tbuckley/cabot-search huggingface dataset:
Maintaining treatment volumes during the COVID-19 pandemic.
Authors: Rachel L. Mitchell, L Johnetta Blakely, Stephen Matthew Schleicher, Stacey L Poole, Natalie R. Dickson, Jeffrey Patton, Davey B. Daniel
Journal: Journal of Clinical Oncology (2020)

103 Background: Uninterrupted care is essential for optimal outcomes in cancer care. The COVID-19 pandemic presented numerous challenges in providing continuity of care for many facilities. Our practice was able to deliver ongoing treatment for a large volume of our patients while maintaining a safe environment. Methods: A practice-wide effort to continue therapy in cancer patients undergoing active treatment began in March 2020 as the peak of the pandemic was beginning in Tennessee. Those patients who were receiving active treatment continued the planned treatment while reducing non-acute treatment visits. We assessed the volume of patients receiving treatments in our facilities for two periods: JanuaryDecember 2019 and January-May 2020. We compared the aggregate number of chemotherapy infusions, therapeutic infusions and injections as well as total treatments. Results: Overall, treatments remained relatively stable without a significant change in treatment volumes. There was a 3.69% decline in total treatment with therapeutic infusions (-9.68%) and injections (-7.85%) which accounted for the majority of deferred treatments. Chemotherapy infusions remained stable with an average increase (1.90%) in treatments. Conclusions: During the COVID-19 pandemic, our facility was able to maintain stable treatment numbers while providing safe care to our patients. We had no known diagnosed COVID-19 cases from potential exposures in our clinics. Decreases in treatment reflected less critical therapies. There did seem to be a delay for chemotherapy/immunotherapy that seemed to resolve as the peak passed for this region. Offloading of less critical treatments can result in continued treatment of cancer patients during a pandemic. [Table: see text]
Protocol concordance and impact of protocol deviations on selected outcomes in delivery of high-dose methotrexate in acute lymphoblastic leukemia in Sri Lanka.
Authors: Sanjeeva Gunasekera, Geeth Vindula, Ryan Combs, Scott C. Howard
Journal: Journal of Clinical Oncology (2020)

17 Background: In Sri Lanka, children with acute lymphoblastic leukemia are treated on the UKALL 2011 protocol, which includes high-dose methotrexate (HDMTX) in high risk patients. Safe delivery of HDMTX is challenging in low resource settings, where deviation from accepted guidelines can occur frequently and result in toxicity, subsequent treatment delays, and in extreme cases, death. The goal of this study was to compare current practices to the treatment and supportive care details described in the protocol to identify the incidence and impact of guideline-discordant care to deliver HDMTX more safely children with cancer in Sri Lanka. Methods: We reviewed medical records to assess guideline concordance in 4 critical aspects of HDMTX delivery: 2 consecutive alkaline urine pH readings in the 2-hour period before starting HDMTX, 24-hour duration of MTX infusion (as opposed to early stop), the first dose of folinic acid administered later than 36 hours from start of HDMTX infusion (no inappropriately early rescue), and the administration of at least 3 folinic acid doses per course (appropriate duration of rescue). We analyzed how each deviation influenced AKI (creatinine increase of 0.3 mg/dL or more), infection, and treatment delays (defined as recovery delayed 7 days or longer from the 14 days expected between courses of HDMTX). Results: We analyzed 309 HDMTX courses in 91 patients younger than 20 years, including 105 girls (34%). In 83 courses (27%) alkaline urine was not documented prior to the start of MTX. Infusion time was less than 24 hours in 239 courses (77%), most of which finished 20-21 hours. In 37 courses (12%), the first folinic acid dose was given inappropriately early, and in 25 courses (8%) less than 3 doses of folinic acid were given. There were 2 episodes of AKI, 43 infections, 11 treatment delays and one death. None of the 4 guideline deviations were significantly associated with AKI or treatment delays. Patient sex was also not associated with any difference in guideline discordance or outcome (p&gt;0.1 in all cases). Conclusions: Significant deviations from HDMTX administration guidelines were common, especially early completion of infusion. However, outcomes were not impacted so quality standards may require adjustment to focus only on extreme deviations likely to impact patient outcomes.
Qki is an essential regulator of microglial phagocytosis in demyelination
Authors: Jiangong Ren, Congxin Dai, Xin Zhou, Joseph A. Barnes, Xi Chen, Yunfei Wang, Liang Yuan, Takashi Shingu, Amy B. Heimberger, Yiwen Chen, Jian Hu
Journal: The Journal of Experimental Medicine (2020)

The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia's phagocytic activity under demyelinating conditions.
Extracellular-vesicles delivered tumor-specific sequential nanocatalysts can be used for MRI-informed nanocatalytic Therapy of hepatocellular carcinoma
Authors: Han Wu, Hao Xing, Meng-Chao Wu, Feng Shen, Yu Chen, Tian Yang
Journal: Theranostics (2020)

