tbuckley/cabot-search huggingface dataset:
The prognostic value of mid-treatment prostate-specific antigen level in patients receiving salvage radiotherapy.
Authors: Jason M. Homza, John T. Nawrocki, Harmar D. Brereton, Christopher A. Peters
Journal: Journal of Clinical Oncology (2018)

e17055 Background: Salvage radiotherapy (SRT) may be employed as a potentially curative intervention for patients experiencing biochemical failure (serum prostate-specific antigen [PSA] ≥ 0.2 ng/mL) after prostatectomy for localized prostate cancer. Patients not showing a favorable response to SRT alone may require additional therapies and may benefit from earlier identification of this need. Methods: 131 consecutive patients received SRT during the timeframe of this study. 76 were deemed eligible based on the following criteria: prostatic adenocarcinoma diagnosis receiving SRT, no clinical evidence of metastasis, no hormone use prior to/during SRT, serum PSA measurement halfway through SRT, and minimum follow-up time of 3 months. Median follow-up time was 51.6 months. Eligible patients were divided into three groups based on PSA response by the midpoint of treatment: no change, decrease, or increase in PSA. The primary endpoint of the study was clinical failure (measured from SRT completion), defined as serum PSA value ≥0.2ng/mL above the post-radiotherapy nadir, initiation of androgen deprivation therapy, development of bone metastasis, or death from prostate cancer. Results: 13.1% of patients experienced no change in PSA halfway through SRT (group 0), 68.4% experienced a decrease (group 1), and 18.4% experienced an increase (group 2). Mean decrease in PSA was 39.0% (st.dev. 21%) for group 1, and mean increase was 37.5% (st.dev. 25%) for group 2. Four-year freedom from clinical failure was 60.0% for group 0, 58.3% for group 1, and 41.7% for group 2. Median time to clinical failure was 71.7 months for group 1, 26.8 months for group 2, and was not reached for group 0. Pairwise multiple comparison demonstrated a significant difference in four-year freedom from clinical failure between groups 1 and 2 (p = 0.036). Conclusions: These data strongly suggest that changes in PSA are apparent midway through SRT and are associated with 4-year freedom from clinical failure. Further study is warranted to determine whether mid-treatment PSA during SRT may be used to identify a subset of patients that may benefit from treatment intensification.
Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration
Authors: Qiuli Liu, Dali Tong, Gaolei Liu, Jie Gao, Lin-ang Wang, Jing Xu, Xingxia Yang, Qiubo Xie, Yiqiang Huang, Jian Pang, Luofu Wang, Yong He, Dianzheng Zhang, Qiang Ma, Weihua Lan, Jun Jiang
Journal: Clinical Cancer Research (2018)

Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.Results: Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well-differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. Clin Cancer Res; 24(22); 5622-34. ©2018 AACR.
B-Type Natriuretic Peptide Predicts Sudden Death in Patients With Chronic Heart Failure
Authors: RudolfBerger, MartinHuelsman, KarinStrecker, AnjaBojic, PetraMoser, BrigitteStanek, RichardPacher
Journal: Circulation (2002)

Background— Given the high incidence of sudden death in patients with chronic heart failure (CHF) and the efficacy of implantable cardioverter-defibrillators, an appropriate tool for the prediction of sudden death is desirable. B-type natriuretic peptide (BNP) has prognostic significance in CHF, and the stimuli for its production cause electrophysiological abnormalities. This study tests BNP levels as a predictor of sudden death. Methods and Results— BNP levels, in addition to other neurohormonal, clinical, and hemodynamic variables, were obtained from 452 patients with a left ventricular ejection fraction (LVEF) ≤35%. For prediction of sudden death, only survivors without heart transplantation (HTx) or a mechanical assist device and patients who died suddenly were analyzed. Up to 3 years, 293 patients survived without HTx or a mechanical assist device, 89 patients died, and 65 patients underwent HTx. Mode of death was sudden in 44 patients (49%), whereas 31 patients (35%) had pump failure and 14 patients...
Prognostic Impact of Residual HPV ctDNA Detection after Chemoradiotherapy for Anal Squamous Cell Carcinoma
Authors: Luc Cabel, Emmanuelle Jeannot, Ivan Bieche, Sophie Vacher, Celine Callens, Louis Bazire, Adeline Morel, Alice Bernard-Tessier, Walid Chemlali, Anne Schnitzler, Astrid Lièvre, Joelle Otz, Mathieu Minsat, Anne Vincent-Salomon, Jean-Yves Pierga, Bruno Buecher, Pascale Mariani, Charlotte Proudhon, François-Clément Bidard, Wulfran Cacheux
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. This study was designed to monitor human papillomavirus (HPV) circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC. Experimental Design: We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR. Results: HPV ctDNA was detected before CRT in 29 of 33 patients with stages II–III ASCC [sensitivity: 88%; 95% confidence interval (CI), 72–95]; ctDNA positivity rate was associated with tumor stage (64% and 100% in stages II and III, respectively; P = 0.008). Among ctDNA-positive patients at baseline, ctDNA levels were higher in N+ than in N− tumors (median 85 copies/mL, range = 8–9,333 vs. 32 copies/mL, range = 3–1,350; P = 0.03). ctDNA detection at baseline had no significant prognostic impact. After CRT, three of 18 (17%) patients displayed residual detectable HPV ctDNA; ctDNA detection after CRT was strongly associated with shorter disease-free survival (P &amp;lt; 0.0001). Conclusions: This is the first proof-of-concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV ctDNA can be detected before CRT and becomes undetectable during CRT. In this study, we show that residual ctDNA levels after CRT are associated with very poor outcome. Clin Cancer Res; 24(22); 5767–71. ©2018 AACR.
Making prepublication independent replication mainstream
Authors: Warren Tierney, Martin Schweinsberg, Eric Luis Uhlmann
Journal: Behavioral and Brain Sciences (2018)

