tbuckley/cabot-search huggingface dataset:
Analytical demands to use whole-genome sequencing in precision oncology
Authors: Manja Meggendorfer, Vaidehi Jobanputra, Kazimierz O. Wrzeszczynski, Paul Roepman, Ewart de Bruijn, Edwin Cuppen, Reinhard Buttner, Carlos Caldas, Sean Grimmond, Charles G. Mullighan, Olivier Elemento, Richard Rosenquist, Anna Schuh, Torsten Haferlach
Journal: Seminars in Cancer Biology (2021)

Interrogating the tumor genome in its entirety by whole-genome sequencing (WGS) offers an unprecedented insight into the biology and pathogenesis of cancer, with potential impact on diagnostics, prognostication and therapy selection. WGS is able to detect sequence as well as structural variants and thereby combines central domains of cytogenetics and molecular genetics. Given the potential of WGS in directing targeted therapeutics and clinical decision-making, we envision a gradual transition of the method from research to clinical routine. This review is one out of three within this issue aimed at facilitating this effort, by discussing in-depth analytical validation, clinical interpretation and clinical utility of WGS. The review highlights the requirements for implementing, validating and maintaining a clinical WGS pipeline to obtain high-quality patient-specific data in accordance with the local regulatory landscape. Every step of the WGS pipeline, which includes DNA extraction, library preparation, sequencing, bioinformatics analysis, and data storage, is considered with respect to its logistics, necessities, potential pitfalls, and the required quality management. WGS is likely to drive clinical diagnostics and patient care forward, if requirements and challenges of the technique are recognized and met.
Personalized DNA neoantigen vaccine in combination with plasmid IL-12 for the treatment of a patient with anaplastic astrocytoma.
Authors: Tanner Michael Johanns, Alfredo Perales-Puchalt, Roger Stupp, Mitchel Berger, William E. Gillanders, Chris Miller, Jasreet Hundal, Michael D. McLellan, S. Peter Goedegebuure, Sarah Rochestie, Neil Cooch, Joann Peters, Gavin P. Dunn, Niranjan Sardesai
Journal: Journal of Clinical Oncology (2021)

e14561 Background: Tumor neoantigens are epitopes derived from tumor-specific mutations that may be incorporated in personalized vaccines to prime T cell responses. DNA vaccines delivered with electroporation have recently shown strong CD8 and CD4 T cell responses in clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. Methods: Two resection samples from a patient with IDH+ MGMT-methylated anaplastic astrocytoma were subject to whole exome and transcriptome sequencing. Epitopes derived from 27 neoantigens and 3 shared tumor-associated antigens were prioritized and included in a personalized vaccine. The patient was treated with surgery, radiotherapy and temozolomide starting June 2018 and received the first dose of the personalized vaccine in June 2019 under a compassionate use single patient IND application with the FDA. Results: As of February 10, 2021, the patient has received 10 doses of the DNA personalized vaccine. No serious adverse events have been reported. Related adverse events are limited to grade 1 injection site reactions. The patient remains progression-free 32 months after surgery and 20 months after starting vaccination. Three weeks following the third dose, a hyperintense image on the tumor bed was identified, which disappeared on the following MRI, 2 weeks following dose 5, being catalogued as pseudo progression. Ex vivo ELISpot have identified T cell responses to 21/30 epitopes (70%), including 18/27 (67%) neoantigens and 3/3 (100%) shared antigens. Flow cytometry analysis has determined that T cell responses are 92.3% CD8 and 69.2% CD4 (30.8% CD8 only; 61.5% both CD8 and CD4; and 7.7% CD4 only). Conclusions: This compassionate use treatment in an adjuvant setting demonstrates manufacturing feasibility, safety, tolerability, immunogenicity, and suggests potential for persistent clinical response of DNA encoded personalized vaccines. The data supports further investigation of DNA-encoded personalized vaccines into newly diagnosed high-grade gliomas.
Changes in the blood-brain barrier properties in vitro after treatment with sera from breast cancer patients with primary cancer and visceral, bone or cerebral metastases.
Authors: Carolin Julia Curtaz, Schmitt Constanze, Patrick Meybohm, Achim Wöckel, Malgorzata Burek
Journal: Journal of Clinical Oncology (2021)

