tbuckley/cabot-search huggingface dataset:
Depression in adults: campaigners and doctors demand full revision of NICE guidance
Authors: Jacqui Thornton
Journal: BMJ (2018)

A coalition of mental health organisations and individual clinicians has described the latest draft guidelines on adult depression by the National Institute for Health and Care Excellence (NICE) as misleading, invalid, and not fit for purpose, saying that they could harm patients.

Fourteen organisations including the Royal College of Psychiatrists and six leading doctors including Simon Wessely, former president of the college, and Clare Gerada, former president of the Royal College of General Practitioners, have signed a position statement sent to NICE.1

It says that the draft revision of NICE’s guideline on depression in adults2 is based on wide ranging and fundamental methodological flaws for establishing effective treatment and falls short of acceptable scientific standards. The guideline development group favours medical trials over psychological trials and particular psychological treatments over others, the statement says, adding that it relies too much on …
LGG-42. RECURSIVE PARTITIONING ANALYSIS OF PROGNOSTIC FACTORS FOR PEDIATRIC LOW-GRADE GLIOMAS TREATED WITH RADIATION THERAPY
Authors: Sahaja Acharya, David Ellison, Ibrahim Qaddoumi, Amar Gajjar, Thomas Merchant
Journal: Neuro-Oncology (2018)

Pediatric low-grade glioma (PLGG) represents a heterogeneous group of tumors. The purpose of this study was to identify clinical prognostic factors for overall-survival (OS) in PLGG treated with radiation therapy (RT). Between 1986 and 2017, 174 patients with non-metastatic, biopsy-proven PLGG were consecutively treated with RT at a single institution. OS was estimated using Kaplan-Meier methods. Prognostic factors were identified using Cox proportional hazards. Recursive partitioning analysis (RPA) was used to stratify patients into high and low-risk prognostic groups. Median follow-up was 11.3 years. Median age was 8.3 years. Common subtypes included: pilocytic astrocytoma (67%), astrocytoma not otherwise specified (12%), and diffuse astrocytoma (DA) (10%). Most were located in the optic pathway/hypothalamus (37%) or thalamus/midbrain (24%). Median tumor dimension was 2.8 cm. On multivariate analysis, tumor size (cm) (Hazard ratio [HR]: 1.81, 95% CI: 1.38-2.37, p<0.001), thalamic/midbrain compared to optic pathway/hypothalamic location (HR: 3.93, 95% CI: 1.17-13.19, p=0.027) and DA compared to pilocytic astrocytoma (HR: 3.33, 95% CI: 1.01-10.97, p=0.048) were independently prognostic for OS. RPA yielded four nodes which were pruned into two groups: low-risk (tumors ≤4.6 cm, non-thalamic/midbrain and non-DA) and high-risk (tumors >4.6 cm or thalamic/midbrain or DA) with 10-year OS of 97% vs. 78% (95% CI: 91%-99% vs. 64%-86%, p <0.001), respectively. In progressive PLGG treated with RT, tumor size, thalamic/midbrain location and diffuse histology may stratify patients into prognostic groups. This clinical model requires validation and might be improved with molecular markers to aid therapy selection.
LGG-08. PROTEOGENOMICS REVEALS TWO DISTINCT BIOLOGICAL PILOCYTIC ASTROCYTOMA SUBGROUPS
Authors: Daniel Picard, Jörg Felsberg, Maike Langini, David Pauck, Viktoria Marquardt, Frauke Meyer, Sarah Göbbles, Anja Stefanski, Kai Stühler, Lucia Roque, Arndt Borkhardt, Guido Reifenberger, Cláudia Faria, Marc Remke
Journal: Neuro-Oncology (2019)

