tbuckley/cabot-search huggingface dataset:
A Deep Learning Algorithm for Prediction of Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration from Color Fundus Photography
Authors: Felix Grassmann, Judith Mengelkamp, Caroline Brandl, Sebastian Harsch, Martina E. Zimmermann, Birgit Linkohr, Annette Peters, Iris M. Heid, Christoph Palm, Bernhard H.F. Weber
Journal: Ophthalmology (2018)

<h3>Purpose</h3> Age-related macular degeneration (AMD) is a common threat to vision. While classification of disease stages is critical to understanding disease risk and progression, several systems based on color fundus photographs are known. Most of these require in-depth and time-consuming analysis of fundus images. Herein, we present an automated computer-based classification algorithm. <h3>Design</h3> Algorithm development for AMD classification based on a large collection of color fundus images. Validation is performed on a cross-sectional, population-based study. <h3>Participants</h3> We included 120 656 manually graded color fundus images from 3654 Age-Related Eye Disease Study (AREDS) participants. AREDS participants were >55 years of age, and non-AMD sight-threatening diseases were excluded at recruitment. In addition, performance of our algorithm was evaluated in 5555 fundus images from the population-based Kooperative Gesundheitsforschung in der Region Augsburg (KORA; Cooperative Health Research in the Region of Augsburg) study. <h3>Methods</h3> We defined 13 classes (9 AREDS steps, 3 late AMD stages, and 1 for ungradable images) and trained several convolution deep learning architectures. An ensemble of network architectures improved prediction accuracy. An independent dataset was used to evaluate the performance of our algorithm in a population-based study. <h3>Main Outcome Measures</h3> κ Statistics and accuracy to evaluate the concordance between predicted and expert human grader classification. <h3>Results</h3> A network ensemble of 6 different neural net architectures predicted the 13 classes in the AREDS test set with a quadratic weighted κ of 92% (95% confidence interval, 89%–92%) and an overall accuracy of 63.3%. In the independent KORA dataset, images wrongly classified as AMD were mainly the result of a macular reflex observed in young individuals. By restricting the KORA analysis to individuals >55 years of age and prior exclusion of other retinopathies, the weighted and unweighted κ increased to 50% and 63%, respectively. Importantly, the algorithm detected 84.2% of all fundus images with definite signs of early or late AMD. Overall, 94.3% of healthy fundus images were classified correctly. <h3>Conclusions</h3> Our deep learning algoritm revealed a weighted κ outperforming human graders in the AREDS study and is suitable to classify AMD fundus images in other datasets using individuals >55 years of age.
Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition
Authors: Kerrin S. Small, Marijana Todorčević, Mete Civelek, Julia S. El-Sayed Moustafa, Xiao Wang, Michelle M. Simon, Juan Fernandez-Tajes, Anubha Mahajan, Momoko Horikoshi, Alison Hugill, Craig A. Glastonbury, Lydia Quaye, Matt J. Neville, Siddharth Sethi, Marianne Yon, Calvin Pan, Nam Che, Ana Viñuela, Pei-Chien Tsai, Abhishek Nag, Alfonso Buil, Gudmar Thorleifsson, Avanthi Raghavan, Qiurong Ding, Andrew P. Morris, Jordana T. Bell, Unnur Thorsteinsdottir, Kari Stefansson, Markku Laakso, Ingrid Dahlman, Peter Arner, Anna L. Gloyn, Kiran Musunuru, Aldons J. Lusis, Roger D. Cox, Fredrik Karpe, Mark I. McCarthy
Journal: Nature Genetics (2018)
Prognostic Impact of Tumor Mutation Burden in Patients With Completely Resected Non–Small Cell Lung Cancer: Brief Report
Authors: Yuki Owada-Ozaki, Satoshi Muto, Hironori Takagi, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Ohsugi, Mika Hoshino, Yutaka Shio, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Hiroyuki Suzuki
Journal: Journal of Thoracic Oncology (2018)

Tumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis.We calculated TMB within individual tumors by whole-exome sequencing analysis using next-generation sequencing. We included that there were 90 patients with NSCLC who underwent surgery in the Hospital of Fukushima Medical University from 2013 to 2016. No patients received chemotherapy or immunotherapy before surgery. We assessed the correlation between TMB and prognosis.TMB greater than 62 was associated with worse overall survival (OS) of patients with NSCLC (hazard ratio [HR] = 6.633, p = 0.0003). Multivariate analysis showed poor prognosis with high TMB (HR = 12.31, p = 0.019). In patients with stage I NSCLC, higher TMB was associated with worse prognosis for both OS (HR = 7.582, p = 0.0018) and disease-free survival (HR = 6.07, p = 0.0072).High TMB in NSCLC is a poor prognostic factor. If high TMB is a predictor of the efficacy of immune checkpoint inhibitors, postoperative adjuvant therapy with immune checkpoint inhibitors may contribute to improvement of recurrence and OS.
Early Chronic Obstructive Pulmonary Disease or Early Detection of Mild Disease?
Authors: Surya P. Bhatt
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

