tbuckley/cabot-search huggingface dataset:
A combined screening approach of Fracture (Fx) Risk Algorithm (FRAX) and Trabecular Bone Score (TBS) to identify osteoporotic-range fracture risk (ORFR) in breast cancer (BC) patients treated with adjuvant aromatase inhibitor (AI).
Authors: David B. Page, Veronica Mariotti, Oksana Davydov, Sujata Patil, Didier Hans, Clifford A. Hudis, Azeez Farooki, Monica Nancy Fornier
Journal: Journal of Clinical Oncology (2015)

574 Background: The NCCN recommends serial bone mineral density (BMD) measurement with dual energy x-ray absorptiometry (DXA) to diagnose and treat AI-associated osteoporosis. The FRAX algorithm identifies additional patients with ORFR who may benefit from anti-resorptive therapy (ART). The TBS, which measures bone microstructure by DXA, is an independent indicator of ORFR. Here, we retrospectively evaluate the utility of a combined screening approach (BMD+FRAX+TBS) in identifying ORFR at baseline and following AI. Methods: Breast cancer patients > 60 years, treated with AI and no ART between 2006-12, who had serial DXA at Memorial Sloan Kettering Cancer Center were identified (n= 74). BMD, FRAX, and TBS were evaluated at baseline (< 3 months from AI initiation) and at 12-24 months, and various screening strategies for identifying ORFR were assessed. Based on National Osteoporosis Foundation criteria and Manitoba TBS study fracture rates, ORFR was defined as: BMD T-score≤-2.5; ≥3% hip or ≥20% osteoporosis-associated 10-year fracture risk by FRAX; or TBS score≤1.2 with BMD T-score< -1.0. Results: Following AI, lumbar spine (LS)-BMD declined in 75% of patients (median: -2.9%; SD: 4.3%) and TBS declined in 58% of patients (median: -1.0%, SD: 7.7%). Declines in LS-BMD and TBS were not correlated (Spearman r=-.16, p=NS) and were not influenced by age, BMI, ethnicity, or chemotherapy (by Wilcoxon rank-sum). Compared to BMD alone, a combined screening approach (BMD+FRAX+TBS) identified an additional 15% of patients with ORFR at baseline. (table) Following AI, an additional 2% developed ORFR by BMD alone, versus 7% by BMD+FRAX+TBS. Conclusions: AIs caused bone loss, leading to ORFR as measured by BMD, FRAX, and TBS. Because FRAX and TBS are derived from DXA and patient history, a combined screening approach may efficiently and cost-effectively identify additional BC patients with ORFR who may benefit from ART. Screening Method Pts with ORFR (%) Before AI After AI BMD alone 3/74 (5%) 5/74 (7%) BMD+FRAX 7/74 (9%) 11/74 (15%) BMD+TBS 12/74 (16%) 16/74 (22%) BMD+FRAX+TBS 15/74 (20%) 20/74 (27%)
KAT8 selectively inhibits antiviral immunity by acetylating IRF3
Authors: Wanwan Huai, Xingguang Liu, Chunmei Wang, Yunkai Zhang, Xi Chen, Xiang Chen, Sheng Xu, Tim Thomas, Nan Li, Xuetao Cao
Journal: The Journal of Experimental Medicine (2019)

The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection–triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus–triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.
ZAP-70 Expression in Non Tumoral B Cells: Role in B Tolerance Breakdown?
Authors: Mickaël Martin, Anne Marie Knapp, Dana Ghergus, Fabien Delmotte, Laurent Vallat, Cédric Schleiss, Raoul Herbrecht, Anne-Sophie Korganow, Frédéric Gros, Sophie Jung, Pauline Soulas-Sprauel, Eric Meffre, Thierry Martin
Journal: Blood (2018)
Breast cancer progression and workplace productivity.
Authors: Wesley Yin, Ruslan Horblyuk, Julia Jane Perkins, Steve Sison, Gregory Smith, Julia Thornton Snider, Yanyu Wu, Tomas J. Philipson
Journal: Journal of Clinical Oncology (2015)

