tbuckley/cabot-search huggingface dataset:
Differences in the immune microenvironment and genomic characteristics of TNBC in African American women compared to other races.
Authors: Borbala Szekely, Anton Mikhailovich Safonov, Thomas Karn, Sanaea Bhagwagar, Brigid K. Killelea, Andrea Silber, Christos Hatzis, Lajos Pusztai
Journal: Journal of Clinical Oncology (2017)

e13028 Background: African American (AA) women are more likely to be diagnosed with triple negative breast cancer (TNBC) compared to other races and have lower pathologic complete response rate to neoadjuvant therapy. Our goal was to assess differences in the immune microenvironment and genomic characteristics of TNBC by race using the TCGA data set. Methods: We compared the expression levels of 13 previously reported immune metagenes (CTL, Mphages, MHC1, T regs , IF1, NK, STAT1, MHC2, Giam, T fh , T inh , T stim , LCK), histologic tumor infiltrating lymphocyte (TIL) count and overall mutational load, neoantigen load, clonal heterogeneity assessed using the MATH score, amplification and deletion loads of between AA (n = 58) and non-AA TNBC (n = 114). Data was downloaded from the TCGA website, immune metagene expression and MATH scores were calculated as previously reported. Distributions between cohorts were compared using the Mann-Whitney U-test. Results: Among the immune metagenes only the cytotoxic T cell (CTL) metagene showed lower expression in AA patients (3.64 versus 4.08, unadjusted p = 0.046). TIL count was available in 51 of 58 AA and 91 of 114 of non-AA cases, and no significant difference was observed between the racial groups (p = 0.55). We also did not observe statistically significant differences in the mutational load (p = 0.36), neoantigen load (p = 0.38), clonal heterogeneity represented by the MATH score (p = 0.54), and amplification and deletion loads (p = 0.23 and 0.83 respectively) between the two TNBC race groups. We also assess the expression distribution of the immune signatures in an independent Affymetrix gene expression dataset including 40 AA and 323 non-AA patients with TNBC. Similar to the TCGA, there were no significant race differences in the immune signatures, including in the CTL metagene. Conclusions: These results suggest that the differences in prevalence and treatment response seen between TNBC in AA and non-AA patients are unlikely to be due to differences in the immune microenvironment and the genomic landscape of TNBC. However, more subtle comparison in the immune biology of these cancers can only be studies with more focused methods.
Proteomics – A new tool for screening for colon cancer?
Authors: AM Lennon, ACT Tan, F Gleeson, A Brannigan, JR Lennon, J O'Sullivan, A White, D Keegan, H Mulcahy, JM Hyland, K Sheahan, DP O'Donoghue, R Brown
Journal: Endoscopy (2005)

Aims: This was a pilot study to determine if protein profiles generated using SELDI-MS could differentiate plasma from patients with colorectal cancer, dysplastic polyps or normal colons.
The association between treatment for metabolic disorders and breast cancer characteristics.
Authors: Hadar Goldvaser, Shulamith Rizel, Daniel Hendler, Victoria Neiman, Daniel Shepshelovich, Tzipora Shohat, Aaron Sulkes, Baruch Brenner, Rinat Yerushalmi
Journal: Journal of Clinical Oncology (2016)

527 Background: There are accumulating data regarding possible association between breast cancer and various metabolic disorders, including obesity, diabetes mellitus, dyslipidemia and hypothyroidism. Medications used to treat patients for these common disorders might have direct impact on breast cancer biology and outcome. The aim of this study was to evaluate the impact of metformin, insulin, statins and levothyroxine on estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative early breast cancer patients regarding tumor characteristics and outcome. Methods: This was a retrospective single center study. All patients diagnosed between 4/2005 and 3/2012 and treated in our institute with early ER positive, HER2 negative breast cancer, whose tumors were sent to Oncotype DX (ODX) analysis were included. Medical records were reviewed for demographics, clinicopathological parameters, chronic medications, treatment and outcome. Patients were grouped according to each of the medications that were evaluated. Every group was compared to the rest of the study population. Results: A total of 671 patients were included in the study cohort. Sixty (9.1%) patients were treated with metformin, 9 (1.4%) with insulin, 208 (31.7%) with statins and 62 (9.4%) with levothyroxine at breast cancer diagnosis. Patients treated with metformin had more intense ER staining (p = 0.032) and a lower ODX recurrence score (RS) (p = 0.035). Patients treated with insulin had a higher rate of anigiolymphatic invasion (p = 0.041), though their Ki67% was lower (p = 0.017). Patients treated with levothyroxine had different histological subtype distribution (p = 0.02) and tendency for lower ODX RS (p = 0.062). Statins usage had no impact on tumor features. Disease free survival and overall survival were comparable in the study groups. Conclusions: Common medications for metabolic disorders were associated with different breast cancer characteristics. Further research is needed to validate our findings and define possible clinical implications.
Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC.
Authors: Scott Joseph Antonia, Sarah B. Goldberg, Ani Sarkis Balmanoukian, Rachel E. Sanborn, Keith Steele, Rajesh Narwal, Paul B. Robbins, Yu Gu, Joyson Joseph Karakunnel, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2015)

