tbuckley/cabot-search huggingface dataset:
EPID-11. SYSTEMATIC REVIEW ON TREATMENT-RELATED HAEMATOLOGICAL ADVERSE EVENTS AFTER TEMOZOLOMIDE FOR A CNS TUMOUR
Authors: Daniel Bos, Anja Gijtenbeek, Annemarie Muller, Antoinette Schouten-van Meeteren
Journal: Neuro-Oncology (2018)

Temozolomide is a widely used alkylating cytostatic drug for CNS tumours. Severe treatment-related haematological adverse events (tHAE) after the application of temozolomide are reported whilst the true incidence is elusive. The aim of this study is to determine the incidence, the risk-factors for, and course of secondary haematological adverse events after treatment with temozolomide in patients with CNS tumours. We reviewed the English literature between 1995-2016 on cases describing treatment-related haematological adverse events after temozolomide and set up a country-wide survey among (paediatric) neuro-oncologists in the Netherlands. In 20 out of 199 manuscripts deriving from the literature search 26 cases (age 0-69, median 40,5 years) were found with a severe tHAE event after temozolomide: 5 aplastic anemia, 5 acute lymphoblastic leukemia, 9 acute myeloblastic leukemia, 1 diffuse large B-cell lymphoma, 6 myelodysplastic syndrome and 1 mixed lineage leukemia. Karyotype was detected in 17/26 cases, mainly monosomy 5&7. Quality check of the literature mainly showed missing data on predisposing family history. Seven additional cases of a t-HAE after TMZ in CNS a tumour were discovered via a clinical survey in the Netherlands. The median latency in developing a t-HAE was 14 months, the survival after t-HAE was median 4,5 months. tHAE is rare and develops relatively early after treatment with temozolomide, while insufficient insight could be found for risk-factors for a t-HAE after temozolomide. Although most patients die from their secondary tHAE, its course differs substantially between individual cases.
Patients with cancer at 20% increased risk of suicide, show figures for England
Authors: Susan Mayor
Journal: BMJ (2018)

Patients with cancer have a 20% higher risk of suicide than the general population, an analysis of national figures for England has reported.1 The risk of suicide was highest in the first six months after diagnosis.

“Receiving a cancer diagnosis can be devastating, which is why it’s so important for every patient and their carers to get the support they need,” said Jem Rashbass, cancer lead at Public Health England. “This study shows how critical the first six months are to improving quality of life and …
Mechanisms and Drug Development in Atrial Fibrillation
Authors: David Calvo, David Filgueiras-Rama, José Jalife
Journal: Pharmacological Reviews (2018)

