tbuckley/cabot-search huggingface dataset:
Abstract P5-13-16: Arthralgia-associated aging perceptions predict adherence to aromatase inhibitors among women with breast cancer
Authors: JJ Mao, DL Chambless, J Chen, T Bao, MJ Brier
Journal: Cancer Research (2017)

Abstract Background:Aromatase inhibitors (AIs) are associated with reduced risk of breast cancer recurrence, yet many women discontinue their treatment prematurely, often due to arthralgia. Empirically, breast cancer survivors who experience AI-associated arthralgia often report that they have aged quickly over a short period of time. Objective: We aimed to determine whether survivors with a heightened sense of aging due to arthralgia were more likely to non-adhere to their AI regimen. Methods: We conducted a prospective cohort study in an urban academic cancer center among post-menopausal women with hormone receptor positive breast cancer who were within the first two years of their aromatase inhibitor therapy. Perceptions of aging due to arthralgia were measured by the previously validated Penn Arthralgia Aging Scale. Non-adherence was defined as interrupting treatment or discontinuing the AI before the prescribed treatment length was over. Trained raters abstracted adherence data from medical charts. We performed Cox proportional hazards regression to evaluate the relationship between perceptions of aging due to arthralgia and time to non-adherence while adjusting for potential confounders. Results: Among 509 participants, most were White (81.2%) and had at least some college education (77.9%). The majority had been prescribed anastrozole (88.0%), followed by letrozole (9.0%), and exemestane (3.0%). During the follow up period, 144 (28.3%) did not adhere to the AIs as originally prescribed. In univariate analysis, women with a heightened sense of aging due to arthralgia were at more than twice the risk of non-adherence compared to women with low levels of aging perceptions (Hazard Ratio [HR], 2.20; 95% CI, 1.50 – 3.21; p &amp;lt; 0.001). After adjusting for arthralgia pain severity, depression, and AI type, aging perceptions remained a statistically significant predictor of adherence (HR, 1.71; 95% CI, 1.10-2.67; p = 0.02). Depression status also uniquely predicted non-adherence risk (HR, 1.63; 95% CI, 1.03 – 2.59; p = 0.04). Arthralgia pain severity, which predicted adherence in univariate analysis, was not a significant predictor in the final model (HR, 1.21; 95% CI, 0.84 – 1.75; p = .30). Conclusions: Breast cancer survivors on AIs who have a heightened sense of aging due to arthralgia are at greater risk of non-adhering to their AI regimen. Interventions are needed to help survivors reduce arthralgia and develop adaptive appraisals of their AI experience to achieve optimal adherence. Citation Format: Mao JJ, Chambless DL, Chen J, Bao T, Brier MJ. Arthralgia-associated aging perceptions predict adherence to aromatase inhibitors among women with breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-13-16.
Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42).
Authors: Ann Mohrbacher, Min H Kang, Allen S. Yang, Susan G. Groshen, Lori Vergara, Martin Gutierrez, Anthony J. Murgo, Shivaani Kummar, Donald Quick, C. Patrick Reynolds, Edward M. Newman, Barry Maurer
Journal: Journal of Clinical Oncology (2012)