3014 Background: The inhibitory PD-L1 and CTLA-4 pathways control T-cell activation. MEDI4736 (M) is a human IgG1 mAb that blocks PD-L1 binding to programmed cell death-1 and CD80 with high affinity and selectivity. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4. M and T have demonstrated acceptable safety profiles and clinical activity as single agents. M and T block distinct interactions contributing to immunosuppression and the combination may provide greater antitumor activity versus either agent alone. Methods: A Phase 1, open-label dose escalation and expansion study (NCT02000947) is assessing the safety/tolerability and antitumor activity of M + T combinations in pts with advanced NSCLC. Results: As of 4 Dec 2014, 61 pts have been treated during the dose escalation phase (table). An MTD has not yet been defined; the Cohort 5a dose exceeded the MTD (n=2 with dose-limiting toxicities; Grade [G] 3 increased AST/ALT, G4 increased lipase). 64% of pts had ≥1 drug-related AE; the most frequent were fatigue (26%), diarrhea (21%), and increased amylase (13%). 31% of pts had ≥1 G3/4 related AE; the most frequent (>5%) were diarrhea (8%) and colitis (7%). Increasing doses of T with a constant dose of M were associated with greater severity and frequency of AEs. 18% of pts had drug-related AEs leading to discontinuation; the most frequent was colitis (7%). All AEs were manageable with standard therapy, including steroids, except G4 myasthenia gravis and G5 polymyositis in 1 pt in Cohort 2a. Of 31 pts with ≥18-week scan, 8 (26%) had partial response (PR) and 11 pts (35%) had stable disease. PRs occurred in 3 of 10 pts with PD-L1-negative tumors. Conclusions: The combination has a manageable safety profile with evidence of clinical activity, including in PD-L1-negative disease. These data support continued study of the combination; recruitment is ongoing. Clinical trial information: NCT02000947. M Q4W M Q2W Cohort 1a 2a 3a 3b 4 4a 5 5a 8 9 Dose M (mg/kg) + T (mg/kg) 3 + 1 10 + 1 15 + 1 10 + 3 20 + 1 15 + 3 15 + 10 20 + 3 10 + 1 10 + 3 n 3 3 11 3 6 11 9 6 3 6 Pts with ≥1 drug- related AE, n All grades 1 3 5 3 2 7 8 5 0 5 Grade 3/4 0 2 2 1 1 2 4 5 0 2 All grades leading to discontinuation 0 1 1 1 0 2 2 3 0 1
Abstract 19337: Transcoronary Delivery of Allogeneic Cardiac Stem Cells Reduces Ventricular Arrhythmia Inducibility in a Post Myocardial Infarction Swine Model
Authors: Gerard Loughlin, Pablo M Ruiz Hernandez, Pablo Avila, Veronica Crisostomo, Ricardo Sanz, Javier Fernandez-Portales, Claudia Baez-Diaz, Claudia Baez-Diaz, Rebeca Blazquez, Tomas Datino, Esteban G Torrecilla, Felipe Atienza, Ester Perez-David, Francisco M Sanchez-Margallo, Javier Bermejo, Francisco Fernandez-Aviles, Angel Arenal
Journal: Circulation (2015)