Atrial fibrillation is a highly prevalent cardiac arrhythmia and the most important cause of embolic stroke. Although genetic studies have identified an increasing assembly of AF-related genes, the impact of these genetic discoveries is yet to be realized. In addition, despite more than a century of research and speculation, the molecular and cellular mechanisms underlying AF have not been established, and therapy for AF, particularly persistent AF, remains suboptimal. Current antiarrhythmic drugs are associated with a significant rate of adverse events, particularly proarrhythmia, which may explain why many highly symptomatic AF patients are not receiving any rhythm control therapy. This review focuses on recent advances in AF research, including its epidemiology, genetics, and pathophysiological mechanisms. We then discuss the status of antiarrhythmic drug therapy for AF today, reviewing molecular mechanisms, and the possible clinical use of some of the new atrial-selective antifibrillatory agents, as well as drugs that target atrial remodeling, inflammation and fibrosis, which are being tested as upstream therapies to prevent AF perpetuation. Altogether, the objective is to highlight the magnitude and endemic dimension of AF, which requires a significant effort to develop new and effective antiarrhythmic drugs, but also improve AF prevention and treatment of risk factors that are associated with AF complications.
Tenofovir-Based Pre-exposure for HIV Infection among African Women
Authors: Jeanne Marrazzo, Gita Ramjee, Barbra Richardson, Kailazarid Gomez, Nyaradzo Mgodi, Gonasagrie Nair, Thesla Palanee, Clemensia Nakabito, Ariane Van Der Straten, Lisa Noguchi, Craig Hendrix, James Dai, S Ganesh, Baningi Mkhize, Marthinette Taljaard, Urvi Parikh, Jeanna Piper, Benoît Masse, Cynthia Grossman, James Rooney, Jill Schwartz, Heather Watts, Mark Marzinke, S. Hillier, Ian McGowan, Mike Chirenje
Journal: New England Journal of Medicine (2014)
ATRT-21. COMPARATIVE INTEGRATIVE ANALYSIS OF PRIMARY AND RELAPSED ATYPICAL TERATOID/RHABDOID TUMORS (AT/RTs)
Authors: Till Holsten, Malik Alawi, Michael Spohn, Martin Hasselblatt, Christine Haberler, Manila Antonelli, Arend Koch, Marcel Kool, Michael Frühwald, Ulrich Schüller
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive malignancy of infancy and early childhood representing the most common CNS tumor in children below the age of one year. AT/RTs harbour germline or somatic mutations in SMARCB1 or SMARCA4 while other recurrent genetic alterations are lacking. Though survival rates have slightly improved over the last years, prognosis remains poor, especially in the case of relapse. Our project aims at understanding molecular events contributing to relapse in AT/RT. To this end, histopathological and molecular features (DNA methylation array and whole exome sequencing) of 21 pairs of primary and relapsed AT/RTs were investigated. On histopathological examination, relapsed AT/RTs showed loss of architecture and significantly increased proliferation as compared to primary tumors. Although molecular subgroups did not change at recurrence, global methylation analysis of matched primary and recurrent tumor samples demonstrated an enrichment of differentially methylated areas at transcribed regions and promoters and distinct changes in trimethylation at H3K27 in a fraction of relapsed cases. CNV profiling revealed recurrent gains at multiple regions, while losses preferentially affected histone genes at chromosome 6. Finally, whole exome sequencing discovered a number of mutations affecting more than 3 relapse samples, but not the respective primary lesions. Our findings may contribute to improve the understanding of biological changes leading to enhanced aggressiveness of relapsed AT/RTs and provide a basis for further functional analyses.
Associated factors with overlooked multiple synchronous gastric epithelial neoplasia
Authors: D. Kang, C. Choi, H. Kim, S. Park, S. Kim, D. Ryu, J. Ko, J. Lee, J. Lee, K. Lee, B. Kwon, H. Kim, H. Nam
Journal: Annals of Oncology (2018)

Introduction: Since endoscopic submucosal dissection (ESD) has been accepted as the treatment of choice for early gastric cancer (EGC) without risk of lymph node metastasis, synchronous gastric epithelial neoplasia is no longer rare in the clinical practice. Knowledge about the characteristics associated with synchronous gastric epithelial neoplasia is of great importance to prevent delayed diagnosis. Methods: Between November 2008 and December 2014, a retrospective study was conducted in a single tertiary referral hospital. Consecutive patients who underwent ESD due to EGC or high-grade dysplasia were analyzed to evaluate the incidence of synchronous gastric epithelial neoplasia and the factors associated with synchronous and overlooked synchronous lesions. Results: A total of 488 patients were analyzed in this study. Synchronous lesions were found in 59 patients (12.1%) during the mean 37.7 months of follow-up. Among 77 synchronous lesions, 25 lesions (32.4%) were overlooked at the time of initial ESD. Age of ≥ 65 years, moderate to severe endoscopic atrophic gastritis, and elevated morphology of primary lesions were associated with synchronous gastric epithelial neoplasia. An important factor associated with overlooked lesions is the non-elevated morphology of lesions. Conclusion: Careful endoscopic examination of the whole stomach is necessary in patients who are older and who have moderate to severe atrophic gastritis and elevated morphology of lesions to prevent delayed diagnosis of synchronous gastric epithelial neoplasia, especially non-elevated lesions.
Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease
Authors: Rachel C. Orme, William A.E. Parker, Mark R. Thomas, Heather M. Judge, Kathleen Baster, Wael Sumaya, Kenneth P. Morgan, Hannah C. McMellon, James D. Richardson, Ever D. Grech, Nigel M. Wheeldon, Ian R. Hall, Javaid Iqbal, David Barmby, Julian P. Gunn, Robert F. Storey, Robert G. Wilcox (chair), John T. Walsh, William Smith, Allan Skene
Journal: Circulation (2018)

Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention for stable coronary artery disease. We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population.
MBCL-39. MEDULLOBLASTOMA IN PATIENTS WITH GORLIN SYNDROME: RESULTS FROM THE HIT STUDY GROUP
Authors: Barbara Meissner, Martin Mynarek, B Ole Juhnke, Katja von Hoff, Torsten Pietsch, Rolf D Kortmann, Monika Warmuth-Metz, Brigitte Bison, Stefan Rutkowski
Journal: Neuro-Oncology (2018)

Gorlin syndrome is an autosomal dominant inherited cancer predisposition syndrome characterized by basal cell carcinomas, odontogenic keratocysts, skeletal and multiple other anomalies, and medulloblastoma (MB). Most patients harbor a heterozygous germline mutation in PTCH1 or SUFU, genes that play a pivotal role in sonic hedgehog (SHH) signaling. We describe 17 patients with Gorlin syndrome diagnosed with MB between 1992 and 2017 who were treated according to HIT studies (HIT’91, SKK’92, HIT2000, and I-HIT-MED registry) and had available data on initial staging and treatment. Diagnosis of Gorlin syndrome was made clinically by fulfilling the syndrome criteria (N=9) or by proven PTCH1 (N=7) or SUFU (N=3) germline mutation. Median age at diagnosis of MB was 0.96 years. MB with extensive nodularity (N=5) and desmoplastic medulloblastoma (N=11) were the predominant histologic diagnoses, both typically associated with sonic hedgehog pathway activation (classical MB N=1). 12 of 17 patients had localized disease, 5 patients had metastases at initial diagnosis. 16 patients received HIT-SKK chemotherapy alone, 1 had primary craniospinal radiotherapy. HIT-SKK therapy was reduced in 3 patients with increased toxicities. Median follow up was 10.3 years. All patients are alive, two suffered from relapse 1.5 and 1.7 years after initial diagnosis. 10 year progression free survival was 82%±12%. Basal cell carcinoma was diagnosed in 2 patients, who were treated with radiotherapy. Gorlin syndrome and genetic counselling should be considered in all young children with SHH activated MB. Radiotherapy can be successfully avoided in most patients by HIT-SKK chemotherapy and is contraindicated within first-line therapy strategies.
HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European inTandem2 Study
Authors: Thomas Danne, Bertrand Cariou, Phillip Banks, Michael Brandle, Helmut Brath, Edward Franek, Jake A. Kushner, Pablo Lapuerta, Darren K. McGuire, Anne L. Peters, Sangeeta Sawhney, Paul Strumph
Journal: Diabetes Care (2018)

OBJECTIVE The objective of this study was to evaluate the efficacy and safety of the dual sodium–glucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c &amp;lt;7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. RESULTS At 24 weeks, placebo-adjusted changes in HbA1c from baseline (7.8%) were −0.37% and −0.35% with sotagliflozin 200 and 400 mg, respectively (P &amp;lt; 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (−0.87 mmol/L; P = 0.008), weight (−2.92 kg; P &amp;lt; 0.001), and total daily insulin dose (−8.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9–10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P &amp;lt; 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypoglycemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. CONCLUSIONS In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).
The ERBB network facilitates KRAS-driven lung tumorigenesis
Authors: Björn Kruspig, Tiziana Monteverde, Sarah Neidler, Andreas Hock, Emma Kerr, Colin Nixon, William Clark, Ann Hedley, Sarah Laing, Seth B. Coffelt, John Le Quesne, Craig Dick, Karen H. Vousden, Carla P. Martins, Daniel J. Murphy
Journal: Science Translational Medicine (2018)

KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.
Is there any association of dose received by pelvic bone marrow in preoperative radiotherapy in rectal cancer with hematological toxicity of subsequent oxaliplatin-based chemotherapy?
Authors: M. Spalek, W. Michalski, K. Bujko, L. Wyrwicz
Journal: Annals of Oncology (2018)

