tbuckley/cabot-search huggingface dataset:
<i>Lactobacillus rhamnosus</i>GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells
Authors: Terrence E Riehl, David Alvarado, Xueping Ee, Aaron Zuckerman, Lynn Foster, Vaishali Kapoor, Dinesh Thotala, Matthew A Ciorba, William F Stenson
Journal: Gut (2018)

Objective Lactobacillus rhamnosus GG (LGG), a probiotic, given by gavage is radioprotective of the mouse intestine. LGG-induced radioprotection is toll-like receptor 2 (TLR2) and cyclooxygenase-2 (COX-2)-dependent and is associated with the migration of COX-2+mesenchymal stem cells (MSCs) from the lamina propria of the villus to the lamina propria near the crypt epithelial stem cells. Our goals were to define the mechanism of LGG radioprotection including identification of the TLR2 agonist, and the mechanism of the MSC migration and to determine the safety and efficacy of this approach in models relevant to clinical radiation therapy. Design Intestinal radioprotection was modelled in vitro with cell lines and enteroids as well as in vivo by assaying clinical outcomes and crypt survival. Fractionated abdominal and single dose radiation were used along with syngeneic CT26 colon tumour grafts to assess tumour radioprotection. Results LGG with a mutation in the processing of lipoteichoic acid (LTA), a TLR2 agonist, was not radioprotective, while LTA agonist and native LGG were. An agonist of CXCR4 blocked LGG-induced MSC migration and LGG-induced radioprotection. LGG given by gavage induced expression of CXCL12, a CXCR4 agonist, in pericryptal macrophages and depletion of macrophages by clodronate liposomes blocked LGG-induced MSC migration and radioprotection. LTA effectively protected the normal intestinal crypt, but not tumours in fractionated radiation regimens. Conclusions LGG acts as a ‘time-release capsule’ releasing radioprotective LTA. LTA then primes the epithelial stem cell niche to protect epithelial stem cells by triggering a multicellular, adaptive immune signalling cascade involving macrophages and PGE2 secreting MSCs. Trial registration number NCT01790035 ; Pre-results.
Commentary: Sex work is here to stay and decriminalisation improves safety and social justice
Authors: Gillian Abel
Journal: BMJ (2018)

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MBRS-25. GENOMIC ANALYSES REVEALED RADIATION-INDUCED GLIOBLASTOMA IN A SUBSET OF RECURRENT MEDULLOBLASTOMAS
Authors: Ji Hoon Phi, Ae Kyung Park, Semin Lee, In-Pyo Baek, Eun-Hye Kim, Hee-Chul Park, Byung Chul Kim, Jong Bhak, Sung-Hye Park, Ji Yeoun Lee, Kyu-Chang Wang, Dong-Seok Kim, Kyun Won Shim, Se Hoon Kim, Chae-Yong Kim, Seung-Ki Kim
Journal: Neuro-Oncology (2018)

Despite advances in medulloblastoma treatment and research, recurrent medulloblastoma is still devastating. Additionally, misidentification of secondary malignancy due to histological ambiguity leads to misdiagnosis and eventual inappropriate treatment. Through deep-sequencing of RNA and whole-exome of recurrent tumors from 17 pediatric medulloblastomas, we found that 3 patients had radiation-induced glioblastoma rather than recurrent medulloblastomas. We also uncovered that PDGFRA is a putative driver in radiation-induced glioblastoma, which gives an insight into the possible application of PDGFRA-targeted therapy. The observation of frequent gain of 7q region containing EZH2 accompanied by its high expression both in primary and recurrent medulloblastomas provides a clue to new a therapeutic target to prevent recurrence.
TBIO-18. LIQUID BIOPSY DETECTION OF GENOMIC ALTERATIONS IN PEDIATRIC BRAIN TUMORS FROM CELL FREE DNA IN PERIPHERAL BLOOD, CSF, AND URINE
Authors: Melanie Pages, Denisse Rotem, Gregory Gydush, Sarah Reed, Justin Rhoades, Gavin Ha, Chris Lo, Adam Tracy, Robert Jones, Sarah Becker, Michaela Haller, Susan Chi, Mark Kieran, Liliana Goumnerova, J Christopher Love, Keith L Ligon, Pratiti Bandopadhayay, Karen Wright, Viktor A Adalsteinsson, Rameen Beroukhim
Journal: Neuro-Oncology (2018)

