tbuckley/cabot-search huggingface dataset:
Disparities in receipt of molecular imaging in biochemical recurrent prostate cancer.
Authors: Hala Borno, Tracy Kuo Lin, Anobel Y. Odisho, Arpita Desai, Vadim S Koshkin, Kalin Werner, Nichole Legaspi, Alexander Bell, Thomas Hope
Journal: Journal of Clinical Oncology (2020)

297 Background: Molecular imaging with novel radiotracers is changing treatment landscape in prostate cancer (PCa). Currently, standard of care includes both conventional and molecular imaging, leaving uncertainty in prescription decision. This study evaluated the determinants of and disparities in utilization of molecular imaging for biochemical recurrent (BR) PCa. Methods: This is an observational, single institution, cohort study within the University of California, San Francisco (UCSF). Data were obtained on all men with BR PCa seen at UCSF from June 2018 to May 2019, regardless of histologic subtype. Multivariate logistic regression models were employed to analyze the primary outcome: receipt of molecular imaging (e.g. Fluciclovine PET, Prostate Specific Membrane Antigen PET) as part of diagnostic work-up for BR PCa. Multivariate linear regression models were used to analyze the secondary outcome: overall healthcare cost (hereafter cost) within a one-year time-frame. Results: The study sample included 245 patients; 88% non-Hispanic White (White), 2 % non-Hispanic Black (Black), 9% Asian/Pacific Islander (Asian), and 10% Other. The majority were 55 years or older (66%) and privately insured (73%). Analysis indicated that a one unit reduction in PSA is associated with 1.4 times higher likelihood of receiving molecular imaging (p&lt;0.01). Analysis found that privately insured patients experienced approximately $500,000 more in cost (p&lt;0.01) as compared to the publicly insured. Additionally, a one unit increase in PSA is associated with $5,075 increase in cost (p&lt;0.05). Correlations between race and imaging type and having received radical prostatectomy (RP) and imaging type were identified but were not statistically significant (p&lt;0.10). Conclusions: Higher PSA was associated with lower likelihood for molecular imaging and higher cost in a one year time-frame. Higher cost was also associated with private insurance, but there was no clear relationship between insurance type and imaging type. This study identified several factors – which may impact prescription pattern – that are worth exploring within a larger patient sample; namely, race/ ethnicity and RP as determinants for receipt of molecular imaging.
Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study
Authors: Pietro Lampertico, Maria Buti, Scott Fung, Sang Hoon Ahn, Wan-Long Chuang, Won Young Tak, Alnoor Ramji, Chi-Yi Chen, Edward Tam, Ho Bae, Xiaoli Ma, John F Flaherty, Anuj Gaggar, Audrey Lau, Yang Liu, George Wu, Vithika Suri, Susanna K Tan, G Mani Subramanian, Huy Trinh, Seung-Kew Yoon, Kosh Agarwal, Young-Suk Lim, Henry L Y Chan
Journal: The Lancet. Gastroenterology & hepatology (2020)
c-myc antisense phosphorodiamidate mopholino oligomer inhibits lung metastasis in a syngeneic lung tumor model.