Background: Conventional therapeutic strategies for advanced hepatocellular carcinoma (HCC) remains a great challenge, therefore the alternative therapeutic modality for specific and efficient HCC suppression is urgently needed. Methods: In this work, HCC-derived extracellular vesicles (EVs) were applied as surface nanocarrier for sequential nanocatalysts GOD-ESIONs@EVs (GE@EVs) of tumor-specific and cascade nanocatalytic therapy against HCC. By enhancing the intracellular endocytosis through arginine-glycine-aspartic acid (RGD)-targeting effect and membrane fusion, sequential nanocatalysts led to more efficient treatment in the HCC tumor region in a shorter period of time. Results: Through glucose consumption as catalyzed by the loaded glucose oxidase (GOD) to overproduce hydrogen peroxide (H2O2), highly toxic hydroxyl radicals were generated by Fenton-like reaction as catalyzed by ESIONs, which was achieved under the mildly acidic tumor microenvironment, enabling the stimuli of the apoptosis and necrosis of HCC cells. This strategy demonstrated the high active-targeting capability of GE@EVs into HCC, achieving highly efficient tumor suppression both in vitro and in vivo. In addition, the as-synthesized nanoreactor could act as a desirable nanoscale contrast agent for magnetic resonance imaging, which exhibited desirable imaging capability during the sequential nanocatalytic treatment. Conclusion: This application of surface-engineering EVs not only proves the high-performance catalytic therapeutic modality of GE@EVs for HCC, but also broadens the versatile bio-applications of EVs.
Prospective Cohort Study of Pre- and Postdiagnosis Physical Activity and Endometrial Cancer Survival
Authors: Christine M. Friedenreich, Linda S. Cook, Qinggang Wang, Renée L. Kokts-Porietis, Jessica McNeil, Charlotte Ryder-Burbidge, Kerry S. Courneya
Journal: Journal of Clinical Oncology (2020)

The aim of this study was to evaluate associations between pre- and postdiagnosis physical activity and survival in survivors of endometrial cancer by physical activity domain, intensity, dose (metabolic-equivalent task [MET]-hours/week/year), and change from pre- to postdiagnosis.We conducted a prospective cohort study in Alberta, Canada, of 425 women who were diagnosed with histologically confirmed invasive endometrial cancer between 2002 and 2006 and observed to 2019. The interviewer-administered Lifetime Total Physical Activity Questionnaire recorded prediagnosis (assessed at a median of 4.4 months after diagnosis) and postdiagnosis physical activity (assessed at a median of 3.4 years after diagnosis). Associations between physical activity and overall and disease-free survival were assessed using Cox proportional hazards models adjusted for age, stage, grade, treatments, body mass index, menopausal status, hormone therapy use, family history of cancer, and comorbidities.After a median follow-up of 14.5 years, there were 60 deaths, including 18 endometrial cancer deaths, and 80 disease-free survival events. Higher prediagnosis recreational physical activity was statistically significantly associated with improved disease-free survival (> 14 v ≤ 8 MET-hours/week/year; hazard ratio [HR], 0.54; 95% CI, 0.30 to 0.96; Ptrend = .04), but not overall survival (HR, 0.56; 95% CI, 0.29 to 1.07; Ptrend = .06). Higher postdiagnosis recreational physical activity (> 13 v ≤ 5 MET-hours/week/year) was strongly associated with both improved disease-free survival (HR, 0.33; 95% CI, 0.17 to 0.64; Ptrend = .001) and overall survival (HR, 0.33; 95% CI, 0.15 to 0.75; Ptrend = .007). Participants who maintained high recreational physical activity levels from pre- to postdiagnosis also had improved disease-free survival (HR, 0.35; 95% CI, 0.18 to 0.69) and overall survival (HR, 0.43; 95% CI, 0.20 to 0.94) compared with those who maintained low physical activity levels.Recreational physical activity, especially postdiagnosis, is associated with improved survival in survivors of endometrial cancer.
Accounting for US public funding in drug development: how can we better balance access, affordability, and innovation?
Authors: Ameet Sarpatwari, Jerry Avorn, Aaron S Kesselheim
Journal: BMJ (2020)

With the price of prescription drugs increasing rapidly, <b>Ameet Sarpatwari</b>, <b>Jerry Avorn</b>, and <b>Aaron Kesselheim</b> explore the ways US public funding supports drug development and identify policy reforms to help ensure that patients can affordably access therapies arising from such support
Clinical impact of molecular point-of-care testing for suspected COVID-19 in hospital (COV-19POC): a prospective, interventional, non-randomised, controlled study
Authors: Nathan J Brendish, Stephen Poole, Vasanth V Naidu, Christopher T Mansbridge, Nicholas J Norton, Helen Wheeler, Laura Presland, Stephen Kidd, Nicholas J Cortes, Florina Borca, Hang Phan, Gavin Babbage, Benoit Visseaux, Sean Ewings, Tristan W Clark
Journal: The Lancet Respiratory Medicine (2020)

