tbuckley/cabot-search huggingface dataset:
Radiotherapy-induced immunogenic effects in bladder cancer.
Authors: Richard Walshaw, Jamie Honeychurch, Joanne Roberts, Jacqueline Swan, Laura Dean, Ananya Choudhury, Tim Illidge
Journal: Journal of Clinical Oncology (2019)

418 Background: Many patients with bladder cancer (BC) undergo radiotherapy (RT) during the course of their treatment. There is emerging evidence that RT can cause immune stimulatory changes within the tumour microenvironment (TME), potentially contributing to its efficacy. We aimed to determine if RT induces immunogenic changes in murine BC cell lines, and develop a pre-clinical model of BC with a TME reflective of de novo tumours in order to test this premise in vivo. Methods: Immunogenic effects of RT were determined using murine vaccination studies with irradiated tumour cells. RT-induced immuno-phenotypic changes in surface antigen expression on tumour cells were ascertained using flow cytometry. An orthotopic BC model was established using MBT2 cells instilled intravesically in C3H/Hen mice, and resulting tumours monitored with ultrasound (US). We used immunohistochemical (IHC) staining to determine the immune contexture of the TME within developing orthotopic tumours. Results: C57BL/6 mice inoculated with irradiated MB49 cells demonstrated improved survival compared to control mice after subsequent rechallenge with viable tumour cells. This effect was not seen in C3H mice implanted with irradiated MBT2 cells. RT led to upregulation of immune stimulatory molecules CD80, MHC I, and Fas on MB49 but not MBT2 cells. Tumours developed in 80% of mice following catheter implant, and visible on US 3-4 weeks after instillation. Profiling of the TME with IHC demonstrated that tumours contained few CD8+ T-cells, but high numbers of myeloid cells. Conclusions: RT induces immune stimulatory effects on murine BC cells, including upregulation of several surface proteins. In future work, we will determine the effects of RT on the TME in the orthotopic model, and correlate these with the expression of various immunogenic cell surface proteins. This may lead to the discovery of a biomarker to predict which patients with BC would benefit from combination of an immunomodulatory agent with RT.
Target Antigen Downregulation and Other Mechanisms of Failure after Axicabtagene Ciloleucel (CAR19) Therapy
Authors: Jean Oak, Jay Y. Spiegel, Bita Sahaf, Yasodha Natkunam, Steven R. Long, Nasheed Hossain, Crystal L. Mackall, Katherine A. Kong, David B. Miklos
Journal: Blood (2018)
Comparison of Laparoscopic 270° Posterior Partial Fundoplication vs Total Fundoplication for the Treatment of Gastroesophageal Reflux Disease
Authors: Bengt S. Håkanson, Lars Lundell, Ami Bylund, Anders Thorell
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Restoration of the esophagogastric junction competence is critical for effective long-term treatment of gastroesophageal reflux disease. Surgical repair results in such restoration, but mechanical adverse effects seem unavoidable. Minimizing these adverse effects without jeopardizing reflux control is warranted. <h3>Objective</h3> To determine whether partial fundoplication (PF) or total fundoplication (TF) is superior in laparoscopic antireflux surgery. <h3>Design, Setting, and Participants</h3> In this double-blind, randomized clinical trial of 1171 patients scheduled for laparoscopic antireflux surgery at a single university-affiliated center between November 19, 2001, and January 24, 2006, 456 patients were randomized and followed up for 5 years. Data were collected from November 2001 to April 2012, and data were analyzed from April 2012 to September 2018. <h3>Interventions</h3> A 270° posterior PF or a 360° Nissen TF. <h3>Main Outcomes and Measures</h3> Esophageal acid exposure at 3 years after surgery. <h3>Result</h3> Of the 456 randomized patients, 268 (58.8%) were male, and the mean (SD) age was 49.0 (11.7) years. A total of 229 patients were randomized to PF, and 227 patients were randomized to TF. At 3 years postoperatively, the median (interquartile range) esophageal acid exposure was reduced from 14.6% (9.8-21.9) to 1.8% (0.7-4.4) after PF and from 16.0% (10.4-22.7) to 2.5% (0.8-6.8) after TF (<i>P</i> = .31). Likewise, reflux symptoms were equally and effectively controlled. Early postoperative dysphagia (6 weeks) was common in both groups but then decreased toward normality. A small but statistically significant difference in favor of PF was noted in the mean (SD) scoring of dysphagia for liquids at 6 weeks (PF, 1.6 [0.9]; TF, 1.9 [1.3];<i>P</i> = .01) and for solid food at 12 months (PF, 1.3 [1.0]; TF, 1.9 [1.4];<i>P</i> &lt; .001) and 24 months (PF, 1.3 [0.9]; TF, 1.7 [1.2];<i>P</i> = .001). Quality of life was reduced before surgery but increased to normal values after surgery and remained so over 5-year follow-up, with no difference between the groups. <h3>Conclusions and Relevance</h3> The results from this randomized clinical trial suggest that although PF and TF could be recommended for treatment of gastroesophageal reflux disease, PF might be superior by inducing less dysphagia. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT03659487
TP53 mutations in circulating tumor DNA in men with metastastic castration-resistant prostate cancer mCRPC.
Authors: Lynne Chapman, Elisa Ledet, Lahiru Ranasinghe, Charlotte Manogue, Patrick Cotogno, Marcus Marie Moses, Bryce Raymon Christensen, Peter Steinwald, Jodi Lyn Layton, Brian E. Lewis, A. Oliver Sartor, Pedro C. Barata
Journal: Journal of Clinical Oncology (2019)