Authors: Harmanjatinder S. Sekhon, Carla A. London, Adams Amantana, Patrick L. Iversen, Gayathri R. Devi
Journal: Cancer Research (2005)

263  c-myc amplification and overexpression has been correlated with progression and chemotherapy resistance in lung cancer. Our laboratory has generated a c-myc targeting phosphorodiamidate Morpholino antisense oligomer (AVI-4126), which has been shown to specifically inhibit c-MYC expression in in vitro and in vivo cancer models and is currently in clinical trials. The present study evaluates the effect of c-MYC inhibition on development of lung metastasis in the Lewis lung syngeneic murine tumor model. In addition to AVI-4126, a neutral PMO agent, a peptide conjugated PMO (AVI-5126) was also synthesized. This PMO shows an increased residence time in tissues compared to AVI-4126. The lung metastasis model in C57BL/6 mice was developed by s.c. implantation of 2 million LLC1 cells. Temporal studies revealed consistent formation of micrometastasis in the lung by day 13 which progressed to larger lesions, and if untreated, to high morbidity by days 25-30. Study 1 involved s.c. administration at local tumor site of saline, AVI-4126, AVI-5126, or respective scrambled (scr) PMOs (50 μg/day) for 3 cycles of 5 days a week starting day 1 post tumor cell implantation. At the end of the study, tumor, lung, spleen, kidneys were removed, weighed, the surface lung lesions were counted, and the tissues processed for histological analysis. AVI-4126 treated group showed a significant reduction in number of animals with surface lung mets (1/6) and lung weights (0.17±0.04) similar to normal mice (0.16±0.008) in comparison to saline (6/6, 0.23±0.009), scr PMO1 (6/6, .30±0.008), AVI-5126 (5/6, 0.19±0.06), and scr PMO2 (6/6, 0.29±0.07). Study 2 compared AVI-4126 with cisplatin, a drug commonly used in lung cancer to which resistance often develops. Mice with well established s.c. tumors were treated i.p. with saline, cisplatin, scr PMO1, AVI-4126 alone or in combination with cisplatin. A cyclical regimen involved cisplatin dosing (83 μg/day) on days 7-9, 18-20 and/or PMO dosing (300 μg/day) on days 11-17 and 22-28. Lung weights, surface lesions and histological analysis revealed a significant reduction in lung tumor burden in the AVI-4126 treated group. HPLC-based analysis of tumor and lung lysates confirmed the presence of intact AVI-4126 and AVI-5126. No PMO-related adverse events were observed. In summary, the data reveal the ability of AVI-4126 to decrease the formation of lung metastasis in this aggressive lung tumor model by local or systemic routes of administration. A recent Phase Ib clinical trial has demonstrated AVI-4126 bioavailability in solid tumors following i.v. administration. These data establish AVI-4126 as a strong clinical candidate for lung cancer. Ongoing studies are addressing the question whether the effect of c-MYC inhibition is on extravasation of cells from the localized tumor or implantation into the distant metastatic site.
Association of abiraterone and higher odds of cardiac complications compared to enzalutamide.
Authors: Eugene Blanchard Cone, Stephen Reese, Maya Marchese, Junaid Nabi, Kerry L. Kilbridge, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2020)

70 Background: The standard of care for advanced prostate cancer is androgen deprivation therapy (ADT). The novel second generation agents abiraterone and enzalutamide were initially approved in castration resistant disease, but are now being used in the hormone sensitive setting. The FDA issued a 2010 warning about cardiovascular risks associated with ADT, but the risk of novel agents is less well understood, especially in comparison to each other. We sought to define the comparative cardiac risk profile of enzalutamide and abiraterone. Methods: We used VigiBase, the World Health Organization database of individual case safety reports, which collects data from more than 130 countries to identify drug associated adverse events (AE). Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac AEs related to abiraterone or enzalutamide therapy for prostate cancer. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR &gt; 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: Vigibase contained 8203 AEs for abiraterone and 26024 for enzalutamide; 808 (9.9%) were cardiac-related for abiraterone, and 1000 for enzalutamide (3.8%). We found no disproportionality signal for cardiac events or any subtype for enzalutamide, but identified significantly higher odds of overall cardiac events (ROR 1.64, 95% CI 1.53—1.76), myocardial infarction (1.34, 1.17—1.58), arrythmia (2.09, 1.87—2.34), and heart failure (3.35, 2.92—3.85) for patients taking abiraterone. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of cardiac events for abiraterone but not for enzalutamide. Clinicians may need to consider these findings in the context of their patients’ comorbidities when prescribing ADT.