Introduction: Post myocardial infarction (MI) patients are at risk of scar related ventricular tachycardia (VT). Hypothesis: Stem cell therapy reduces post-MI scar size, potentially leading to a reduction in the risk of ventricular arrhythmias (VA). Methods: A post-MI scar model of VT was created by transient occlusion of the mid left anterior descending artery in 56 swine. Five weeks after infarct creation 29 subjects were treated with allogeneic cardiac stem cells (CSC): 10 underwent transcoronary delivery of CSC, 9 direct transepicardial delivery (via a minithoracotomy) and 10 underwent a combined transcoronary and VT substrate guided (late potentials) direct transendocardial CSC delivery procedure using an electroanatomic mapping system. Of the remainder, 8 subjects underwent a “sham” transepicardial procedure and 19 served as controls. Seventeen weeks after infarct creation an electrophysiological study was performed in each subject to assess for ventricular arrhythmia inducibility. VA inducibility was compared in each group vs. the control group. Results: Of the 19 control subjects, 17 were inducible (89,5 %). As presented in the figure, CSC delivery with a combined transcoronary/transendocardial approach was associated with a significant reduction in VT inducibility rates compared to controls (20 % vs. 89,5 %; p value 0,001). Subjects treated with transcoronary CSC also experienced significantly lower VA inducibility rates (40 % vs. 89,5 %; p value 0,009). There were no differences in VA inducibility compared with controls in patients in the “sham” (62,5 % vs 89,5 %; p value 0,136) or the transepicardial group (66,7 % vs 89,5 %; p value 0,290). Conclusions: Combined transcoronary and VT substrate-guided transendocardial CSC delivery is associated with a significant reduction in VA inducibility in a post-MI swine model. Future human studies should evaluate the effects of allogeneic CSC therapy on ventricular arrhythmia burden in post-MI patients.
Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
Authors: Audrey Laroche-Clary, Vanessa Chaire, Marie-Paule Algeo, Marie-Alix Derieppe, François L. Loarer, Antoine Italiano
Journal: Journal of Hematology & Oncology (2017)

MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume. RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival. Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting.
Validation of Portuguese version of the MD Anderson Symptom Inventory (MDASI) for patients with head and neck cancer.
Authors: Ana Filipa Martins Ferreira Castro, Joana Febra, Andreina Amorim, Andreia Machado Coelho, Alexandra Vieira De Araujo, Maria Gloria Ferreira, Antonio M.F. Araujo
Journal: Journal of Clinical Oncology (2016)

e18225 Background: The concern and importance of quality of life (QoL) of cancer patients have been increasingly recognized, which is due in part, to the progress made in controlling the disease. Quality of life is a multidimensional and subjective concept, which aims to provide a comprehensive view of the patient's perception of himself and of himself in worldwide. Patients with head and neck cancer (HNC) may suffer severe symptoms due to the anatomical location and extent of the tumor. Furthermore, in case of locally advanced HNC, therapeutic approaches are aggressive and may show acute and long term, which often cause deterioration of basic functions, and occasionally cause aesthetic changes that can adversely affect the QoL of these patients. The MD Anderson Symptom Inventory (MDASI) is a short questionnaire developed to identify and quantify the symptoms of the tumor itself and related to treatment, which can help guide specific patient assessments. The MDASI was designed to tumors of different localizations and their treatments, and the specific module for patients with the HNC is MDASI-HN. The aim is to evaluate the psychometric properties of the Portuguese version.This validation process is essential to check systematically whether this questionnaire is valid in the Portuguese cultural context. Methods: Following forward and backward translation of items of the English MDSAI-HN into Portuguese, we evaluated the 28 items that characterize the quality of life. We also evaluated the easy of response with the cognitive debriefing to HNC patients. Statistical analysis was performed using the SPSS v22. Results: From October to December 2015, 30 patients with diagnosis of HNC (15 for curative treatment, follow-up at 6 and 14 for palliative treatment) completed the MDASI-HN. All of questionnaires were completed, with an average time of 7.5 minutes response (between 5-14 minutes). The results suggest the overall ease of understanding and interest of this scale translated, and no patients suggested the omission of any of the evaluated items. Conclusions: The Portuguese version of MDASI-HN seems to be linguistically and valid self-report tool that can be used in the future as a clinical tool in clinical trials.
Актуальність визначення спектра жирних кислот у біологічних субстратах у діагностиці гастроентерологічних захворювань
Authors: V.I. Didenko, I.A. Klenina, S.O. Babii, V.A. Karachynova
Journal: GASTROENTEROLOGY (2017)

