tbuckley/cabot-search huggingface dataset:
MBRS-43. MODELLING MEDULLOBLASTOMA INVASION AND CHEMORESISTANCE IN A 3D HYALURONAN HYDROGEL SYSTEM
Authors: Franziska Linke, Catherine L R Merry, Anna M Grabowska, Snow Stolnik-Trenkic, Ian D Kerr, Beth Coyle
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant paediatric brain tumour. High rates of metastasis and chemoresistance demand new, subgroup specific therapy approaches. The development of reliable and realistic model systems will allow us to investigate and compare processes such as invasion and chemoresistance as well as the underlying pathways. We are using a hyaluronan (HA) based hydrogel system that mimics the cerebellum and can be further modified to higher complexity using additional extracellular matrix components. The four different molecular MB subgroups are characterized by different metastatic patterns and aspects of these are reflected by our model system. Group 3 cell lines demonstrate laminar coating whereas group 4 and SHH cells show mainly nodular growth. Using an isogenic and recurrent metastatic group 4 cell line pair we have been able to demonstrate that the cell lines grow and establish small tumour masses with diameters of more than 1mm when they are embedded in the HA hydrogel for several months. Those tumour cell masses attract single surrounding cells as well as smaller cell clusters. Interestingly, the recurrent cell line grows more aggressively in 3D and tumour cells are more resistant to chemotherapeutic reagents in the gel model. Our results highlight the potential of 3D model systems for MB clinical target evaluations. Further characterization of MB cell lines embedded in the hydrogel model will provide deeper insight into potential subgroup specific molecular targets in order to better treat and potentially prevent metastasis and chemoresistance.
Closing the Loop on Managing Youth With Type 1 Diabetes: Children Are Not Just Small Adults
Authors: Jennifer L. Sherr
Journal: Diabetes Care (2018)

As hybrid closed-loop (HCL) insulin delivery systems permeate clinical practice, it is critical to ensure all with diabetes are afforded the opportunity to benefit from this technology. Indeed, due to the suboptimal control achieved by the vast majority of youth with type 1 diabetes (T1D), pediatric patients are positioned to see the greatest benefit from automated insulin delivery systems. To ensure these systems are well poised to deliver the promise of more targeted control, it is essential to understand the unique characteristics and factors of childhood. Herein, the developmental and physiological needs of youth with T1D are reviewed and consideration is given to how HCL could address these issues. Studies of HCL technologies in youth are briefly reviewed. As future-generation closed-loop systems are being devised, features that could make this technology more attractive to youth and to their families are discussed. Integration of HCL has the potential to minimize the burden of this chronic medical condition while improving glycemic control and ultimately allowing our pediatric patients to fulfill the primary goal of childhood, to be a kid.
Long-term Patient-Reported Outcomes in Postmastectomy Breast Reconstruction
Authors: Katherine B. Santosa, Ji Qi, Hyungjin M. Kim, Jennifer B. Hamill, Edwin G. Wilkins, Andrea L. Pusic
Journal: JAMA Surgery (2018)