Computerized mimotope surface scan identifies the cetuximab epitope on EGFR
Authors: Angelika B. Riemer, Georg Kraml, Otto Scheiner, Christoph C. Zielinski, Erika Jensen-Jarolim
Journal: Cancer Research (2005)

6141  The epidermal growth factor receptor (EGFR, also known as HER-1, ErbB1) is essential in the regulation of cell proliferation and differentiation. Ligand binding induces a conformational change, allowing receptor dimerization and consecutive intracellular signaling. Uncontrolled receptor activation is associated with oncogenic transformation. Consequently, therapeutics targeting EGFR were developed. The monoclonal antibody cetuximab competes with ligand binding and is approved for metastatic colon cancer therapy since 2004. Here we report the identification of the cetuximab epitope on EGFR. Using the phage display technique, we defined three peptides structurally mimicking this epitope. Their sequence information was used for pattern matching by a newly developed computer-aided algorithm, comparing characteristics of mimotope peptides with surface exposed amino acids of the antigen. The defined cetuximab epitope overlaps with the binding sites of two EGFR ligands, epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). Importantly, the epitope is only accessible in the inactive form of the receptor, and is hidden once ligand-induced conformational change has occurred. Thus, we conclude that cetuximab exerts its inhibitory actions not only through ligand displacement, but also through fixation of the receptor in the inactive state.
Association of area social determinants of health with prostate cancer mortality.
Authors: John Clark Henegan
Journal: Journal of Clinical Oncology (2020)

49 Background: Validated clinical nomograms prognosticate survival for men with metastatic castrate resistant prostate cancer. In addition to clinical factors, significant disparities in survival in advanced prostate cancer are associated with social determinants of health (SDH). We performed a study of county-level data to evaluate SDH associated with prostate cancer mortality. Methods: County-level data regarding prostate cancer crude mortality rate (dependent variable) and crude incidence rate was extracted from the ten states with information at www.cancer-rates.info for the years 2006-2015. The 2014 Robert Wood Johnson County Health Rankings dataset was used for information regarding county demographics, clinical information, and available SDH(independent variables). A correlation analysis was performed between independent variables and only one variable was analyzed if a criterion of a correlation of ≥ 0.65 was present. All counties with ≤ 30 death in the specified time period or with incomplete independent variable information were excluded from analysis. A univariate linear regression analysis was performed. All individual independent variables with a statistically significant (p ≤ 0.05) association with the dependent variable were included in a multivariate linear regression model. Results: 275 counties were available for analysis. On multivariate analysis, independent variables statistically significantly associated with the crude rate of prostate cancer mortality included household income and the percentage of: a population ≥ 65 years of age, the population &lt; 18 years of age, African Americans, the population classified as rural, women reporting a screening mammography, smokers, and uninsured patients. The multivariate model was associated with a R-squared of 0.62. Conclusions: In addition to differences in baseline clinical factors, prostate cancer quality metrics that evaluate survival should account SDH. Information from this study, if validated in subsequent work, could be used to develop a stepwise model to adjust for both clinical factors and SDH when measuring survival as a quality metric.
Improvements in first-line systemic mRCC therapy: Challenging insights from a cross trial comparison of overall survival and subsequent therapies in recent phase III trials.
Authors: Jochen Casper, Samantha Henderson, Hannah Casper, Claus-Henning Kohne
Journal: Journal of Clinical Oncology (2020)