Brain tumors often require invasive neurosurgical procedures for diagnosis and tissue acquisition to guide precision medicine. Detection of tumor-derived cell-free DNA (cfDNA) would facilitate tumor profiling without risk of surgery-related morbidity and provide a means of tumor surveillance. Our aim is to validate a sample collection procedure and develop highly sensitive and specific methodologies to detect tumor-derived cfDNA in CSF, plasma and urine from pediatric patients with brain tumors to identify clinically relevant genomic alterations. Since July 2016, we have collected blood, urine and CSF samples from 192 patients across all histological subtypes at Dana-Farber Cancer Institute/Boston Children’s Hospital. In parallel, we sequenced the tumors to identify tumor-specific genomic alterations. We optimized a method to process cfDNA and perform ultra-low pass whole genome sequencing (ULP-WGS) using unique molecular identifiers, confirming we can reliably construct sequencing libraries from CSF-, plasma- and urine-derived cfDNA. ULP-WGS has also been used to assess sequencing library quality, copy number variations (CNVs) and tumor fraction. The vast majority of samples undergoing ULP-WGS exhibited no CNVs, consistent with either absence in the tumor or low levels of tumor-derived cfDNA. To distinguish between these, we developed a hybrid capture sequencing panel covering 46 genes, allowing identification of specific mutations and fusions more common in pediatric brain tumors. We are currently assessing the specificity and sensitivity of our assays for detection of tumor-derived cfDNA. Our results will provide insights regarding the feasibility of cfDNA assays to guide clinical care in children with brain tumors.
Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML
Authors: Oscar Brück, Sami Blom, Olli Dufva, Riku Turkki, Himanshu Chheda, Antonio Ribeiro, Panu Kovanen, Tero Aittokallio, Perttu Koskenvesa, Olli Kallioniemi, Kimmo Porkka, Teijo Pellinen, Satu Mustjoki
Journal: Leukemia (2018)

Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.
NURS-14. SUPPORTING ONGOING SCHOOL EDUCATION FOR CHILDREN WITH A CENTRAL NERVOUS SYSTEM TUMOUR DIAGNOSIS
Authors: Kate Fernandez
Journal: Neuro-Oncology (2018)

A diagnosis of cancer often/usually results in prolonged school absences and disengagement with formal education and peers. The importance of maintaining links with schools/education providers to assist with continuity of learning and social connections has been recognized and documented. As is also well documented, children diagnosed with a central nervous system (CNS) tumour have an even greater potential for ongoing learning issues due to treatment side effects. In 2015, the Women’s and Children’s Hospital Oncology Education Advisory Group (OEAG) was established including nursing, hospital education service (HES) leaders, allied health and psychology staff. The aim of this group was to implement an education support program for children for the duration of their cancer treatment and beyond. The Cancer Care Coordinator Central Nervous System Tumours (CCCCNST) nurse works closely with this group to ensure that a thorough plan is in place for children diagnosed with a CNS tumour. This includes but is not limited to, initial discussions with HES and CCCCNST to formulate an individual plan in collaboration with the family, school visit provided by CCCCNST, HES staff and other community support services as required, ongoing support for the school, access to tutoring programs for the child with a neuro oncology diagnosis, review of education plan at significant time points and long term follow up. The program has proved to be very successful with positive feedback from teaching staff and families. An overview of the model will be presented with feedback to date.
Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment
Authors: Takuya Kato, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Satoshi Komoto, Ryoichi Katsube, Takayuki Ninomiya, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara
Journal: Clinical Cancer Research (2018)

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression.Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3+ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues.Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820-33. ©2018 AACR.
EAPH-08. A PHASE I TRIAL OF TTFIELDS WITH AND WITHOUT CONCOMITANT TEMOZOLOMIDE AND BEVACIZUMAB IN PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMA
Authors: Derek Hanson
Journal: Neuro-Oncology (2018)

High-grade gliomas (HGG) comprise 8–12% of brain tumors in children and include anaplastic astrocytoma or glioblastoma multiforme (GBM) pathology. Treatment involves surgical resection, adjuvant radiation and chemotherapy. The prognosis of these tumors is poor and new therapies must be investigated to improve clinical outcomes for this patient population. Tumor Treating Fields (TTFs) is a non-invasive antimitotic treatment comprised of low-intensity alternating electric currents delivered through the Optune device approved for adults with GBM. This phase 1 study [NCT03128047] will include 2 cohorts of pediatric patients (N= 6–12), age ≥1 and <18 years, with histologically-confirmed supratentorial newly-diagnosed or recurrent HGG. This study will have two safety endpoints to assess the safety and tolerability of TTFields for the treatment of pediatric HGG both alone and in combination with temozolomide (TMZ) and bevacizumab (BEV). Cohort 1 will receive TTFields (200kHz 18 hours/day). Cohort 2 will receive TTFs plus BEV 10mg/kg/dose and TMZ 200 mg/m2/day. Safety endpoints will be determined by a standard 3 + 3 phase I study design based on the incidence and severity of adverse events and toxicities (CTC V4). There are no primary efficacy endpoints for this study. Patients will be followed to assess their progression-free and overall survival as the efficacy data gained from this study may be useful in designing future phase II/III investigations. The sample size will be determined by the number of observed severe adverse events related to therapy. A minimum of two and a maximum of twelve patients will be needed to complete this study.
Médecins Sans Frontières is focus of new sex scandal in charity sector
Authors: Sophie Arie
Journal: BMJ (2018)

The international medical charity Medecins Sans Frontieres (MSF) is facing allegations of abuse of power by its staff in Africa, where using local women for sex is “blatant and widespread” and sexual harassment of colleagues is “endemic,” eight former MSF staff have said.