2026 Background: The progression of brain metastases during breast cancer correlates with poor overall survival, but also with a reduced quality of life. During the metastatic progression of breast cancer, the key event for entry into the brain is the migration of cancer cells across the blood-brain barrier (BBB). To date, it is still controversial which serum factors play a role in cerebral expansion and what effects they have on the BBB. We hypothesize that sera from breast cancer patients with cerebral metastases contain unique factors that can affect BBB integrity. Methods: We used the CD34 + cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) in co-culture with brain pericytes, which was validated in our previous studies, to analyse the BBB properties after patient sera treatment. We used paracellular permeability measurements for fluorescein (400 Da), immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. We collected serum samples from five patient cohorts (30 patient per group planned/150 in total/ current recruited patients 130): 1) healthy donors (current recruited patients- 23), 2) breast cancer patients with primary cancer (recruited patients- 30), 3) breast cancer patients with bone metastases (recruited patients- 29), 4) visceral metastases (recruited patients- 30), or 5) cerebral metastases (current recruited patients- 18). We then used 2% patient sera in cell culture medium to treat the cells for 24 hours. Results: Sera from breast cancer patients with cerebral and bone metastases led to a significant increase in the paracellular permeability for fluorescein. This could also be visualized by immunostaining cells with anti-claudin-5 antibody. Tight junction protein claudin-5 and occludin mRNA was reduced in BLECs, while mRNA of efflux pumps Breast cancer resistance protein (BCRP) and P-glycoprotein (P-GP) was induced in BLECs treated with serum from breast cancer patients with primary cancer, cerebral and visceral metastases. At the protein level, efflux pumps BCRP and P-GP were induced in cells treated with sera from breast cancer patients with cerebral metastases, while they were reduced in cells treated with sera from breast cancer patients with bone metastases. Conclusions: Sera from breast cancer patients with primary cancer and breast cancer metastases have an effect on the integrity of BBB in vitro. Reduced barrier properties of brain endothelial cells can contribute to the formation of cerebral metastases in advanced stages of breast cancer. Keywords: metastatic breast cancer, blood-brain barrier, in vitro models
Does Intraoperative Artificial Intelligence Decision Support Pose Ethical Issues?
Authors: Charles E. Binkley, Brian P. Green
Journal: JAMA Surgery (2021)

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High Hopes for Very Preterm Infants in Neonatal Intensive Care Units in China
Authors: Gauthami Soma, Lei Chen
Journal: JAMA Network Open (2021)

Siyuan Jiang, MD, PhD; Xiangyuan Huang, BS; Lan Zhang, MD; Junyan Han, MD; Yi Yang, PhD; Weiping Wang, MD, PhD; Shoo K. Lee, PhD; Weili Yan, PhD; Yun Cao, MD, PhD; Reduction of Infection in Neonatal Intensive Care Units Using the Evidence-Based Practice for Improving Quality (REIN-EPIQ) Study Group; Yun Cao; Siyuan Jiang; Yong Ji; Shuping Han; Sannan Wang; Zhankui Li; Shiwen Xia; Changyi Yang; Chuanzhong Yang; Ling Chen; Ruobing Shan; Ling Liu; Bin Yi; Yang Wang; Jiangqin Liu; Ling He; Mingxia Li; Xinnian Pan; Yan Guo; Cuiqing Liu; Qin Zhou; Xiaoying Li; Hong Xiong; Yujie Qi; Mingyan Hei; Yong Han; Shuping Wang; Sannan Li; Zhankui Xia; Shiwen Yang; Chuanzhong Lin; Zhenlang Chen; Ling Shan; Ruobing Liu; Ling Yi; Bin Wang; Yang Liu; Jiangqin He; Ling Li; Mingxia Pan; Xinnian Guo; Yan Liu; Cuiqing Zhou; Qin Li; Xiaoying Xiong; Hong Qi; Yujie Hei
Health and Economic Outcomes Associated With COVID-19 in Women at High Risk of HIV Infection in Rural Kenya
Authors: Nolan M. Kavanagh, Noora Marcus, Risper Bosire, Brian Otieno, Elizabeth F. Bair, Kawango Agot, Harsha Thirumurthy
Journal: JAMA Network Open (2021)