The management of the COVID-19 pandemic is hampered by long delays associated with centralised laboratory PCR testing. In hospitals, these delays lead to poor patient flow and nosocomial transmission. Rapid, accurate tests are therefore urgently needed in preparation for the next wave of the pandemic.
Noninvasive Detection of Urothelial Carcinoma by Cost-effective Low-coverage Whole-genome Sequencing from Urine-Exfoliated Cell DNA
Authors: Shuxiong Zeng, Yidie Ying, Naidong Xing, Baiyun Wang, Ziliang Qian, Zunlin Zhou, Zhensheng Zhang, Weidong Xu, Huiqing Wang, Lihe Dai, Li Gao, Tie Zhou, Jiatao Ji, Chuanliang Xu
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Urothelial carcinoma is a malignant cancer with frequent chromosomal aberrations. Here, we investigated the application of a cost-effective, low-coverage whole-genome sequencing technology in detecting all chromosomal aberrations. Experimental Design: Patients with urothelial carcinomas and nontumor controls were prospectively recruited in clinical trial NCT03998371. Urine-exfoliated cell DNA was analyzed by Illumina HiSeq XTen, followed by genotyping with a customized bioinformatics workflow named Urine Exfoliated Cells Copy Number Aberration Detector (UroCAD). Results: In the discovery phase, urine samples from 126 patients with urothelial carcinomas and 64 nontumor disease samples were analyzed. Frequent chromosome copy-number changes were found in patients with tumor as compared with nontumor controls. A novel diagnosis model, UroCAD, was built by incorporating all the autosomal chromosomal changes. The model reached performance of AUC = 0.92 (95% confidence interval, 89.4%–97.3%). At the optimal cutoff, |Z| ≥ 3.21, the sensitivity, specificity, and accuracy were 82.5%, 96.9%, and 89.0%, respectively. The prediction positivity was found correlated with tumor grade (P = 0.01). In the external validation cohort of 95 participants, the UroCAD assay identified urothelial carcinomas with an overall sensitivity of 80.4%, specificity of 94.9%, and AUC of 0.91. Meanwhile, UroCAD assay outperformed cytology tests with significantly improved sensitivity (80.4% vs. 33.9%; P &amp;lt; 0.001) and comparable specificity (94.9% vs. 100%; P = 0.49). Conclusions: UroCAD could be a robust urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests. It may be used as a noninvasive approach for diagnosis and recurrence surveillance in urothelial carcinoma prior to the use of cystoscopy, which would largely reduce the burden on patients.
Digital engagement preferences of individuals aged 65 and older with cancer.
Authors: Matthew Allison, Jonathan Patterson, Stephen Burton, Dhiren Patel, Kelly Jean Brassil
Journal: Journal of Clinical Oncology (2020)

289 Background: Recent reviews suggest that digital solutions play a prominent role in the context of geriatric oncology. While interventions ranging from remote monitoring to nutrition and physical activity support have demonstrated feasibility in older adults (aged 65 and older), little is known about facilitators and barriers to eHealth uptake in older adults diagnosed with cancer. Insights into the digital engagement preferences of older adults with cancer may help to inform which platforms may be best aligned to optimal engagement and outcomes. Methods: A retrospective analysis was conducted to examine patient engagement preferences (phone, text and/or email) among older adults with cancer enrolled in a digital health coaching program. Descriptive statistics were used to summarize patient characteristics. Chi-square tests were used to evaluate differences in patient engagement preferences by race. Results: Of 513 individuals, the majority (n = 308; 60%) preferred information be provided by phone, email and text, while 20% (n = 105) requested content by phone and text only. Less than 10% of the sample requested content via phone only (n = 45; 8%), phone and email, (n = 31; 6%), email only (n = 11, 2%), or by email and text (n = 9; 2%). Interestingly, adults aged 65 and older had a significant predisposition to phone only communication (8.77%) compared to 2.25% in the general oncology population (p &lt; 0.001). Among adults aged 65 and older with a phone preference, there were on average 8.39 calls over the course of the program with an average of 9.51 minutes per call over the course of 12-weeks. For those with text message preference, there were an average of 14.17 outbound and 8.30 inbound texts over the 12-week engagement, and for those with email preference a 62.38% open rate was observed. Retention over a three month coaching period was highest among those engaged via phone, text and email (56.17%), and email only (54.55%). Race was significantly related to engagement preference, with black members twice as likely (p &lt; 0.001) to choose phone and text, and three times as likely (p &lt; 0.001) to choose phone only compared with white members. However, no differences emerged between race and retention. Conclusions: Engagement preference was associated with differences in retention and race. Our results highlight the importance of offering different mechanisms for patient engagement and the need for attention to specific demographic differences such as race, which may impact access to and preference for engagement types when employing digital health solutions for older adults with cancer.
Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening
Authors: Xiaofei Chen, Yunlong Wu, Chun Chen, Yanqiu Gu, Chunyan Zhu, Suping Wang, Jiayun Chen, Lei Zhang, Lei Lv, Guoqing Zhang, Yongfang Yuan, Yifeng Chai, Mingshe Zhu, Caisheng Wu
Journal: Acta Pharmaceutica Sinica B (2020)