Previous outcome studies comparing implant and autologous breast reconstruction techniques have been limited by short-term follow-up, single-center design, and a lack of rigorous patient-reported outcome data. An understanding of the expected satisfaction and breast-related quality of life associated with each type of procedure is central to the decision-making process.To determine outcomes reported by patients undergoing postmastectomy breast reconstruction using implant or autologous techniques 2 years after surgery.Patients were recruited from 11 centers (57 plastic surgeons) across North America for the Mastectomy Reconstruction Outcomes Consortium study, a prospective, multicenter trial, from February 1, 2012, to July 31, 2015. Women undergoing immediate breast reconstruction using implant or autologous tissue reconstruction after mastectomy for cancer treatment or prophylaxis were eligible. Overall, 2013 women (1490 implant and 523 autologous tissue reconstruction) met the inclusion criteria. All patients included in this analysis had 2 years of follow-up.Procedure type (ie, implant vs autologous tissue reconstruction).The primary outcomes of interest were scores on the BREAST-Q, a validated, condition-specific, patient-reported outcome instrument, which were collected prior to and at 2 years after surgery. The following 4 domains of the BREAST-Q reconstruction module were evaluated: satisfaction with breasts, psychosocial well-being, physical well-being, and sexual well-being. Responses from each scale were summed and transformed on a 0 to 100 scale, with higher numbers representing greater satisfaction or quality of life.Of the 2013 women in the study (mean [SD] age, 48.1 [10.5] years for the group that underwent implant-based reconstruction and 51.6 [8.7] years for the group that underwent autologous reconstruction), 1217 (60.5%) completed questionnaires at 2 years after reconstruction. After controlling for baseline patient characteristics, patients who underwent autologous reconstruction had greater satisfaction with their breasts (difference, 7.94; 95% CI, 5.68-10.20; P < .001), psychosocial well-being (difference, 3.27; 95% CI, 1.25-5.29; P = .002), and sexual well-being (difference, 5.53; 95% CI, 2.95-8.11; P < .001) at 2 years compared with patients who underwent implant reconstruction.At 2 years, patients who underwent autologous reconstruction were more satisfied with their breasts and had greater psychosocial well-being and sexual well-being than did those who underwent implant reconstruction. These findings can inform patients and their clinicians about expected satisfaction and quality of life outcomes of autologous vs implant-based procedures and further support the adoption of shared decision making in clinical practice.
Precise theranostic nanomedicines for inhibiting vulnerable atherosclerotic plaque progression through regulation of vascular smooth muscle cell phenotype switching
Authors: Sai Ma, Seyed Mohammad Motevalli, Jiangwei Chen, Meng-Qi Xu, Yabin Wang, Jing Feng, Ya Qiu, Dong Han, Miaomiao Fan, Meiling Ding, Li Fan, Weisheng Guo, Xing-Jie Liang, Feng Cao
Journal: Theranostics (2018)

Coronary heart disease is a prevalent and fatal killer caused by vulnerable atherosclerotic plaques (VASPs).However, the precise detection and treatment of VASPs remains a difficult challenge.Here, we present the development of noninvasive human serum albumin (HSA)-based theranostic nanomedicines (NMs) for the specific diagnosis and effective therapy of VASPs.Methods: The ICG/SRT@HSA-pept NMs were formulated to contain payloads of the near-infrared (NIR) fluorescent dye indocyanine green (ICG) and the sirtuin 1 (Sirt1) activator SRT1720, and modified with a peptide moiety targeting osteopontin (OPN).The in vivo atherosclerotic mouse model was established with the high-fat diet (HFD).The in vitro vascular smooth muscle cells (VSMCs) phenotypic switching was induced using the ox-LDL stimulation.Results: Due to the overexpression of OPN in activated VSMCs and VASPs, the targeted NMs specifically accumulated within the VASPs region after intravenous injection into the atherosclerotic mice, achieving the precise detection of VASPs.In addition, in the presence of SRT1720, the NMs could activate intracellular Sirt1 and activate an antiatherogenesis effect by inhibiting the phenotypic switching of VSMCs, which is an essential contributor to the vulnerability and progression of atherosclerotic plaques.After therapeutic administration of the ICG/SRT@HSA-pept NMs for two weeks, the physiological sizes and plaque compositions of VASPs were markedly improved.Furthermore, ICG/SRT@HSA-pept NMs-treated mice presented a more favorable plaque phenotype than that was observed in free SRT1720-treated mice, suggesting the enhanced delivery of pharmaceutical agents to the atherosclerotic lesions and improved therapeutic efficacy of NMs compared with free SRT1720.Conclusions: The theranostic ICG/SRT@HSA-pept NMs showed great potential for the precise identification and targeted treatment of atherosclerotic diseases.
International prospective multi-center clinical trial with adherence to surgical and pathological quality measures: Influence of body mass index (BMI) on outcome in colon cancer
Authors: M. Protic, A. Bilchik, A. Nissan, S. Usaj Knezevic, B. Kukic, M. Kresoja, R. Veljkovic, M. Zivojinov, A. Stojadinovic
Journal: Annals of Oncology (2018)