<h3>Importance</h3> COVID-19 lockdowns may affect economic and health outcomes, but evidence from low- and middle-income countries remains limited. <h3>Objective</h3> To assess the economic security, food security, health, and sexual behavior of women at high risk of HIV infection in rural Kenya during the COVID-19 pandemic. <h3>Design, Setting, and Participants</h3> This survey study of women enrolled in a randomized trial in a rural county in Kenya combined results from phone interviews, conducted while social distancing measures were in effect between May 13 and June 29, 2020, with longitudinal, in-person surveys administered between September 1, 2019, and March 25, 2020. Enrolled participants were HIV-negative and had 2 or more sexual partners within the past month. Surveys collected information on economic conditions, food security, health status, and sexual behavior. Subgroup analyses compared outcomes by reliance on transactional sex for income and by educational attainment. Data were analyzed between May 2020 and April 2021. <h3>Main Outcomes and Measures</h3> Self-reported income, employment hours, numbers of sexual partners and transactional sex partners, food security, and COVID-19 prevention behaviors. <h3>Results</h3> A total of 1725 women participated, with a mean (SD) age of 29.3 (6.8) years and 1170 (68.0%) reporting sex work as an income source before the COVID-19 pandemic. During the pandemic, participants reported experiencing a 52% decline in mean (SD) weekly income, from $11.25 (13.46) to $5.38 (12.51) (difference, −$5.86; 95% CI, −$6.91 to −$4.82;<i>P</i> &lt; .001). In all, 1385 participants (80.3%) reported difficulty obtaining food in the past month, and 1500 (87.0%) worried about having enough to eat at least once. Reported numbers of sexual partners declined from a mean (SD) total of 1.8 (1.2) partners before COVID-19 to 1.1 (1.0) during (difference, −0.75 partners; 95% CI, −0.84 to −0.67 partners;<i>P</i> &lt; .001), and transactional sex partners declined from 1.0 (1.1) to 0.5 (0.8) (difference, −0.57 partners; 95% CI, −0.64 to −0.50 partners;<i>P</i> &lt; .001). In subgroup analyses, women reliant on transactional sex for income were 18.3% (95% CI, 11.4% to 25.2%) more likely to report being sometimes or often worried that their household would have enough food than women not reliant on transactional sex (<i>P</i> &lt; .001), and their reported decline in employment was 4.6 hours (95% CI, −7.9 to −1.2 hours) greater than women not reliant on transactional sex (<i>P</i> = .008). <h3>Conclusions and Relevance</h3> In this survey study, COVID-19 was associated with large reductions in economic security among women at high risk of HIV infection in Kenya. However, shifts in sexual behavior may have temporarily decreased their risk of HIV infection.
Adverse consequences of the COVID-19 pandemic on breast cancer stage distribution and breast cancer disparities.
Authors: Genevieve A. Fasano, Yalei Chen, Solange Bayard, Melissa Davis, Vivian Bea, Michele B. Drotman, Elizabeth Kagan Arleo, Jennifer Marti, Manmeet Malik, Rache M. Simmons, Alexander J. Swistel, Rulla Tamimi, Lisa A. Newman
Journal: Journal of Clinical Oncology (2021)

