tbuckley/cabot-search huggingface dataset:
Trends of testing for and diagnosis of α<sub>1</sub>-antitrypsin deficiency in the UK: more testing is needed
Authors: Joan B. Soriano, Sarah J. Lucas, Rupert Jones, Marc Miravitlles, Victoria Carter, Iain Small, David Price, Ravi Mahadeva
Journal: European Respiratory Journal (2018)

α 1 -antitrypsin deficiency (AATD) significantly increases the risk of developing chronic obstructive pulmonary disease (COPD), and testing of all COPD patients for AATD is recommended by the World Health Organization, European Respiratory Society and Global Initiative for Chronic Obstructive Lung Disease (GOLD). We aimed to determine trends for testing and diagnosing AATD from 1990 to 2014. This study analysed all patients diagnosed with COPD from about 550 UK Optimum Patient Care Research Database general practices, including a subgroup of those diagnosed before the age of 60 years. We identified 107 024 COPD individuals, of whom 29 596 (27.6%) were diagnosed before 60 years of age. Of them, only 2.2% (95% CI 2.09–2.43%) had any record of being tested for AATD. Of those tested, 23.7% (95% CI 20.5–27.1%) were diagnosed with AATD. Between 1994 and 2013 the incidence of AATD diagnosis generally increased. A diagnosis of AATD was associated with being male, being an ex-smoker, more severe COPD with a lower forced expiratory volume in 1 s % pred and higher GOLD 2017 stages (all p&lt;0.05). Despite an increase in the frequency of AATD testing since 1990, only 2.2% of patients diagnosed with COPD before the age of 60 years were tested. AATD prevalence was 23.7% in those tested. Thus, it appears that AATD remains markedly underdiagnosed in COPD patients.
Residual cancer burden (RCB) as prognostic in the I-SPY 2 TRIAL.
Authors: William Fraser Symmans, Christina Yau, Yunn-Yi Chen, Brian Datnow, Shi Wei, Michael D Feldman, Jon Ritter, Xiuzhen Duan, Beiyun Chen, Ronald Tickman, Husain Sattar, Anthony Martin Magliocco, Bhaskar Kallakury, Megan Troxell, Smita Asare, Minetta C. Liu, Angela DeMichele, Douglas Yee, Donald A. Berry, Laura Esserman
Journal: Journal of Clinical Oncology (2018)

520 Background: I-SPY2 is a multicenter phase 2 trial in high risk stage II/III breast cancer (BC) using adaptive randomization within biomarker subtypes to evaluate novel treatment agents added to standard neoadjuvant chemotherapy (NAC) in different phenotypic subsets of breast cancer. Residual cancer burden (RCB) quantifies the extent of residual disease (RD) for patients who did not achieve pathologic complete response (pCR = RCB-0). Methods: Local site pathologists reported RCB in the I-SPY2 trial. We performed a pooled analysis of 678 patients in I-SPY2 with RCB data and known follow-up (median 2.5 years). Cox models for event-free survival (EFS) were evaluated for RCB index (continuous) and RCB classes (hazard ratio; 95% CI) in all patients and in subtypes defined by hormone receptor (HR) and HER2 status. We separately compared experimental and control arms (Wilcoxon rank sum test) in a pooled analysis of RCB index (498 patients in total) from the first six treatment comparisons that "graduated" a therapy based on ≥85% predicted probability of increasing pCR rate over control therapy in a future 300-patient phase 3 trial. Results: RCB index was prognostic overall (hazard ratio; 95% CI: 1.86; 1.62-2.14) and in each subtype: TNBC (2.09; 1.70-2.57, N = 224), HR-/HER2+ (2.91; 1.79-4.73, N = 69), HR+/HER2+ (1.41; 1.00-1.99, N = 134), and HR+/HER2- (2.08; 1.54-2.81, N = 251). Overall, estimates of 3-year EFS for RCB classes were: pCR 94%, RCB-I 87%, RCB-II 80%, RCB-III 62%. The distribution of RCB index decreased with graduating treatments, relative to control therapy, in TNBC (p < 0.001) and HER2+ (p = 0.03), but not in HR+/HER2- (p = 0.21). In those with RD (excluding pCR), there was a trend for decreased RCB index with graduating treatments, relative to control therapy, in TNBC (P = 0.08), but not in HER2+ (p = 0.43) or HR+/HER2- cancers (p = 0.94). Conclusions: RCB determined by local site pathologists was prognostic in all subtypes of breast cancer. Observed differences in RCB index distribution between randomized treatments suggested different patterns, possibly by class of experimental treatment and phenotype of disease. Clinical trial information: NCT01042379.
Maintenance of health-related quality of life in elderly patients treated with ribociclib + letrozole in MONALEESA-2.
Authors: Howard A. Burris, Sara M. Tolaney, Lowell L. Hart, Anne Favret, Carlos A. Alemany, Gena H. Volas-Redd, Mikhail Shtivelband, David Chandiwana, D. Das Purkayastha, Nicola Caria, Johan Baeck, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2018)