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA tumorigenesis. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapeutic approaches. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing, DNA methylation profiling and LC/MS-based proteomic profiling data from a cohort of 75 primary PA samples. Similarity Fusion Network (SNF) analysis was conducted to discern the biological heterogeneity of PA. Integrative genomics was used to identify aberrant pathway activation in these biological subgroups. Lastly, we utilized a drug screening pipeline to evaluate selective therapeutic activity of conventional anti-cancer and phase III/IV clinical trial drugs in PA culture models. Pilocytic astrocytomas segregate into two groups with distinct clinical and molecular features. Age is significantly associated with the SNF groups. BRAF fusions were predominantly observed in Group 1, while Group 2 PAs largely harbored other alterations leading to MAPK activation. Importantly, we could confirm these two distinct biological subgroups in two independent, non-overlapping cohorts. Pathway enrichment analyses reveal genesets involved in ion channel activity, neurotransmitter signaling and cellular respiration, whereas largely SYK-related immune response signatures are associated with Group 1. Confirming this analysis, the SYK inhibitor R788 was specifically active in Group 1 PAs, and less active in other brain tumor models (n=13).
MBRS-36. IDENTIFICATION OF TWO PROTEIN-SIGNALING STATES DELINEATING TRANSCRIPTIONALLY HETEROGENEOUS HUMAN MEDULLOBLASTOMA
Authors: Walderik Zomerman, Sabine Plasschaert, Siobhan Conroy, Frank Scherpen, Tiny Meeuwsen-de Boer, Harm-Jan Lourens, Sergi Guerrero Llobet, Marlinde Smit, Lorian Slagter-Menkema, Annika Seitz, Corrie Gidding, Esther Hulleman, Pieter Wesseling, Lisethe Meijer, Leon van Kempen, Anke van den Berg, Daniel Warmerdam, Frank Kruyt, Floris Foijer, Marcel van Vugt, Wilfred den Dunnen, Eelco Hoving, Victor Guryev, Eveline de Bont, Sophia Bruggeman
Journal: Neuro-Oncology (2018)

Medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a cohort of SHH, Group 3 and Group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed DNA damage, apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of Group 3 patients exhibited the MYC-like protein-signaling profile, the other Group 3 subset and Group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis highlighted cell cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.
DIPG-52. ACTIVE CHROMATIN IN H3K27M DIPG REVEALS DISTINCT EPIGENETIC SUBTYPES AND SUBTYPE-SPECIFIC MECHANISMS OF PATHOGENESIS
Authors: Surya Nagaraja, Michael Quezada, Shawn Gillespie, Anna Geraghty, Volker Hovestadt, Mariella Filbin, Mario Suva, Javad Nazarian, Michelle Monje
Journal: Neuro-Oncology (2018)

DIPG is the leading cause of pediatric brain tumor-related death and remains without effective clinical treatment. Through numerous genomic studies, the H3K27M mutation has emerged as the molecular hallmark of DIPG. While this mutation causes global chromatin remodeling and a broadly oncogenic transcriptional signature, the core molecular pathways driving DIPG pathobiology remain to be defined. In this study, we characterize the active chromatin epigenomic landscape of DIPG in a large cohort of primary tumor samples and identify novel epigenetic subgroups within histone-mutant DIPG. We uncover distinct signaling pathways controlling oncogenic state for each subgroup, elucidating novel mechanisms mediating proliferation and treatment resistance. Utilizing a human iPSC developmental model introducing the histone mutation at progressive stages of neural precursor differentiation, we will describe the developmental cell state most closely resembling DIPG tumors from each genomic subgroup and identify the specific molecular pathways by which the H3K27M mutant drives transformation. Taken together, this study identifies functional molecular heterogeneity between primary DIPG tumors and characterizes novel targets for potential therapeutic development.
Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation
Authors: Boyoung Shin, Robert L. Kress, Philip A. Kramer, Victor M. Darley-Usmar, Susan L. Bellis, Laurie E. Harrington
Journal: The Journal of Experimental Medicine (2018)