We agree that from a clinical perspective, standardization of a single, universally adopted, evidence-supported definition of a hypopnea event is an important goal.Many of the variations in the apnea-hypopnea index (AHI) that arise from different hypopnea definitions are, in effect, rescaled metrics of OSA disease severity.For example, in a comparison of recommended (AHI Rec ) and alternative (AHI Alt ) hypopnea definitions proposed by the American Academy of Sleep Medicine in 2007 (2), Ruehland and colleagues (3) found that although the more liberal AHI Alt definition produced z80% higher mean AHIs, the correlation between AHI Rec and AHI Alt was high (0.93).Similarly, when Dean and colleagues (4) compared AHIs that (all else being equal) varied with the desaturation cutoff point (4% vs. 3%) and according to whether or not arousals were incorporated into the hypopnea definition, they also found that although the mean values varied substantially, the AHIs were highly correlated (generally .0.9).This suggests that for many patients, AHIs that use various hypopnea definitions contain similar information presented on different scales.Given this, it is indeed bizarre that the same cutoff points (e.g., 5, 15, or 30 events/h) should be used to define OSA severity categories whatever the hypopnea definition.Thus, for OSA classification in a clinical context, we agree that either a single standardized definition of hypopnea is required or different absolute cutoff points for OSA classification should be used for varying hypopnea definitions, with the former being the more parsimonious approach.From a research perspective, however, we believe standardization of a single hypopnea definition would be needlessly limiting, given the current state of knowledge.Even though AHIs using different hypopnea definitions are highly correlated, they are not perfectly so.Thus, it may be that some definitions are more predictive of some outcomes.For example, Dean and colleagues found that an AHI definition that classified hypopneas by an oxygen desaturation of at least 4% (without considering arousals) was most consistently predictive of systolic blood pressure (4).However, it may be that definitions that incorporate arousals or lesser desaturations are better predictors of, say, long-term cognitive decline.Thus, in a research context, the scoring of polysomnograms in a manner that allows multiple definitions of breathing events to be flexibly generated is of substantial value.We hope that the next 25 years will bring nonproprietary computer algorithms for polysomnography interpretation that can rapidly and ever more accurately and reliably generate multiple characterizations of OSA to permit further exploration of important unanswered questions.
Prevalence and clinical implications of T-cell immunoglobulin mucin type-1 (TIM-1) in multiple tumor types.
Authors: Abdel Halim, Rebecca G. Bagley, Christopher D. Turner, Tibor Keler
Journal: Journal of Clinical Oncology (2017)