Introduction: Various prognostic factors significantly influence oncological outcomes across various stages of colon cancer (CC). The prognostic influence of BMI for CC remains incompletely defined. We hypothesized that BMI significantly influences outcomes in node-negative (NN) CC. Methods: Patients with non-metastatic CC were prospectively enrolled in a trial with strict adherence to quality metrics (ClinicalTrials.gov: NCT00949312; UECC Trial), and stratified according to nodal status (NN and N+). Patients were stratified according to WHO BMI classification to assess the prognostic influence of BMI using univariate and multi-variate analyses. Results: Of 456 patients 285 were NN and 171 N+. Number of NN patients by WHO BMI classification was: BMI<18.5: 2 (2.1%); BMI 18.6-24.9: 123 (43.2%); BMI 25-29.9: 102 (35.8%); and, BMI>30: 54 (18.9%); in N+ patients the distribution was: 2.9%, 35.7%, 46.2%, 15.2%, respectively. NN patients with normal BMI (18.5-24.9) had significantly more right sided (65.5%; p = 0.02) and fewer low grade tumors (26.1%; p = 0.015), more examined nodes (20.9; p = 0.003), lower recurrence rate (2.5%; p = 0.036) and higher DFS (96.1 mos.; p = 0.033). These factor and outcome differences were not seen in N+ patients. BMI and number of nodes were significantly associated with DFS in the NN group. In the multivariate model BMI and total number of nodes were independent predictors of DFS. Tumor size and number of positive nodes were associated with DFS in the N+ group, and # positive nodes were an independent predictor of DFS. Conclusion: This is the first prospective trial to show BMI-associated differences in CC when surgical and pathological quality standards are strictly adhered to. Normal BMI is associated with improved DFS in node-negative CC. Normal BMI and number of resected nodes are independent predictors of DFS in Stage I/II CC. Further studies are needed to determine how and why BMI influences colon cancer biology.
Prescribe parkrun, not drugs, GPs are told
Authors: Gareth Iacobucci
Journal: BMJ (2018)

General practices are being encouraged to develop closer links with their local parkrun scheme and “prescribe” outdoor physical activity rather than drugs to patients, under a new initiative backed by the Royal College of General Practitioners.

There are currently over five hundred 5 km parkrun events and 220 junior parkrun events operating across the UK, coordinated by local volunteers.

The new initiative, launched by the RCGP in partnership with parkrun, aims to increase awareness of the events among GP practices, …
EAPH-16. DISCOVERY OF CT-179: A SMALL MOLECULE INHIBITOR OF THE OLIG2 TRANSCRIPTION FACTOR WITH POTENT ANTI-TUMOR IN PEDIATRIC BRAIN CANCER
Authors: Terrance Johns, Sameer Greenall, Charlotte Chen, Bryan Day
Journal: Neuro-Oncology (2018)