10555 Background: The COVID-19 surge in March 2020 resulted in a hiatus placed on screening mammography programs in support of shelter-in-place mandates and diversion of medical resources to pandemic management. The COVID-related economic recession and ongoing social distancing policies continued to influence screening practices after the hiatus was lifted. We evaluated the effect of the hiatus on breast cancer stage distribution on the diverse patient population of a health care system in New York City, the first pandemic epicenter in the United States. Methods: Breast cancer patients diagnosed January 1, 2019 to December 31, 2020 were analyzed, with comparisons of stage distribution and mammography screen-detection for three intervals: Pre-Hiatus, During Hiatus (March 15, 2020 to June 15, 2020), and Post-Hiatus. Results were stratified by African American (AA), White American (WA), Asian (As) and Hispanic/Latina (Hisp) self-reported racial/ethnic identity. Results: A total of 894 patients were identified; of these, 549 WA, 100 AA, 104 As, and 93 Hisp comprised the final race/ethnicity-stratified study population. Overall, 588 patients were diagnosed Pre-Hiatus, 61 During-Hiatus, and 245 Post-Hiatus. Nearly two-thirds (65.5%) of the Pre-Hiatus cases were screen-detected versus 49.2% During-Hiatus and 54.7% Post-Hiatus (p = 0.002). Frequency of tumors diagnosed &lt; 1 cm declined from 41.9% Pre-Hiatus to 31.7% Post-Hiatus (p = 0.035). WA patients were more likely to have screen-detected disease compared to AA in the Pre-Hiatus period (69.1% vs. 56.1%; p = 0.05) but non-significantly more likely to have screen-detected disease compared to As and Hisp patients (66.2% vs. 56.9%; p = 0.08). In the Post-Hiatus period, the frequency of screen-detected disease was highest among WA patients (63.0%) compared to all other racial/ethnic groups (AA; 48.1%, As-33.3%, and Hisp-40%; p = 0.007). Similar patterns were observed for frequency of tumors diagnosed ≤1cm Pre-Hiatus (WA-44.3% vs AA-26%, p = 0.02; and vs. As-41.3%, Hisp-48%; p = 0.09), and Post-Hiatus (WA-37.7% vs. AA-18.2%, As-30.8%, Hisp-23.5%; p = 0.25). Conclusions: The 3-month pandemic-related mammography screening hiatus resulted in a more advanced stage distribution for New York City breast cancer patients, and worsened pre-existing race/ethnicity-associated disparities, especially for AA pts.
Pneumococcal vaccine uptake and vaccine effectiveness in older adults with invasive pneumococcal disease in Germany: A retrospective cohort study
Authors: Stephanie Perniciaro, Mark van der Linden
Journal: The Lancet Regional Health - Europe (2021)

Invasive pneumococcal disease (IPD) in people ≥60 years old is on the rise in Germany. There has been a recommendation for pneumococcal vaccination in this age group since 1998.
Extracting knowledge of NCI research directions from funding data using language processing.
Authors: Peter Beidler, Mark Nguyen, John Kang
Journal: Journal of Clinical Oncology (2021)

e13547 Background: In fiscal year (FY) 2019, 42% of the $6 billion NCI budget went towards nearly 5,000 research project grants, of which about 60% are R01 type. Given the enormity of allocated resources, there is a need for the scientific community to have a more rigorous understanding of the cancer research landscape. While the NCI Budget Fact Book publishes statistics based on pre-designated codings, it is unclear if this method yields the best representation of fields within oncology. Open questions include: how many distinguishable areas of cancer research are being funded? Are there differences in growth rate, publication rate and geographic distribution among those areas? Addressing these questions in a systematic manner is a well-suited problem for unsupervised machine learning. Methods: We analyzed 55,362 R-type grants from FY 2010-2021 (up to 1/31/21) from NIH ExPORTER. Preprocessing was done on ‘Project Terms’ to weight their importance using TF*IDF vectorization and principal component analysis. We used minibatch K-means clustering repeated 100 times, with the best iteration chosen by Calinski-Harabasz clustering quality score. Over 100 repetitions, the Adjusted Rand Index was 0.9907±0.0037 (mean ±standard deviation), indicating robustness to initial conditions of K-means. For publication rate analysis, FY 2020 and 2021 grants were excluded, and 2021 grants were excluded for trajectory analysis. Optimal cluster number was determined based on a combination of inertia, Calinski-Halabasz, and silhouette scores. Results: We found the optimal number of 24 clusters to best represent separation of the R-type grant research directions. These 24 clusters clearly represent topics such as immunotherapy, cohort risk-factor studies, and imaging. Notable trends include increased funding of immunotherapy and targeted inhibitor clusters averaging +$9.9M and +$9.2M growth per year respectively over 10 years, and decreased funding of pathway regulation and genetics clusters averaging -$7.8M and -$5.7M per year. These examples suggest a broader trend that funding is shifting from basic to translational science. Further analysis shows that the targeted inhibitor cluster is most geographically skewed, with 30% of grants going to institutions in just three cities. The number of journal articles (per grant) also shows a bias, with development/training and genetics clusters having publication rates of 32.6 and 20.8 and randomized control trials having a publication rate of 6.3. The average publication rate of NCI was 14.8. Conclusions: Using a novel framework for unsupervised clustering of NCI grant key-phrases, we can organize research projects more holistically than keyword searching, and more efficiently than manual categorization. Our model identifies growing and shrinking areas of research and points out biases in location and publication rate across these areas.
Efficacy of TIP (paclitaxel, ifosfamide and cisplatin) as salvage chemotherapy for relapsed germ cell cancer patients stratified by the modified International Prognostic Factors Study Group (IPFSG) score: The Northern Ireland (NI) Experience.
Authors: Adam Uprichard, Julie-Anne Scott, James Mcaleer, Judith Carser, Olabode Oladipo
Journal: Journal of Clinical Oncology (2021)