The female whistleblowers, who spoke anonymously to the BBC, described the misconduct that they had seen in different African countries, all involving non-medical staff. In Kenya, one whistleblower said that senior staff brought local girls rumoured to be sex workers back to the agency’s accommodation. “They’d been there for a long time and took advantage of their exalted status as Western aid …
DIPG-64. REST MODULATES NEOVASCULATURE VIA REGULATION OF GREMLIN EXPRESSION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Shavali Shaik, Bridget Kennis, Shinji Maegawa, Keri Schadler, Yang Yanwen, Keri Callegari, Rishi Lulla, Stewart Goldman, Javad Nazarian, Veena Rajaram, Jason Fangusaro, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2018)

Children with diffuse intrinsic pontine glioma (DIPG) have an extremely poor survival. This underscores the desperate need for novel, biology-driven therapies. Here, we investigated the involvement of RE1 Silencing Transcription Factor (REST), a chromatin remodeler and regulator of brain development, in DIPG pathology. We discovered that when compared to normal controls, REST protein is significantly elevated in DIPG patient samples with H3K27M mutation. Compared to isogenic DIPG cell lines with endogenous REST expression, cells engineered to express higher levels of human REST transgene exhibited enhanced tumor growth. Surprisingly, REST elevation also caused an increase in tumor vasculature. In vitro, REST loss in DIPG cells caused a decrease in tube formation by human umbilical vein endothelial cells (HUVECs) and human brain microvascular endothelial cells (HBMECs), indicating that REST regulates the DIPG microenvironment. Mechanistically, we identified a bone morphogenic factor (BMP) signaling antagonist and ligand for VEGFR2, Gremlin-1 (GREM-1), as a downstream effector of REST-dependent changes in tumor vasculature. REST-dependent GREM-1 secretion promoted activation of AKT signaling in HUVECs and HBMECs. VEGFA-C levels were not significantly altered between normal and H3K27M mutant DIPGs and did not correlate with REST expression. In summary, our study is the first to demonstrate both tumor intrinsic and tumor extrinsic functions for REST in DIPG. The latter is of particular significance because it opens the door for re-evaluation of anti-angiogenic therapies targeting GREM-1, in DIPGs with REST elevation, possibly in combination with standard of care.
PCLN-06. NOVEL TUMOR-DERIVED MODELS OF CNS HGNET-BCOR PROVIDE INSIGHTS INTO UNDERLYING MOLECULAR MECHANISMS AND INNOVATIVE THERAPEUTIC OPTIONS
Authors: Johannes Gojo, Dominik Kirchhofer, Daniela Lötsch, Thomas Mohr, Christine Pirker, Kristian W Pajtler, Konstantin Okonechnikov, Bernhard Englinger, Bernd Boidol, Charles-Hugues Lardeau, Thomas Czech, Stefan Kubicek, Dominik Sturm, Stefan M Pfister, Andreas Peyrl, Christine Haberler, Marcel Kool, Walter Berger, Irene Slavc
Journal: Neuro-Oncology (2018)

