tbuckley/cabot-search huggingface dataset:
IMMU-05. SAFETY AND EFFICACY OF INTRAVENTRICULAR 131I-LABELED MONOCLONAL ANTIBODY 8H9 TARGETING THE SURFACE GLYCOPROTEIN B7-H3
Authors: Kim Kramer, Brian Kushner, Shakeel Modak, Neeta Pandit Taskar, Ursula Tomlinson, Maria Donzelli, Suzanne Wolden, Pat Zanzonico, John Humm, Sofia Haque, Mark Souweidane, Jeffrey Greenfield, Ellen Basu, Stephen Roberts, Jorge Carrasquillo, Jason Lewis, Serge Lyashchenko, Steven Larson, Nai-Kong Cheung
Journal: Neuro-Oncology (2018)

Tumors metastasizing to the CNS are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting B7-H3 in patients with CNS tumors. Tumor B7-H3 expression was assessed by immunohistochemistry. Patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments -phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Dosimetry was based on serial CSF, blood samplings and ROI analyses on nuclear imaging. . Toxicity was defined by the CTCAE v.3.0. Repeat injections were permitted if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. 131 patients received 383 injections [median age 5.4 years (1.2- 53.6)] Injections were well tolerated. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST/ALT and 1 injection with grade 3 ALT elevation (dose level 3)., Myelosuppression occurred in patients with prior craniospinal radiation and at dose levels 6 and higher (>60 mCi). Of 93 patients treated for CNS neuroblastoma, an improved overall survival was noted compared to survival reported with conventional therapies. Interpatient variability for total absorbed dose to the CSF and blood was observed; mean absorbed CSF dose was 104.9 cGy/mCi by CSF sampling, and 2.6 cGy/mCi to the blood. Intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and has clinical utility for high risk primary and metastatic CNS tumors.
Pancreatic head resections: Impact factors, perioperative morbidity, mortality and long-term survival
Authors: B. Ilijevec, S. Potrc
Journal: Annals of Oncology (2018)

Introduction: One of the toughest procedures for pancreatic surgeon is the resection of the head of the pancreas. The procedure is accompanied by high morbidity and complications. Better patient selection, advancements in perioperative care and in surgical technique have improved perioperative mortality. The main goal of this study was to identify potential impact factors for perioperative morbidity and mortality as well as consequences of perioperative morbidity on long-term survival in pancreatic head resections. Methods: A retrospective study of clinical-pathological factors of 240 patients which were divided into two chronological groups (period 1 (P1): from January 1, 2008 to December 31, 2012 (96 pts); and period 2 (P2): from January 1, 2013 to March 31, 2017 (144 pts)) and underwent pancreatic head (PD) or total pancreatic (TP) resection were analyzed for correlations with morbidity, 30- and 90-day mortality, and long-term survival. Complications were graded according to Clavien-Dindo classification, grade II and more being defined as overall complications (OAC). Clinical-pathological factors were correlated with OAC, all surgical (ASC), general (AGC) and specific types of complications including leaks from the pancreatoenteric anastomosis (PEA) or pancreatic fistula (PF, type A, B and C), leaks from other anastomoses (OL), bleeding (BD) and abscesses (AA). Results: In the 9-year period, altogether 240 patients (131 men and 109 women, mean age 66,04 years) had pancreatic resection. The incidence of OAC was 37.1%, ASC 29.2% and AGC 15.8%. ASC were presented as PL, OL, BD and AA in 19% (of 208 PD), 5.8%, 5.8%, and 2.5% respectively. Age, ASA score, amylase on drains, and pancreatic fistulas B and C correlated significantly with various types of complications. Overall 30- and 90-day mortality were 5 and 7.9%, with 7,3 and 11,5% in P1 and decreased to 3.5 and 5% in P2. Conclusion: Most subtypes of complications did not compromise the long-term survival in analyzed cohort of patients. Exceptions were correlated with PLs and BDs. Independent indicators of morbidity were high amylase on drains and consequently PF B and C, OAC, PL and BD. PL and BD were shown to be an independent predictor for 30-day mortality, and OAC and PF C for 90-day mortality.
CDX2 immunohistochemistry as a prognostic biomarker for colorectal cancer
Authors: A. Fatimilehin, C. Mikropoulos, J. Summers, L. Rajakumar, M. Hill
Journal: Annals of Oncology (2018)