OLIG2 is a protein transcription factor (TF) expressed exclusively in progenitor cells in the brain and spinal cord during development and is re-expressed in most adult and pediatric brain cancers. Expression of OLIG2 drives the growth, invasiveness, and resistance to radiation in brain cancer cells and tumors in animal models. CT-179 is a novel small molecule (M.W. 397) that is a disruptor of OLIG2 function. We now show that CT-179 profoundly inhibited the growth, and induced apoptosis, in a range of patient-derived adult and pediatric cell lines at low nM concentrations, including diffuse intrinsic pontine glioma and medulloblastoma. Treated cells showed substantial degradation of OLIG2 protein that was associated with G2/M arrest and mitotic catastrophe. CT-179 also caused significant down-regulation of receptor tyrosine kinases associated with tumorigenicity, including EGFR and PDGFR. Orally administered CT-179 (20 mg/kg) crossed the blood-brain-barrier of intact mice reaching levels sufficient to inhibit patient-derived xenografts. Indeed, patient-derived xenografts in mice was significantly inhibited by CT-179. Our studies have provided the impetuses for moving CT-179 into the clinic as a novel therapy for patients with a range of brain cancers.
DIPG-55. TARGETING SENESCENT CELLS WITH ABT-263 ENHANCES CELL DEATH INDUCED BY BMI1 INHIBITION AND IONIZING RADIATION IN DIPG
Authors: Ilango Balakrishnan, Krishna Madhavan, Angela Pierce, Nathan Dahl, Rakeb Lemma, Susan Fosmire, Dong Wang, Eric Prince, Irina Alimova, Rintaro Hashizume, Esther Huellman, Cynthia Hawkins, Angel Montero Carcaboso, Nalin Gupta, Michelle Monje, Keneth Jones, Adam Green, Nicholas Foreman, Rajeev Vibhakar, Sujatha Venkataraman
Journal: Neuro-Oncology (2018)

Ionizing Radiation (IR) is a key treatment modality for DIPG, but it provides only temporary relief as the tumor cells develop resistance to radiation. Recently, we and others have shown that inhibition of BMI1 either alone or in combination with radiation attenuates DIPG cell proliferation in vitro. While we are demonstrating the in vivo efficacy of pharmacological inhibition of BMI1 and understanding the mechanism of anti-tumor effect of BMI1 inhibition in DIPG, the existence of treatment-resistant cells remains a major obstacle for a prolonged cure. Both IR and genetic or pharmacological inhibition of BMI1 induces cellular senescence as a mechanism to suppress tumor cell proliferation, implying that senescence can be considered as tumor suppressor. Paradoxically, recent studies have shown that accelerated senescence can mediate tumor recurrence due to the development of pro-oncogenic environment. In line with this, we are investigating whether clearance of treatment-induced senescent cells enhances treatment outcomes. DIPG cells exposed to different doses of radiation followed by treatment with ABT-263 (Navitoclax), a drug which selectively clears the senescent cells, resulted in increased radiosensitization. Treatment of pre-radiated DIPG cells with ABT-263 decreased the activity of senescence-associated beta-galactosidase and anti-apoptotic protein expression. Similarly, chemical inhibition of BMI1 in combination with ABT-263 showed synergistic killing of DIPG cells. The synergy was most pronounced in DIPG cells harboring wildtype p53. Our study highlights the importance of eliminating treatment-induced senescent cells while inhibiting proliferation of DIPG tumors, a combination which can immensely improve therapeutic efficacy in DIPG patients.
$100m alcohol study is cancelled amid pro-industry “bias”
Authors: Owen Dyer
Journal: BMJ (2018)

The US National Institutes of Health (NIH) has cancelled its $100m (£76m; €87m) prospective study into the health effects of moderate drinking, after an internal investigation found that government scientists seeking to win alcohol industry funding for the research had told executives that the study could offer the “level of evidence necessary if alcohol is to be recommended as part of a healthy diet.”

The NIH investigation report concluded, “Interactions among several NIAAA [National Institute on Alcohol Abuse and Alcoholism] staff and industry representatives appear to intentionally bias the framing of the scientific premise in the direction of demonstrating a beneficial health effect of moderate alcohol consumption.”1

The Moderate Alcohol and Cardiovascular Health (MACH 15) trial was due to recruit 7800 participants and randomly assign them to moderate drinking (one drink a day) or no drinking. It was run by the NIAAA, an NIH agency.