1041 Background: First-line ribociclib + letrozole significantly prolongs progression-free survival vs letrozole alone in patients aged ≥65 y with hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC). Despite the efficacy benefits observed with combination therapy, elderly patients may be receiving single-agent therapy because of toxicity and health-related quality of life (HRQoL) concerns. Here we present key HRQoL outcomes in patients aged ≥65 y in MONALEESA-2. Methods: Postmenopausal patients with HR+, HER2− ABC (N = 668) were randomized 1:1 to receive either first-line ribociclib 600 mg or placebo once daily (QD) for 3 wk on, 1 wk off, + letrozole 2.5 mg QD. Patient-reported outcomes were the EORTC QLQ-C30 questionnaire for overall HRQoL/symptom scores and the breast cancer–specific QLQ-BR23 questionnaire for breast symptom score; changes from baseline were determined by a linear mixed-effect model, including responses through treatment cycle 28 day 1 and at end of treatment. Time to 10% deterioration in HRQoL was compared between treatment arms via a stratified log-rank test. Results: Among 295 patients aged ≥65 y in this analysis (ribociclib group, n = 150; placebo group, n = 145), HRQoL was maintained with ribociclib + letrozole treatment and at the end of treatment with no significant difference between treatment groups (mean difference, −1.88; 95% CI, −4.58–0.82). Median time to 10% deterioration of HRQoL was similar between the ribociclib group (27.7 mo) and placebo group (28.0 mo; HR, 1.03; 95% CI, 0.69–1.55). In an analysis of the EORTC QLQ-C30 symptom scales, a clinically relevant improvement ( > 5 points) was observed for mean pain score in the ribociclib group through the first year of treatment, while mild improvement was observed with the placebo group. Results of the QLQ-BR23 questionnaire showed similar breast symptom scores between treatment groups through end of treatment. Conclusions: Consistent with the full study population of MONALEESA-2, HRQoL was maintained in patients aged ≥65 y treated with ribociclib + letrozole. Preliminary analysis indicated a clinically meaningful improvement in pain score for patients aged ≥65 y treated with ribociclib + letrozole. Clinical trial information: NCT01958021.
Image-based risk score to predict recurrence of ER+ breast cancer in ECOG-ACRIN Cancer Research Group E2197.
Authors: Nishant Verma, Dave Harding, Amir Mohammadi, Lori J. Goldstein, Hannah L. Gilmore, Michael D Feldman, John Tomaszewski, Ajay Basavanhally, Mark Lloyd, Pingfu Fu, Shridar Ganesan, Nancy E. Davidson, Anant Madabhushi, James Monaco
Journal: Journal of Clinical Oncology (2018)

540 Background: Tumor grade is a predictor of breast cancer recurrence, independent of gene expression assays such as Oncotype Dx (ODx). However, grade suffers from significant intra- and inter-observer variability, limiting its clinical utility. Advances in whole slide imaging facilitate computerized analysis of H&E slides. We have developed a prognostic assay called Image-based Risk Score (IbRiS) which extracts and leverages morphometric signatures from H&E slides to classify patients into low- vs. high-risk groups for recurrence. Methods: IbRiS was evaluated on 378 ER+ patients treated with chemo-hormonal therapy obtained from ECOG-ACRIN study E2197; patients had 0-3 positive axillary nodes and H&E slides of acceptable quality; 60 patients suffered recurrence. A subset of 124 patients (27 recurrences) were HER2-. Another (enriched) subset (116 patients with 27 recurrences) had accompanying ODx scores. To establish IbRiS low- and high-risk groups, we determined (over the 378 patients) a cutoff such that the low-risk group had a 10-year recurrence rate of ~10%. We evaluated IbRiS risk groups using Cox proportional hazard analysis, controlling for node status, age, and tumor size. We also compared the recurrence rates in the IbRiS risk groups to those of ODx and a combined assay (IbRiS + ODx). Results: IbRiS risk groups predicted recurrence with a hazard ratio of 2.41 (n = 378, 95% CI = 1.21-4.79, p = 0.01) and 2.52 (n = 124, 95% CI = 0.85-7.46, p = 0.09) for the HER2- subset. Over the 378 patients, IbRiS classified as low-risk 35.3% of the patients who did not suffer recurrence. Table 1 compares the low-/high- risk stratifications of IbRiS, ODx, and the combined assay. Conclusions: IbRiS assay is a significant predictor of breast cancer recurrence and contributes prognostic information independent of ODx. The combined genomic and morphometric assay outperforms either individual assay. Also, while ODx was reported to lose prognostic ability when restricted to HER2- patients in E2197, IbRiS remains a predictor of recurrence. Performance of assays (N = 116). % of patients without recurrence classified as low-risk 10-year recurrence rate in low-risk group IbRiS 37.5% 17.2% ODx 56.3% 19.6% IbRiS + ODx 75.0% 20.0%
Assessment of long-term alopecia after adjuvant taxane therapy for early breast cancer: A cross-sectional survey.
Authors: Jennifer Wen Ying Lim, Jane McNeil Beith, Catriona M. McNeil, Michelle L. Harrison, James Paterson, Rebecca Asher
Journal: Journal of Clinical Oncology (2018)