Abstract The widespread replication of research findings in independent laboratories prior to publication is suggested as a complement to traditional replication approaches. The pre-publication independent replication approach further addresses three key concerns from replication skeptics by systematically taking context into account, reducing reputational costs for original authors and replicators, and increasing the theoretical value of failed replications.
Abstract 18670: Ischemic Stunning in Patients Suffering VT/VF Cardiac Arrests
Authors: Pranitha P Reddy, Suraj Patel, Eamon Linskey, Mark S Link
Journal: Circulation (2016)

Introduction:  Left ventricular ejection fractions (LVEF) are frequently evaluated following cardiac arrests (CA). LVEFs may be affected by the circumstances of the arrest, or may be relevant in the causation of the arrest. We evaluate immediate LVEF in patients with CA and compare to subsequent LVEF during the index hospitalization.   Hypothesis:  We expect transient reversible stunning to be present in all patients with CA.   Methods:  Patients were identified by query of billing for CA from Jan 2010 to May 2014. Records were reviewed for confirmation of CA during that time period, and then demographics and echocardiographic information were collected.   Results:  Of 145 patients meeting criteria for the study, 80 had a ventricular tachycardia/ fibrillation (VT/VF) arrest and 65 had either an asystolic or pulseless electrical activity (PEA) arrest. The mean initial LVEF was lower in those suffering VT/VF compared to asystolic/PEA arrests (36.4% +/- 16.7 vs 42.4% +/- 19.6; p=0.05). However, there was no difference in subsequent LVEFs (43.7% +/- 16.3 vs 46.1% +/- 17.8; p=0.58). Those diagnosed with STEMI had markedly lower initial LVEFs compared to those without STEMI (29.2% +/- 14.4 vs 41.4% +/- 18.1; p=0.002), but subsequent LVEFs were similar (41.4 +/- 16.8 vs 45.9 +/- 16.7; p=0.33).   Conclusions:  Patients suffering from VT/VF arrests have lower initial LVEF compared to those with asystolic/PEA arrests. LVEF improve in patients suffering from VT/VF arrests but not in those with asystolic/PEA arrests. Similarly those with STEMI in the context of an arrest suffer from ischemic stunning. Reduced LVEFs in the setting of VT/VF and STEMI arrests should be expected to improve in most patients, arguing for reversible cardiac stunning in those patients.
The hepatitis B epidemic and the urgent need for cure preparedness
Authors: Jeffrey V. Lazarus, Timothy Block, Christian Bréchot, Anna Kramvis, Veronica Miller, Michael Ninburg, Capucine Pénicaud, Ulrike Protzer, Homie Razavi, Laura A. Thomas, Jack Wallace, Benjamin C. Cowie
Journal: Nature Reviews Gastroenterology & Hepatology (2018)
Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study
Authors: E. Van Cutsem, T. Yoshino, H.J. Lenz, S. Lonardi, A. Falcone, M.L. Limón, M. Saunders, A. Sobrero, Y.S. Park, R. Ferreiro, Y.S. Hong, J. Tomasek, H. Taniguchi, F. Ciardiello, J. Stoehr, Z. Oum’Hamed, S. Vlassak, M. Studeny, G. Argiles
Journal: Annals of Oncology (2018)

BackgroundAngiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.Patients and methodsEligible patients (Eastern Cooperative Oncology Group performance status 0–1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review.ResultsFrom October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n= 384; placebo n= 381). Median follow-up was 13.4 months (interquartile range 11.1–15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86–1.19; P=0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49–0.69; P< 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).ConclusionsThe study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.ClinicalTrials.gov numberNCT02149108 (LUME-Colon 1).
Abstract 1683: Ca2+/Redox-Sensitive Tyrosine Kinase PYK2 Promotes Atherogenesis through OxLDL/ROS/p21-Dependent Premature Senescence and Cytokine Induction in Endothelium
Authors: Asako Katsume, Mitsuhiko Okigaki, Akihiro Matsui, Shinichiro Yamaguchi, Eigo Kishita, Hiroyuki Yamada, Hiroaki Matsubara
Journal: Circulation (2008)

Background: Calcium/redox-sensitive tyrosine kinase PYK2 plays crucial roles in cell migration. Analysis of PYK2-deficient macrophages has been reported that their directional migration was impaired due to dysfunction of PI3K, small GTPase Rho, and Ca (2+)-mobilization. Since monocyte/macrophage plays crucial role in atherogenesis, we newly generated the PYK2-knock-out mice and investigated the role of PYK2 in atherogenesis. Methods: PYK2−/− mice (P-KO) were crossbred with ApoE−/− mice (E-KO), and PYK2−/−/ApoE−/− double knockout (D-KO) mice were established. Four-week-old mice were fed with high-fat-diet for 8 weeks, and the thoracic aorta and aortic root were histologically analyzed. Then we studied the mechanisms of the difference in atherogenesis. Results: At the 8th week, atherosclerotic area of thoracic aorta in D-KO was less than E-KO (~54%, P &lt; 0.01, n = 15, respectively). Numbers of infiltrating macrophage in D-KO mice was also reduced (~52%, P &lt; 0.01, n = 15). We also verified that no significant difference in atherosclerotic area between E-KO recipient with D-KO bone marrow and D-KO recipient with E-KO bone marrow. At the 7th day, the expression of VCAM1, and MCP-1 in the thoracic aorta in D-KO mice was inhibited (~43 to 58%, n = 5, P &lt; 0.01, respectively). Inflammatory cells were barely detected in the region at that time. TNF-alpha and MCP-1 mRNA of peripheral blood-leukocytes in D-KO was also 38% lower (P &lt; 0.05, n = 5 each). In the primary-cultured P-KO endothelial cells, TNF-alpha-induced expressions of VCAM-1 and MCP-1 was decreased to 31 and 32% respectively, compared to the wild-type (WT) (each n = 5, P &lt; 0.01). Lysophosphatidylcholine (LPC), the component of Oxidized LDL, -induced Reactive Oxygen Species (ROS)-production was attenuated to 54% of the WT (p &lt; 0.05) using DCF staining, and the high cholesterol diet induced ROS-production in endothelium in D-KO were decreased by 8-OHDG staining. Senescence-associated-beta-gal-stained area and ROS-dependent expression of p21 in the thoracic aorta in D-KO-mice was diminished. In P-KO ECs, LPC-induced p21 expression via Ets-1 or STAT1 was also decreased markedly. Conclusion: PYK2 promotes atherogenesis by inducing ROS/p21-dependent premature senescence and cytokine induction in endothelium.
Targeting Gastrointestinal Transport Proteins to Control Hyperphosphatemia in Chronic Kidney Disease
Authors: Denis Fouque, Marc Vervloet, Markus Ketteler
Journal: Drugs (2018)