6586 Background: A significant fraction of women with breast cancer leave employment due to their disease. However, little is known about the effects of breast cancer progression on productivity among those who remain employed Methods: Linking commercial health claims to employer records on workplace productivity, we created a cohort of employed U.S. women ages 18-64 who were treated for breast cancer between 2005 and 2012. Disease stage was measured through diagnosis codes and treatments observed, to classify women into the following breast cancer groups in each 90-day quarter: local; locally advanced; other non-metastatic; metastatic, 1st line therapy; metastatic, 2nd line therapy; metastatic, ≥ 3rd line therapy; metastatic, end-of-life care. Productivity was defined as work hours missed per quarter. We performed linear regression analysis to predict hours missed as a function of disease stage, age, comorbidities, industry of occupation, region and a time trend. To explore possible selection bias, we used a Cox survival model to test whether women whose cancer progressed were more likely to exit our employment-based dataset, controlling for age, comorbidities, industry and region. Results: In our cohort of 19,496 women with breast cancer,stage varied as follows:23% local; 1% locally advanced; 69% other non-metastatic; 5% metastatic 1st line; 1% metastatic 2nd line; < 1% metastatic ≥ 3rd line; 1% metastatic, end-of-life care. Women treated for breast cancer missed an average of 79 hours (about 10 days) per quarter. Disease progression was associated with greater work hours missed. In adjusted analysis, hours missed varied by stage as follows: other non-metastatic, 77h; local, 81h; locally advanced, 83h; metastatic 1st line, 87h; metastatic 2nd line, 112h; metastatic ≥ 3rdline, 106h; metastatic end-of-life care, 126h. Women whose cancer progressed were more likely to exit our employment-based dataset. Thus our estimated productivity effects are likely conservative. Conclusions: Breast cancer progression is associated with impaired workplace productivity, with greater impairment among those with more advanced disease. Avoiding or delaying disease progression could bring productivity gains to the workplace in addition to the benefits to the patient.
Survival and prognostic factors analysis in resected colorectal liver metastasis after neoadjuvant chemotherapy: results of the first retrospective study conducted in San Jose, Costa Rica.
Authors: Paula Quesada-Soto, Maria Amalia Matamoros, Allan Ramos, Denis Ulises Landaverde
Journal: Journal of Clinical Oncology (2015)

e14687 Background: Hepatic resection for colorectal cancer metastasis (CRCm) is now considered a standard of care and preoperative chemotherapy may improve outcomes. Also there are many prognostic factors described. In our retrospective study we decided to explore the outcomes, Disease Free Interval (DFI), Overall Survival (OS) as well as prognostic factors in resected CRC liver metastasis. This is the first study conducted in this setting in Costa Rica. Methods: The Liver and Pancreato-Biliary Unit database was reviewed, and we analyzed patients who underwent hepatic resections between 2009 and 2013. Prognostic factors were evaluated with multivariate analysis. Survival rates were analyzed using the log-rank test. Results: A total of 170 hepatic resections were performed between 2009-2013, 63 were due to CRCm, we were able to obtain 51 cases. 71% received neoadjuvant chemotherapy. 55% were males, the mean age was 56 years. 55% of all cases had metastatic disease at the moment of diagnostic. 53% received XELOX neoadjuvantly alone, and 33,3% were treated with either FOLFOX or FOLFIRI plus bevacizumab. 57% of the cases had more than one metastatic lesion liver confined. With a median follow up after the surgical intervention of 28,3 months, the OS was 44.13 months and DFI 34.2 months. A comparison between XELOX alone vs. chemotherapy plus Bevacizumab showed no statistical diferences in terms of DFI or OS. For DFI (XELOX alone 33.5 months (17.6 – 49.4), chemotherapy plus bevacizumab: 34.3 months (9.6 – 59.0) log-rank test: p = 0.52). For OS (XELOX alone 41.8 months (39.2 – 44.4) vs. chemotherapy plus bevacizumab: 41.8 months (34.0 – 49.6) log-rank test: p = 0.53). Metastatic lesions less than 3 cm of size were asociated with a statistical significant favorable prognoses in terms of OS (p = 0.03). Conclusions: There is no clear benefit of adding bevacizumab to chemotherapy neoadjuvantly in terms of DFI and OS in the Costa Rican population. We need prospective studies to show differences between chemotherapy regimens. Metastatic lesions less than 3 cm were associated with better OS.
The impact of chemotherapy on hospitalizations and emergency care in older adults with advanced cancer.
Authors: Elena B. Elkin, Caitriona O'Neill, Coral L. Atoria, Eileen Mary O'Reilly, Peter Bach
Journal: Journal of Clinical Oncology (2015)