249 Background: Genes involved in mCRPC, including the tumor suppressor gene TP53, can be monitored with ctDNA but implications are unclear. Methods: Between 8/6/15 to 9/19/18, patients with mCRPC with available ctDNA genomic data using Guardant360 (Guardant360, Redwood City, CA) were included. Relationships between various lines of therapy and TP53 mutational status were analyzed. Patients positive for TP53 mutants were categorized using mutant allelic fraction of &gt; 0%, ≥0.5%, ≥1% and ≥5%. Results: This study included 215 patients with mCRPC, median age 70 (41-90), and 80% Caucasians who had ctDNA after one line treatment for CRPC that included abiraterone (55%), enzalutamide (22%), and sipuleucel T (21%). Frequent co-alterations with TP53 mutants after 1 line of CRPC therapy included AR (14%), NF1 (5%), EGFR (4%), and PIK3CA (4%). See Table for relationships between lines of therapy and mutant TP53 allelic fraction. Conclusions: In this cohort of men with mCRPC, a higher mutational burden of TP53 in ctDNA was frequent and particularly associated with multiple lines of therapy. [Table: see text]
Duke University Global Cancer Program: A multidisciplinary approach to partnerships in global cancer care.
Authors: Laura W. Musselwhite, Kristin Schroeder, Manisha Bhattacharya, Sky Breeden Vanderburg, Nestory Andrew Masalu, Mammen Chandy, Edmundo Mauad, John Bartlett, Michael B. Kastan, Michael Merson, Nelson Jen An Chao
Journal: Journal of Clinical Oncology (2015)

e17584 Background: In 2014, the Duke Global Health Institute (DGHI) and Duke Cancer Institute (DCI) launched the Duke Global Cancer Program to expand cancer care, prevention, research, and education in low- and middle-income countries (LMIC). Establishing a global cancer research initiative serves to consolidate and build upon ongoing efforts by Duke faculty and trainees interested in contributing to best practices in clinical care, institutional support for capacity-building, and disseminating innovation in global oncology. Methods: Potential partnership locations were evaluated by Duke Global Cancer Program leadership and selected based on the following criteria: pathology and laboratory infrastructure, treatment and research capacity, and mutual interest in building a global cancer community. Four partnership locations were selected including Tata Medical Center (Kolkata, India), Hospital de Cancer de Barretos (Barretos, Brazil), Bugando Medical Center (Mwanza, Tanzania) and Kilimanjaro Christian Medical Center (Moshi, Tanzania). Individualized needs assessments were conducted to identify strengths, areas for improvement, and local priorities. Relationships between the Duke Global Cancer community and collaborating local leadership were established to support individualized capacity development. Results: Needs-based assessment results were addressed utilizing four categories: 1) personnel, 2) medical record-keeping, 3) research, and 4) clinical care. Location-specific needs were identified and addressed through South-South partnerships, trainee twinning for educational support, and investment in information technology. Conclusions: In its first year, the Duke Global Cancer Program has developed significant partnerships spanning three diverse countries with unique challenges and opportunities. We anticipate continued location-directed growth with our partnership institutions to improve cancer prevention and treatment globally with the potential to add more collaborative locations over the next three years.
Abstract 14278: The Impact of American-Style Football Participation on Left Ventricular Systolic Function
Authors: Jeffrey Lin, James Deluca, Francis Wang, Brant Berkstresser, Meagan Wasfy, Adolph Hutter, Rory Weiner, Aaron Baggish
Journal: Circulation (2015)

