tbuckley/cabot-search huggingface dataset:
Osimertinib induced cardio-toxicity: A retrospective review of FDA adverse events reporting system (FAERS).
Authors: Kartik Anand, Joe Ensor, Barry Trachtenberg, Eric Bernicker
Journal: Journal of Clinical Oncology (2019)

9044 Background: Osimertinib is an oral third generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). In the FLAURA trial (a Phase III randomized-control trial) Osimertinib arm had higher rate of cardio-toxicity compared to standard EGFR-TKIs. We queried FAERS database to find out rate of cardio-toxicity caused by Osimertinib compared to other EGFR-TKIs. Methods: We queried FAERS for “Cardiac failure”, “Electrogram QT-prolonged”, “Atrial Fibrillation(A.fib)”, “Myocardial Infarction(MI)”, “Cardiac failure congestive(CFC)” and “Pericardial Effusion(PE)” secondary to “Osimetinib”, “Erlotonib”, “Afatinib” and “Gefitinib” from 2016-2018. Disproportionality signal analysis was done by calculating Reporting Odds Ratio (ROR) with 95% confidence interval (CI). ROR was considered significant when lower limit of 95% CI was &gt; 1. Results: Total AEs from all drugs were 5,138,230. Total AEs from all 4 TKIs were 8450, 2454 due to Osimertinib, 5836 due to other TKIs and 160 due to combination of both Osimertinib plus any of other 3 TKIs. ROR for Cardiac failure, A.fib, QT prolongation, MI, PE and CFC due to Osimertinib was 6.4(4.7-8.7), 4(2.8-5.8), 11.2(7.9-15.8), 1.6(0.9-2.6), 8.2(4.8-14) and 3.9(2.4-6.3) respectively. ROR for Cardiac failure, A.fib, QT prolongation, MI, PE and CFC on comparing Osimertinib vs other TKIs was 2.1(1.3-3.2), 2.1(1.3-3.5), 6.6(3.4-12.8), 1.2(0.6-2.3), 1.6(0.8-3.3) and 2.3(1.2-4.6) respectively. Findings are summarized in Table. Conclusions: Rate of QT prolongation, cardiac failure, CFC and A.fib were found to be higher due to Osimertinib compared to other TKIs. EKG monitoring for QT prolongation and monitoring for signs/symptoms of heart failure should be considered while using Osimertinib. [Table: see text]
Pattern of expression of CDX2 in colorectal cancer and its role in prognosis.
Authors: JAGDEEP SINGH
Journal: Journal of Clinical Oncology (2019)

e15115 Background: CDX2 (Caudal Type Homeobox 2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumourogenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (colorectal cancer) and its association with prognosis. Methods: We performed CDX2 staining by Immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done by semi-quantitative method. Results: 286 patients were registered during study period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33 (30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33 (30%) patients had stage II disease, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 expression was significantly associated with advanced stage, rectal site, poor grade of differentiation, and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative patients compared to 67% CDX2 positive (P=0.009), while OS (overall survival) at 2 years was 46% for CDX2 negative versus 77% for positive patients (p=0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as a poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.
Young-onset colorectal cancer patients disproportionately diagnosed with advanced disease: Patient self-reported journey of symptom duration and misdiagnosis.
Authors: Ronit Yarden, Kim Lynn Newcomer
Journal: Journal of Clinical Oncology (2019)

