tbuckley/cabot-search huggingface dataset:
Edmonton Prostate Interdisciplinary Cancer Clinic (EPICC): Real-world efficacy outcomes of a multidisciplinary clinic for metastatic castration-resistant prostate cancer.
Authors: Graeme Follett, Derek Tilley, Naveen S. Basappa, Brita Lavender Danielson, Michael Chetner, Michael Paul Kolinsky, Scott A. North, Sarah Rayner-Myers, Gerry Todd, Adrian S. Fairey
Journal: Journal of Clinical Oncology (2020)

36 Background: Multidisciplinary management improves complex treatment decision making in cancer care but its impact for metastatic castration resistant prostate cancer (M1 CRPC) has not been documented. The Edmonton Prostate Interdisciplinary Cancer Clinic (EPICC) is a multidisciplinary specialized clinic focused on the delivery of novel therapeutics (Androgen Receptor Axis Therapy; ARAT) to men with chemotherapy-naïve M1 CRPC. The objective of the current study was to assess the efficacy of ARAT in the EPICC. Methods: The study was a retrospective quality assurance analysis. Eligible patients had a new diagnosis of chemotherapy-naïve M1 CRPC with minimal symptoms. EPICC patients were assessed and treated by a multidisciplinary cancer control team that included nursing oncology, pharmacy oncology and physician oncology (urologic, medical and radiation). Patients were treated in first line with an ARAT (abiraterone (AA) or enzalutamide (EZ)) from October 2017 to March 2018. The main efficacy outcome was overall survival (OS). The Kaplan-Meier method and Cox regression model were used to analyze survival data. Statistical tests were two-sided (p≤0.05). Results: From October 2017 to March 2018, 160 chemotherapy-naïve M1 CRPC patients were assessed in the EPICC. Median age at EPICC admission was 77 years (range, 54-92 years). Median PSA level at EPICC admission was 26.6 ng/mL (range, 0.1-5000 ng/mL). 84 out of 160 (53%) patients had received prior radical local therapy (RLT) with curative intent. 83 (57%) patients were treated with EZ and 64 (43%) patients were treated AA. Median OS for the entire cohort was 23 months. In multivariable analysis, absence of prior RLT (HR 3.6, 95% CI 1.9 to 6.6, p &lt; 0.001), PSA &gt; 20 ng/mL (HR 3.2, 95% CI 1.4 to 7.2, p = 0.004), and higher ECOG performance status (1 vs 0: HR 2.4, 95% CI 1.3 to 4.4, p = 0.005; 2 versus 0: HR 3.5, 95% CI 1.5 to 8.0, p = 0.003; and 3 versus 0: HR 12.7, 95% CI 2.5 to 63.8, p = 0.002) were independently associated with poorer OS. Conclusions: Multidisciplinary management of chemotherapy-naïve M1 CRPC with ARAT is feasible. Real world efficacy of ARAT in EPICC are similar to data reported in phase 3 trials.
Long-Lived IgE Plasma Cells Reside in The Bone Marrow During Chronic Allergen Exposure and Maintain IgE Serological Memory
Authors: Andre Limnander, Jamie Orengo, Seblewongel Asrat, Xia Liu, Daisuke Kajimura, matthew sleeman, Li-Hong Ben, Andrew Murphy, Navneet Kaur
Journal: Journal of Allergy and Clinical Immunology (2020)
Preliminary results of a prospective assessment of androgen receptor splice variants in mCRPC patients undergoing androgen receptor targeted agents.
Authors: Giulio Francolini, Mauro Loi, Beatrice Detti, Monica Mangoni, Isacco Desideri, Cristina Muntoni, Lucia Pia Ciccone, Michele Aquilano, Pamela Pinzani, Francesca Salvianti, Sara Lucidi, Matteo Mariotti, Pietro Garlatti, Giulia Salvatore, Mariangela Sottili, Lorenzo Livi
Journal: Journal of Clinical Oncology (2020)