Central nervous system high-grade neuroepithelial tumor with BCL6-corepressor alteration (CNS HGNET-BCOR) is a recently discovered molecular brain tumor entity characterized by genomic alterations of BCOR, a central component of a non-canonical polycomb repressive complex. However, the underlying oncogenic mechanisms and their consequences for tumor-specific anti-cancer therapy remain widely enigmatic. We systematically analyzed genomics, transcriptomics, and drug-sensitivity patterns in three tumor-derived models (two cell-lines, one primary cell-culture) from three consecutive intracranial CNS HGNET-BCOR metastases of one patient. All models harbored a unique frameshift mutation within BCOR resulting in a truncated protein lacking functionally important c-terminal protein domains. Re-expression of BCOR wild-type in our CNS HGNET-BCOR cell-models resulted in decreased cell proliferation and increased apoptosis. Interestingly, genes downregulated upon re-expression of BCOR wild-type were also derepressed in CNS HGNET-BCOR tumor tissues harboring BCOR-alterations different from our case (e.g. internal tandem duplication in BCOR). Via comparison with a chromatin immunoprecipitation DNA-sequencing dataset, we determined that a significant proportion of the corresponding gene promoters are occupied by BCOR in BCOR wild-type cancer cells. An additional drug-screen demonstrated hypersensitivity of CNS HGNET-BCOR cells against histone deacetylase inhibitors and histone methyltransferase inhibitors. Matching of drug sensitivity patterns to upregulated target-genes determined bortezomib, dasatinib, and crizotinib as promising tumor-specific therapeutics against CNS HGNET-BCOR. Taken together, our results suggest that dysfunction of BCOR-mediated gene repression determines the oncogenic behavior and transcriptomic profile of CNS HGNET-BCOR. Moreover, we provide preliminary results for potential pharmacological interventions against this aggressive tumor type.
Preoperative short course of radiotherapy in selected high risk patients
Authors: M. Caro Gallarín, H. Rosales González, J. Jové Teixidó, E. Luguera Sánchez, I. Planas Toledano, Y. Luis Dorta, G Antelo Redondo, E. Baena González, A. Álvarez Gracia, C. Bugés Sánchez, I. Camps Ausàs, S. Villà Freixa
Journal: Annals of Oncology (2018)

Introduction: Preoperative short course radiotherapy (SCRT) is considered a standard treatment in the management of locally advanced rectal cancer. However, in southern European countries, preoperative chemoradiotherapy is the preferred option, leaving SCRT only for those patients not suitable for combined treatment. Our aim was to retrospectively analyze the outcome of patients who have been treated with SCRT in our Institution. Methods: From 2006 to 2017, 68 patients (p) (50 men and 18 women) with a proven biopsy of adenocarcinoma of the rectum were treated with SCRT in our Department. The median age at diagnosis was 74 years (42-86). All patients were evaluated in a multidisciplinary tumor board and the reasons to indicate SCRT were: age> 80 years (25p), presence of synchronous metastases at diagnosis (21p), heart disease (7p), synchronous intestinal tumors (12p), unknown reason (3p). Dose delivered was 25 Gy in 5 fractions of 5 Gy, administered in prone position by 3D-conformal radiotherapy (3DCRT), with photons of 6-18 MV. In 65 (95.5%) patients, surgery was performed in the week following the end of 3DCRT. Results: With a mean follow up of 40 months, no acute or chronic toxicity was observed. Median overall survival (OS) was 42 months, median specific cancer survival (SCS) was 59 months and median disease-free survival (DFS) was 56 months. The 5 years OS, SCS and DFS was 43.5%, 59.6%, and 48.7% respectively. Only 2 local recurrences were observed, one of them in a patient who refused surgery once 3DCRT was finished. In the univariate data analysis, no significant difference was observed in the SCS or OS nor in the analysis of the SCRT indication subgroups, neither in the location of the tumor (lower 31%, middle 47%, upper 20% or unknown 2%). According to the staging we did not observe any differences in survival. However, for patients with T4 tumors median survival was 16 months, versus no T4 patients, in whom median was not reached (p < 0.001). In patients with a positive margin in the surgical specimen, the median survival was 43 months compared with negative margin patient subgroup in which median survival was not reached, with trend to significance (p 0.056). Adjusted to the state of the surgical margin, only T4 tumor was an independent factor in multivariate analysis for worse survival, with an estimated risk of death 5 folds higher than the rest of the stages (p 0.022). Conclusion: Despite being a group of selected patients with poor vital prognosis (due to age, metastasis or heart disease), we obtain a median overall survival of 59 months and only 2 local recurrences, with an excellent profile of acute and chronic toxicity, for all subgroups of patients and all tumor locations. In our analysis only T4 was a predictor for worse results.
Vascular Compartmentalization of Functional Hyperemia from the Synapse to the Pia
Authors: Ravi L. Rungta, Emmanuelle Chaigneau, Bruno-Félix Osmanski, Serge Charpak
Journal: Neuron (2018)

Functional hyperemia, a regional increase of blood flow triggered by local neural activation, is used to map brain activity in health and disease. However, the spatial-temporal dynamics of functional hyperemia remain unclear. Two-photon imaging of the entire vascular arbor in NG2-creERT2;GCaMP6f mice shows that local synaptic activation, measured via oligodendrocyte precursor cell (OPC) Ca2+ signaling, generates a synchronous Ca2+ drop in pericytes and smooth muscle cells (SMCs) enwrapping all upstream vessels feeding the activated synapses. Surprisingly, the onset timing, direction, and amplitude of vessel diameter and blood velocity changes vary dramatically from juxta-synaptic capillaries back to the pial arteriole. These results establish a precise spatial-temporal sequence of vascular changes triggered by neural activity and essential for the interpretation of blood-flow-based imaging techniques such as BOLD-fMRI.