Dysregulated CD4 T cell responses are causally linked to autoimmune and chronic inflammatory disorders, yet the cellular attributes responsible for maintaining the disease remain poorly understood. Herein, we identify a discrete population of effector CD4 T cells that is able to both sustain and confer intestinal inflammation. This subset of pathogenic CD4 T cells possesses a unique gene signature consistent with self-renewing T cells and hematopoietic progenitor cells, exhibits enhanced survival, and continually seeds the terminally differentiated IFNγ-producing cells in the inflamed intestine. Mechanistically, this population selectively expresses the glycosyltransferase ST6Gal-I, which is required for optimal expression of the stemness-associated molecule TCF1 by effector CD4 T cells. Our findings indicate that the chronicity of T cell-mediated inflammation is perpetuated by specific effector CD4 T cells with stem-like properties.
Students are underused and undervalued in quality improvement
Authors: Binay Gurung
Journal: BMJ (2018)

Allwood and colleagues discuss the importance of quality improvement.1 More than two decades after the UK government made it statutory for all health organisations to seek quality improvement through clinical governance,2 the collective effect of improvement projects is still far below the potential. One of the reasons for this is the failure to recognise the role and contribution of students.

Students are highly capable …
DIPG-15. THE ROLE OF THE G-PROTEIN-COUPLED RECEPTOR, GPR17 IN PAEDIATRIC DIFFUSE MIDLINE GLIOMA
Authors: Katie Loveson, Eva Lepinay, Samuel Robson, Helen Fillmore
Journal: Neuro-Oncology (2018)

Pediatric diffuse midline glioma (pDMG), an incurable, aggressive childhood malignancy, arises in a region- and age-specific nature. The underlying pathophysiology suggests dysregulation of postnatal neurodevelopmental processes causing aborted cell differentiation. The cell of origin is as yet unclear, but recent data suggests an oligodendrocytic lineage. This is supported by the over-expression of transcription factors such as Olig1 & Olig2 in 80% of pDMG cases. Results from in-depth bioinformatics and principal component analysis (PCA) of genes involved in brain development and pDMG led us to explore GPR17. GPR17, an orphan G protein-coupled receptor has been identified in a number of physiological and pathological processes, such as oligodendrocyte differentiation, spinal cord injury and brain injury. Bioinformatic analyses of publicly available mRNA datasets (GSE26576), indicated a significant up-regulation of GPR17 in pDMG patients compared to normal brainstem (p = 0.0037) and normal brain (p < 0.0001). PCA analysis shows GPR17 clusters closely to Olig1 and Olig2. GPR17 expression was confirmed in cell lines (VUMC-DIPG-A and VUMC-DIPG-08) and FFPE tissue at protein level using Western blot, IHC and Flow Cytometry and mRNA level using RT-qPCR. To gain further understanding of the role of GPR17, we are currently using agonists, antagonists and shRNA to modulate GPR17 expression and activity in functional and mechanistic, signalling pathway studies. Preliminary results suggest that GPR17 may be associated with the biology of pDMG. Our study hopes to provide insight into the mechanism of action and to identify targets for this receptor as a potential approach for therapeutic intervention.
Phase II trials of erlotinib or gefitinib in patients with recurrent meningiomas
Authors: A. D. Norden, J. J. Raizer, K. R. Lamborn, L. E. Abrey, S. M. Chang, M. R. Gilbert, T. F. Cloughesy, M. D. Prados, F. Lieberman, P. Wen
Journal: Journal of Clinical Oncology (2009)

2062 Background: No effective treatment is available for recurrent meningiomas when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00–01) and erlotinib (NABTC 01–03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Methods: Patients with recurrent histologically confirmed meningiomas and no more than two previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Results: Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and nine (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and eight (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 29%, 12-month PFS (PFS12) 0%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical/malignant tumors, PFS6 was 25%, PFS12 19%, OS6 81%, and OS12 68%. There were no significant PFS or OS differences by histology. Of 21 evaluable patients, there were no responses; eight patients (38%) had stable disease, and 13 (62%) had progressive disease. Treatment was well-tolerated. Rash was not a significant predictor of PFS or OS. Conclusions: Neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear but evaluation of EGFR inhibitors in combination with other targeted molecular agents may be warranted. No significant financial relationships to disclose.
Simultaneous versus staged resections of liver metastases in patients with advanced colorectal cancer
Authors: O. Kolesnik, A. Lukashenko, Y. Ostapenko, N. Chorna
Journal: Annals of Oncology (2018)