e12502 Background: Alopecia is a distressing side-effect of taxane chemotherapy & evidence suggests that docetaxel (DOC) leads to chronic alopecia. We measured rates of satisfaction with hair regrowth among women who received adjuvant DOC compared with paclitaxel (PTX) to identify a difference in outcomes. Methods: We identified adult female patients who received PTX or DOC chemotherapy for early breast cancer from 2010-2015. They were screened to ensure they were alive, without metastatic relapse or a new cancer. Eligible participants were sent an introductory letter, consent, a Dermatology Life Quality Index (DLQI) questionnaire, a Visual Analogue Score (VAS) & the European Organisation for Research & Treatment of Cancer (EORTC) general & breast-specific quality of life. The primary outcomes were the DLQI: a 10-item questionnaire scored on a 0-3 scale (higher scores indicating distress & dissatisfaction) & the VAS (scored out of 4). Secondary outcomes were the global health status, function, symptom score & breast specific outcomes shown by the EORTC QLQ-C30 & EORTC QLQ-BR23. Results: There were 88 responders from 210 letters (response rate 42%); 38 (43%) had DOC & 50 (57%) had PTX. They were aged 26-90 (median: 59).There was a significant difference in DLQI scores, with the DOC group having a higher median score (DOC: 4 vs PTX: 1, p = 0.01). A significantly higher proportion of patients reported no effect of hair loss in the PTX group (p = 0.02). Similarly, there was a significant difference in VAS scores with the DOC group having a higher median score (DOC: 1 vs. PTX: 0.5, p = 0.002). Secondary outcomes did not reach statistical significance. There was no association with aromatase inhibitor exposure. Conclusions: Our study shows that adjuvant DOC chemotherapy is associated with statistically significant higher rates of dissatisfaction & chronic alopecia than PTX chemotherapy. This supports literature & should be discussed prior to administering DOC regimens. Table 1: DLQI and VAS scores Docetaxel (n = 38) Paclitaxel (n = 50) p-value DLQI Score Median (IQR) 4 (1-10) 1 (0-5) 0.01 Effect of patient’s life: 0.09 No effect at all 13 (34%) 29 (58%) VAS 1 (1-3) 0.5 (0-1) 0.002
Nine in 10 children who die from TB went untreated
Authors: Jacqui Thornton
Journal: BMJ (2018)

Javier Galeano/The Union

Five year old Ugandan boy Isaac (pictured) is one of the estimated one million children under the age of 15 years who become sick with tuberculosis every year, nearly a quarter of whom (239 000) die. Luckily for him, Isaac was one of the minority of children who were treated.

Of the children who die from the disease, nine in 10 had not been treated. Most cases, a new report argues,1 are preventable, treatable, and curable with simple, cost effective public health measures.

On 23 May the organisation behind the report, the International Union against Tuberculosis and Lung Disease, launched a call to action …
Somatic mutation landscape of appendiceal cancer.
Authors: John P. Shen, Miriam T. Jacobs, Ingrid L Fuh, Joel Micah Baumgartner, Paul T. Fanta, Andrew M. Lowy, Olivier Harismendy
Journal: Journal of Clinical Oncology (2018)