8073 Background: Fenretinide (4-HPR) is a cytotoxic retinoid with broad anticancer activity in preclinical studies. Due to limited bioavailability of a capsule formulation an intravenous intralipid-like emulsion formulation (4-HPR ILE) was developed to increase systemic exposures. Methods: 4-HPR was administered as a continuous intravenous infusion for 120 hrs every 21 days. Systemic toxicities, responses, and pharmacokinetics were assessed. Accelerated Simon design proceeded until moderate or dose-limiting toxicities (DLT) were scored on Course 1. Doses were 80 mg/m 2 /day to 1810 mg/m 2 /day. Patients with asymptomatic hypertriglyceridemia were scored separately. All patients were heavily pretreated. Results: Toxicity-evaluable patients = 25. At 1810 mg/m 2 /day, two patients experienced DLT hypertriglyceridemia, one with transient Grade 2 pancreatitis; at 1280 mg/m 2 /day (8 pts), two had asymptomatic Grade 4 hypertriglyceridemia, one experienced DLT pleural effusions; at 905 mg/m 2 /day (6 pts) 2 experienced asymptomatic Grade 4 hypertriglyceridemia; All 5 pts at 640 mg/m2/day tolerated treatment. Pharmacokinetics showed a dose-to-plasma level relationship with mean steady-state 4-HPR levels of ~mid-20’s μM (640 mg/m 2 ); ~mid-30’s μM (905 mg/m2/day); and ~mid-50’s μM (1280 mg/m 2 ). Responses to date include a 64% CR+PR+SD response rate (36% CR+PR response rate) in 11 relapsed T-cell lymphomas which included histone deacetylase inhibitor-refractory patients, and a PRu response in a NHL B-cell lymphoma. Reversible hypertriglyceridemia related to the intralipid vehicle accounted for 6/7 DLTs. Conclusions: MTD = 1280 mg/m 2 /day x 5 days, every three weeks. 4-HPR ILE was safely administered and obtained 4-HPR plasma levels 6 -7 times higher than previously obtained using oral capsules. Durable complete responses were observed in T-cell lymphomas from 905 – 1810 mg/m 2 /day. An expanded cohort is accruing to a dosing schedule modified to decrease asymptomatic hypertriglyceridemia of 600 mg/m 2 on Day 1 (to allow for induction of serum lipases) followed by 1200 mg/m 2 Days 2-5. Supported by NCI U01 CA062505 and CPRIT RP10072.
Adaptive Reprogramming of <i>De Novo</i> Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer
Authors: Kristin K. Brown, Jessica B. Spinelli, John M. Asara, Alex Toker
Journal: Cancer Discovery (2017)

Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of TNBC cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the de novo pyrimidine synthesis pathway. Pharmacologic inhibition of de novo pyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the de novo pyrimidine synthesis pathway, induces regression of TNBC xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of TNBC.Significance: The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of de novo pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of de novo pyrimidine synthesis, to sensitize TNBC cells to chemotherapy. Cancer Discov; 7(4); 391-9. ©2017 AACR.See related article by Mathur et al., p. 380This article is highlighted in the In This Issue feature, p. 339.
Sustainability and transformation plans for the NHS in England: radical or wishful thinking?
Authors: Kieran Walshe
Journal: BMJ (2017)

Greater commitment from the government is vital

Planning is back in fashion in the NHS. Over the past 15 months, NHS England has overseen the production of sustainability and transformation plans (STPs) for health and care services in 44 geographical areas or “footprints” covering the whole country.1 They have been produced by local NHS organisations, with varying levels of involvement from local authorities, senior clinicians, professional associations, patient groups, and the public. The King’s Fund think tank has described how they have been produced2 and analysed the content of all 44 STPs.3