3567 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death among males and females in the US. Despite a decrease in overall incidence and mortality, there has been an alarming increase of CRC diagnosis among young adults (20-49 years old). The Colorectal Cancer Alliance launched a comprehensive survey for young-onset CRC patients and survivors via social media to track the self-reported clinical, psychosocial, financial and quality of life experiences of this often overlooked, group. Methods: The survey was completed by 1195 living patients and survivors. The majority of participants (57%) were diagnosed between the ages of 40 and 49, 33% of patients/survivors were diagnosed between the ages 30-39 and about 10% were diagnosed before the age of 30. Only 8% of the respondents were diagnosed with Lynch syndrome although about 28% reported some family history. Results: Our survey revealed a higher proportion of the young-onset patients and survivors (71%), diagnosed with advanced stage tumors, compared with ACS report for overall CRC patients (60%). The late stage diagnosis subjected young patients to aggressive therapies and a substantial decrease in quality of life including neuropathy, anxiety, clinical depression, and sexual dysfunctions. Most respondents (63%) waited 3-12 months before visiting a doctor, with higher proportion of females waited more than 12 months compared with males (22% vs. 15% p = 0.02). Moreover, even when visited their doctors, most patients indicated that they were initially misdiagnosed. The majority of the respondents (67%) saw at least 2 physicians, and some more than 4 physicians, prior to their diagnosis. Patients that saw 3 or more physicians prior to diagnosis were more likely to be diagnosed with advanced disease. Interestingly, half of the patients that were seen by one physician also claimed they were initially misdiagnosed. Conclusions: Our survey indicates that medical professionals and young adults need to be aware of the increasing incidence of young-onset CRC, and the importance of timely screening when signs and symptoms are present, regardless of age. Yet, 50% of physicians did not explain to the patients’ family members about their elevated risk of the disease and their need for screening.
Real-time sharing of comprehensive clinical genomics sequencing data in St. Jude Cloud.
Authors: Scott Newman, Clay McLeod, Michael Macias, Kirby Birch, Alexander Gout, Scott Foy, Antonina Silkov, Chimene Kesserwan, Joy Nakitandwe, Sheila Shurtleff, Elizabeth M. Azzato, Lu Wang, Michael C Rusch, Kim Nichols, Amar J. Gajjar, Alberto S. Pappo, Charles Grenfell Mullighan, David W. Ellison, Jinghui Zhang, James Downing
Journal: Journal of Clinical Oncology (2019)

10019 Background: As tumor and germline genomic data from pediatric cancer patients is scarce in existing genomic databases, there is an urgent need for more comprehensive datasets. Such data will allow us to fully assess the actionable pediatric cancer genome, facilitate biomarker discovery, and identify new clinical associations. Methods: We sequenced 1002 tumor/normal pairs as part of a real-time clinical genomics service including whole genome, exome and transcriptome for 775 and exome/transcriptome for 227 samples. Tumor types were representative of the common and rare diseases treated at our institution (37% hematological, 31% brain and 32% solid tumors). A multidisciplinary team assessed every case, and after clinical reporting was complete, genomics data and basic clinical information (primary diagnosis, age, sex, ethnicity, primary/relapse/metastasis status), was made securely available online through St. Jude Cloud (www.stjude.cloud). Results: Based on analysis of 253 initial cases from the Genomes for Kids study, our multi-platform sequencing approach uncovered diagnostic, prognostic and/or therapeutically relevant findings in 78% of patients. We estimate 11-16% of clinically-relevant gene mutations could be missed by less comprehensive sequencing approaches. One quarter of patients had a potentially druggable mutation. This surprisingly high proportion was driven, in part, by BRAF fused low-grade gliomas and diverse JAK/STAT pathway alterations in B-Cell acute lymphoblastic leukemias. Whole genome/transcriptome sequencing allowed us to detect rare and novel gene fusions in 8% of cases and facilitated discovery of a new recurrent fusion gene in pediatric melanoma. All data is available online for others to mine and it is likely that additional clinically-relevant mutations can be uncovered. Conclusions: These data demonstrate the value of incorporating comprehensive sequencing into clinical diagnostics and patient care. We endeavor to make this large and richly annotated dataset available to others in real time rather than holding it back for months or years until publication. We anticipate adding approximately 500 additional cases per year at regular intervals, and as the resource grows, expect users to identify new targetable alterations that may be incorporated into patient care.
The Renal Circulation
Authors: A. C. Barger, J. A. Herd
Journal: New England Journal of Medicine (1971)

