tbuckley/cabot-search huggingface dataset:
Edward Shotter: dean emeritus of Rochester, who founded the <i>Journal of Medical Ethics</i>
Authors: Rebecca Wallersteiner
Journal: BMJ (2019)

Photo credit: Emma Dalzel-Job

Edward Shotter, dean emeritus of Rochester, founded the Journal of Medical Ethics , the Institute of Medical Ethics, and the London Medical Group. He was born in Grimsby, to Frank Shotter (a businessman) and Minnetta (a housewife). His early education was disrupted by the wartime bombing of Lincolnshire, and he moved school several times; according to his widow, Jane, this “perhaps sowed seeds of his later adaptability and imperturbability.” Later he attended Humberstone Foundation School in Cleethorpes, north east Lincolnshire, where he developed an interest in domestic architecture.

He went on to study at the Durham University School of Architecture, and the subject remained an interest all his life. Sensing a religious vocation and encouraged by the Reverend Gervase Markham, vicar of Grimsby, Shotter moved on to St David’s College, Lampeter, to read for a BA in theology before training for ordination at St Stephen’s House, Oxford.

After his ordination in 1960, Shotter served his first curacy at St Peter’s in Plymouth, but was soon recruited by the Student Christian Movement (SCM), as one of the London intercollegiate secretaries. His work with the London medical deaneries led to his founding of the London Medical Group (LMG) in 1963, and he was its director of studies for 26 years, bringing untiring energy to the role.

In 1978 he married Jane Edgcumbe and became a devoted husband and loving father. 