246 Background: Different treatment options for metastatic castrate resistant prostate cancer (mCRPC) are currently available, including Androgen Receptor Targeted Agents (ARTA) and Taxane based chemotherapy. However, selection criteria aiming to drive the therapeutic choice in this setting are lacking, and no standardized therapeutic sequence is validated. In our institution, a prospective study testing predictive value of circulating tumor cells (CTC) in patients (pts) receiving a first line ARTA for mCRPC is currently ongoing (PRIMERA). Here, we present preliminary results from the first enrolled cohort. Methods: Pts affected by mCRPC eligible for Androgen Deprivation Therapy (ADT) plus ARTA were prospectively enrolled and underwent baseline determination of androgen-receptor splice variant 7 (AR-V7) and androgen-receptor-full length (ARFL) variants on CTC at baseline (ARTA start). Fisher Exact Test was conducted to explore the correlation between baseline features and CTC detection rate. Results: Overall, 26 pts were enrolled and baseline results are available for 13 pts. CTC were found in 5 (38.5%) pts. No significant difference was reported in terms of CTC detection probability for pts with high vs low burden of disease according to CHARTEED definition (p=0.42), neither for pts with PSA at CRPC diagnosis &lt; or &gt; 10 ng/ml, (p=0.2). However, a PSA &gt; 10 ng/ml at ADT start in metastatic hormone sensitive setting (mHSPC) was significantly related to CTC detection probability (p=0.01). AR-V7 variants were found in 1 out 5 (20%) CTC-positive pts. Conclusions: PSA at ADT start may significantly be related to CTC detection rate. CTC detection could be particularly useful in pts with a high burden of disease at the beginning of systemic therapy. Metastatic disease could remain dormant until development of CRPC status, with consequent release of increased amount of CTC, more likely to be detected in this setting. AR-V7 expression was found in 20% of CTC positive pts, in line with literature data.[Table: see text]
Sex differences in mineralocorticoid receptor antagonist trials: a pooled analysis of three large clinical trials
Authors: Xavier Rossello, João Pedro Ferreira, Stuart J. Pocock, John J.V. McMurray, Scott D. Solomon, Carolyn S.P. Lam, Nicolas Girerd, Bertram Pitt, Patrick Rossignol, Faiez Zannad
Journal: European Journal of Heart Failure (2020)
Abstract P018: Lifestyle Interventions that Benefit the Heart Also Improve Depression Among Geriatrics
Authors: Francisco E Ramirez, Neil Nedley
Journal: Circulation (2017)

Objective: Plant-based nutrition, exercise, proper rest, relaxation techniques and other healthy behaviors can be beneficial to the cardiovascular system. We assess the impact that this healthy behaviors have before and after an 8-week educational community-based program. Participants and Methods: The program was developed by the Nedley Clinic in Ardmore, Oklahoma, USA. This medical clinic trained and certified lay and professional people around the world in 4 continents. The program does not create a doctor-patient relationship. Recruitment is done by, for example radio, TV, handouts, newspaper and word of mouth. Those who chose to participate met once a week for 8 weeks for a 2 hour program, it consisted of a 45 minute DVD presentation by a physician experienced in lifestyle interventions and a facilitated small group discussion together with weekly practical assignments. The program was available in Spanish and English. The Nedley Depression Recovery Program Assessment Test (registration TX 7-398-022) was used. It assessed depression level based on DSM-5 [The Diagnostic and Statistical Manual of Mental Disorders Volume 5] criteria, demographics, anxiety, emotional intelligence and patient history. The depression was classified into 4 categories as the DSM-5, as none (0-6), mild (7-10), moderate (11-19) or severe (20 or more). Participants that finished the program from 2007 to 2016 that were of geriatric age (55 years old and older at baseline) were included. Both depressed and non-depressed participated on the program. Results: From 5997 participants that finished the program n=2928 were geriatrics. Mean age 64.7 SD 7.2, n=2075 (70.8%) were females. Demographic were White 2598 (88.7%), Black 107 (3.6%), Hispanic 144 (4.9%) and other (2.8%). Participants were from Africa, Europe, Oceania and America. At baseline mean group depression was 11.2 (Moderate), SD 7.3. That group was composed of 960 (32.7%) with none depression, 474 (16.1%) with mild depression, 981 (33.5%) with moderate depression and 513 (17.5%) with severe depression. By the end of the 8-weeks mean depression was 6 (none), SD 5.7. That group was composed of 1854 (69.3%) with none depression, 476 (16.2%) with mild depression, 506 (17.2%) with moderate depression and 92 (3.1%) with severe depression. Conclusion: It seems that the intervention effectively improves mental health in this geriatric population with different levels of depression responding well to the program. This seems to be an effective way to apply community wide interventions to improve population-wide health. A control group and further follow up would be recommended.
Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function
Authors: Monika Seidel, Camille Rabesahala de Meritens, Louisa Johnson, Dimitris Parthimos, Mark Bannister, Nia Lowri Thomas, Esizaze Ozekhome-Mike, Francis Anthony Lai, Spyros Zissimopoulos
Journal: Cardiovascular Research (2020)