34 Background: TIM-1 (KIM-1, HAVcr-1) is a type 1 transmembrane glycoprotein. Expression is limited in healthy tissues but upregulated after kidney injury, in ovarian cancer and renal cell carcinoma (RCC). TIM-1 is associated with a more malignant RCC phenotype and immune response regulation. CDX-014, an antibody drug conjugate, contains a fully human IgG 1 monoclonal antibody (mAb) conjugated to the potent cytotoxin MMAE. CDX-014 is in a Ph 1/2 trial for RCC (NCT02837991). The prevalence of TIM-1 in other cancers was investigated to explore the broader potential for CDX-014. Methods: Tumors and normal adjacent tissues (NAT) were provided (Mosaic Labs) via IRB-reviewed protocol MOS001 for in vitro analysis of remnant, anonymized human samples. The study included 188 tumors: 30 renal, 45 ovarian, 34 endometrial, 2 cervical, 2 vaginal, 15 bile duct, 15 CRC, 30 NSCLC and 15 thymoma plus 75 NAT. Mosaic performed a validated immunohistochemistry assay on FFPE tissues. A FITC-conjugated, anti-TIM-1 mAb was applied after slide deparaffinization and antigen retrieval. Anti-FITC (Novus Bio), Envision+ HRP and DAB (Dako) were used for visualization. A pathologist scored hematoxylin-counterstained slides for % positive cells and staining intensity. A cut-off of &gt; 2% of cells staining at any intensity was deemed positive. Results: TIM-1 was universally prevalent in renal papillary (14/14) and clear cell carcinoma (CCC [13/13]) plus vaginal CCC (2/2). TIM-1 was also seen in ovarian CCC (12/15; 80%), endometrial CCC (9/21; 43%), adeno NSCLC (2/15; 13%), serous ovarian (1/10; 10%), adeno endometrial (1/13; 8%) and CRC (1/15; 7%). There was no staining in chromophobe RCC (3/3), cervical CCC, endometrioid or mucinous ovarian (10 each), bile duct carcinoma, squamous NSCLC or thymoma. There was minimal to no TIM-1 in NAT except for 7/10 kidney samples (possibly from unappreciated kidney injury). Conclusions: The data suggest that in addition to renal and ovarian cancer, TIM-1 targeted therapy such as CDX-014 warrants exploration in patients with endometrial CCC, vaginal CCC and adeno NCSLC. These results support the ongoing first in human Ph 1/2 study in RCC and potential broader clinical development of CDX-014 in other indications.
Potent anti‐leukemia activities of humanized CD19‐targeted Chimeric antigen receptor T (CAR‐T) cells in patients with relapsed/refractory acute lymphoblastic leukemia
Authors: Jiang Cao, Gang Wang, Hai Cheng, Chen Wei, Kunming Qi, Wei Sang, Li Zhenyu, Ming Shi, Huizhong Li, Jianlin Qiao, Bin Pan, Jing Zhao, Qingyun Wu, Lingyu Zeng, Mingshan Niu, Guangjun Jing, Junnian Zheng, Kailin Xu
Journal: American Journal of Hematology (2018)

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single-chain variable fragment (scFv) of the CAR may limit CAR-T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 106 /kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR-T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR-T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia-free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the nonrelapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1-2 cytokine release syndrome (CRS), 4 patients developed grade 3-5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B-ALL, especially in patients who received a reinfusion of murine CAR-T.
Erratum: Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury
Authors: Enrico Velardi, Jennifer J Tsai, Stefan Radtke, Kirsten Cooper, Kimon V Argyropoulos, Shieh Jae-Hung, Lauren F Young, Amina Lazrak, Odette M Smith, Sophie Lieberman, Fabiana Kreines, Yusuke Shono, Tobias Wertheimer, Robert R Jenq, Alan M Hanash, Prema Narayan, Zhenmin Lei, Malcolm A Moore, Hans-Peter Kiem, Marcel R M van den Brink, Jarrod A Dudakov
Journal: Nature Medicine (2018)
Correlation of PD-L1 with VEGF and KI-67 index in patients with primary glioma.
Authors: Song Xue, Man Hu, Jinming Yu, Bingjie Fan, Ji Ma
Journal: Journal of Clinical Oncology (2017)

94 Background: The treatment strategies for glioma, especially glioblastoma multiforme, are not effective. The programmed death ligand 1 (PD-L1) immune escape and increased angiogenesis may be two of the underlying sources of treatment resistance. However, the relationship between these pathways in human glioma is still unknown. Methods: Data for 64 patients with primary glioma recorded from June 2007 to December 2013 in Shan Dong Cancer Hospital were immunohistochemically evaluated for the expressions of PD-L1, VEGF, MMP-9 and KI-67 index. Image ProPlus software was used to quantify the mean optical density (MOD) of the immunohistochemical image. Results: PD-L1 expression was observed in 65.22% of low-grade glioma and 90.24% of high-grade glioma, respectively. The whole expression rate of PD-L1 in glioma was 81.25%. The expression of PD-L1 is significantly related to pathological grade ( p &lt;0.001), VEGF ( p= 0.017) and KI-67 index ( p= 0.009). The mean of PD-L1 MOD in High-grade group was 0.1144±0.02754, higher than that in low-grade group, 0.005129±0.001441 ( p= 0.004). In addition, Expression of VEGF, MMP-9 and KI-67 was significantly different between low-grade and high-grade gliomas ( p= 0.008, 0.04, 0.004 for VEGF, MMP-9 and KI-67, respectively). When analyzed as a continuous variable, the expressions of PD-L1 was positively correlated with VEGF (r = 0.392, p= 0.001) and KI-67 (r = 0.388, p= 0.001). Conclusions: These data suggest, for the first time, that PD-L1 play an important role in glioma angiogenesis and proliferation potential, providing the possibility for considering additional combinations of targeted VEGF therapies and anti-PD-L1 immunotherapy for the treatment of human brain glioma.
Susceptibility of HER2+ breast cancer cells to poly (ADP-ribose) polymerase (PARP) inhibition independent of an inherent DNA repair defect.
Authors: Eddy Shih-Hsin Yang, Somaira Nowsheen, Tiffiny Cooper, Albert F. LoBuglio, James A. Bonner
Journal: Journal of Clinical Oncology (2012)