Shotter’s close friend, Kenneth Boyd, professor emeritus …
P11.28 Alteration of blood brain barrier (BBB) permeability by Tumor Treating Fields (TTFields) in vivo
Authors: A F Keßler, E Salvador, D Domröse, M Burek, C Tempel Brami, T Voloshin Sela, M Giladi, R Ernestus, M Löhr, C Förster, C Hagemann
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Alternating electric fields with intermediate frequency (100 - 300 kHz) and low intensity (1 - 3 V/cm), known as Tumor Treating Fields (TTFields), have been established as a novel adjuvant therapy for glioblastoma (GBM) patients. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Due to this regulation, the BBB may block delivery of drugs for treatment of brain tumors, in particular GBM. In this study, we investigated the influence of TTFields on BBB permeability in vivo. MATERIAL AND METHODS For determination of BBB permeability, rats were treated with 100 kHz TTFields for 72 h. At the end of treatment, rats were i.v. injected with Evan′s Blue (EB), which binds Albumin (~70 kDa) upon injection to the blood. EB was extracted after brain homogenization and quantified at 610 nm. In addition, cryosections of rat brains were prepared following TTFields application at 100 kHz for 72 h, and sections were stained for Claudin 5, Occludin and immunoglobulin G (IgG) to assess vessel structure. Moreover, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent (Gd) was performed before and after TTFields application. RESULTS In vivo, the EB accumulation in the brain was significantly increased by application of TTFields to the rat head. Claudin 5 and Occludin staining was visible in vessel endothelial cells and localized at the cells’ edges in control cryosections of rat brains. In TTFields-treated rats, the vessel structure became diffuse; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue and not solely inside the vessels, as it is normally the case. Serial DCE-MRI demonstrated significantly increased accumulation of Gd in the brain, detected directly after 72 h of TTFields application. 96 h after end of TTFields treatment the effect on the BBB disappeared and no difference in contrast enhancement between controls and TTFields treated animals was observable. CONCLUSION Application of TTFields at 100 kHz could have the potential to deliver drugs to the brain, which normally are unable to cross the BBB by altering BBB integrity and permeability. Utilizing TTFields to open the BBB and its subsequent recovery, as demonstrated by the data presented herein, could lead to a clinical approach of drug delivery for treatment of malignant brain tumors and other diseases of the central nervous system. These results will be further validated in clinical trials.
OS1.7 Plasmatic differential scanning fluorimetry profiles discriminate glioma patients from healthy controls
Authors: E Tabouret, P Tsvetkov, R Eyraud, T Peel, S Malesinski, D Figarella-Branger, O Chinot, F Devred
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND differential scanning fluorimetry (DSF) has been recently proposed to be used to perform high throughput biofluids profiling by following protein denaturation. Our objective was to discriminate patients with glioma from healthy controls using plasmatic DSF profiles. MATERIAL AND METHODS We included 78 glioma patients and 44 healthy controls. Plasmas were collected using EDTA tubes and analyzed in duplicate using nanoDSF Prometheus NT.Plex instrument (Nanotemper). The following DSF data were analyzed: protein fluorescence at 330 and 350 nm, first derivation of the ratio of fluorescence at 330 and 350 and the absorbance at 350 nm. Then we ran several machine learning algorithms to differentiate gliomas from healthy controls: Logistic Regression (LR), Support Vector Machine (SVM), Neural Networks (NN), Random Forest (RF) and Adaptive Boosting (AdaBoost). All these methods have been tested using a leave-one-out approach where each datum is used once as test while the other are used to train the automatic classifiers. RESULTS We included 78 patients with a median age of 57.8 years (range, 21.8 - 89.9). Thirteen patients (17%) presented with a 1p/19q codeleted IDH mutated oligodendroglioma, 12 patients (15%) with an IDH mutated astrocytoma and 53 patients (68%) with an IDH wild-type astrocytoma, including 26 patients with a recurrent grade IV IDH wild-type astrocytoma. DSF data were independent from classical prognostic factors or patient characteristics: age, Karnofsky Performans Status, IDH mutation status, 1p19q codeletion, grade, initial or recurrent setting, steroid doses, patient size and weight, tumor size and location. The different datasets of the DFS output were tested independently and in combination as input of the machine learning algorithms. Results were obtained using the tuned best parameters on 157 data. The best obtained accuracy was 95.54% with 2% of fake positives and 5% of fake negatives (algorithm: SVM). Others achieved ≥ 90% of correct classification: LR accuracy was 89.17%, NN accuracy was 92.99%, RF accuracy was 91.72% and Adaboost accuracy was 92.36%. CONCLUSION DSF profiles analyzed by machine learning algorithms could allow us to identify glioma patients from healthy controls with an accuracy of more than 95%. These results suggest that DSF of biofluid could be a useful and non-invasive tool to monitor glioma patients. Further investigations, including longitudinal profile analyses are ongoing.