Introduction: Surgical management of metastatic colorectal cancer remains the best method to use which significantly improves overall 5-year survival. There are two well-known possible approaches of surgical treatment of patients with synchronous colorectal liver metastasis. The former includes synchronous resection of the colorectal primary with the following resection of the liver metastases and the latter is a staged resection approach. However, at present the issue of feasibility and effectiveness of simultaneous operations for metastatic liver lesions in patients with synchronous metastatic colorectal cancer (SMCLC) is negotiated and remains uncertain. This study aimed to compare the surgical outcomes and survival benefit between synchronous and staged resections of the colorectal liver metastases. Methods: Data of 144 patients with colorectal cancer and synchronous liver metastases was analyzed between 2008-2017. There were two groups of patients. Fifty-eight patients from group A were undergone synchronous liver and colon resection whereas eighty-six patients from group B - staged resection of colon and liver, respectively. Results: Overall 3-year survival in group A with synchronous resections was 41% and in the group B - 50% (р>0.001). There were no significant differences in overall level of post-operative complications in the groups A and B after surgical stages finishing, 30.5%(n = 44) and 36.1%(n = 52), respectively (р>0.001). Shorter duration of the operation was observed in the group A – 316.3 (±10.3) min in comparison with the group B 484.1(±18.3) min (р<0.001). Patients after staged resection stayed longer in clinic - 23.3±0.8 bed-days, then those who undergone synchronous resections -10.2±0.4 bed-days (p < 0.001) provided with shorter recovery terms in post-operative period. Conclusion: Analysis of our research has indicated necessity of the development of differentiated approach in SMCLC surgical treatment. Subsequent research should be directed towards study of prognosis factors and criteria for patients' selection for surgical treatment groups, assessment of economic efficacy and patients' life quality.
Activity of larotrectinib in patients with TRK fusion GI malignancies
Authors: M. Nathenson, G. Demetri, U. Lassen, D. Hong, V. Boni, J. Deeken, A. Dowlati, M. Cox, N. Ku, S. Cruickshank, H. Qamoos, A. Drilon
Journal: Annals of Oncology (2018)

Introduction: TRK fusions arise from aberrant rearrangements of neurotrophic receptor kinase genes NTRK1-3 with a variety of gene partners; these are constitutively active ligand-independent oncogenic drivers in a broad range of solid tumors. The highly selective TRK inhibitor larotrectinib achieved objective responses of 75% by independent review (80% by investigator assessment) in patients with a wide variety of TRK fusion cancers (Drilon et al., NEJM, 378:731-739, 2018). We report here on the activity and safety of larotrectinib in the treatment of GI malignancies from three separate studies (NCT02122913, NCT02637687, and NCT02576431). Methods: Patients with locally advanced or metastatic solid tumors who had received prior standard therapy or had no treatment alternatives were eligible. Evidence of a NTRK gene fusion as detected by CLIA or equivalently certified laboratory was required. Larotrectinib (100 mg or 150 mg po bid) was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed by investigators and by independent radiologic review using RECIST version 1.1. Results: As of 17th July 2017, a total of 55 patients across 17 cancer types were enrolled in the overall study and constitute the safety population. A sub-group of 12 patients (age range 32-74 years) had a GI malignancy, including 4 with colorectal cancer, 3 with GIST, 2 with cholangiocarcinoma, and one each with adenocarcinoma of the appendix, pancreas and a peri-rectal soft tissue sarcoma. Nine of those patients had fusions involving NTRK1; all 3 GIST patients had ETV6-NTRK3 gene fusions. Objective responses were documented in 8 of 12 patients (75%; per investigator), including colon cancer, pancreatic carcinoma, cholangiocarcinoma and GIST, with one complete response (GIST) and 7 partial responses. Stable disease noted as best response in 3 patients including a patient with appendiceal cancer, and one patient with cholangiocarcinoma exhibited primary progressive disease. Responses were rapid with maximum time to first response < 2 months. Duration of response ranged from 3.5 months (pancreas) to 22.9 months (GIST; ongoing). Adverse events across all study patients were principally grade 1 or 2. The most common grade 3 events were anemia (11%), increased ALT or AST (7%), increased body weight (7%), or decreased neutrophil count (7%). No patient discontinued larotrectinib due to a drug-related adverse event. Conclusion: TRK inhibition with larotrectinib in patients with TRK fusion GI malignancies was well tolerated and resulted in rapid induction of durable responses
Immediate and long-term results of liver resections with metastatic lesion
Authors: S. Lukmonov, O. Usmanov, M. Ismailov, K. Madatov, U. Kurbankulov, U. Allazarov
Journal: Annals of Oncology (2018)