For this essay which I plan will perhaps shed light upon the structure of the kidney. Do not stop to question whether these ideas are new or old, but ask, more properly, whether they harmonize with Nature. And be assured of this one thing, that I never reached my idea of the structure of the kidney by the aid of books, but by the long, patient, and varied use of the microscope. I have gotten the rest by the deductions of reason, slowly, and with an open mind, as is my custom. [Malpighi, 1666]1 RATE of renal blood flow in . . .
Effect of p-PAQR3<sup>Thr32</sup> on PD-L1 expression and immune evasion in gastric cancer.
Authors: Zhi-Qiang Ling
Journal: Journal of Clinical Oncology (2019)

e15571 Background: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in some solid tumors. We have now examined PD-L1 expression and its regulation in gastric cancer with p-PAQR3 Thr32 protein. Methods: The expression of PD-L1 at the protein and mRNA levels in gastric cancer cell lines was examined by flow cytometry, real-time RT-PCR and western blot analysis, respectively. The expression of PD-L1 and p-PAQR3 Thr32 protein in 319 surgically resected gastric cancer specimens was evaluated by immunohistochemical analysis. Results: The PD-L1 expression level was higher in gastric cancer cell lines positive for p-PAQR3 Thr32 protein induced by glucose starvation than in those negative for the p-PAQR3 Thr32 protein. Forced expression of p-PAQR3 Thr32 protein in gastric cancer cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in p-PAQR3 Thr32 protein positive gastric cancer cells was attenuated by treatment with PAQR3 siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the IRF1 and STAT1 in IFNs-PDL1 signaling pathway in gastric cancer cells positive for p-PAQR3 Thr32 protein. At clinical tissue level, the expression level of PD-L1 was positively associated with the presence of p-PAQR3 Thr32 protein in gastric cancer specimens. Moreover, the expression level of p-PAQR3 Thr32 protein was negatively correlated with CD3, CD8, GZMA (CD8 T cell secretory factor) and positively correlated with CD68 (macrophage marker). Conclusions: Our findings that p-PAQR3 Thr32 protein induced by glucose deficiency upregulate PD-L1 by activating IFNs-PDL1 signaling pathway in gastric cancer reveal a direct link between p-PAQR3 Thr32 protein and PD-L1 expression. It is suggested that p-PAQR3 Thr32 protein may be involved in tumor immunosuppression by inhibiting the proliferation and activity of CD8 T cells in gastric cancer tissues.
Phase II multi-institutional study of nivolumab (Nivo), cabiralizumab (Cabira), and stereotactic body radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer (LAUPC).
Authors: Deirdre Jill Cohen, Benjamin Medina, Kevin Lee Du, Andrew L. Coveler, Gulam Abbas Manji, Paul Eliezer Oberstein, Serena K Perna, George Miller
Journal: Journal of Clinical Oncology (2019)