We have had almost three decades of health reforms in the English NHS emphasising competition and markets, patient choice, provider autonomy, and the like.4 A journey that started in the early 1990s with Kenneth Clarke’s introduction of NHS trusts, GP fundholding, and the internal market concluded with Andrew Lansley’s abolition of strategic health authorities, primary care trusts, and much of the organisational infrastructure of the NHS, just leaving clinical commissioning groups, NHS and …
The Impact of Atrial Fibrillation on Subsequent Survival of Patients Receiving Ibrutinib As Treatment of Chronic Lymphocytic Leukemia (CLL): An International Study
Authors: Philip A Thompson, Vincent Levy, Constantine S. Tam, Chadi al Nawakil, Francois Xavier Goudot, Anne Quinquenel, Loic Ysebaert, Anne-Sophie Michallet, Marie Sarah Dilhuydy, Eric W Van Den Neste, Jehan Dupuis, Michael Keating, Christophe Meune, Florence Cymbalista
Journal: Blood (2016)
Long-Term Follow-up of Patients with HIV-Related Diffuse Large B-Cell Lymphoma (DLBCL) Treated in the Phase II Study with Rituximab and CHOP (R-CHOP)
Authors: Josep-Maria Ribera, Mireia Morgades, Albert Oriol, Eva González-Barca, Pilar Miralles, Armando Lopez-Guillermo, Santiago Gardella, Andrés López, Eugènia Abella, Blanca Xicoy, Marta Garcia, Evarist Feliu
Journal: Blood (2011)
Earlier Administration of Rituximab Allows Higher Rate of Long-Lasting Response in Adult Patients with Autoimmune Thrombocytopenia.
Authors: Francesco F. Zaja, Nicola N. Vianelli, Marta M. Battista, Alessandra A. Sperotto, Francesca F. PAtriarca, Valentina V. Tomadini, Carla C. Fili, M. Tani, Michele M. Baccarani, Renato R. Fanin
Journal: Blood (2005)
Unpredictable Pharmacokinetics of Once-Daily Intravenous Busulfan When Combined with Fludarabine in Pediatric Patients: Phase I Clinical Study for Determination of Optimal Once-Daily Busulfan Dose Using Pharmacokinetic Modeling.
Authors: Ji Won Lee, Hyoung Jin Kang, SeungHwan Lee, Kyung-Sang Yu, Nam Hee Kim, Yen Ju Yuk, Mi Kyoung Jang, Eun Jong Han, Hyery Kim, In-Jin Jang, Hee Young Shin, Hyo Seop Ahn
Journal: Blood (2009)
Fabrication, characterization, in vitro drug release and glucose uptake activity of 14-deoxy, 11, 12-didehydroandrographolide loaded polycaprolactone nanoparticles
Authors: Nagalakshmi Kamaraj, Pooja Yashwanthi Rajaguru, Praveen kumar Issac, Sujatha Sundaresan
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Biodegradable polymer based novel drug delivery systems brought a considerable attention in enhancing the therapeutic efficacy and bioavailability of various drugs. 14-deoxy 11, 12-didehydro andrographolide (poorly water soluble compound) loaded polycaprolactone (nano-DDA) was synthesized using the solvent evaporation technique. Nano-DDA was characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS) studies. Fourier Transform InfraRed Spectroscopy (FTIR) was used to investigate the structural interaction between the drug and the polymer. Functional characterization of the formulation was determined using drug content, cellular uptake and in vitro drug release. 2-deoxy-D-[1-3H] glucose uptake assay was carried out to assess the antidiabetic potential of nano-DDA in L6 myotubes. The nano-DDA displayed spherical shape with a smooth surface (252.898 nm diameter), zeta potential, encapsulation and loading efficiencies of -38.9 mV, 91.98 ± 0.13% and 15.09 ± 0.18% respectively. No structural alteration between the drug and the polymer was evidenced (FTIR analysis). Confocal microscopy studies with rhodamine 123 loaded polycaprolactone nanoparticles (Rh123-PCL NPs) revealed the internalization of Rh123-PCL NPs in a time dependent manner in L6 myoblasts. A dose dependent increase in glucose uptake was observed for nano-DDA with a maximal uptake of 108.54 ± 1.42% at 100 nM on L6 myotubes, thereby proving its anti-diabetic efficacy. A biphasic pattern of in vitro drug release demonstrated an initial burst release at 24 h followed by a sustained release for up to 11 days. To conclude, our results revealed that nano-DDA formulation can be a potent candidate for antidiabetic drug delivery.
Sickle Cell Trait and the Risk of ESRD in Blacks
Authors: Rakhi P. Naik, Marguerite R. Irvin, Suzanne Judd, Orlando M. Gutiérrez, Neil A. Zakai, Vimal K. Derebail, Carmen Peralta, Michael R. Lewis, Degui Zhi, Donna Arnett, William McClellan, James G. Wilson, Alexander P. Reiner, Jeffrey B. Kopp, Cheryl A. Winkler, Mary Cushman
Journal: Journal of the American Society of Nephrology (2017)