Introduction: The caudal-type homeobox transcription factor 2 (CDX2) gene is expressed in intestinal epithelial cells. The encoded protein regulates genes involved in cell growth and differentiation. We performed a retrospective study to assess the impact of loss of expression of CDX2 in our cohort of patients at Kent Oncology Centre diagnosed with colorectal cancer on outcomes. Methods: Results from all histology samples with CDX2 immunohistochemistry testing performed between January 2011 and November 2013 were obtained. 147 samples were initially included. Duplicate samples and patients with insufficient data on outcomes were subsequently excluded, leaving a total of 78 patients. Data collected included age at diagnosis, tumour stage, performance status, tumour location, KRAS and BRAF status, CDX2 status, time to relapse and time to death. Results: Our 78-patient cohort had a median age of 70.5. 57.7% had a performance status of 2 or better, 24.4% had no performance status recorded. 48.7% of patients had left sided tumours, 48.7% had right sided tumours. 1.3% had disseminated disease, and 1.3% had unknown primary. 15 (19.2%) patients had CDX2 negative samples, and 58 patients (74.4%) were CDX2 positive. We were unable to obtain CDX2 test results for 5 patients (6.4%). 34 patients (43.6%) had metastatic disease on presentation compared to 44 (56.4%) patients without metastases. 34 patients (43.6%) were KRAS wild type, 8 (10.3%) were KRAS mutant. 36 patients (46.2%) had unknown KRAS status. 24 patients (30.8%) were BRAF wildtype, 12 (15.4%) were BRAF mutant. 42 (53.8%) had unknown BRAF status. For all stages of CRC the median overall survival was 27.8 months in CDX2 negative patients compared to 36.4 months in CDX2 positive patients. The hazard ratio for death in the CDX2 negative group compared to the positive group was 1.27 (95% CI 0.59 – 2.71 p = 0.5608). In the metastatic colorectal cancer group, there were 34 patients in total, 8 (23.5%) of who were CDX2 negative. In this subgroup, the median overall survival in the CDX2 negative group was 4 months. In contrast, the mean survival in the CDX2 positive group was 13.8 months. The hazard ratio for death in this subgroup was 2.40 (95 CI 0.85 -6.81, p = 0.0210). Conclusion: mCRC CDX2 negative patients have a poorer prognosis. This was not confirmed in early stage CRC.
MBRS-52. TARGETING PRUNE-1 IN A GEMM OF METASTATIC MEDULLOBLASTOMA: A POTENTIAL ROUTE OF INHIBITION FOR NEW FUTURE THERAPIES
Authors: Veronica Ferrucci, Pasqualino de Antonellis, Francesco Paolo Pennino, Fatemeh Asadzadeh, Roberto Siciliano, Antonella Virgilio, Aldo Galeone, Lucia De Martino, Lucia Quaglietta, Maria Elena Errico, Vittoria Donofrio, Daniel Picard, Marc Remke, Louis Chesler, Fredrik Swartling, William Weiss, Michael Taylor, Giuseppe Cinalli, Massimo Zollo
Journal: Neuro-Oncology (2018)

Genetic modifications during development of paediatric Group3 Medulloblastoma (MBGroup3) are responsible for its highly metastatic properties and poor patient survival rates. We found PRUNE-1 to be highly expressed in metastatic MBGroup3, which is characterised by TGF-β signalling activation and OTX2 expression. The molecular mechanism was identified underlying the metastatic dissemination of those PRUNE-1-driven-MBGroup3. PRUNE-1, through its binding to NDPK-A (NME-1), enhances the canonical TGF-β pathway activation, upregulates OTX2 and SNAIL, and inhibits PTEN. We also identified a new non-toxic small molecule pyrimido-pyrimidine derivative (AA7.1) with the ability to enhance PRUNE-1 degradation and to impair tumour progression and metastases in vivo using orthotopic xenograft models with metastatic MBGroup3 cells. Using whole exome sequencing technology in primary human metastatic MB cells, we also defined new deleterious ‘non-synonymous homozygous’ gene variants with effects on immune cells activation/differentiation, as part of a protein network of relevance for metastatic processes (Ferrucci et al., Brain In Press, 2018). We developed a Genetically Engineered Mouse Model (GEMM) of PRUNE-1-driven-metastatic MB. This GEMM (MATH1-PRUNE-1/Cyclin-B2-LUC) was generated by overexpressing PRUNE-1 in the developing cerebellum (using MATH1 promoter) together with the Luciferase gene (under the control of Cyclin-B2 promoter) in a background TP53-/-, thus generating Medulloblastoma. Chemotherapeutic drugs for high-risk MB together with AA7.1 were tested in combination on medullospheres showing an impairment of cell index proliferation. In vivo, in xenografted studies, we showed tumour inhibition at both the primary and metastatic sites together with immunonomodulatory effects. Altogether these results are of importance for future targeted therapies of high risk metastatic MBGroup3.
PCLN-03. ORTHOTOPIC TRANSPLANTATION OF PAEDIATRIC GLIOMA STEM CELLS IN MICE MIRRORS THE CLINICAL COURSE OF THE PATIENT
Authors: Anna Wenger, Susanna Larsson, Sándor Dósa, Magnus Sabel, Teresia Kling, Helena Carén
Journal: Neuro-Oncology (2018)