But the ambitious …
A hyperpigmented intermammary patch
Authors: Xiao Ke Liu, Jun Li
Journal: BMJ (2018)

A 21 year old woman presented to the dermatology department with an asymptomatic, hyperpigmented patch on the chest (fig 1). The lesion began as a single tan coloured macule that, over two years, multiplied and subsequently fused into the solitary lesion visible on presentation. On examination, the patch was well demarcated with fine scale covering it. The woman’s medical history was otherwise unremarkable. What is the most likely diagnosis?



Fig 1 
Well demarcated hyperpigmented patch on the intermammary skin with fine scale



Well demarcated, hyperpigmented lesions on the chest with …
Real world data in colorectal cancer: A retrospective analysis of overall survival in metastatic colorectal cancer patients between 2011-2015 treated in Spain, preliminary results (RWD-ACROSS study)
Authors: C. Pericay, J. Gallego, A. Fernandez Montes, H. Oliveres, H. Asensio-Martínez, J. Garcia-Gómez, J. Fernandez-Plana, M. Marín-Alcalá, M. Ballester-Espinosa, M. Salgado, I. Macías Declara, L. Gómez-González, L. Iglesias-Rey, l Cirera
Journal: Annals of Oncology (2018)

Introduction: Colorectal cancer is a global problem due the incidence and prevalence. Clinical trials do not represent treatment of real life population effectiveness, so real world data trials are needed. Aim: We present preliminary results based on a registry for Spanish metastatic colorectal cancer (mCRC) patients. Methods: Cohort study including 4 hospitals in Spain. Inclusion criteria: Aged≥18 years(y), histological confirmation mCRC, at least 1 cycle of chemotherapy(CT) administered, mCRC diagnosed between 01/2011-12/2015. Overall survival(OS) was calculated from time of mCRC diagnosis to death or date of last contact. Kaplan-Meier curves were used to estimate median survival and survival rates. The study was approved by Ethics Committees. Results: 804pts were analyzed. Median age: 65.7y. Ratio male/female: 64.9%/35.1%. Synchronous or metachronous tumors: 5.7%. RAS-mutations were seen in 50.1%, BRAF-mutations in 1.6% and RAS/BRAF-wild type in 48.3% of pts. MSI (Microsatellite Instability) was in 3.4%. Ratio left/right: 73.4%/26.1%. Metastatic site location at diagnosis: liver 36.6%, lung 8.6%, peritoneal 8.7%, liver+lung 10.1% and liver+peritoneal 6.1%. 63.8%pt received 2 lines, 28.5% 3 lines and 9.1% 4 or more lines. In the cohort analysed, 74.8%pt had died. Relation of lines of therapy and drugs used are shown in Table1. Chemotherapy 1st line: alone 51.6%, plus antibody 48.4% (EGFR 46.0%, VEGF 53.2%), oxaliplatin 55.3%, irinotecan 27.4%, 5FU 12.4%. Chemotherapy 2nd line: alone 51.5%, plus antibody 48.5% (EGFR 38.8%, VEGF 60.7%), oxaliplatin 26.3%, irinotecan 57.5%, 5FU 9.0%. Chemotherapy 3rd line: alone 59.2%, plus antibody 40.8% (EGFR 36.3%, VEGF 49.5%), oxaliplatin 23.6%, irinotecan 32.5%, 5FU 20.2%. mOS: 23.4 months(m). mPFS (Progression free survival): 1stline: 9.6m, 2ndline: 7.6m and 3rdLine: 6.7m. OS left/right: 25.2m vs 18.0m (HR:0.634, P <.001). The probability of surviving beyond 12m was 73.3%, beyond 24m was 48.2%, beyond 36m was 30.7% and beyond 48m was 21.1%. Conclusion: The RWD-ACROSS study is the first data-base for mCRC patients in Spain including information on CT, biologics, OS, PFS, and prognostic and predictive factors. Funded by Merck, S.L. (Merck KGaA, Darmstadt, Germany).
HGG-26. DRAMATIC RESPONSE IN A CHILD TREATED FOR GLIOBLASTOMA WITH IMMUNE CHECK POINT INHIBITOR NIVOLUMAB
Authors: Christine Dahl, Gorm Von Ottingen, Britt Elmedal Laursen, Yasmin Lassen
Journal: Neuro-Oncology (2018)