705 Background: Using sunitinib (SUN) as the comparator, two out of three recent phase III clinical trials have shown an overall survival (OS) benefit in the alternative treatment arm (Checkmate 214 (C), Keynote 426 (K)). The Javelin 101(J) trial has yet to show a significant improvement. Methods: A cross-study comparison of OS for the sunitinib arms of C, K and J was carried out. Special focus was given to risk group stratification and subsequent therapies. Data from the SUN pivotal trial (SP) was also taken into account. Results: Across the C, K and SP trials, OS was similar at approximately 78%. Despite a lower percentage of favourable risk patients compared to K and SP, an OS of 82% was observed in J. At 18 months, OS survival curves split ranging from 65% ©, 72.1% (K) to 76% (J). OS in the SUN arm in J at 18 months was comparable to OS of Nivolumab/Ipilimumab in C (78%). The rate of subsequent therapies ranged from 34.3% (K), 39.2% (J) to 54% (C) in the SUN arms. At the time of the SP trial almost no subsequent therapy options existed. In the experimental arms, the rate of subsequent therapies was 51.8% ©, 20.5% (K) and 20.8% (J). The existing data give no clear evidence of a correlation between subsequent therapies and OS. However, an analysis of the subsequent therapies/patients discontinuing therapy ratio (ST/DIS) and type of subsequent therapy (PD1/L1 directed or therapy with proven OS benefit (pOS) in randomized trials) in the SUN arms may be more conclusive (see table). The rate of subsequent therapies (ST/DIS) as well as PD(L)1 or pOS therapies were highest in J, followed by K and C. Conclusions: Despite the difficulties of a cross trial comparison, this data should raise awareness of the influence of a more intense subsequent therapy. It points to the necessity to standardize subsequent therapies in 1st line trials if OS is a primary study aim. Given this analysis, it may be pertinent to ask if an optimal or near optimal subsequent therapy following SUN might be equal to a 1 st line IO/IO therapy with regards to OS.[Table: see text]
Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development
Authors: Chew Yee Ngan, Chee Hong Wong, Harianto Tjong, Wenbo Wang, Rachel L. Goldfeder, Cindy Choi, Hao He, Liang Gong, Junyan Lin, Barbara Urban, Julianna Chow, Meihong Li, Joanne Lim, Vivek Philip, Stephen A. Murray, Haoyi Wang, Chia-Lin Wei
Journal: Nature Genetics (2020)
Clinician Identification of Birth Asphyxia Using Intrapartum Cardiotocography Among Neonates With and Without Encephalopathy in New Zealand
Authors: Cynthia M. Farquhar, Sarah Armstrong, Vicki Masson, John M. D. Thompson, Lynn Sadler
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Despite improvements in antenatal care and increasing cesarean delivery rates, birth asphyxia leading to neonatal encephalopathy (NE) continues to contribute to neonatal death and long-term neurodevelopmental disability. Cardiotocography (CTG) has been used in labor for several decades to detect a stressed fetus so that delivery can be expedited and NE avoided. <h3>Objective</h3> To investigate whether experienced clinicians can detect and respond to abnormal readings from CTGs during the penultimate hour before birth in infants with moderate to severe NE but no acute peripartum event. <h3>Design, Setting, and Participants</h3> This case-control study included 10 practicing obstetricians and midwives at maternity hospitals in New Zealand. Participants, who were masked to the perinatal outcome, were asked to assess CTG tracings from 35 neonates with NE and evidence of birth hypoxia (ie, cases) and 105 neonates without NE or birth hypoxia (ie, controls), all of whom were born in 2010 to 2011. Data analysis was conducted from May to December 2017. <h3>Exposures</h3> Brief clinical details and 1 hour of CTG tracings from the penultimate hour before birth were provided for each baby. Clinicians assessed the CTG tracings and recommended a plan. <h3>Main Outcomes and Measures</h3> Intra-assessor and interassessor agreement on CTG findings and action plans as well as sensitivity (ie, detection of NE) and specificity (ie, ruling out those without NE) for the assessment of abnormal CTG readings leading to immediate action (ie, fetal blood sample or immediate delivery) were reported. <h3>Results</h3> A total of 35 infants (mean [SD] gestational age, 40 [1.4] weeks; 16 [45.7%] cesarean deliveries) were designated cases, and 105 infants (mean [SD] gestational age, 39.4 [1.2] weeks; 22 [21.0%] cesarean deliveries) were designated controls. No infants had congenital anomalies. The mean (range) sensitivity for detection of abnormal CTG results and for recommending immediate action for all assessors was 75% (63%-91%) and 41% (23%-57%), respectively, with a mean (range) specificity of 67% (53%-77%) and 87% (65%-99%), respectively. A sensitivity analysis including only assessors with 80% or more interassessor agreement only differed from the main analysis by 6% or less (mean [range] sensitivity for detection, 76% [63%-91%]; sensitivity for action plan, 36% [25%-49%]; specificity for detection, 71% [53%-77%]; and specificity for action plan, 93% [88%-99%]). <h3>Conclusions and Relevance</h3> Experienced clinicians detected 3 of 4 infants who were subsequently diagnosed with NE. Action to expedite delivery was recommended for more than 40% of infants with NE. These results indicate that CTG does not identify all infants at risk of NE, and that there is a need for further investment in new approaches to fetal surveillance in labor.
Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence
Authors: Sevana Khaloian, Eva Rath, Nassim Hammoudi, Elisabeth Gleisinger, Andreas Blutke, Pieter Giesbertz, Emanuel Berger, Amira Metwaly, Nadine Waldschmitt, Matthieu Allez, Dirk Haller
Journal: Gut (2020)

Objective Reduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn’s disease (CD). PCs reside in proximity to Lgr5 + intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance. Design Ileal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60 Δ/ΔISC ) and CD-like ileitis (TNF ΔARE ), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function. Results In patients with CD and TNF ΔARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNF ΔARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNF ΔARE mice-derived crypts to form organoids. Conclusion We provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.
Utilization of renal mass biopsy in patients with localized renal cell carcinoma: A population-based study utilizing the National Cancer Database.
Authors: Devin Patel, Fady Ghali, Sunil Patel, Nathan Miller, Aaron Bradshaw, Margaret Meagher, Gerant Rivera-Sanfeliz, James Don Murphy, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

662 Background: Recent guidelines suggest an increasing role for renal mass biopsy (RMB) in the management of renal cell carcinoma (RCC) prior to ablative therapy and in patients in whom active surveillance (AS) is being considered. Methods: We queried the National Cancer Database for cases of localized (cT1-cT3N0M0) RCC between 2004-2015. Unadjusted temporal trends in receipt of RMB were characterized over the study period based on type of treatment [partial nephrectomy (PN), radical nephrectomy (RN), ablation, and surveillance], tumor size, age and Charlson Comorbidity Index and compared using analysis of variance. Multivariable logistic regression was used to test for the association between patient, tumor and treatment variables and use of RMB. Results: 338,252 patients were analyzed, with 11.9% (40,276) undergoing RMB. Use of RMB increased from 1,586 (7.6%) in 2004 to 5,629 (16.2%) in 2015 (p&lt;0.001). On treatment strategy, use of RMB increased the greatest in association with ablation from 27% to 63% across the study period (p&lt;0.001). On tumor size, use of RMB increased the greatest for tumors 2-4 cm from 9% to 20% (p&lt;0.001). Conversely, utilization of RMB increased proportionally across different age (p=0.17) and comorbidity (p=0.18) groups over time. Multivariable logistic regression revealed that year of diagnosis (OR 1.06; p&lt;0.001), black race (OR 1.04; p=0.02), higher education (OR 1.09; p&lt;0.001) and insured status (OR 1.23; p&lt;0.001) were associated with increased RMB. However, increasing age (p=0.23) and comorbidity (p=0.35) were not. Compared to tumors &lt;2 cm in size, tumors 2-4 cm (OR 1.36; p&lt;0.001), 4-7 cm (OR 1.18; p&lt;0.001) and &gt;7 cm (OR 1.05; p=0.03) were associated with higher RMB. Compared to treatment with RN, treatment with PN was not associated with increased RMB (p=0.92); however, treatment with ablation (OR 10.90; p&lt;0.001) and with surveillance (OR 4.83; p&lt;0.001) were. Conclusions: The largest increase in RMB was associated with ablation treatment. Rates of RMB for tumors &lt;2 cm and for older, sicker patients not undergoing treatment have correspondingly increased less, indicating RMB may not be as highly used for surveillance.
Local release of NECA (5′-(N-ethylcarboxamido)adenosine) from implantable polymeric sheets for enhanced islet revascularization in extrahepatic transplantation site
Authors: Tiep Tien Nguyen, Fakhrossadat Emami, Simmyung Yook, Hanh Thuy Nguyen, Tung Thanh Pham, Shiva Pathak, Shobha Regmi, Jong Oh. Kim, Chul Soon Yong, Jae-Ryong Kim, Jee-Heon Jeong
Journal: Journal of Controlled Release (2020)