Exposure-Response Analysis of Venetoclax in Combination with Hypomethylating Agents or Low-Dose Cytarabine in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia
Authors: Suresh Agarwal, Sathej Gopalakrishnan, Sven Mensing, Jalaja Potluri, John Hayslip, Anna Friedel, Rajeev Menon, Ahmed Hamed Salem
Journal: Blood (2018)
A long acting nanoformulated lamivudine ProTide
Authors: Nathan Smith, Aditya N. Bade, Dhruvkumar Soni, Nagsen Gautam, Yazen Alnouti, Jonathan Herskovitz, Ibrahim M. Ibrahim, Melinda S. Wojtkiewicz, Bhagya Laxmi Dyavar Shetty, JoEllyn McMillan, Howard E. Gendelman, Benson Edagwa
Journal: Biomaterials (2019)
P14.06 Phase II randomized trial of short course hypofractionated radiotherapy with or without temozolomide in elderly patients with Glioblastoma
Authors: R Madan, S Thakur, P Salunke, C Ahuja, D Khosla, B S Yadav, R Kapoor, N Kumar
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary brain tumor. Although treatment advances and introduction of temozolomide has improved the outcome in young patients, it is still a concern in elderly patients. Elderly population is often excluded from the trials, thus established treatment guidelines are not available. Trials have shown that short course hypofractionated radiotherapy (HRT) is equally effective in terms of overall survival (OS) and progression free survival (PFS) as compared to standard RT in elderly population. While the benefit of adding Temozolomide (TMZ) to standard dose radiotherapy is well established, there is lack of evidence that addition of TMZ to HRT improves survival in elderly patients.We conducted this study to see if addition of temozolomide to HRT improves OS, PFS and quality of life (QOL) in elderly GBM patients. MATERIAL AND METHODS The study was conducted over a period of 21 months from January 2017 to September 2018. Histologically proven 70 newly diagnosed Glioblastoma patients (age&gt;60 years) were enrolled and randomized into two arms (Arm I- HRT alone, Arm II- HRT and TMZ) using computer generated randomization table (1:1 ratio). The radiotherapy dose in both arms was same and consisted of a dose of 25Gy in 5 daily fractions over 1 week. In addition, arm II patients received daily concurrent TMZ 75mg/m2 1 hour prior to RT followed by adjuvant TMZ 175mg/m2 from Day1-5 for 6 cycles (q 4weeks), started after a month of RT completion. Quality of life score and global health status was assessed in both arms at baseline, 1, 3, 6 and 9 months after the treatment using QOL questionnaire EORTC QLQ-C 30 and QLQ-BN20. Data entry was done in Microsoft Excel 2016 and analysis was done in SPSS version 18. Kaplan Meier survival analysis was done for OS and PFS. To see the trend of time related observations at different point of time repeated ANOVA was used. A p value of &lt;0.05 was taken significant. RESULTS The median OS in arm I and II was 121 (range 40–360 days) and 146 (range 40–450 days) days respectively (P=0.146). The median PFS in arm 1 and arm 2 were 77 (range 30–300 days) and 109.50 (range 30–300) days respectively (p-0.028). On further analysis, the prognostic factors were type of surgery (Median PFS 159 days in gross total excision and 129 days in subtotal excision or biopsy, p-0.03) and KPS (0.04). QOL score for symptom and functional domain was comparable in both arms. However score of nausea and vomiting was higher during concurrent chemoradiotherapy. A non significant improvement in QLQ BN 20 score was observed at 9 months in arm I. CONCLUSION Addition of Temozolomide to HRT is a compelling option in elderly Glioblastoma patients as it significantly improves the PFS and a non significant improvement in OS without compromising quality of life.
Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study
Authors: Kimberly K Scarsi, Yoninah S Cramer, Susan L Rosenkranz, Francesca Aweeka, Baiba Berzins, Robert W Coombs, Kristine Coughlin, Laura E Moran, Carmen D Zorrilla, Victor Akelo, Mariam Aziz, Ruth K Friedman, David Gingrich, Shobha Swaminathan, Catherine Godfrey, Susan E Cohn, Liz Barr, Christina Blanchard-Horan, Elizabeth Connick, Mary Allegra Cermak, Nahida Chakhtoura, Cecelia Chang-Ching, Andee Fox, David W. Haas, Alan Landay, Mey Leon, Jeong-Gun Park, Kristine Patterson, Thucuma Sise, Greg Spear, David Shugarts, Pamela Tshandu, Charles R Wira
Journal: The Lancet HIV (2019)
Chinese largest cohort data from NCT03120846: Efficacy and safety of VEGFR2 inhibitor apatinib for metastatic soft tissue sarcomas.
Authors: Jilong Yang, Zhichao Liao, Xinyue Liu
Journal: Journal of Clinical Oncology (2019)