Abstract Aims The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. Methods and results We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the β8–β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The β8–β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8–β9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8–β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the β8–β9 domain in channel closing. Conclusion These results suggest that efficient N-terminus inter-subunit communication mediated by the β8–β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.
Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms
Authors: Peng Jin, Lily Yeh Jan, Yuh-Nung Jan
Journal: Annual Review of Neuroscience (2020)

Activation of mechanosensitive ion channels underlies a variety of fundamental physiological processes that require sensation of mechanical force. Different mechanosensitive channels adapt distinctive structures and mechanotransduction mechanisms to fit their biological roles. How mechanosensitive channels work, especially in animals, has been extensively studied in the past decade. Here we review key findings in the functional and structural characterizations of these channels and highlight the structural features relevant to the mechanotransduction mechanism of each specific channel.
In-vivo activity of ABT-627, a selective Endothelin-A-receptor antagonist, in bladder cancer xenograft tumors
Authors: Christian Wülfing, Arne Tiemann, Thorsten Persigehl, Pia Wülfing, Elke Eltze, Lothar Hertle, Christoph Bremer
Journal: Cancer Research (2005)

3039  Introduction: The Endothelin-axis (Endothelin-1 (ET-1)and its receptors (ET-AR and ET-BR)),plays an emerging role in cancer, being frequently overexpressed and affecting angiogenesis and mitogenesis.Recently,we reported overexpression of the ET-axis in bladder cancer.Here,we analyzed the role of ABT-627, a selective ET-AR-antagonist, in treating bladder cancer xenografts. Materials and Methods: 20 nude mice (Charles River Inc.) were divided into two different treatment groups. All animals had been injected with 2x10exp6 cells in the flank, derived from a cultured KU-19-19 bladder cancer cell line, expressing ET-1 and ET-AR, but not ET-BR. 22 days after tumor seeding, the treatment groups were intraperitoneally treated with 2x2.5 mg/kg/day ABT-627 or 0.25 N NaHCO3 alone. After 16 days of treatment mice were sacrificed and tumors completely excised. Fresh frozen and paraffin-embedded tumor specimens were processed for RT-PCR and immunohistochemistry (IHC), respectively. Microvessel density (MVD), as well as conventional histology including assessment of tumor necrosis were assessed. Results: The absolute tumor size after completion of treatment did not differ significantly in both groups (median 2.87 ml [ABT-627] and 2.66 ml [control]) and no cytoreduction of tumors was observed. However, comparing tumor volume at beginning and end of treatment (tumor vol. at end of treatment / tumor vol.on day of first measurement), there was a difference in median tumor growth rate: tumors in the ABT-627 group had a 25% decreased tumor growth rate compared to tumors in the control group. This difference was even more pronounced in small tumors (
<i>JEM</i> women in STEM: Unique journeys with a common purpose
Authors: Anne O’Garra, Yasmine Belkaid, Arlene Sharpe, Susan Kaech, Sara Cherry, Emmanuelle Passegué
Journal: The Journal of Experimental Medicine (2020)