Blacks, compared with whites, have an increased risk of progression to end-stage renal disease (ESRD). Emerging evidence suggests that, in addition to APOL1 high-risk genotypes, hemoglobin variants, including sickle cell trait (SCT) and hemoglobin C trait, have a role in kidney disease in blacks. However, the association between these hemoglobin traits and ESRD remains unknown. In a large population-based cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we evaluated 9909 self-reported blacks (739 with SCT and 243 with hemoglobin C trait). Incident ESRD occurred in 40 of 739 (5.4%) individuals with SCT, six of 243 (2.5%) individuals with hemoglobin C trait, and 234 of 8927 (2.6%) noncarriers. The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT and 4.0 per 1000 person-years for noncarriers. Compared with individuals without SCT, individuals with SCT had a hazard ratio for ESRD of 2.03 (95% confidence interval, 1.44 to 2.84). Hemoglobin C trait did not associate with prevalent CKD or ESRD. The incidence rate for ESRD among participants with APOL1 high-risk genotypes was 6.6 per 1000 person-years, with a hazard ratio for ESRD of 1.77 (95% confidence interval, 1.31 to 2.38) for participants with, compared with those without, APOL1 high-risk genotypes. In this cohort, SCT strongly associated with risk of progression to ESRD in blacks, and this degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes. These results may have important public policy implications for genetic counseling of SCT carriers.
Breath analysis as a noninvasive biomarker for early detection of lung cancer.
Authors: Nir Peled, Manal Abud-Hawa, Ori Liran, Maya Ilouze, Naomi Gai-Mor, Dekel Shlomi, Alon Ben-Nun, Amir Onn, Jair Bar, Douglas Johnson, John Wells, Stuart Millstone, Paul A. Bunn, York E Miller, Robert L Keith, Brad Rikke, Fred R. Hirsch, Hossam Haick
Journal: Journal of Clinical Oncology (2014)

7560 Background: The search for non-invasive diagnostic methods of lung cancer (LC) has led to new avenues of research, including the exploration of the exhaled breath. Previous studies have shown that LC can be detected through exhaled-breath analysis. This study evaluated the potential of exhaled-breath analysis for the distinction of early and advanced LC and for control (COPD) and lung cancer patients in an international setting. Methods: Breath samples were taken from untreated lung cancer patients and matching COPD controls. Patients were enrolled in Israel, Colorado and Florida. All samples were analyzed in a central lab (Technion Institute; Haifa, Israel). Analysis was performed by both gold nanoparticle-based Artificial Olfactory System (NaNose) and gas-chromatography linked with mass-spectrometry (GC-MS). Pattern recognition methods were used to analyze the results obtained from GC-MS and NaNose to correlate the results with the clinical data. Results: A total of 358 subjects were enrolled in this study (Israel: 174; Denver: 111; Florida: 73). 213 patients had lung cancer, among 62 early disease and 143 were at advanced stage. 145 patients did not have cancer. In our preliminary sub-analysis, of 80 cancer patients (64 advanced stage) and 31 COPDs subjects: discriminant function analysis of the signals of the sensor array distinguished significantly between control versus early LC (p < 0.0001; accuracy 85.11%), between control and advanced LC (p < 0.0001; 82.11%) and between early and advanced LC (p< 0.0001; 78.75%). Conclusions: In this multi-national pilot study, breath analysis discriminated malignant disease from benign conditions in a high-risk cohort based on LC-related volatile organic compound profiles. Furthermore, it discriminated between early versus advanced disease. These achievements stand in consistency with the requirements of society for rapid and early diagnosis of diseases as a part of therapeutic approach and facilitating rapid treatment. Clinical trial information: NCT01386203.
A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa
Authors: J.W. Frew, D.A. Vekic, J. Woods, G.D. Cains
Journal: British Journal of Dermatology (2017)

Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.
Abstract P5-08-07: The long-term prognosis of breast cancers patients diagnosed ≤40 years in the absence of adjuvant systemic therapy
Authors: GMHE Dackus, ND Ter Hoeve, M Opdam, W Vreuls, EA Koop, Z Varga, SM Willems, CHM Van Deurzen, EJ Groen, A Cordoba-Iturriagagoitia, J Bart, AL Mooyaart, JG Van den Tweel, V Zolota, J Wesseling, A Sapino, E Chmielik, A Ryska, A Broeks, N Stathonikos, K Jozwiak, M Hauptmann, GS Sonke, E Van der Wall, S Siesling, PJ Van Diest, SC Linn
Journal: Cancer Research (2017)

Abstract This abstract was withdrawn by the authors.
Debugging the Black Box
Authors: James C. Yang
Journal: Cancer Discovery (2017)

Abstract Summary: A better understanding of the mechanisms by which tumor rejection succeeds and fails is needed to improve immunotherapies. Here, Anagnostou and colleagues find that mutations predicted to be the most immunogenic are preferentially lost when cancer progresses through checkpoint blockade. Cancer Discov; 7(3); 250–1. ©2017 AACR. See related article by Anagnostou et al., p. 264.
Lipocalin‐2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa
Authors: K. Wolk, J. Wenzel, A. Tsaousi, E. Witte‐Händel, N. Babel, C. Zelenak, H.‐D. Volk, W. Sterry, S. Schneider‐Burrus, R. Sabat
Journal: British Journal of Dermatology (2017)

Acne inversa (AI)/hidradenitis suppurativa is a chronic inflammatory disease characterized by painful axillary, inguinal and perianal skin lesions with deep-seated nodules, abscesses and fistulae.This study aimed to identify and characterize the key players in AI pathogenesis.Epidemiological and anamnestic data for patients with AI were collected, and blood and skin samples were also taken. Healthy participants and patients with psoriasis served as controls. Assessment of samples and cultures of primary cells was performed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction on reverse transcribed mRNA, and immunohistochemistry.Of 35 mediators quantified in the blood of patients with AI, lipocalin-2 (LCN2) appeared as one of the most significantly upregulated parameters compared with healthy participants [85·8 ± 12·2 (n = 18) vs. 41·8 ± 4·2 (n = 15); P < 0·001]. Strongly elevated LCN2 expression was present in AI lesions, with granulocytes and keratinocytes being sources of this expression. In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor (TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels (rs = 0·55, P = 0·011; n = 20) was evident for AI. LCN2 blood levels correlated with AI disease severity (rs = 0·65, P < 0·001; n = 29), but not with disease duration, age, sex, body mass index or smoking habit. Detailed analyses revealed a link with the number of skin regions containing nodules and fistulae, but not scars.LCN2 might serve as a blood biomarker for the objective assessment of inflammatory activity in AI. We suggest a self-amplification loop comprising TNF-α, neutrophilic granulocytes and LCN2, which contributes to the recurrent skin neutrophil infiltration in AI, clinically evident as pus.
The Flip Side of NIFTP: an Increase in Rates of Unfavorable Histologic Parameters in the Remainder of Papillary Thyroid Carcinomas
Authors: Kristine S. Wong, Kyle C. Strickland, Trevor E. Angell, Matthew A. Nehs, Erik K. Alexander, Edmund S. Cibas, Jeffrey F. Krane, Brooke E. Howitt, Justine A. Barletta
Journal: Endocrine Pathology (2017)
Exercise and psychological interventions reduce cancer related fatigue, review finds
Authors: Susan Mayor
Journal: BMJ (2017)

Exercise and psychological interventions effectively reduce fatigue during and after cancer treatment, a meta-analysis of randomised trials has found. The authors recommend that these should be prescribed as first line treatments.1

Cancer related fatigue is one of the most common and troublesome adverse events that patients experience during and after cancer treatment. It sometimes limits people’s ability to complete their medical treatment and can persist for …