621 Background: HER2 overexpression in breast cancer confers increased tumor aggressiveness. Targeted therapy against HER2 has improved outcomes, but resistance and disease progression ultimately occurs, thus necessitating novel therapeutic strategies. PARP inhibitors target homologous recombination (HR) deficient tumors, such as the BRCA-associated breast and ovarian cancers. In this study, we report unexpected susceptibility of HER2+ breast cancer cells to PARP inhibition alone independent of an inherent HR deficiency. Methods: Cell viability was measured using colony formation and ATPLite assays. Tumor growth delay was assessed in vivo in mice bearing breast cancer xenografts. Proteins were detected by immunoblotting. HR was assayed using radiation (IR)-induced Rad51 foci or a GFP-based HR assay. NFκB activity was measured using a NFκB-driven luciferase assay. Results: Surprisingly, PARP inhibition with ABT-888 alone reduced the colony forming ability and cell viability of the HER2+ breast cancer cell lines BT474, SKBR3, MDA-MB361, and HCC1954 (~70 – 99% reduction at 10μM). This susceptibility did not correlate with an inherent HR deficit. Interestingly, HER2 overexpression itself may be one mechanism of susceptibility to ABT-888 as evidenced by increased cellular cytotoxicity and in vivo tumor growth delay of MCF7 cells stably expressing HER2. Further dissection of the mechanism revealed that NFκB transcriptional activity was significantly inhibited by ABT-888 (&gt;95%) which corresponded with reduced levels of phosphorylated p65 and total IKKα, and a concomitant increase in IkBα. Furthermore, overexpression of p65 abrogated cellular sensitivity to ABT-888. Conclusions: HER2+ breast cancer cells are highly susceptible to PARP inhibition despite being HR proficient. This may be, in part, due to inhibition of NFκB. Further investigation of whether the addition of PARP inhibition to HER2 targeted therapy will delay the onset of resistance to therapy is warranted to potentially improve outcomes in HER2+ breast cancer patients.
Nano-liposomal irinotecan and 5-FU/LV (N+F) for the treatment of advanced PDAC: Memorial Sloan Kettering (MSK) Single Cancer Center Evaluation.
Authors: Danielle C. Glassman, Avni Mukund Desai, Geoffrey Yuyat Ku, Jia Li, James J. Harding, Anna M. Varghese, Eileen Mary O'Reilly, Kenneth H. Yu
Journal: Journal of Clinical Oncology (2018)

471 Background: Therapy options for advanced pancreatic adenocarcinoma (PDAC) are finite. NAPOLI-1, a phase III randomized trial, demonstrated the efficacy of N+F following progression on gemcitabine (G) based therapy (mPFS 3.1 mo, mOS 6.1 mo). There are limited additional data on the safety and efficacy of N+F following FDA approval in October 2015. We examined the post approval safety, tolerability and effectiveness of N+F in advanced PDAC patients at MSK. Methods: A retrospective chart review was conducted of all patients treated with N+F from Feb 2016 and ending in Aug 2017. Using the EMR and institutional database, information was extracted pertaining to demographics, performance status (ECOG), prior therapies, dose, duration of N+F, adverse events, PFS, OS and treatment response per RECIST. Results:N = 56 identified. Demographics: M/F 29/27, age 68 (range 42-88), prior lines of palliative chemotherapy (0/1/2/3/ &gt; 3, 4/20/21/11). Median PFS was 2.9 months and median OS was 5.3 months. There was a significant difference in PFS, OS and prior lines of therapy between patients who previously progressed on irinotecan (N = 27) versus not (N = 29); PFS = 2.4 v 4.8 mo, p = 0.0154; OS = 3.9 v 8.4 mo, p = 0.0021; 2 v 1 line. ECOG score was not predictive of PFS or OS. There were 19 dose reductions (DR), most frequent reasons: fatigue (42%) and diarrhea (37%). Regarding RECIST: PR = 2 (4%), SD = 19 (34%). 10/43 (23%) experienced &gt; 50% CA 19-9 reduction. Dose reductions were not associated with worse outcomes, in fact, patients with 1 or more DR experienced significantly longer PFS v none (DR 2, not reached; DR 1, 5.2 mo; DR 0, 2.5 mo, p = 0.0185). For the subset who received sequential therapy with G+nab-paclitaxel (P) followed by N+F (N = 25) mOS of 25.4 mo. Conclusions: These data support the safety and efficacy of N+F, re-inforcing results of NAPOLI-1. Patients whose disease previously progressed on irinotecan fared significantly worse than patients who did not, when treated with N+F. N+F appears active even in patients requiring DR. Sequential therapy with G+P followed by N+F demonstrates encouraging mOS. Collectively these findings underscore the utility of N+F in the therapy of advanced PDAC.
Watchdog bans “misleading” ads for online GP consultation service Push Doctor
Authors: Clare Dyer
Journal: BMJ (2018)