Management of hyperphosphatemia in patients with dialysis-dependent chronic kidney disease remains a major challenge, requiring a multifaceted approach that includes dietary phosphate restriction, dialysis, and phosphate binders. However, these treatments fail to meet serum phosphate targets in many patients, potentially further exacerbating the significant morbidity and mortality burden associated with the disease. Recent advances in our understanding of the mechanisms underlying phosphate homeostasis have shed new light on the issue and suggest that gastrointestinal transport proteins may be promising targets for new hyperphosphatemia treatments. Drugs that inhibit or downregulate these transport proteins, and thus reduce phosphate uptake from the gut, may overcome some of the limitations of existing phosphate-lowering strategies, such as interdialytic rises in serum phosphate levels, poor adherence to dietary and phosphate-binder regimens, and maladaptive responses that can increase gastrointestinal phosphate absorption. Here, we review the latest preclinical and clinical data for two candidates in this novel drug class: tenapanor, a small-molecule inhibitor of the sodium/hydrogen ion-exchanger isoform 3, and nicotinamide, an inhibitor of sodium–phosphate-2b cotransporters. We also discuss how potential synergies in their mechanisms of action suggest that coadministering phosphate binders with sodium–phosphate-2b cotransporter inhibitors may yield additive benefits over traditional phosphate-binder therapy.
Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia
Authors: E. Genescà, A. Lazarenkov, M. Morgades, G. Berbis, N. Ruíz-Xivillé, P. Gómez-Marzo, J. Ribera, J. Juncà, A. González-Pérez, S. Mercadal, R. Guardia, M. T. Artola, M. J. Moreno, J. Martínez-López, L. Zamora, P. Barba, C. Gil, M. Tormo, A. Cladera, A. Novo, M. Pratcorona, J. Nomdedeu, J. González-Campos, M. Almeida, J. Cervera, P. Montesinos, M. Batlle, S. Vives, J. Esteve, E. Feliu, F. Solé, A. Orfao, J. M. Ribera
Journal: Journal of Hematology & Oncology (2018)

Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.
JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation
Authors: Bärbel Edelmann, Nibedita Gupta, Tina M. Schnoeder, Anja M. Oelschlegel, Khurrum Shahzad, Jürgen Goldschmidt, Lars Philipsen, Soenke Weinert, Aniket Ghosh, Felix C. Saalfeld, Subbaiah Chary Nimmagadda, Peter Müller, Rüdiger Braun-Dullaeus, Juliane Mohr, Denise Wolleschak, Stefanie Kliche, Holger Amthauer, Florian H. Heidel, Burkhart Schraven, Berend Isermann, Andreas J. Müller, Thomas Fischer
Journal: Journal of Clinical Investigation (2018)

JAK2-V617F–positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1– (VCAM1-) and intercellular adhesion molecule 1–coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti–VLA-4 and anti–β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.
A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy (NACT) for early breast cancer: Three-year follow-up data.
Authors: Andreas Schneeweiss, Amparo Ruiz, Alexey Manikhas, Alberto Bottini, Pedro Sanchez Rovira, Kambiz Mansouri, Gbenga Kazeem, Thomas Bauknecht
Journal: Journal of Clinical Oncology (2012)

1059 Background: NACT for early breast cancer allows in vivo chemosensitivity testing. Primary results of this randomized, non-comparative 2-arm study have been published (Schneeweiss et al, Ann Oncol 2011). Here we provide 3-year follow-up data for disease-free survival (DFS) and safety. Methods: 257 patients (pts) with untreated operable T2–T4a–c N0–2 M0 breast cancer were randomly assigned to receive either four cycles of doxorubicin 60 mg/m² plus pemetrexed 500 mg/m² every 3 weeks (q3w) followed by four cycles of docetaxel 100 mg/m² q3w (AP-D; 135 pts), or four cycles of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² q3w followed by four cycles of docetaxel 100 mg/m² q3w (AC-D; 122 pts). Both arms were stratified according to hormone receptor (HR) status (estrogen and/or progesterone receptor positive vs both negative) and study center. Surgery was carried out within 2 months after last chemotherapy. Primary objective was pathological complete response (pCR) rate in the breast (ypT0/is). Secondary objectives included long-term efficacy and safety measures. DFS and adverse event data were collected from all patients for 3 years or until progression or death. The Kaplan-Meier (KM) analysis technique and Cox regression method were used as statistical measures. KM analyses were performed on HR-positive and -negative pts subgroups. Results: As reported earlier, pCR rates were 16.5% for AP-D and 20.2% for AC-D. The 3-year DFS rate was 76% and 77% for AP-D and AC-D, respectively. Cox regression analysis for the overall enrolled population (regardless of treatment) revealed significantly longer DFS in HR-positive than in HR-negative pts (hazard ratio 0.35; 95% CI 0.22–0.58; p &lt; 0.001). In HR-positive pts, the 3-year DFS rate was 88% (95% CI: 81–95%) with AP-D and 83% (95% CI: 74–91%) with AC-D. In HR-negative pts, the 3-year DFS rate was 55% (95% CI: 40–70%) for AP-D and 68% (95% CI: 53–82%) for AC-D. The 3-year follow-up data did not reveal any changes in the safety profile compared to the previously published results. Conclusions: The 3-year DFS rates of both NACTs are in line with published studies.