Lianhuaqingwen (LHQW) capsule, a herb medicine product, has been clinically proved to be effective in coronavirus disease 2019 (COVID-19) pneumonia treatment. However, human exposure to LHQW components and their pharmacological effects remain largely unknown. Hence, this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities. Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach, leading to detection of 132 LHQW prototype and metabolite components, which were absorbed via the gastrointestinal tract and formed via biotransformation in human, respectively. Together with data from screening by comprehensive 2D angiotensin-converting enzyme 2 (ACE2) biochromatography, 8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation. Results show that rhein, forsythoside A, forsythoside I, neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2. For the first time, this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human. It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.
Intestinal attenuation of COVID-19 inflammation
Authors: Aljawharah Alrubayyi
Journal: Nature reviews. Immunology (2020)

NATuRe RevIewS | Immunology in inflammatory lung diseases compared with in healthy lungs.Compared with controls, Adamts4 -/-mice showed improved survival following a lethal dose of influenza virus, and this was associated with reduced inflammation and improved lung function.The lungs of infected Adamts4 -/-mice also showed higher levels of intact versican, and a series of additional experiments suggested that degradation of versican by ADAMTS4-expressing DRFibs permits the recruitment of CD8 + T cells, which are one of the main drivers of immunopathology during influenza virus infection.
Signaling through the type 2 cannabinoid receptor regulates the severity of acute and chronic graft-versus-host disease
Authors: Cheng Yin Yuan, Vivian Zhou, Garrett Sauber, Todd Stollenwerk, Richard Komorowski, Alicia López, Rosa María Tolón, Julian Romero, Cecilia J. Hillard, William R. Drobyski
Journal: Blood (2020)
Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma
Authors: Jeffrey C Thompson, Christiana Davis, Charuhas Deshpande, Wei-Ting Hwang, Seth Jeffries, Alexander Huang, Tara C Mitchell, Corey J Langer, Steven M Albelda
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB). Methods This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM ( B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, and HSP90AB1 ). Associations were made for therapeutic response, progression-free survival (PFS) and overall survival (OS). Results In NSCLC, the APM score was significantly higher in responders compared with non-responders (p=0.0001). An APM score above the median value for the cohort was associated with improved PFS (HR 0.34 (0.18 to 0.64), p=0.001) and OS (HR 0.44 (0.23 to 0.83), p=0.006). The APM score was correlated with an inflammation score based on the established T-cell-inflamed resistance gene expression profile (Pearson’s r=0.58, p&lt;0.0001). However, the APM score better predicted response to ICB relative to the inflammation score with area under a receiving operating characteristics curve of 0.84 and 0.70 for PFS and OS, respectively. In a cohort of 14 high-risk resectable stage III/IV melanoma patients treated with neoadjuvant anti-PD1 ICB, a higher APM score was associated with improved disease-free survival (HR: 0.08 (0.01 to 0.50), p=0.0065). In an additional independent melanoma cohort of 27 metastatic patients treated with ICB, a higher APM score was associated with improved OS (HR 0.29 (0.09 to 0.89), p=0.044). Conclusion Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.
Ethics, cancer, and COVID
Authors: Arthur Caplan
Journal: Clinical Cancer Research (2020)

This talk will review (1) the impact of the covid-19 outbreak on treating cancer patients who were infected with thevirus with unapproved and off-label agents under a philosophy of compassionate use including disclosure ofconflicts of interest;(2) the ethics of withholding diagnosis and treatment from patients with cancer or who mighthave acquired cancer in the USA once social isolation, quarantines, and restriction of “nonessential” services began;(3) decisions about how to define “essential” services during the onset of the pandemic in severely impacted areasof the U S ;(4) the management of those who died during the pandemic as lessons for future clinical care of cancerpatients;(5) decisions about how to decide how much risk to permit those involved in clinical care for cancer or forreassigned duties to assume during an ongoing pandemic;and (6) how to prioritize future cancer research as theviral outbreak continues and resources remain restricted