Before one can think of the challenges that face women in science and the hurdles that impair their development into leadership positions, it is worth considering the diversity within the collective of women scientists at the level of culture and past experience and life events.
A phase II study of sEphB4-HSA in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Michael C. Burns, Vinay Sagar, Borko Jovanovic, Alicia K. Morgans, David James VanderWeele, David I. Quinn, Walter Michael Stadler, Sarki Abdulkadir, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2020)

TPS274 Background: The EphB4/EphrinB2 pathway is a promising therapeutic target for patients with mCRPC. EphB4 expression is increased in prostate cancer tissue and cell lines, and retained in castration resistant states. EphB4 crosstalks with the PI3K/AKT and MAPK pathways to regulate cell survival and proliferation, and its interaction with the transmembrane ligand EphrinB2 leads to T-cell suppression and immune evasion. A soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) binds to EphrinB2 and blocks interaction with the cell surface EphB4 receptor to promote immune infiltration and induce tumor cell death. Here we report an ongoing phase II study exploring the preliminary efficacy and safety of sEphB4-HSA in patients with progressive disease after frontline therapy for mCRPC. Methods: Eligibility criteria include mCRPC with disease progression after second generation AR targeted therapy (i.e., abiraterone or enzalutamide), ECOG PS ≤ 2, and adequate renal, hepatic and hematological functions. Pts having received 4 or more prior treatment therapies for mCRPC are excluded. The primary objective is efficacy as reflected by PSA response using PCWG3 criteria. Secondary objectives include safety and tolerability by CTCAE v 5.0, time to PSA progression, overall response by RECIST 1.1 and PCWG3 (bone) criteria, and rPFS. Translational endpoints include expression of EphB4 and EphrinB2 in metastatic tumor samples by immunohistochemistry and correlation with alterations in MYC, PTEN/PI3K, AR, and p53 pathways. sEphB4-HSA is administered as IV infusion over 60 min every 14 days with spacing to every 21 days after 6 cycles. Therapy will continue till disease progression, unacceptable toxicity, treatment delay ≥4 weeks, or patient withdrawal. Preliminary efficacy will be assessed using PSA response rate (PR and CR) with a Simon two stage minimax trial design assuming the undesirable overall response rate (null hypothesis) to be approximately 10% or less, and the alternate hypothesis suggesting success to be approximately 30% or more. Toxicity will be evaluated by the DSMC after the first stage including 15 patients. If 2 or more respond, then an additional 10 patients will be added. Clinical trial information: NCT04033432.
Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer
Authors: Himisha Beltran, Alessandro Romanel, Vincenza Conteduca, Nicola Casiraghi, Michael Sigouros, Gian Marco Franceschini, Francesco Orlando, Tarcisio Fedrizzi, Sheng-Yu Ku, Emma Dann, Alicia Alonso, Juan Miguel Mosquera, Andrea Sboner, Jenny Xiang, Olivier Elemento, David M. Nanus, Scott T. Tagawa, Matteo Benelli, Francesca Demichelis
Journal: Journal of Clinical Investigation (2020)

Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%–20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE–associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.
Does delay in time to surgery impact outcome in renal cell carcinoma: Analysis based on tumor size utilizing the National Cancer Database.
Authors: Devin Patel, Fady Ghali, Margaret Meagher, Aaron Bradshaw, Sunil Patel, James Don Murphy, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