Introduction: To evaluate the effectiveness of surgical treatment of metastatic liver damage. Methods: The analysis of the results of 29 liver resections performed on the basis of the Department of Oncology and Radiology of the Tashkent Medical Academy, performed for metastatic liver damage from 2002 to 2012 inclusive, is presented. Patients were distributed as follows: with metastases of colorectal cancer - 22 (75.86%), non-cortical - 7 (24.14%). The study included 11 (38%) men, the average age was 56.4 ± 8.4 years, and 18 (62%) women, the average age was 61.8 ± 7.9 years. A total of 21 (72.4%) large resection of the liver and 8 (27.6%) of small ones, including anatomical resections: segmentectomy - 1; bisegmentectomy - 2; atypical - 5. Results: Early postoperative lethality (during the first 30 days after surgery) during surgical treatment of patients with metastases of colorectal cancer in the liver was 9.1%, non-cortical - 22%. The incidence of postoperative complications is 27.6%. According to the analysis of cumulative survival by the Kaplan-Mayer method, the median survival in the group of patients with colorectal cancer metastases in the liver is 24 months, non-cortical cancer is 12 months, the three-year survival is 27.5 and 0%, respectively, the five-year survival is 9.1%. Conclusion: Liver resection is the only radical treatment for patients with metastatic lesions, improving the prognosis and providing a five-year survival rate of up to 9.1%. Improving the results of liver resections in patients with metastatic lesions implies the need to improve technique and the desire to perform anatomical resections in order to reduce early postoperative lethality and specific complications.
Representation of Patients With Chronic Kidney Disease in Trials of Cancer Therapy
Authors: Abhijat Kitchlu, Joshua Shapiro, Eitan Amir, Amit X. Garg, S. Joseph Kim, Ron Wald, Ziv Harel
Journal: JAMA (2018)

Representation of Patients With Chronic Kidney Disease in Trials of Cancer TherapyChronic kidney disease (CKD) is common in patients with cancer, with reported prevalence ranging from 12% to 53% at cancer diagnosis. 1Cancer patients with concomitant CKD have worse cancer outcomes than those with normal kidney function. 2Despite the prevalence of kidney dysfunction and its prognostic implications, there is limited evidence to guide cancer treatment in patients with CKD.One reason may be the exclusion of CKD patients from clinical trials (as has been documented in cardiovascular studies). 3We sought to quantify and characterize the exclusion of patients with CKD in randomized clinical trials of anticancer drugs.Methods | We performed a systematic search of MEDLINE for randomized trials of drugs for the 5 most common solid cancers (bladder, breast, colorectal, lung, and prostate) in 6 highprofile general medicine and oncology journals (selected based on impact factor, and listed in Table 1) from January 2012 through December 2017.We excluded trials of surgery, radiation, and supportive care.Nonrandomized studies and pooled analyses were also excluded.Two reviewers independently assessed published articles, protocols, and supplementary materials for each trial to determine whether patients with CKD were excluded.Corresponding authors were contacted in cases of ambiguity regarding exclusions.Multivariable logistic regression was used to assess for trial characteristics associated with exclusion of CKD.Analyses were performed using SAS (SAS Institute), version 9.4.Two-sided P values less than .05were considered statistically significant.from novel cancer therapies while balancing the potential risk of adverse events.