Introduction: Participation in American-Style Football (ASF) has been associated with the development of hypertension and left ventricular hypertrophy (LVH). To date, data defining the impact of ASF participation on myocardial function are lacking. We hypothesized that the LVH developed among ASF participants is accompanied by relative impairment in systolic function as measured by LV global longitudinal strain (GLS), a well-established marker of subclinical LV dysfunction. Methods: Collegiate ASF athletes were studied before (preseason) and after (postseason) a single competitive season with transthoracic echocardiography. LV systolic function was assessed using complementary parameters including GLS (speckle tracking) and ejection fraction (EF, 2D biplane). Analyses were stratified as a function of lineman (LM, n=30) versus non-lineman (NLM, n=57) field position. Results: Among 87 athletes analyzed, ASF participation was associated with significant increases in systolic blood pressure (SBP, 119±10 vs. 124±13 mmHg; p&lt;0.05), BSA-indexed LV mass (LVMI, 95±15 vs. 104±13 g/m2; p&lt;0.05), and prevalent LVH (8% vs. 25%, p&lt;0.05). The majority of LM with LVH (9/11, 82%) had concentric geometry while hypertrophied NLM (8/10, 80%) had eccentric geometry. In this context, LM demonstrated a significant decrease in GLS which was associated with changes in LV mass and SBP while NLM demonstrated an increase in GLS unrelated to either mass or SBP (Figure). Left ventricular EF was similar at both time points and did not differ by field position. Conclusions: The geometry and functional correlates of LVH among ASF participants vary by field position. Athletes at the LM position appear to be at risk for developing concentric LVH with relative impairment of GLS, while NLM athletes tend to harbor eccentric LVH without decrement in GLS. The underlying mechanisms, reversibility, and long-term prognostic significance of these findings represent important areas of future study.
Abstract P352: The Yoga-meditation Heart Connection: a Pilot Study Looking to Improve Women’s Heart Health
Authors: Sasha Y De Jesus, Emily Schultz, Rachel M Bond
Journal: Circulation (2019)

Introduction: Stress, anxiety and depression are nontraditional risk factors for cardiovascular disease (CVD) that are more common in women. Yoga and meditation have shown to improve patient’s overall levels of depression, anxiety, and stress, and possibly decrease CVD risk. Hypothesis: We hypothesize that regular, supervised sessions of chair yoga and meditation can be a complementary measure to decrease the level of anxiety, stress and depression in women with or at risk for CVD, and pursue lifestyle modifications. Methods: An anonymous survey was provided to the participants of a weekly complimentary chair yoga/meditation workshop supervised by a trained cardiac yoga therapist. The surveys were distributed on day 1 and on week 24 to assess any changes in their reported level of stress, depression, anxiety and lifestyle. Results: A total of 16 and 10 female participants with or at risk for CVD completed the initial and follow up survey respectively, which included validated screening tools for depression, anxiety and stress. The Patient Health Questionnaire-9 from the initial session to the follow up survey, showed an increase in the score (2.25 vs 3.2 respectively [P = 0.199]). Despite this increased trend, the severity remained within the definition of minimal depression. The mean Generalized Anxiety Disorder-7 went from 7 in the initial visit down to 4.9 (P = 0.138) for the follow up survey (decreased from a definition of mild anxiety to no clinical anxiety). Lastly, the Perceived Stress Score demonstrated a mean reduction from 18.25 to 15.2 (P = 0.106), both remaining as moderate perceived stress. Participants also endorsed a trend towards integrating more low saturated fat foods, and 37.5% endorsed a 3-9 lbs weight loss. Conclusion: Although more research and larger studies are yet to be done to demonstrate a definitive benefit in meditation and gentle chair yoga in CVD risk reduction, our pilot study demonstrated a trend towards overall improvement of novel risk factors for CVD, which predominantly affect women. Given the low harm and cost of these measures, they can be done as adjuvants to our standard of care to increase the patient’s overall well being by improving the psychological aspect of their lives which in turn could reflect on their physical health.
The impact of age on sipuleucel-T-induced immune responses.
Authors: James L. Gulley, Ravi Amrit Madan, Harpreet Singh, Todd E. Gray, James B. Trager, Nadeem A. Sheikh, Candice McCoy, Douglas G. McNeel
Journal: Journal of Clinical Oncology (2015)

