disease progression, beginning in July, 2017. One week after treatment initiation, he was noted to have increasing abdominal girth, and CT abdomen and pelvis revealed liver, omental, and pleural based disease, which were confirmed to be metastatic ependymoma on biopsy. We performed next generation sequencing using MSK-IMPACTTM (Integrated Mutation Profiling of Actionable Cancer Targets) on samples for the primary and recurrent brain tumor, as well as metastatic disease. In the metastatic sample only, we identified a novel acquired t(9;11) translocation resulting in a PTCH1-INPPL1 fusion, t(9;11)(q22.32;q13.4)(chr9:g.98211830::chr11:g.71941318) with PTCH1 exons 1–21 fused with INPPL1 exons 10–28. Treatment with vismodegib was attempted, but not tolerated by the patient due to advanced disease. Our data suggests that inactivation of PTCH1 may drive extraneural metastasis of ependymoma, providing a target for molecular targeted therapy using sonic hedgehog pathway inhibitors. A patient derived xenograft from this patient’s tumor is pending confirmation of engraftment, and should provide opportunities for functional validation and therapeutic testing of the novel PTCH1-INPPL1 fusion.
DEV-17. WHO ARE THE HIGH RISK MEDULLOBLASTOMA SUBGROUPS IN JORDAN?
Authors: Nisreen Amayiri, Maisa Swaidan, Ahmad Ibrahimi, Nader Hirmas, Awni Musharbash, Eric Bouffet, Maysa Al-Hussaini, Vijay Ramaswamy
Journal: Neuro-Oncology (2018)

Medulloblastoma is comprised of four distinct molecular subgroups (WNT, SHH, Group3,Group4) with unique clinical and prognostic implications. However, this relationship is rarely reported in the Middle East. We assembled an institutional cohort of children<18 years diagnosed with medulloblastoma and received radiotherapy at KHCC/Jordan between 2003–2015 and subgrouped tumours using limited gene expression analysis. Eighty-one patients were identified (36% females) with median age 7.3years (2.9–17.6years). Twenty-six patients (32%) were M1-M3. Twenty-eight patients were treated as standard risk (SR, 47%) and 43 as high risk (HR, 53%). Subgrouping revealed 27 Group4 (33%), 20 SHH (25%), 20 Group3 (25%) and 14 Wnt (17%). The median time between craniotomy and radiotherapy was 45 days (17-155days). Median duration of radiotherapy was 44days (36-74days). Overall 5year EFS was 70.5 ± 6% and OS 68.8 ± 6.1%; statistically not significant between SR and HR (p=0.1). Absence of metastasis had survival advantage (OS 81.3 ± 6.9% for M0 and 43.6 ± 11% for M1-M3, p=0.001). SHH and Group4 tumors had very good OS (79.7 ± 10.7% and 81.5 ± 9.8% respectively). Metastatic Group4 did very well (OS 80 ± 17.9%) while metastatic Group3 had dismal OS (33.3 ± 13.5%). Unexpectedly, WNT patients had relatively poor OS (67.9 ± 15.9%). SHH and Group4 medulloblastomas had an excellent survival comparable to developed countries despite treatment delays. Strikingly, we observed lower survival of WNT subgroup, suggesting possible background differences compared to other cohorts. This highlights the importance of validation of molecular stratification in the developing world, and suggests that background genetic differences may underlie differences in therapy response.