Glioblastoma is not curable with current available therapies. Evidence has shown that tumours with a high mutational load can respond to immune check point inhibitors. PATIENT AND We present the case of an 11 year old boy treated for intracranial malignant nerve sheet tumour at the age of five with gross total resection and radiation therapy with 59.4 Gy. After 6 years, he presented with tumour recurrence in the same location. Safe tumour resection was performed, histology showed glioblastoma. The recurrent tumour harboured TP53 mutations and also lack of MGMT gene methylation, both known to be poor prognostic markers. Molecular analysis revealed a very high mutational load of 34151. There was no family history of cancer and the boy did not show any café-au lait spots. Sanger sequencing for germ line TP53 and bMMRD (MMR genes including POLD1 and POLE) did not reveal changes. Immunohistochemistry on tumour tissue showed less than 1% of tumour cells PD-L1 positive. Tumour showed microsatellite instability explaining the high mutational load. Tumourbed was partly re- irradiated with 54 Gy. Antineoplastic treatment with temozolomide and lomustin was administered. After six months MRI revealed tumour recurrence. Treatment with Nivolumab was initiated. MRI performed after 4 doses of Nivolumab showed nearly complete tumour regression. We report a dramatic response of recurrent glioblastoma to Nivolumab in a tumor with a very high mutational load. No germ line bMMRD was found and we speculate that hypermutation in tumour is a consequence of treatment as previous reported.
Assessment of a Predictive Scoring Model for Dermoscopy of Subungual Melanoma In Situ
Authors: Jungyoon Ohn, Gwanghyun Jo, Youngjoo Cho, Sarah Lee Sheu, Kwang Hyun Cho, Je-Ho Mun
Journal: JAMA Dermatology (2018)

Subungual melanoma in situ (SMIS) is a malignant neoplasm that requires early diagnosis and complete surgical excision; however, little is known about the usefulness of the detailed dermoscopic features of longitudinal melanonychia (LM) to predict the diagnosis of SMIS.To investigate the characteristic dermoscopic findings of SMIS and to establish a predictive scoring model for the diagnosis of SMIS in patients with adult-onset LM affecting a single digit.A cohort study of 19 patients with biopsy-proven SMIS and 26 patients with benign LM diagnosed in a tertiary referral hospital in Seoul, South Korea, from September 1, 2013, to July 31, 2017.Patient demographics, frequency of specific dermoscopic findings, and a predictive scoring model.Of the total 45 patients with pigmented nails, the 19 patients with SMIS included 14 women and had a mean (SD) age of 52.0 (14.4) years, and the 26 patients with benign LM included 18 women and had a mean (SD) age of 48.1 (13.2) years. Asymmetry (odds ratio [OR], 34.00; 95% CI, 3.88-297.70), border fading (OR, 9.33; 95% CI, 2.37-36.70), multicolor (OR, 11.59; 95% CI, 2.21-60.89), width of the pigmentation of at least 3 mm (OR, 5.31; 95% CI, 1.01-28.07), and presence of the Hutchinson sign (OR, 18.18; 95% CI, 2.02-163.52) were features of LM that were significantly associated with SMIS. A predictive scoring model incorporating these dermoscopic features of SMIS was assessed. The model, ranging from 0 to 8 points, showed a reliable diagnostic value (the receiver operating characteristic curve had an area under the curve [C statistic] of 0.91) in differentiating SMIS from benign LM at a cutoff value of 3, with a sensitivity of 89% and a specificity of 62%.This study suggests characteristic dermoscopic features for SMIS. A predictive scoring model based on these morphologic features may help differentiate SMIS from benign LM.