e16009 Background: Studies of viral vaccines suggest that the magnitude of immune responses (IRs) declines in aging populations. Moreover, preclinical cancer immunotherapy studies indicate that T cells are responsible for their anti-tumor effects. This analysis evaluates the potential impact of age on IRs induced by sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the treatment of certain patients with metastatic castration-resistant prostate cancer. Methods: Data on sip-T product parameters (antigen presenting cell [APC] activation [as measured by CD54 upregulation], CD54+cell counts, and total nucleated cell [TNC] counts) and PA2024 (the immunizing antigen for sip-T)- and prostatic acid phosphatase (PAP)-specific IRs (antibody titers, T cell proliferation, and IFN-γ ELISPOT]) were pooled across 5 sip-T prostate cancer trials (NCT: 00065442, 00715078, 00901342, 01487863, and 01981122). Potential associations of age with cellular parameters and IRs were evaluated with linear regression analyses. To control for the potential impact of disease burden, prostate-specific antigen (PSA) in combination with age was analyzed separately. Results: Sip-T induced APC activation and IRs to PA2024 and PAP regardless of age. No significant associations were detected between age and APC activation, TNC counts, or peripheral cellular IRs or between age and T cell proliferation or IFN-γ ELISPOT responses. A slight but statistically significant inverse correlation with age and antibody titers for PA2024 and PAP was observed in the IMPACT trial; a non-significant, similar trend was evident in the other 4 trials. Moreover, a small but significant trend was observed between decreased CD54+cell count and increased age. The effect of age on all parameters appeared independent of PSA. Conclusions: Sip-T generated IRs regardless of age. Although a slight decline in antibody responses was observed with increasing age, APC activation and T cell responses were unaffected by age. The ongoing ability of sip-T to elicit antigen-specific T cell responses is important, as these cells are presumed critical for sip-T’s mechanism of action. These data suggest sip-T can mobilize key IRs independent of patient age. Clinical trial information: NCT00065442, 00715078, 00901342, 01487863, and 01981122.
Impact of the USPSTF recommendations on prostate cancer stage migration and de-novo metastatic prostate cancer.
Authors: Yu-Wei Chen, Ruby Gupta, Moshe Chaim Ornstein, Brian I. Rini, Timothy D. Gilligan, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2019)

166 Background: The US Preventive Services Task Force (USPSTF) recommended against prostate specific antigen (PSA) screening for men aged≥75 in 2008 and all men in 2012 in an effort to reduce overdiagnosis and overtreatment of men with prostate cancer (PCa). This recommendation may delay diagnosis of clinically significant PCa. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was used to identify men diagnosed with PCa between 2004-2015. PCa stage was categorized as localized (N0M0), nodal (N1M0) and metastatic (NxM1). Trend analysis was stratified on age group (PSA screening eligible was defined as age 55-69 according to the 2018 updated USPSTF recommendation). Multivariable logistic regression was used to identify predictors for nodal and metastatic disease. Results: Between 2004-2015, there were 603,323 men with PCa identified. Metastatic disease accounted for 2.8% of PCa in 2004-2008, 3.7% in 2009-2012, and 6.1% in 2013-2015. In men eligible for PCa screening, metastatic disease increased from 1.9% in 2004-2008, to 2.6% in 2009-2012, to 4.2% in 2013-2015; nodal disease increased from 1.4% to 1.6% to 2.6%, respectively (both p-value for trend&lt; 0.0001). This stage migration was also observed in non-screening eligible groups (age &gt;70 and &lt;55). Compared with PCa diagnosed in 2009-2012, PCa diagnosed in 2013-2015 had higher odds of metastatic disease (AOR: 1.70, p-value&lt;0.0001) or nodal disease (AOR: 1.71, p-value&lt;0.0001). Conclusions: Men diagnosed with PCa in 2013-2015 were more likely to have metastatic or nodal disease, suggesting PCa stage migration since PSA screening was recommended to be discontinued in 2012. Although the impact of PSA screening on PCa mortality remains debatable, the reduced quality of life with advanced Pca should not be overlooked. Future population studies are warranted to investigate the influence of the updated 2018 USPSTF recommendation. [Table: see text]
Assessment of a Deep Learning Model Based on Electronic Health Record Data to Forecast Clinical Outcomes in Patients With Rheumatoid Arthritis
Authors: Beau Norgeot, Benjamin S. Glicksberg, Laura Trupin, Dmytro Lituiev, Milena Gianfrancesco, Boris Oskotsky, Gabriela Schmajuk, Jinoos Yazdany, Atul J. Butte
Journal: JAMA Network Open (2019)