The leading cause of cancer-related mortality among children is brain tumours and glioblastoma multiforme (GBM) has the worst prognosis. Epigenetic deregulation is believed to be a driver as these patients have few mutations compared to adults. New treatments are urgently needed but few pre-clinical in vivo models exist. One approach of generating these is to transplant tumour tissue into mice, but it yields highly variable results and requires serial passaging in mice, which is time-consuming, expensive and ethically questionable. We therefore aimed to establish a cell line-based orthotopic mouse model representative of the patient tumour. Patient-derived cancer stem cell (CSC) lines from paediatric GBM were orthotopically transplanted into immunodeficient mice. The xenograft tumours were evaluated by histology for glioma features. Genome-wide DNA methylation analysis was performed on the CSC, xenograft and patient tumours. All CSC lines initiated tumours and the survival of the mice correlated with the survival of their respective patient. The xenograft tumours had key glioma features and were classified as GBM by histology and methylation profiling. The methylation profile of the xenograft tumour clustered together with the patient tumour (<3% of CpG sites changed methylation status) and the injected CSC line. We have established a robust and reproducible xenograft model for GBM based on primary CSC lines. The xenograft tumours accurately reflected the patient tumours and mirrored the clinical course of the patient. This model is therefore ideal for accurately predicting patient response from pre-clinical studies of new treatment schedules.
HGG-02. EXTRACRANIAL METASTASIS OF GLIOBLASTOMA- - A REPORT OF THREE PEDIATRIC PATIENTS
Authors: Chelsee Greer, Virginia Harrod, Chandra Krishnan, Timothy George
Journal: Neuro-Oncology (2018)

Extracranial metastasis of glioblastoma is an exceedingly rare event and is thought to be present in less than 2% of cases. Review of the literature yields few case reports with regards to the pediatric population over a lengthy time frame. Here, we describe three cases over the last six years of pediatric extracranial metastasis in glioblastoma patients. All patients were male with age ranging from 7 month to 12 years old. They were treated similarly with small variations in maintenance therapy. Time to extracranial metastasis varied between 6-23 months. One patient had a ventriculoperitoneal (VP) shunt in place prior to extracranial metastasis. Extracranial metastasis were in bone (n=2) and liver (n=1). All patients died of disease within 3-6 weeks after extracranial metastatic disease was first noted. This data suggests that new life-prolonging treatment strategies in glioblastoma are possibly leading to extended life and increased incidence of extracranial disease spread. Genomic analysis of subclassification of tumors may give insight into subtypes of glioblastoma likely to spread outside the CNS. This may aid in future strategies for treatment and possible increased imaging surveillance in a subset of patients.
GERM-21. PRELIMINARY RESULTS OF RESPONSE ASSESSMENT WITH 18F-FET PET FOR INTRACRANIAL GERM CELL TUMORS IN ADOLESCENTS
Authors: Lisbeth Marner, Karsten Nysom, Astrid Sehested, Lise Borgwardt, René Mathiasen, Peder Skov Wehner, Otto Mølby Henriksen, Michael Lundemann, Carsten Thomsen, Lars Bøgeskov, Jane Skjøth-Rasmussen, Helle Broholm, David Scheie, Marianne Juhler, Liselotte Højgaard, Ian Law
Journal: Neuro-Oncology (2018)