TPS4163 Background: Treatment of LAUPC most commonly involves chemotherapy +/- RT. Patients(pts) who can be downstaged and undergo R0 resection have significant improvement in overall survival, but conventional chemoRT converts &lt; 10% of patients with LAUPC. If the effects of RT can be augmented then higher R0 resection rates may be achieved and improve survival. In pre-clinical models, RT leads to increased expression of M-CSF from pancreatic tumor cells and marked immune suppression within the tumor microenvironment via expansion of tumor associated macrophages (TAMs). Concurrent blockade of M-CSF with RT reduces TAM infiltration, prevents the generation of tumor promoting T cell populations, and increases the therapeutic effect of RT. RT also induces up-regulation of PD-L1 in TAMs, another mode of immune suppression that can account for RT resistance in LAUPC. (Seifert et al. 2016). These data suggest the efficacy of RT in LAUPC is limited by its promotion of innate and adaptive immune suppression. CSF1R blockade with Cabira combined with PD-1 blockade with Nivo may enhance the efficacy of SBRT by reprogramming the TAM compartment in tumors, thereby preventing an immune suppressive phenotype and augmenting T-cell mediated anti-tumor response. Methods: Single arm phase II study designed to evaluate safety, tolerability, and surgical resection rate in LAUPC pts treated with concurrent Nivo, Cabira, and SBRT. Exploratory endpoints include immune changes within blood and tissue following treatment and correlation with clinical endpoints. Key eligibility: completion of 2- 6 months standard induction chemotherapy, normal organ and marrow function, pre- and on-treatment biopsy, and PS ≤ 1. Following initial biopsy and placement of fiducials, Cabira 4mg/kg and Nivo 240mg are given D1 of every 14 day cycle. SBRT 6.6 Gy x 5 consecutive fractions starts D8. After 2 cycles, repeat biopsy and imaging is performed. Treatment with Cabira and Nivo continues every 2 weeks and imaging is done every 8 weeks, at which time pt is assessed for surgical resection. If pt is downstaged, treatment is discontinued and pt proceeds to surgery. Preliminary 6 pt safety cohort is monitored for unacceptable toxicities. If &lt; 3 unacceptable toxicities in the first 6 subjects enrolled, then plan for expansion phase with 14 more pts. As of abstract submission, 3 pts have been enrolled. Clinical trial information: NCT03599362.
Abstract 14799: Effect of Sodium-Glucose Cotransporter 2 Inhibitors on Reducing Residual Cardiovascular Risk and Improving Vascular Endothelial Function in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Takaaki Sakai, Shinichiro Miura
Journal: Circulation (2018)

Introduction: The sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of anti-diabetic agent, have shown beneficial cardiovascular effects. SGLT2 inhibitors suppress the enhancement of s...
Digitally captured step counts for evaluating performance status in advanced cancer patients: A single cohort, prospective trial (Digi-STEPS).
Authors: Gillian Gresham, Andrew Eugene Hendifar, Jun Gong, Arash Asher, Christine S. Walsh, BJ Rimel, Edwin M. Posadas, Marcio Diniz, Maurice Herring, Bethy Woubeshet, Rachel Baynes, Robert A. Figlin, Brennan Spiegel, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2019)

TPS6651 Background: Advanced cancer patients undergo dynamic changes in their functionality and physical activity over the course of their treatment. Monitoring patient function is important because it can inform treatment decisions and allow for timely and appropriate intervention. Current scales that assess patient function, such as the ECOG Performance Status (PS), are limited in their ability to capture the wide range in activity that cancer patients can experience on a daily basis outside of the clinic setting. Given recent technological advances in wearable activity monitors, we can collect real-time, objective information about a patient’s daily activity including steps, stairs, heart rate, sleep, and activity intensity. Thus, the primary objective of this study is to determine whether longitudinal changes in objectively-assessed activity are associated with change in physician-rated ECOG PS. Methods: This is a prospective, single cohort trial being conducted at Cedars-Sinai Medical Center. Stage 3/4 cancer patients who are English or Spanish-speaking, ambulatory (assistive walking devices are allowed) and expected to be seen for treatment or follow-up with their oncologist at least every 8 weeks are eligible for study. Consenting patients will be asked to wear a Fitbit Charge HR continuously for 8 weeks during the study period and for one week prior to the 6 month and 1 year follow-up visits. Primary outcomes are change in average daily step counts and ECOG PS at 8 weeks from baseline. Secondary outcomes include: 1) Change in NIH PROMIS patient-reported outcomes (physical function, pain, sleep, emotional distress, and fatigue), 2) Change in frailty status at 8 weeks, 3) Occurrence of adverse events, and 4) 6-month and 1-year survival outcomes. Baseline assessments include a physical exam, medical history, and frailty assessment. The attending oncologist will rate the patient's ECOG PS at baseline and at the end-of-study visit. Weekly NIH PROMIS questionnaires will be administered online over the 8-week study and again at 6 months and 1 year follow-up. The occurrence of serious cancer-related adverse events, chemotherapy-associated toxicities, and hospitalizations will be documented up to 12 weeks from baseline. Survival will be assessed at 6 months and 1 year. Accrual is ongoing with 20 patients currently enrolled of a target sample size of 60 patients. Clinical trial information: NCT03757182.
Impact of treatment on patient-reported pain and fatigue in early breast cancer patients receiving adjuvant radiotherapy.
Authors: Bo Angela Wan, William Pidduck, Liying Zhang, Caitlin Yee, Katie Wang, Selina Chow, Stephanie Chan, Leah Drost, Hany Soliman, Eric Leung, Philomena Sousa, Donna Lewis, Carlo DeAngelis, Prince Taylor, Edward Chow
Journal: Journal of Clinical Oncology (2019)