Knowing the future condition of a patient would enable a physician to customize current therapeutic options to prevent disease worsening, but predicting that future condition requires sophisticated modeling and information. If artificial intelligence models were capable of forecasting future patient outcomes, they could be used to aid practitioners and patients in prognosticating outcomes or simulating potential outcomes under different treatment scenarios.To assess the ability of an artificial intelligence system to prognosticate the state of disease activity of patients with rheumatoid arthritis (RA) at their next clinical visit.This prognostic study included 820 patients with RA from rheumatology clinics at 2 distinct health care systems with different electronic health record platforms: a university hospital (UH) and a public safety-net hospital (SNH). The UH and SNH had substantially different patient populations and treatment patterns. The UH has records on approximately 1 million total patients starting in January 2012. The UH data for this study were accessed on July 1, 2017. The SNH has records on 65 000 unique individuals starting in January 2013. The SNH data for the study were collected on February 27, 2018.Structured data were extracted from the electronic health record, including exposures (medications), patient demographics, laboratories, and prior measures of disease activity. A longitudinal deep learning model was used to predict disease activity for patients with RA at their next rheumatology clinic visit and to evaluate interhospital performance and model interoperability strategies.Model performance was quantified using the area under the receiver operating characteristic curve (AUROC). Disease activity in RA was measured using a composite index score.A total of 578 UH patients (mean [SD] age, 57 [15] years; 477 [82.5%] female; 296 [51.2%] white) and 242 SNH patients (mean [SD] age, 60 [15] years; 195 [80.6%] female; 30 [12.4%] white) were included in the study. Patients at the UH compared with those at the SNH were seen more frequently (median time between visits, 100 vs 180 days) and were more frequently prescribed higher-class medications (biologics) (364 [63.0%] vs 70 [28.9%]). At the UH, the model reached an AUROC of 0.91 (95% CI, 0.86-0.96) in a test cohort of 116 patients. The UH-trained model had an AUROC of 0.74 (95% CI, 0.65-0.83) in the SNH test cohort (n = 117) despite marked differences in the patient populations. In both settings, baseline prediction using each patients' most recent disease activity score had statistically random performance.The findings suggest that building accurate models to forecast complex disease outcomes using electronic health record data is possible and these models can be shared across hospitals with diverse patient populations.
Impact of bowel resection on overall survival after neoadjuvant chemotherapy in advanced epithelial ovarian cancer.
Authors: Charles-Andre Philip, Aurelie Pelissier, Claire Bonneau, Coraline Dubot, Thibault De La Motte Rouge, Emile Darai, Elisabeth Chereau, Thierry O. Philip, Roman Rouzier, Nicolas Pouget
Journal: Journal of Clinical Oncology (2015)

e16568 Background: Bowel involvement in ovarian cancer is responsible of an increased surgical effort. However, it have been demonstrated that complete cytoreduction (CC-0) remains the only significant survival prognosis factor in primary debulking surgery (PDS). Nowadays, neoadjuvant chemotherapy (NAC) followed by surgery is widely used when CC-0 is not achievable in PDS. Our objective was to assess if the need of bowel resection (BR), before and after NAC, impacts overall survival according to the cytoreduction status. Methods: We included 118 patients with unresectable advanced epithelial ovarian cancer (FIGO IIIc and IV) diagnosed between 2002 and 2009 at Institut Curie. All the patients were treated with NAC followed by interval debulking surgery. Patients who did not undergo primary surgical evaluation or underwent incomplete primary surgery were excluded. We proceeded to a systematic blinded review of all the surgical reports pre and post NAC performed by 2 different surgeons to assess the surgical procedures required to achieve CC-0. The median overall survival (mOS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: A total of 97 patients met the inclusion criteria. Before NAC, at least 84 patients (87%) would have required BR to obtain a CC-0 resection. At interval debulking surgery, 47 (49%) still required a BR, which corresponds to a decrease of 38% (p < .0001). The mOS among CC-0 patients with or without BR was 57 months (CI95 [25-90]) and 50 months (CI95 [43-57]), respectively (p = 0.71). The overall survival among patients without CC-0 was significantly worst at a median of 21 months (CI95 [17;32], p < .0001). There were no significant differences in survival between patients who required BR and those who did not during the initial evaluation (mOS 39 vs 52 months, p = 0.46). The mOS was significantly worst in patients who still theoretically required a BR after NAC based on the univariate analysis (mOS 23.8 vs 49.9 months, p = 0.0007). Conclusions: BR after NAC is associated with better survival if the debulking surgery is complete. NAC significantly decreases the need and the rate of BR.