Intracranial germinoma (WHO grade IV) has a good prognosis as over 90% can be cured with chemo- and radiotherapy, while intracranial nongerminomatous germ cell tumors (NGGCT) also have a good although somewhat less favorable outcome. We evaluated the use of 18F-fluoro-ethyltyrosine (18F-FET) positron emission tomography (PET) for response assessment in intracranial germinoma and NGGCT. Six patients (5 males, age 13-17 years) diagnosed with intracranial germinoma (n=4) or NGGCT (elevated alpha-fetoprotein (AFP)) (n=2) were included and 18F-FET PET scans were performed at baseline and after 9-12 weeks of chemotherapy (treated according to SIOP CNS GCT 2). One germinoma patient declined follow-up 18F-FET PET. All germinoma and one NGGCT patients had partial or complete response on MRI and were subsequently treated with proton radiation therapy, and are in clinical complete response (cCR). The second NGGCT patient had normalisation of AFP but progression on MRI; he was subsequently operated where histology showed only residual teratoma. He received further chemo- and radiotherapy and is in cCR. All patients with follow-up PET showed marked decrease of 18F-FET activity uptake after chemotherapy. Maximal tumor-to-background ratio decreased from 2.2 ± 0.4 before chemotherapy to 1.4 ± 0.3, p=0.001 (paired t-test). In five patients treated successfully for intracranial germ cell tumors, 18F-FET PET showed a marked decrease in activity uptake in response to chemotherapy. The results are promising for further studies of the use of 18F-FET PET in response assessment in this disease, possibly to assist radiation therapy dosing with the aim to reduce late effects.
EAPH-01. PSYCHOLOGICAL INTERVENTION APPLIED TO MINIMIZING THE USE OF SEDATIVES IN 3–14 YEARS OLD CENTRAL NERVOUS SYSTEM TUMORS UNDERGOING RADIOTHERAPY
Authors: Xing Zhang, Yuliang Xiang, Mingyao Lai, Qiaomin Zhou, Qing Xiao, Rishun Luo, Xiuqiong Chen, Linbo Cai, Jinfeng Wen
Journal: Neuro-Oncology (2018)

This article describes the application evaluation of psychological interventions in 3–14 years old central nervous system tumor children undergoing radiotherapy, furthermore, to promote optimal psychological interventions for local Chinese children. Between January 2016 and November 2017, 166 children patients received radiotherapy in Department of Oncology, Guangdong 999 Brain Hospital, 53 children (33 boys and 20 girls) of them with medical fear. Therefore, the medical team conducted psychological interventions to them before radiotherapy. Specially designed psychological intervention program included: Psychological scales, medical games, psychologists participated in the whole course of radiotherapy. The nurse recorded the usage of sedatives and heart rate, and the radiotherapist calculated the positioning setup errors. Psychological interventions worked successfully with 45 (85%)children behaved cooperative (without showing any resistances by crying and screaming) at first radiotherapy and keeping still until the session was completed. For the aged-3-year-old group, 64% (7/11) children was successfully behaved cooperative; 4-year-old children in the success rate of 77% (10/13); 5 and 6-year-old children in the success rate of 100%(16/16);7 -year-old children in the success rate of 80% (4/5), above 8-year-old children in the success rate of 100%. For those failed cases, 1child used anesthesia during the whole radiotherapy sessions; 6 children were take sedatives from the first to third session of radiotherapy. There is a notable efficiency of psychological interventions for children diagnosed with CNS tumor across the radiotherapy trajectory. Children, parents and clinical decisions preferred psychological intervention methods. Further research is required to strengthen the evidence base for psychological interventions in minimizing the use of anaesthesia.
MBCL-07. 5-YEAR EVENT-FREE SURVIVAL (EFS) AND NEUROCOGNITIVE OUTCOME IN CHILDREN WITH MEDULLOBLASTOMA (MB) BETWEEN 3 AND 5 YEARS OF AGE: RESULTS OF CHILDREN’S ONCOLOGY GROUP STUDY ACNS0331
Authors: Roger Packer, Yimei Li, Kristina Hardy, Anna Janss, Catherine Billups, Leanne Embry, Yuanyuan Han, Patricia Cullen, Thomas Merchant, Nancy Tarbell, Ian Pollack, Amar Gajjar, Sarah Leary, Maryam Fouladi, Jeff Michalski
Journal: Neuro-Oncology (2018)