e22532 Background: There is no standard treatment for stage IV soft tissue tumor (STS) after the failure of Adriamycin-based chemotherapy. This opening, single-arm, multi-center phase II study (NCT03120846) assessed the efficacy and safety of Apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV soft tissue tumor after the failure of chemotherapy. Methods: Between September 2015 and February 2018, we recruited 42 patients with stage IV STS who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Secondary endpoint was overall survival (OS). Treatment-related adverse effects (AEs) were evaluated. Results: Patients (19 men, 23 women; 14-83 years, average age: 47.67years) received 500 mg apatinib on Days 1–28 of 4-week cycles (median 5.7 cycles; range: 0–23 cycles). Median follow-up was 9 months (range: 1–28 months). We assessed 42 patients for AEs and 38 for efficacy. At 12 weeks, PFR was 70% and the ORR was 26.32% (10/38) and DCR was 86.84% (33/38). For the overall responses, the ORR was 23.68% (9/38) and DCR was 57.89% (22/38). The median PFS was 7.87 months and median OS was 17.55 months. The top AEs included hypertension ( n= 18, 42.86%), hand-foot-skin reaction ( n= 15, 35.71%), Apositia (13, 30.95%), and proteinuria ( n= 11, 26.19%). No patients had grade-4 AEs. 11 (26.19%) had grade-3 AEs. 2 patients (4.76%) quit because the AE. Notably, the 26 patients (61.90%) who suffered hypertension, hand-foot-skin reaction or proteinuria had significantly longer OS than those without these AEs (20.94 vs. 8.93 months; Log Rank (Mantel-Cox) = 12.94, P= 0.0003). Conclusions: Apatinib is effective and well tolerated in patients with advanced soft tissue sarcomas. The adverse events hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in STS patients. Clinical trial information: NCT03120846.
P13.04 Transcriptional profiling differentiates spinal cord ependymal tumours from other glial tumours in children
Authors: A A Sobocińska, M Niemira, A Szałkowska, B Wojtaś, J Trubicka, W Grajkowska, E Matyja, M Łastowska
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Spinal cord tumours in children include ependymal and other tumours of glial origin, all of them displaying GFAP marker. Some tumours may present difficulties in histopathological diagnosis e.g. due to intratumour heterogeneity. Therefore, molecular approach should be examined for its diagnostic usefulness. We investigated a series of originally diagnosed spinal cord ependymal tumours, using transcriptional profiling, to confirm if molecular classification is compatible with histopathological diagnosis. MATERIAL AND METHODS Overall, 9 patients diagnosed between 2001 and 2014 in The Children’s Memorial Health Institute (CMHI) in Warsaw, Poland, were included in the analysis. 4 patients were diagnosed with GI myxopapillary ependymomas, 3 patients with GII and 2 patients with GIII grade ependymal tumours. Total RNA was extracted from FFPE tumour samples using RNeasy kits (Qiagen). Transcriptional profiling was performed using NanoString nCounter system analysis. Tumours were analysed according to the manufacturer’s procedures for hybridization, detection and scanning. Raw counts for each gene underwent technical and biological normalization using nSolver software. A custom NanoString CodeSet consisted of 8 marker genes: GFAP as a glial marker, CAPS and FAM81B as the markers for ependymal tumours and OLIG1, OLIG2, PMP2, KLRC3 and C1orf61 as the markers for other gliomas. Marker genes were identified by re-analysis of publically available microarrays data from childhood brain tumour samples. Histopathological reassessment of tumour preparations was performed by two experienced neuropathologists. RESULTS Hierarchical clustering of 9 samples revealed that two tumours clustered separately and displayed low expression of ependymal markers but high expression of all other glioma markers. Subsequent histopathological re-analysis of preparation of the later 2 tumours showed that one of them displayed features of pilocytic astrocytoma with loose, microcytic and fibrillary areas accompanied by advanced myxoid degenerative changes mimicking the picture of myxopapillary ependymoma. The second tumour revealed heterogeneous morphology with areas of diffuse low grade astrocytoma, pilocytic astrocytoma and fragments displaying ependymal features, including angiocentric pattern with ependymoma-like perivascular arrangement of neoplastic cells. CONCLUSION The results of analysis indicate that RNA expression profiling from FFPE tumour samples using NanoString nCounter system may be a useful approach in differentiation of ependymal tumours from other glial tumours with misleading morphology located in the spinal cord in children. Funded by the National Science Centre, Poland (2016/21/B/NZ2/01785 and 2016/23/B/NZ2/03064).
An “EZ” Epigenetic Road to Leukemia Stem Cell Metabolic Reprogramming?
Authors: Meng Li, Ari M. Melnick
Journal: Cancer Discovery (2019)