Introduction: Preoperative radio(chemo)therapy in rectal cancer may irreversibly damage pelvic bone marrow (PBM) and impair the tolerance of subsequent chemotherapy. The aim of the study was to assess the association between irradiated volume of PBM and the tolerance of subsequent FOLFOX-4 chemotherapy in rectal cancer. Methods: The target population was a retrospective cohort of consecutive patients with adenocarcinoma of rectum who received FOLFOX-4 as adjuvant or because of cancer relapse in our institution between 2011-2016. The PBM was automatically contoured and divided into iliac (IM), lumbosacral (LSM), and lower pelvic (LPM) marrow. We assessed mean dose, and percentage of volume receiving 10-90% (V10%-V90%) of the prescribed dose for PBM, IM, LSM, LPM. To evaluate the association between mean dose, V20% and V40% with ≥2 (TOX2) and ≥ grade 3 (TOX3) hematological toxicity, Chi-2 and T-test were used. Generalized linear model (GLM) was used to test an influence of dose-volumes distribution on TOX2 and TOX3. Results: 39 patients met eligibility criteria. 26 of them received preoperative 5x5 Gy, 7 of them underwent 5x5 Gy with consolidative 3 cycles of FOLFOX-4, 6 of them received 25x2 Gy with concomitant 5-FU/LV. No dependence of V20% and V40% of PBM and its areas on toxicity was found. We found no influence of dose-volume distribution on TOX2 and TOX3. Conclusion: No relationship between doses received by pelvic bone marrow in preoperative radio(chemo)therapy in rectal cancer and hematological tolerance of subsequent FOLFOX-4 chemotherapy was found.
EPEN-08. A SPATIAL AND PROGNOSTIC ANALYSIS OF IMMUNE CELL INFILTRATE IN PAEDIATRIC EPENDYMOMA
Authors: Timothy A Ritzmann, Francesca Francis, Sarah-Louise Brudenell, Hazel A Rogers, Alex Virasami, Thomas S Jacques, Simon Ml Paine, Richard G Grundy
Journal: Neuro-Oncology (2018)

Ependymoma is the second most common malignant brain tumour of childhood. The immune environment has been implicated in recurrence, but more research is needed to understand its role. We performed immunohistochemistry on tumour sections for the T-cell markers CD4 and CD8, B-cell marker CD20 and inflammatory markers CD45 and CD68. 55 paired primary and first recurrent tumours plus 19 non-recurrent tumours were included. Baseline clinical and DNA methylation characteristics were representative of other paediatric ependymoma cohorts. Levels of CD4, CD8 and CD20 were low within the tumour parenchyma but higher for CD45 and CD68. All markers, other than CD68, were more highly expressed in non-parenchymal than parenchymal areas (p<0.001). Higher levels were also seen in perivascular regions. There was a significant fall in CD45 cells at first recurrence compared to primary (p=0.009) and this appeared to be restricted to posterior fossa tumours. There was no difference at relapse for other markers. Higher CD45 and CD68 expression was associated with tumours that relapsed (p=0.019 and p<0.001). Infiltration with CD20+ and CD8+ cells at primary diagnosis were associated with poorer survival for patients who recurred (p=0.007, p=0.009). The spatial distribution of infiltrating immune cells supports a hypothesis that paediatric ependymoma is a T-cell excluded tumour. The fall in inflammatory (CD45) infiltrate at recurrence indicates a possible immune subversion process. Mechanisms of immune cell exclusion from the tumour parenchyma need to be better characterised in order to understand the implications for immunotherapy. The association between recurrence and inflammatory infiltrate needs further investigation.
EMBR-15. DIAGNOSTIC RE-EVALUATION AND POOLED CLINICAL DATA ANALYSIS OF PATIENTS WITH PREVIOUS DIAGNOSIS OF CNS-PNET
Authors: Katja von Hoff, Christine Haberler, Giles Robinson, David Sumerauer, Jaeho Cho, Martin Mynarek, Eugene Hwang, Sandra Jacobs, Theresa de Rojas, Martha Perek, Christelle Dufour, Matija Snuderl, Richard Grundy, Maria Joao Gil da Costa, Dannis van Vuurden, Irene Slavc, Nicolas U Gerber, Jessica Pickles, Amar Gajjar, Barry Pizer, Stefan Rutkowski, David Capper, Dominik Sturm, Brent Orr, Pieter Wesseling, Peter Hauser, Maria Lastowska, Andrey Korshunov, Tom Jacques, Felice Giangaspero, Cynthia Hawkins, Dominique Figarella, Charles Eberhart, Peter Burger, Marco Gessi, Stefan M Pfister, Torsten Pietsch, Marcel Kool
Journal: Neuro-Oncology (2018)