Primarily due to concerns about severe neurocognitive sequelae, immediate post-surgical craniospinal radiotherapy (CSRT) is often avoided in young children (<5 years of age) with MB; the price paid for such an approach in relative loss of disease control or the cognitive benefits are poorly characterized. In ACNS0331, 226 participants, aged 3-7, were randomized to either 18 or 23.4 Gy CSRT, along with local-boost RT and chemotherapy. We report outcomes for the subset between 3-5 years at diagnosis (n=83). 5-year EFS was 72 ± 5% and was similar in the 32 less than 4 years (67 ± 9%) and the 51 between 4 and 5 years of age (76 ± 7%). Although not adequately powered, there was no statistical difference in EFS based on CSRT dose (p=0.88). 81 neurocognitive assessments were obtained on 56 children. Initial median IQ was 97 (range 50-127) and dropped a median of 3 points at the second timepoint (27-48 months from diagnosis). Those <4 had a 9-point median drop compared to 2.5 in older children; there was extensive individual variability in the degree of IQ change (range = -23 to 13). There was no statistical difference in IQ as a function of CSRT, although sample size was small (p=0.52). Omissions in CSRT in this age cohort should be done cautiously, especially in those between 4 and 5, given the 5 year EFS and the concerning, but not devastating, neurocognitive declines. Pending molecular subgrouping may help in deciding which patients have the most to lose or gain by CSRT avoiding regimens.
Margaret McCartney: The NHS’s slow decline is a preventable disease
Authors: Margaret McCartney
Journal: BMJ (2018)

The NHS is 70, and although I want to celebrate the endurance of a moral pact that illustrates our collective best, I feel so dismayed at the way it’s treated that pride hardly feels appropriate.

The NHS’s formation was contested by many doctors and, famously, by the BMA. Charles Hill, BMA secretary at the time, found “no reason whatever to bring doctors into the position of the civil service as full time officers,” with “the cold hand of bureaucratic control . . . administered by the state.”1

The first wave of the NHS was about caring for people’s unmet needs. The early …
Developing cardiovascular disease risk programs in India—Why location and wealth matter
Authors: David Peiris, Dorairaj Prabhakaran
Journal: PLoS Medicine (2018)

CVD risk stratification for population healthAssessment of a person's total or absolute risk of a cardiovascular disease (CVD) event based on multiple risk factors is superior to assessment of single risk factors when identifying who is at greatest risk of a CVD event [1].In this issue of PLOS Medicine, a study by Rifat Atun and colleagues outlines the use of CVD risk prediction equations for population health rather than for clinical purposes [2].This has inherent appeal because risk stratification of a population could be used to drive policy and health service planning, inform funding decisions around subsidising treatments, and identify particular subgroups for more intensive intervention strategies.Atun and colleagues used 2012 and 2014 household health survey data to assess sociodemographic and geographic variation in CVD risk profiles across most states and union territories in India.Cross-sectional estimates of 10-year CVD risk were derived using the Framingham risk equation (FRE) for people aged 30 to 74 years, calibrated for India using 2015 Global Burden of Disease data.Sensitivity analyses were conducted using three other risk prediction equations that have also been calibrated with Indian data.The main finding is the identification of regional 'hotspots' of relatively higher CVD risk scores regardless of which risk prediction equation was used.Furthermore, positive associations were found with increasing household and district wealth in both rural and urban areas.Although urban areas overall had a stronger positive association with higher CVD risk scores, the district wealth gradient was more pronounced in rural compared with urban areas, and the household wealth gradient was greater for females compared with males.The multivariable, absolute risk paradigm is now commonplace in many management guidelines around the world; however, there remain challenges with its implementation.First, the validity of cohort-derived risk prediction equations applied to other populations is frequently questioned [3].Second, when risk factor prevalence rates and CVD incidence rates are rapidly changing due to demographic and socioeconomic changes in the community, the need to recalibrate such equations becomes important [4].Third, when assessing the effectiveness of risk-based interventions, most studies are based on simulation studies [5] rather than empirical trial data [6].Finally, although risk prediction equations were designed to guide decisions on management and intervention, the evidence that use of risk scores improves clinical outcomes remains unclear [7].The limitations of Atun and colleagues' study are related to these broader challenges of implementing the risk-based paradigm.First, none of the equations used have been validated
Imaging γ-Glutamyltranspeptidase for tumor identification and resection guidance via enzyme-triggered fluorescent probe
Authors: Haidong Li, Qichao Yao, Feng Xu, Ning Xu, Ran Duan, Saran Long, Jiangli Fan, Jianjun Du, Jingyun Wang, Xiaojun Peng
Journal: Biomaterials (2018)
Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis
Authors: Ma Ai Thanda Han, Osama Altayar, Shadi Hamdeh, Varun Takyar, Yaron Rotman, Ohad Etzion, Eric Lefebvre, Rifaat Safadi, Vlad Ratziu, Larry J. Prokop, Mohammad Hassan Murad, Mazen Noureddin
Journal: Clinical Gastroenterology and Hepatology (2018)