У статті розглянуто роль вільних жирних кислот у патогенезі метаболічних і гастроентерологічних захворювань. Обґрунтовано доцільність використання методу газової хроматографії для визначення жирнокислотного складу біологічних рідин (сироватка крові, сеча, кал тощо). Показано, що вільні жирні кислоти беруть участь у формуванні структурних компонентів клітин, енергетичному гомеостазі й виконують роль сигнальних молекул або їх попередників, тому порушення регуляції метаболізму жирних кислот може призвести до системного порушення дії інсуліну, а також обміну глюкози в жировій тканині, м’язах і печінці. При різних патологічних станах відбувається збільшення окремих фракцій ліпідного спектра, що відмічається раніше, ніж зміна активності ферментів чи діагностичних маркерів білкового походження. Так, коротколанцюгові жирні кислоти можуть бути використані для встановлення синдрому надлишкового бактеріального росту в кишечнику. Зростання фракції поліненасичених жирних кислот може активізувати процеси запалення, імунні реакції, гіперкоагуляцію крові, підвищувати активність процесів перекисного окиснення ліпідів. Також маркерами запальних процесів можуть бути арахідонова (С20:4), додеканоїнова (С12:0) і лінолева (С18:3) вільні жирні кислоти. Окрім збільшення вмісту жирних кислот у біологічних рідинах, має значення їх дефіцит, що неможливо визначити за допомогою стандартних лабораторних методів. Доведеним фактом є те, що дефіцит ессенціальних жирних кислот може бути однією з причин формування метаболічного синдрому, неалкогольної жирової хвороби печінки та інших захворювань, пов’язаних з обміном речовин. Отже, хроматографія на сьогодні є єдиним методом, що дозволяє визначити жирнокислотний склад. Перевагою методу газової хроматографії є швидкість виконання і висока чутливість методу, завдяки чому можливо виявити найменші концентрації сполук у дослідному зразку (до 10–12 моль). Упровадження цього методу в клінічну практику лікарів-гастроентерологів дозволить діагностувати захворювання на ранньому етапі розвитку й допоможе вибирати правильний метод лікування.
Overall survival (OS) by line of therapy (LOT) in Medicare-enrolled glioblastoma multiforme (GBM) patients (pts).
Authors: Abdalla Aly, Prianka Singh, Beata Korytowsky, Homa Dastani, Lisa Ling, Marc Botteman, Andrew David Norden
Journal: Journal of Clinical Oncology (2017)

2039 Background: In clinical trials, the median OS of elderly GBM pts on standard treatment (tx) is ~9 months (mos) from diagnosis (dx), but has not been described in the real world (RW). This analysis describes RW OS for US Medicare GBM pts by LOT. Methods: GBM pts aged ≥66 years (y) were identified in SEER-Medicare (2007–2011). Pts were followed from dx to death, Medicare disenrollment or 12/31/2013. Systemic tx patterns were characterized as untreated (0L), ≥first line (1L+) and ≥second line (2L+). OS was estimated by the Kaplan-Meier method from dx for 0L, and from LOT start for 1L+ and 2L+. Results: Among 2533 eligible GBM pts (median age: 74 y; Charlson comorbidity index [CCI] ≥2: 13%), 49.9% received 1L+ and only 16.3% received 2L+. Median (1-year) OS for all pts was 5.3 mos (26%), range 1.6–10.7 mos (3–45%) depending on LOT, surgical resection (R) or Biopsy alone (B), tumor size, age, and CCI (Table). Conclusions: Receipt of tx has a significant impact on OS in Medicare GBM pts. This RW study shows that only 50% of pts receive tx, even though each LOT is associated with additional OS benefit. This suggests an unmet need for more efficacious therapies to allow additional treatment and improve outcomes. [Table: see text]
Physical activity and healthy ageing: A systematic review and meta-analysis of longitudinal cohort studies
Authors: C. Daskalopoulou, B. Stubbs, C. Kralj, A. Koukounari, M. Prince, A.M. Prina
Journal: Ageing Research Reviews (2017)