CNS-PNET is no longer regarded a single disease but encompassed many distinct molecular entities. After removal of the term from the 2016 WHO classification of CNS tumours, diagnostic and therapeutic uncertainty remains. Through a world-wide collaboration, tumour samples from patients with the “historic” diagnosis of CNS-PNET were re-evaluated by DNA methylation profiling (n=405) and blinded neuropathological panel review (n=256). Clinical data on treatment and outcome were pooled with data on previously published patients. The given numbers represent preliminary data of the ongoing project. The re-evaluation by DNA methylation identified many distinct entities as expected, including high grade glioma (HGG, n=70), embryonal tumors with multilayered rosettes (ETMR, n=57) and CNS-neuroblastoma with FOXR2 alteration (CNS-NB-FOXR2, n=42) as the most frequent molecular diagnostic categories. Poor clinical outcome was confirmed for patients with HGG (5y-PFS 12%/5y-OS 12%, n=24), and ETMR (5y-PFS 12%/5y-OS 18%, n=62), while most patients with CNS-NB-FOXR2 survived (5y-PFS 52%/5y-OS 96%, n=31). Seven of 12 relapses/progressions of CNS-NB-FOXR2 occurred in radiotherapy-naïve patients. Classification into other newly described and less common entities included HGNET-MN1 (n=19), HGNET-BCOR (n=11), and EFT-CIC (n=13). Independent neuropathological review demonstrated that samples of these entities presented as non-embryonal tumours. Furthermore, marked clinical differences exist (HGNET-MN1: 5y-PFS 25%/5y-OS 95%, n=22; HGNET-BCOR: 5y-PFS 0%/5y-OS 44%, n=16; CNS-EFT-CIC: 5y-PFS 40%/5y-OS 60%, n=10). Our results show that implementation of DNA methylation profiling together with histopathological analysis will improve prospective diagnostic accuracy and facilitates the retrospective outcome analysis of treatment protocols used for this variety of biologically distinct entities.
DIPG-42. CAN WE CHANGE THE LANDSCAPE OF PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)? FIRST DEMONSTRATION OF CLINICAL AND RADIOGRAPHIC RESPONSE IN A PEDIATRIC H3-K27M MUTATED DIPG TO THE DRD2-ANTAGONIST ONC201
Authors: Matthew Hall, Yazmin Odia, Joshua Allen, Rohinton Tarapore, Ziad Khatib, Ossama Maher, Toba Niazi, Doured Daghistani, Lee Schalop, Andrew Chi, Wolfgang Oster, Minesh Mehta
Journal: Neuro-Oncology (2018)

DIPG is uniformly fatal, with a median survival of 8–9 months. We report the first pediatric patient with H3-K27M mutated DIPG treated with conventional radiotherapy and the small molecule DRD2-antagonist ONC201, with a sustained radiographic and clinical response after 8 months of therapy. A 10-year-old female presented with House-Brackmann Grade IV facial palsy and unilateral hearing loss in 2/2017. MRI demonstrated a 2.3x2.1x2.7 cm medullopontine tumor. Stereotactic biopsy confirmed H3-K27M mutated diffuse midline glioma. She completed intensity-modulated radiotherapy (59.4 Gy/33 fractions) in 5/2017. MR imaging 1-month post-radiotherapy demonstrated reduction in tumor volume (2.0x1.9x2.7 cm) with persistent Grade IV facial palsy.The patient began oral ONC201 (500 mg weekly) as a single agent in 6/2017 on an IRB-approved compassionate use protocol with MRI every 2 months. ONC201 is a first-in-class DRD2-antagonist that crosses the blood-brain barrier and has shown efficacy in high grade glioma preclinical models through a p53-independent mechanism. Tumor volume sequentially decreased by 30.6, 33.2, and 41.9% over the next three MRIs, reaching 1.8x1.7x1.9 cm at 6 months from initiation of ONC201. Ipsilateral hearing was restored and the facial palsy improved to House-Brackmann Grade I by 16 weeks after starting ONC201. The patient remains clinically improved and without adverse events 8 months after starting ONC201 and 11 months from diagnosis. This case provides initial proof-of-concept for this novel agent targeting H3-K27M DIPG. Phase II trials are ongoing to evaluate the efficacy of ONC201 in adult and pediatric patients with H3-K27M gliomas.