671 Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, which has prevented the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease. Standard treatment generally follows consensus guidelines for colorectal cancer; however, there are currently no standards to guide chemotherapy selection in the adjuvant or metastatic setting. Methods: Somatic mutation profiles covering ~300 frequently mutated genes were obtained for 385 primary appendiceal tumors (Foundation Medicine). A retrospective review was performed to gather clinico-pathologic data. The primary objective was to assess the somatic mutation profile of each subtype of appendiceal cancer and to compare these to colorectal cancer. Colorectal data was obtained from TCGA cohort via cBioPortal. Results: Appendiceal adenocarcinoma (non-mucinous) and mucinous adenocarcinoma had shared somatic mutations albeit with differing frequencies. The most common mutations were KRAS (60.1% and 80.5%, respectively), GNAS (32.4%, 58.5%), TP53 (42.8%, 19.5%), and SMAD4 (14.8%, 14.6%). Tumors with goblet cell (adenocarcinoid) histology had lower prevalence of KRAS (16.0%) and GNAS mutations (8.0%), but similar prevalence of TP53 mutation (24.0%) and a greater prevalence of ARID1A mutation (20.0%). The mutation profiles of all appendiceal histologies differed from colorectal adenocarcinoma with markedly lower prevalence of ATM (7.9% vs. 71.0%). Chemotherapy data was available for 30 metastatic patients; these patients received an average of 1.76 lines of therapy (range 1-4). All 30 were treated with either 5-FU or capecitabine, 11 (36.7%) with oxaliplatin, 23 (76.7%) with irinotecan and 19 (63.3%) with bevacizumab. Analysis of survival data and correlation with molecular and histologic features is ongoing. Conclusions: Despite clear molecular differences between appendiceal and colorectal tumors, appendiceal tumors are primarily treated with colorectal chemotherapy regimens. There remains a pressing need for both pre-clinical and clinical investigation to develop treatment regimens specific to appendix cancer.
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer
Authors: Joseph A. Sparano, Robert J. Gray, Della F. Makower, Kathleen I. Pritchard, Kathy S. Albain, Daniel F. Hayes, Charles E. Geyer, Elizabeth C. Dees, Matthew P. Goetz, John A. Olson, Tracy Lively, Sunil S. Badve, Thomas J. Saphner, Lynne I. Wagner, Timothy J. Whelan, Matthew J. Ellis, Soonmyung Paik, William C. Wood, Peter M. Ravdin, Maccon M. Keane, Henry L. Gomez Moreno, Pavan S. Reddy, Timothy F. Goggins, Ingrid A. Mayer, Adam M. Brufsky, Deborah L. Toppmeyer, Virginia G. Kaklamani, Jeffrey L. Berenberg, Jeffrey Abrams, George W. Sledge
Journal: New England Journal of Medicine (2018)

The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score.We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death).Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).
2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling
Authors: Eduarda G Z Centeno, Helena Cimarosti, Angela Bithell
Journal: Molecular Neurodegeneration (2018)

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field.
DNA methylation as an epigenetic signature predictive of response to neodjuvant treatment in TNBC patients.
Authors: Begona Pineda, Jose Alejandro Perez-Fidalgo, Angel Díaz-Lagares, Octavio Burgues, Ines Gonzalez-Barrallo, Ana Belen Crujeiras, Juan Sandoval, Manel Esteller, Pilar Eroles, Ana Lluch
Journal: Journal of Clinical Oncology (2018)

e12658 Background: Prediction of response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients is an unmet medical need. NAC with anthracyclines/taxanes achieves about 30-40% pathological complete response (pCR) in TNBC. The aim of our study was to identify a predictive epigenomic signature of pCR to NAC in TNBC Methods: A prospective study was performed in samples from biopsy of TNBC patients performed before NAC administration. Patients were classified as responders (RCB = 0) and non-responders (RCB > 0). A DNA methylome study (Infinium HumanMethylation450 array, Illumina) was performed from a discovery cohort (DC, n = 24). Differentially methylated genes obtained from this study were validated by pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) in a validation independent cohort (VC, n = 30) and in TN cell. In the same way, expression studies (qPCR) of the validated genes were performed both in patients and cell lines. Sample size was calculated in order to find differences in the proportion of pCR from 10% to 45% in 52 patients (with 15% drop-out). A predictive score with methylated genes and a ROC curve was calculated. Results: Array analysis showed a different methylation pattern between responder and non-responder patients. Selecting those differentially methylated CpGs located only in promoter regions, 9 genes were identified: 6 presented higher methylation in non-responder patients (gene 1 to 6) and 3 increased methylated genes in responders (gene 7 to 9). These genes were related to epithelial-mesenchymal transition and cell migration. After validation, the predictive ability of methylation of these genes for response (RCB = 0) or no response (RCB ≠ 0) was evaluated using a statistical model obtaining a predictive capacity of pCR of 72.7% for gene 7 and 9 with a ROC curve (AUC) 0.898 (CI95% = 0.788- 1.000). Gene expression studies correlated with methylation levels in both patients and cell lines. Conclusions: The 2-gene methylation panel with genes 7 and 9 accurately predicted response to NAC in TNBC. Further validation in prospective trials is warranted.