5028 Background: Salvage therapy for relapsed or refractory germ cell tumours (GCTs) after first-line treatment (1LT) failure remain controversial. The ongoing TIGER trial aims to compare conventional-dose chemotherapy (CDCT) using TIP with high-dose chemotherapy (HDCT) and to validate a modified version of the IPFSG stratification system as a secondary objective. We retrospectively analysed data from patients treated with TIP at our institution and stratified by the modified IPFSG (mIPFSG) groupings, correlating this with clinical outcomes. Methods: Data from all GCT patients who received TIP in NI between 2005 and 2014 was collected. Patients were scored using known IPFSG factors including progression-free interval (0-1), metastasis site (0-3), response to 1LT (0-2), primary tumour site (0-3), HCG (0-1), AFP (0-2), and histology (-1 to 0), and categorised into the modified strata. Descriptive and inferential statistics using SPSS compared survival measure outcomes and the favourable response rate (FRR) i.e the proportion of patients achieving either a complete response or partial response with normal serum tumour markers, according to mIPFSG group. Results: Thirty patients were identified, all of whom received 4 cycles of TIP. The median age was 37 years (range 17-57), 28 patients were non-seminoma histology with 2 patients seminoma. The cohort comprised predominantly of patients with more adverse mIPFSG features and the FRR of the group was 30%, with a median progression-free survival (PFS) of 9 months and 2-year overall survival (OS) of 50%. Clinical outcomes differed by mIPFSG score as shown below. Conclusions: Our study shows TIP efficacy comparable to published data, and to our knowledge is the first to show correlation between clinical outcomes with the regimen and the new mIPFSG model. The differences in outcomes to CDCT using TIP across risk groups in real world practice shows potential for a stratified approach to patient selection for salvage therapy, as is under investigation by the TIGER study.[Table: see text]
Identifying and Tracking SARS-CoV-2 Variants — A Challenge and an Opportunity
Authors: Scott J. Becker, Jill Taylor, Joshua M. Sharfstein
Journal: New England Journal of Medicine (2021)

Identifying and Tracking SARS-CoV-2 Variants Funding designated for increasing understanding of SARS-CoV-2 variants could be used in ways that would help guide the current pandemic response and yie...
Inflammatory signaling regulates hematopoietic stem and progenitor cell development and homeostasis
Authors: Amélie Collins, Carl A. Mitchell, Emmanuelle Passegué
Journal: The Journal of Experimental Medicine (2021)

Inflammation exerts multiple effects on the early hematopoietic compartment. Best studied is the role of proinflammatory cytokines in activating adult hematopoietic stem and progenitor cells to dynamically replenish myeloid lineage cells in a process known as emergency myelopoiesis. However, it is increasingly appreciated that the same proinflammatory signaling pathways are used in diverse hematopoietic scenarios. This review focuses on inflammatory signaling in the emergence of the definitive hematopoietic compartment during embryonic life, and tonic inflammatory signals derived from commensal microbiota in shaping the adult hematopoietic compartment in the absence of pathogenic insults. Insights into the unique and shared aspects of inflammatory signaling that regulate hematopoietic stem and progenitor cell function across the lifespan and health span of an individual will enable better diagnostic and therapeutic approaches to hematopoietic dysregulation and malignancies.