e12019 Background: Patients who receive radiotherapy (RT) for breast cancer often report pain and fatigue which contribute negatively to quality of life (QoL). We aim to identify demographic, treatment, and disease characteristics associated with pain and fatigue using the Edmonton Symptom Assessment Scale (ESAS). Methods: We identified all patients diagnosed with non-metastatic breast cancer from 2011 Jan-2017 Jun at the Odette Cancer Centre with at least one ESAS completed pre- and post-RT. Data on systemic treatment, RT, demographics, and disease stage were extracted. To identify factors associated with pain and fatigue pre- and post-RT and their changes, univariate and multivariable linear regression analysis was conducted. p &lt; 0.05 was considered statistically significant. Results: This study included 1222 female patients (mean age 59 years old) who completed ESAS on average 28- and 142-days pre-RT (baseline) and post-RT respectively. In multivariable analysis, higher baseline pain scores associated with adjuvant chemotherapy (p &lt; 0.001) and eventual receipt of locoregional (p = 0.026) or chest wall RT (p = 0.003), whereas higher baseline fatigue scores associated with higher disease stages (p = 0.001) and locoregional RT (p &lt; 0.001). Post-RT symptom severity correlated only with locoregional RT (higher pain scores, p &lt; 0.001). Reductions in pain was associated with adjuvant chemotherapy (p = 0.002) and chest wall RT (p = 0.031). Reduction in fatigue was associated with adjuvant chemotherapy (p = 0.011) and locoregional RT (p = 0.007) although both had higher pre-RT scores in univariate analysis. Conclusions: Patients at higher disease stages or who received chemotherapy or chest wall RT tended to experience more severe short-term morbidity. However, patients who received locoregional RT tended to have greater pain that persisted after RT completion compared to those who did not.
The moral psychology of obligation
Authors: Michael Tomasello
Journal: Behavioral and Brain Sciences (2019)

Although psychologists have paid scant attention to the sense of obligation as a distinctly human motivation, moral philosophers have identified two of its key features: First, it has a peremptory, demanding force, with a kind of coercive quality, and second, it is often tied to agreement-like social interactions (e.g., promises) in which breaches prompt normative protest, on the one side, and apologies, excuses, justifications, and guilt on the other. Drawing on empirical research in comparative and developmental psychology, I provide here a psychological foundation for these unique features by showing that the human sense of obligation is intimately connected developmentally with the formation of a shared agent "we," which not only directs collaborative efforts but also self-regulates them. Thus, children's sense of obligation is first evident inside, but not outside, of collaborative activities structured by joint agency with a partner, and it is later evident in attitudes toward in-group, but not out-group, members connected by collective agency. When you and I voluntarily place our fate in one another's hands in interdependent collaboration - scaled up to our lives together in an interdependent cultural group - this transforms the instrumental pressure that individuals feel when pursuing individual goals into the pressure that "we" put on me (who needs to preserve my cooperative identity in this "we") to live up to our shared expectations: a we > me self-regulation. The human sense of obligation may therefore be seen as a kind of self-conscious motivation.