Older people constitute a significant proportion of the total population and their number is projected to increase by more than half by 2030. This increasing probability of late survival comes with considerable individual, economic and social impact. Physical activity (PA) can influence the ageing process but the specific relationship with healthy ageing (HA) is unclear. We conducted a systematic review and meta-analysis of longitudinal studies examining the associations of PA with HA. Studies were identified from a systematic search across major electronic databases from inception as January 2017. Random-effect meta-analysis was performed to calculate a pooled effect size (ES) and 95% CIs. Studies were assessed for methodological quality. Overall, 23 studies were identified including 174,114 participants (30% men) with age ranges from 20 to 87 years old. There was considerable heterogeneity in the definition and measurement of HA and PA. Most of the identified studies reported a significant positive association of PA with HA, six reported a non-significant. Meta-analysis revealed that PA is positively associated with HA (ES: 1.39, 95% CI = 1.23–1.57, n = 17) even if adjusted for publication bias (ES: 1.27, 95% CI = 1.11–1.45, n = 20). There is consistent evidence from longitudinal observational studies that PA is positively associated with HA, regardless of definition and measurement. Future research should focus on the implementation of a single metric of HA, on the use of objective measures for PA assessment and on a full-range of confounding adjustment. In addition, our research indicated the limited research on ageing in low-and-middle income countries.
<i>NF-</i><i>κΒ</i><i>2</i> SNPs, rs7897947, and rs12769316 and survival outcome of NSCLC patients.
Authors: Fotinos-Ioannis D. Dimtrakopoulos, Anna G Antonacopoulou, Anastasia E Kottorou, Stella Maroussi, Nikolaos Panagopoulos, Ioulia Koukourikou, Chrisoula D Scopa, Thomas Makatsoris, Helen Papadaki, Dimitrios Dougenis, Haralabos Kalofonos
Journal: Journal of Clinical Oncology (2016)

e13012 Background: Lung cancer remains the leading cause of cancer-related deaths worldwide. Recently, NF-kB2 was implicated in NSCLC pathogenesis. Here, we further studied the role of NF-kB2 in NSCLC by assessing the prognostic value of the single nucleotide polymorphisms (SNPs) rs7897947 (T/G) and rs12769316 (G/A). Methods: We genotyped 272 NSCLC patients and 279 healthy donors for the2 NF-kB2 SNPs. The enrolled patients were of stages I-IV and were medically managed at the University Hospital of Patras. Results: Rs7897947 TT homozygotes were associated with poorer overall survival (OS), compared to G allele carriers, after 2 and 3 years of observation (P = 0.013 and P = 0.033, respectively). These differences were pronounced for 2-, 3- and 5-year survival of stages III and IV patients (P = 0.001; HR, 2.271, P = 0.022; HR, 1.629 and P = 0.035; HR, 1.551, respectively), while no association was found regarding survival of stage I and II patients. The prognostic significance of the TT genotype for 2- and 3-year OS persisted in multivariate analysis (P = 0.030; HR, 1.591 and P = 0.028; HR, 1.503, respectively), but not in the 5-year follow-up (P = 0.069; HR, 1.360). Interestingly, rs7897947 was also associated with the OS of patients who received first-line chemotherapy (n = 69) with TT homozygotes displaying worse 2- or 3-year OS (P = 0.006; HR, 2.576 and P = 0.014; HR, 2.064, respectively). In addition, rs12769316 was related to OS of stage I and II patients. In particular, stage I A allele carriers were associated with worse 3-year OS not only in univariate (P = 0.031; HR, 2.426), but also in multivariate analysis (P = 0.047; HR, 2.353). Interestingly, stage II GG homozygotes displayed worse 5-year survival compared to A allele carriers in univariate analysis (P = 0.006; HR, 3.049) and in multivariate analysis (P = 0.029; HR, 3.022), reflecting a possible relation with the different treatment approaches of the two stages. Conclusions: The present study suggests that rs7897947 and rs12769316 SNPs may be useful as independent prognostic biomarkers in NSCLC.
The molecular pathogenesis of the NUP98-HOXA9 fusion protein in acute myeloid leukemia
Authors: A Rio-Machin, G Gómez-López, J Muñoz, F Garcia-Martinez, A Maiques-Diaz, S Alvarez, R N Salgado, M Shrestha, R Torres-Ruiz, C Haferlach, M J Larráyoz, M J Calasanz, J Fitzgibbon, J C Cigudosa
Journal: Leukemia (2017)

unchanged over this period when adjusted for age, stage at diagnosis, time from diagnosis to transplant and disease status at transplant.VRD has become the most common pretransplant induction regimen after 2010.Only, half of patients are placed on post-transplant treatment at day 100 after AHCT, with lenalidomide as the most frequently used agent.Counterintuitively, we did not see an increase in the use of maintenance treatment in the most recent period.Despite these impressive gains in the field, progression of MM remains the most frequent cause of death.