Advertisements for the commercial online GP consultation service Push Doctor have been banned by the Advertising Standards Authority (ASA) for implying that the services were provided by the NHS and for not making it clear that patients have to pay to use it.1

A poster campaign that ran on London Underground trains in August 2017 stated, “You will never go to the doctor’s again.” It continued, “The UK’s most popular online doctor service is open 6 am-11 pm, 7 days a week, allowing you to access an NHS GP whenever you want.” …
1O Integration of tissue and circulating parameters identifies a favorable immune profile in NSCLC patients treated with nivolumab
Authors: G. Mazzaschi, F. Facchinetti, D. Madeddu, S. Buti, F. Gelsomino, A. Ardizzoni, F. Aversa, G. Missale, F. Quaini, M. Tiseo
Journal: Journal of Thoracic Oncology (2018)
Is very short-course antibiotic therapy possible in postoperative intra-abdominal infections? Discussion on “Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial”
Authors: Alejandro Suarez-de-la-Rica, Fernando Gilsanz, Emilio Maseda, Philippe Montravers, Sigismond Lasocki, Thomas Lescot, Herve Dupont
Journal: Intensive Care Medicine (2018)
19P Single sample predictor of non-small cell lung cancer histology based on gene expression analysis of archival tissue
Authors: A. Karlsson, H. Cirenajwis, K. Ericson-Lindqvist, C. Reuterswärd, M. Jönsson, A. Patthey, A.F. Behndig, M. Johansson, M. Planck, J. Staaf
Journal: Journal of Thoracic Oncology (2018)
Extended survival analysis of ipilimumab for the treatment of advanced malignant melanoma in pretreated patients: Five-year long-term follow-up of the South African expanded access program.
Authors: Bernardo Leon Rapoport, Daniel A. Vorobiof, Lydia Mary Dreosti, Adam L. Nosworthy, Georgina Laird McAdam, Johann Petrus Jordaan, Helen Miller-Janson, Janetta Catharina de Beer, Margreet de Necker
Journal: Journal of Clinical Oncology (2017)

84 Background: Ipilimumab is a human monoclonal IgG1 antibody against CTLA-4 that has been shown to prolong the overall survival of patients with advanced pretreated melanoma. In 2015, a retrospective, multi-centre, non-interventional analysis was performed on data collected from the ipilimumab expanded access programme in South Africa, with last follow-up date (or death) in December 2014. The current study extends this analysis by follow-up on the long-term survival of pre-treated metastatic patients up to September 2016. Methods: Follow-up questions were sent to participating investigators, who had patients who were still alive (29) or for whom it was not known whether they were still alive (11) following the last ipilimumab infusion. Investigators had to confirm whether patients were still alive, the date of death or last contact, clinical response at last contact, and whether the patient was still responding to ipilimumab. Results: Of the 108 patients, 84 (78%) had cutaneous melanoma and 24 patients (22%) had non-cutaneous melanoma, including uveal, mucosal, and melanoma of unknown primary. Twenty patients previously received two or more lines of treatment for metastatic melanoma. The median age was 59 years (range 27 – 86) and there were 73 (68%) males and 35 (32%) females. Baseline ECOG PS was 0 in 33%, PS 1 in 58% and PS 2 in 6% of patients. The longest follow-up time available was 5.4 years. The median OS was 9.36 months (95% CI 7.48 – 11.84). One-year survival was 39% (95% CI 29% - 48%), 2-year survival was 22% (95% CI 15% - 30%), 3-year survival was 19% (95% CI 12% - 27%), 4- and 5-year survival was 15% (95% CI 8% - 21%). In the group of cutaneous melanoma patients, the 4- and 5-year survival was 17% (95% CI 9% - 25%) while in the non-cutaneous group the 4- and 5-year survival was 6% (95% CI 0% - 16%). Conclusions: Ipilimumab at a dose of 3mg/kg is an effective treatment for patients with pre-treated advanced (unresectable or metastatic) melanoma and is associated with durable remissions and long-term survival.