6545 Background: The benefits of systemic chemotherapy for metastatic disease vary by tumor type and must be weighed against potential side effects. In patients receiving chemotherapy for advanced cancer, toxicity-related hospitalizations and emergency room (ER) visits may reduce the quality of an already limited life expectancy, particularly in the face of modest or uncertain expected benefit. Methods: In the population-based SEER-Medicare dataset, we identified patients 66 years or older diagnosed in 2001-2009 with metastatic cancer originating in one of 10 disease sites. The cohort was limited to patients who died by December 31, 2010. Chemotherapy recipients were matched to non-recipients by age, sex, race, geographic region, comorbidity and survival duration. The impact of chemotherapy on toxicity-related and any-cause hospitalizations and ER visits were estimated by cancer site in multivariable regression models, controlling for additional demographic characteristics. Results: Of 18,486 patients who received systemic chemotherapy for metastatic cancer, 92% had a hospitalization and 83% had an ER visit. Among their matched peers who did not receive chemotherapy, rates of hospitalization and ER visit were 83% and 72%, respectively. Controlling for patient and disease characteristics, chemotherapy was associated with a significantly increased risk of toxicity-related hospitalization in all 10 cancers: bladder, breast, prostate, colorectal, esophageal, pancreatic, stomach, ovarian, small cell and non-small cell lung cancers [adjusted odds ratios from 1.40 (95% CI 1.19-1.65) in prostate cancer to 3.16 (95% CI 2.79-3.57) in small-cell lung cancer] and similarly increased risks of toxicity-related ER visit in all 10 cancers [adjusted odds ratios from 1.26 (95% CI 1.10-1.53) in prostate cancer to 2.84 (95% CI 2.51-3.22) in small-cell lung cancer]. Conclusions: Hospitalizations and ER visits are common in patients with incurable advanced malignancies, and more likely among those who receive chemotherapy. Understanding common causes of these events may help reduce adverse effects of chemotherapy for metastatic cancer, and help patients and their families make informed treatment decisions.
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
Authors: Donna K. Arnett, Roger S. Blumenthal, Michelle A. Albert, Andrew B. Buroker, Zachary D. Goldberger, Ellen J. Hahn, Cheryl Dennison Himmelfarb, Amit Khera, Donald Lloyd-Jones, J. William McEvoy, Erin D. Michos, Michael D. Miedema, Daniel Muñoz, Sidney C. Smith, Salim S. Virani, Kim A. Williams, Joseph Yeboah, Boback Ziaeian
Journal: Circulation (2019)
Abstract P228: Relationships of Dietary and Supplement Magnesium Intake and Its Urinary Metabolomic Biomarkers With Blood Pressure: The INTERMAP Study
Authors: Queenie Chan, Chung-Ho E Lau, Rachel Gibson, Elena Chekmeneva, Goncalo Dos Santos Correia, Rueyleng Loo, Timothy M Ebbels, Joram M Posma, Alan R Dyer, Katsuyuki Miura, Hirotsugu Ueshima, Liancheng Zhao, Martha L Daviglus, Paul Elliott, Jeremiah Stamler, Elaine Holmes, Linda Van Horn
Journal: Circulation (2019)

Background: Magnesium (Mg) and other mineral intakes are vital contributors to a healthy diet and appear to have a modest effect on the risk of hypertension. Studies suggest that supplemental Mg can significantly lower blood pressure (BP). Here, we investigate associations of total Mg consumption with the level of its urinary metabolomic biomarkers, and BP. Method: We used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) on 4269 men and women aged 40-59 years from Japan, China, United Kingdom, and United States (US). Regression coefficients with BP per 2 standard deviation (SD) higher dietary Mg from food plus supplement (obtained from 24-hr dietary recalls), urinary Mg (measured by atomic absorption flame photometry) and small molecules (analysed by direct injection mass spectrometry) were estimated using multivariable models, adjusted for age, gender, population sample, intake of total energy and other confounders (see Table). To estimate overall association, country-specific regression coefficients were pooled, weighted by inverse of their variance. Results: Average Mg intakes were 454 (SD=207) mg/day for 770 persons who reported Mg supplementation (89% from US), and 300 (SD=101) mg/day for those who did not. High correlation was found between Mg intake from food plus supplements with urinary Mg ( r =0.38, P&lt;0.0001). Partial correlations of small molecules with total Mg intake ranged from -0.007 to 0.19 for ascorbic acid (P&lt;0.0001). Total Mg intake higher by 261.87 mg/day (2SD) was associated with a systolic BP difference of -2.65 mm Hg ( P =6x10 -5 ). Urinary Mg excretion higher by 2.66 mmol/day was associated with a diastolic BP difference of -1.02 mm Hg (P=0.02). There was a non-significant inversed association between ascorbic acid and BP in some multivariable regression models. Conclusion: Higher intake of Mg, including supplements, was associated with lower BP levels.
Neoadjuvant durvalumab +/- tremelimumab affects the expression of immune checkpoint (IC) molecules on myeloid derived suppressor cells (MDSC) in patients (pts) with locally advanced renal cell carcinoma (RCC).
Authors: Jaleh Fallah, C. Marcela Diaz-Montero, Patricia A. Rayman, Wei (Auston) Wei, Laura S. Wood, Allison Martin, Kimberly D Allman, Timothy D. Gilligan, Moshe Chaim Ornstein, Jorge A. Garcia, Brian I. Rini
Journal: Journal of Clinical Oncology (2019)