664 Background: The impact of delay in treatment for localized renal cell carcinoma (RCC) is controversial. We sought to determine the survival impact of time to definitive surgical treatment stratified by tumor size in a group of young, healthy patients from the National Cancer Database (NCDB). Methods: The NCDB was queried for cases of localized RCC (cT1-T3N0M0) in patients &lt;60 years of age with Charlson comorbidity score of 0 from 2004-2015. Quartiles were formed from the range of time to surgery of the entire cohort in days, with delayed treatment as the fourth quartile. Tumors were stratified into size of &lt;2 cm, 2-4 cm, 4-7 cm and &gt;10 cm. Overall survival (OS) between early and delayed groups was calculated with Kaplan-Meier analysis (KMA) and multivariable cox proportional hazards (MVA) and stratified by tumor size. Logistic regression was performed to determine factors associated with delay in surgical care. Results: 44,149 patients were analyzed. Median time to treatment was 35 days (IQR 19-61). Early (n = 33,144) and delayed (&gt;61 days, n =11,005) groups had a mean follow-up of 61.5 and 57.5 months, respectively (p &lt; 0.001). KMA showed worse 5-yr OS in patients with surgery delay versus no delay for tumors 2-4 cm in size (5-yr OS 49% vs. 54%; p&lt;0.001), 4-7 cm (5-yr OS 47% vs. 53%; p&lt;0.001), &gt;7 cm (5-yr OS 45% vs. 49%;p=0.0002), but not for tumors &lt;2 cm (5 yr OS 49% vs. 51%: p=0.5848). MVA showed worse OS with surgery delay compared to no surgery delay in patients with tumor size 2-4 cm (HR 1.24; 95%CI 1.09-1.42), 4-7 cm (HR 1.32; 95%CI 1.16- 1.50) and &gt;7 cm (HR 1.14; 95%CI 1.01-1.30) but not tumors &lt;2 cm (HR 0.83; 95% CI 0.65-1.05). Delay in treatment was higher with older age (OR 1.01; p&lt;0.001), male gender (1.11; p&lt;0.001), non-private insurance (OR 1.44; p&lt;0.001), black race (OR 1.60; p&lt;0.001), decreased education (OR 1.11; p&lt;0.001) and tumors &gt;2 cm (OR 1.23; p&lt;0.001). Conclusions: In patients &lt;60 years of age and CCI of 0, delay in treatment was associated with worse OS for tumors &gt;2 cm but not for RCC &lt;2 cm in size. While these findings support data suggesting that active surveillance for RCC &lt; 2 cm in size is appropriate even in young and healthy patients, caution should be exercised in patients with tumors &gt; 2 cm.
Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children’s Oncology Group Trial ACNS0333
Authors: Alyssa T. Reddy, Douglas R. Strother, Alexander R. Judkins, Peter C. Burger, Ian F. Pollack, Mark D. Krailo, Allen B. Buxton, Chris Williams-Hughes, Maryam Fouladi, Anita Mahajan, Thomas E. Merchant, Ben Ho, Claire M. Mazewski, Victor A. Lewis, Amar Gajjar, Louis-Gilbert Vezina, Timothy N. Booth, Kerry W. Parsons, Vicky L. Poss, Tianni Zhou, Jaclyn A. Biegel, Annie Huang
Journal: Journal of Clinical Oncology (2020)

Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT.Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored.Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients.The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
Abstract 15042: A Triadic Approach to Managing Heart Failure Using Group Medical Visits: Qualitative Analysis
Authors: Vanessa Marshall, Lauren Stevenson, Jeneen Shell-Boyd, Rene Hearns, Julie Gee, Kimberley Schaub, Sharon LaForest, Melanie Parent, Wen-Chih Wu, Sandesh Dev, Sherry Ball
Journal: Circulation (2018)

Introduction: Heart failure (HF) affects nearly 6 million people in the United States and little is known about the perceptions and expectations of the role of the patient-caregiver-provider interv...