Abstract Summary: In this issue of Cancer Discovery, Gu and colleagues developed a mouse model of myeloproliferative neoplasm driven by NrasG12D and Ezh2−/−, which cooperated to induce malignant transformation and metabolic reprogramming of leukemic stem cells at least in part through loss of normal epigenetic regulation of gene expression. Furthermore, their findings point to Ezh1 and branched chain amino acid metabolism as biological dependencies and potential therapeutic targets in myeloid neoplasms. See related article by Gu et al., p. 1228.
Whorlton Hall: substantial investment needed to protect vulnerable people
Authors: Matt Hoghton, Kirsten Lamb
Journal: BMJ (2019)

Murphy’s editorial on Whorlton Hall describes the institutional abuse of vulnerable patients that continues despite improved safeguarding training, care home environments, and regulatory systems.1 The Social Care Institute for Excellence has identified many factors associated with institutional abuse including management, staff recruitment, staffing levels, adherence to policy and procedure, staff training, record keeping, choice of service levels, and dehumanisation.2

Beadle-Brown and colleagues argued that just moving people out of institutions into community …
Sustainability assessment of Indian diets: a modelling study
Authors: Abhishek Chaudhary
Journal: The Lancet Planetary Health (2019)

BackgroundTransitioning from current to sustainable diets that have low environmental impacts and high nutrition and are culturally acceptable can contribute greatly towards the achievement of several national Sustainable Development Goals (SDGs). With a population of 1·3 billion, widely prevalent malnutrition and increasing incomes, India's per capita consumption patterns will also play a key role over next decade in deciding the fate of United Nations 2030 global SDGs.MethodsHere we assess how the intake amounts of different food items in Indian diets must change in order to the meet the daily-recommended levels for 29 macro and micro nutrients while maintaining environmental footprints below the five food-related per capita planetary boundaries (carbon emissions, water, land, nitrogen and phosphorus use). We also put several cultural acceptability constraints to avoid obtaining an unrealistic diet.FindingsA considerable departure from current dietary behaviour is needed to transition from current to sustainable diets in India. While the daily per capita environmental footprints of current Indian diets are well below the respective planetary boundaries, the daily recommended levels for vitamins B12, E, and K, fibre, potassium, and choline are not being met currently, suggesting the need to pay special attention to them. The required changes include high increases (>200 g per capita per day) in fruits and vegetable intake, moderate increases in the intake of other grains (eg, millet, sorghum, rye), pulses, roots and tubers, fish and meat (about 30 g each) and a high reduction in intake of rice and dairy products (>100 g each).InterpretationFuture research should assess the potential of different leverage points from both the production side (eg, reducing food loss, filling yield gaps, improving technologies, biofortification) and the consumption side (eg, taxes, subsidies, campaigns, changes in physical microenvironment) to help transition towards sustainable diets.FundingInitiation Grant of IIT Kanpur, India (number 2018386).
Advocating for Equity in Cancer Care
Authors: James McCanney, Terrell Johnson, Lindsey A.M. Bandini, Shonta Chambers, Lynette Bonar, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2019)

Demographic factors such as race, socioeconomic status, gender identity, area of residence, native language, and cultural barriers have an effect on outcomes in cancer care. To identify unmet needs, challenges, and opportunities in achieving high-quality, patient-centered cancer care for all, NCCN conducted a yearlong environmental scan, which involved stakeholder meetings with patients and patient advocacy groups to discuss these topics. The findings from this scan informed the corresponding NCCN Patient Advocacy Summit: Advocating for Equity in Cancer Care, held in Washington, DC, on December 10, 2018. In addition to the many patient advocacy groups, the summit featured a number of other stakeholders that advocate for equity in cancer care. This article encapsulates the findings of the environmental scan and the discussion from the NCCN Patient Advocacy Summit.
P09.03 Array-CGH analysis in meningiomas adds further information of biological behavior
Authors: C Calatozzolo, A Rizzo, V Girgenti, A Saladino, M Patanè, F Di Meco, B Pollo, F L Sciacca
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Meningioma is the most common primary tumor of CNS, usually a benign tumor (grade I) successfully treated by surgical resection, while in the 25–30% of cases is a more aggressive neoplasm with high recurrence rate and poor prognosis (grade II-III). In the last years some studies tried to investigate the genomic profile of meningioma to find additional prognostic factors and potential therapeutic targets. Aim of our study was to use the array-CGH (aCGH) to investigate possible indicators of recurrence risk in meningiomas. MATERIAL AND METHODS We retrospectively selected two group of patients: 34 with meningioma WHO grade I (24 F, 10 M, median age at diagnosis 56 yrs) and 19 with meningioma WHO grade II (9 F, 10 M, median age 59 yrs), in order to compare cases recurrent and non-recurrent in each group. We also analyzed 5/18 recurrences WHO grade I and 10/11 WHO grade II. Genomic profiles were investigated by aCGH. RESULTS We observed an increase in number of genomic imbalances related to grading and in non-recurrent versus recurrent tumors. 9 WHO I meningiomas were without alterations. The mainly alterations observed were deletions and duplications, moreover we also identified chromothripsis of a single chromosome in 2/18 WHO I recurrent and 2/8 WHO II non recurrent meningiomas, and chromothripsis of multiple chromosomes in 5/11 WHO II recurrent meningiomas. As well we detected the presence of mosaicism, mainly in WHO I recurrent and in grade II meningiomas. In 7/14 WHO I meningiomas we found differences in genomic profile analyzing two samples obtained from two distinct areas. 6/15 recurrences showed the same alterations of the primary tumor. We didn’t detected an association between alteration of 1p and 22q and recurrence risk, as previously suggested, as those were the most diffused imbalances in all meningiomas. CONCLUSION In our patients we found a difference in genomic imbalances between grade I and grade II meningiomas, but we also identified additional details of the complexity of alterations in meningioma with the detection of chromothripsis and mosaicism. This latter aspect is a new issue and suggests the presence of more aggressive cell clones that could be predictive of recurrence in grade I meningioma. Moreover, we observed a spatial heterogeneity in half of grade I meningioma analyzed. Our preliminary results suggest that the aCGH, a technique routinely used in many laboratories, could be used to better stratify meningioma patients.