587 Background: In a single arm, open label phase 1b clinical trial the safety of neoadjuvant durvalumab +/- tremelimumab was studied in pts with (w) locally advanced RCC. Expression of IC molecules on immunomodulatory cells in peripheral blood (PB) and tumor (T) and the association w treatment (tx) was investigated. Methods: Pts with ≥ T2bN0-1M0 RCC received either durvalumab or combination durvalumab + tremelimumab prior to surgery. Blood samples were drawn prior to neoadjuvant tx, prior to surgery, and approximately 30 days after surgery before adjuvant tx. The percentage of MDSC (CD33+/HLADR-) and subtypes in PB and T and expression of PD1, PD-L1, and V-domain Ig suppressor of T cell activation (VISTA) were measured. MDSC subtypes included polymorphonuclear (PMN; CD15+/CD14-), monocytic (M; CD15-/CD14+) and uncommitted (UC; CD15-/CD14-). Linear mixed model was used for each MDSC subtype to estimate and compare cohorts over time. Results: Eighteen pts were enrolled: 4 women and 14 men, median age 62, 17 pts had T3-4 and 4 pts had N1 disease. Six pts received 1 dose of durvalumab and 12 pts received 1 dose of durvalumab + tremelimumab before surgery. Tx-related grade 3 adverse events (per CTCAE, v5.0) included thrombocytopenia, bilateral lower extremity weakness, hyperglycemia, chest pain, and diabetic ketoacidosis.One pt had grade 4 elevated lipase. One pt had sudden death from a non-drug related cardiac event 9 days after receiving combination therapy prior to surgery. PB and T samples from 17 pts were available. Expression of VISTA on M-MDSC and UC-MDSC were positively correlated in PB and T (Spearman’s rho = 0.61; P=0.03 for both). VISTA expression on UC-MDSC in PB was significantly higher in pts who received durvalumab monotherapy compared to those treated w durvalumab + tremelimumab (P=0.04). Frequencies of PD-L1 expression on M-MDSC and UC-MDSC in PB decreased significantly from pre- to post-neoadjuvant tx (P &lt; 0.01). Conclusions: Neoadjuvant durvalumab + tremelimumab in pts w locally advanced RCC is feasible and affects the expression of IC molecules (PD-L1 and VISTA) on M-MDSC and UC-MDSC. Clinical trial information: NCT02762006.
Abstract P425: V <sub>max</sub> Prescribed Cardiovascular Exercise Paired With Gross Whole Body Movement Increases High-Density Lipoprotein Cholesterol
Authors: Brian Betancourt, Francisco Jou, Shaniece D Witte, Amett E Pino, Matthew Romney, Ivan Saavedra, Maribeth Rouseff, Teresa Ochoa, Doris D Brown, Sankalp Das
Journal: Circulation (2019)

Introduction: Previous literature shows an “appeared linear dose-response between activity levels and HDL cholesterol levels” However, long duration physical activity may decrease HDL and LDL cholesterol. Intensity may better dictate the change in cholesterol. Methods: Group 18 of My Unlimited Potential (worksite wellness program for Baptist Health South Florida Employees) performed a preprogram fitness assessment that included resting, testing, and post-test physiological values such as blood pressure and resting HR. Anthropometric measures such as height, weight, 7 and 6 site girth measurements for men and women. Percentage of body fat using Bio electric impedance. The cardiovascular assessment consisted of a V max (Velocity Max) test on the treadmill. The participants received an exercise prescription (ERX) based on the fitness assessment. Group 18 used the speed and grade of the cardiovascular portion of the fitness assessment to create an ERX. During the course of the 12 weeks V max was reassessed every 2 weeks to determine a new intensity for cardiovascular exercise. The exercise protocol during the first 12 weeks consisted of 20 minutes of interval cardiovascular training and 40 minutes of whole body gross movement resistance training two times a week. The length of each high intensity interval was determined by the participant’s own tolerance. Resistance training consisted of whole body gross movements, the use of free weights and a metabolic exercise, at the individuals ERX. Results: Independent sample t-test showed mean improvement of 3.2 points in group 18 when compared to other cohorts (Table 2). Adjusted regression analysis where dependent variable was HDL showed improvement when compared to other groups (Table 3). Discussion: With V max the intensity is given in a clear speed and incline that must be achieved irrelevant of the interval length performed during cardiovascular activity. We have had 18 total cohorts complete 12 weeks. Only group 18 had a significant increase in HDL. Only group 18 followed this protocol.
First survival outcomes and additional secondary analyses from PURE-01: Pembrolizumab (pembro) before radical cystectomy (RC) in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Andrea Necchi, Marco Bandini, Andrea Gallina, Marco Bianchi, Daniele Raggi, Elena Farè, Antonella Messina, Jon Chung, Siraj Mahamed Ali, Russell Madison, Andrea Anichini, Maurizio Colecchia, Giorgio Gandaglia, Nicola Fossati, Simone Luca Antonio Scuderi, Filippo Pederzoli, Renzo Colombo, Alberto Briganti, Francesco Montorsi
Journal: Journal of Clinical Oncology (2019)

391 Background: PURE-01 is a phase 2 study of Pembro before RC in MIBC: the primary endpoint (pathologic complete response [pT0]) was met in advance ( Necchi et al. JCO 2018). While the study is still recruiting patients (pts), we analyzed the interim long-term outcomes in terms of relapse-free survival (RFS) and the role of multiparametric bladder magnetic resonance imaging (mpMRI) in predicting major pathologic response (pT&lt;2) in RC. Methods: Pts with clinical stage T2-3bN0M0 received 3 courses of 200mg Pembro, before RC. Pts were staged and re-assessed with mpMRI before RC. 1-y RFS (overall and by pathologic stage) after Pembro and RC was compared with that from clinical stage-matched cohort of San Raffaele Urological Institute (URI, n=1021) and of the RISC multicenter database (n=719, Bandini et al, Eur Urol Oncol 2018). mpMRI were performed in all pts through bladder catheterization. The apparent diffusion coefficient (ADC) changes post-Pembro were matched with pathologic response, qPCR and genomic data from RC samples (FoundationONE). Results: 70 pts have completed treatment thus far: with 27 pT0 (38.6%) and 44 pT&lt;2 (62.9%), activity was confirmed. 21 pts had ≥1y follow-up and were analyzed. Overall, 1-y RFS (95% CI) in PURE-01, URI and RISC were: 95.2 (86.6-100), 79.0 (76-82), and 69.7 (66.2-73.4). 1-y RFS after neoadjuvant chemotherapy and RC in URI and RISC were: 76.7 (61-97), and 76.5 (71-83). 1-y RFS for pT3-4 and/or pN+ pts were: 88.9 (71-100), 71.2 (67-76), and 57.1 (52-62). 39/70 pts had measurable disease for pre-post mpMRI changes. Pts with pT&lt;2 (n=16) on RC showed a median “mean ADC” of 0.98 mm 2 /s vs 0.84 mm 2 /s of non-responders (NR, n=23, p=0.098), despite an increased T-cell infiltrate. Pts with cell-cycle gene alterations in RC (n=8) were all NR and showed lower median “mean ADC” values (p=0.074). Conclusions: The early efficacy data further support the role of single-agent IO as neoadjuvant therapy in MIBC. Pembro may be beneficial at long-term also in pathologically high-risk pts, thus questioning the value of PD-L1 for pt selection. mpMRI and genomic data might help identifying those pts who may need re-TURB only instead of RC. Clinical trial information: NCT02736266.