tbuckley/cabot-search huggingface dataset:
ATRT-07. DEFINING LOST AND GAINED TRANSCRIPTIONAL REGULATORY NETWORKS IN ATYPICAL TERATOID RHABDOID TUMOR
Authors: Cody Nesvick, Liang Zhang, Alex Wixom, Feda Hamdan, Steven Johnsen, David Daniels
Journal: Neuro-Oncology (2021)

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system cancer of infancy and early childhood that may occur anywhere along the neuraxis and is associated with a high rate of mortality. While contemporary multimodal therapeutic approaches have significantly improved overall survival, targeted therapy remains elusive, and treatment is often associated with significant morbidity. ATRT is unique in its genomic stability, with the only recurrent genetic abnormality being bi-allelic loss of the SMARCB1 gene, which encodes a core subunit of the BAF chromatin remodeling complex. The epigenetic mechanisms by which SMARCB1 loss leads to tumorigenesis are not yet well-defined and addressing this gap in understanding is necessary for creating efficacious, targeted therapeutics. To better understand the epigenetic features gained and lost in ATRT, we re-expressed SMARCB1 in a library of patient-derived and established ATRT cell lines of multiple molecular subtypes. SMARCB1 restoration significantly reduced or eliminated the proliferative and clonogenic capacity of each cell line. We performed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) and RNA sequencing (RNA-Seq) to define putative transcriptional regulatory networks that are gained and lost in ATRT. SMARCB1 restoration was associated with global changes in chromatin openness consistent with the creation of new regulatory elements throughout the genome, and these were associated with induction of a diverse developmental transcriptional signature. Motif enrichment analysis of regions with increased accessibility defined a small but consistent number of centrally enriched transcription factor motifs across cell lines indicative of putative pioneer factors whose functions may be lost in ATRT. Pertinent chromatin immunoprecipitation with sequencing (ChIP-Seq) data will be discussed in the context of lost and gained transcriptional regulatory networks in ATRT and normal cellular development.
Laser ablation of multifocal breast carcinoma: Assessing viability for patients not accepting surgery.
Authors: Rusy Bhalla
Journal: Journal of Clinical Oncology (2021)

e12584 Background: Breast carcinoma is a major public health problem in India and world. It is the leading cause of cancer in women in India. The overall 5 year survival rate in western countries is over 90%. In India it drops to 40 to 60%. The various factors responsible for this include presenting late due to unacceptability of many women for mutilation of their breasts. Breasts being a very important feminine cosmetic benchmark. Methods: Laser ablation of Breast tumours is now a USFDA and CE approved procedure. The aim of this observational study was to observe completion of tumour ablation by intralesional laser ablation. Laser Ablation was performed as a single procedure in 10 women over a 7 year period. All women who consented to the procedure were in stage late stage 2 and 3 with multifocal and/or multilocational disease. As such they were not candidates for Breast Conservation surgery. Pre laser PET scans confirmed the absence of Metastatic disease outside breast and Axilla. Results: All Post Menopausal patients showed a complete necrosis of the tumour and axillary lymph nodes on a follow up of 2 to 7 years. The findings were confirmed on serial PET scans after 6 months and 2 years. Pre menopausal women showed recurrence in non laserised areas and were given follow up Laser Ablation procedure. Conclusions: Laser Ablation is a viable procedure for patients unwilling for mastectomy in stage 3 Breast cancer. The skill sets required for the procedure are new and surgeons will have to be trained for the procedure.
Independent validation of simbiosys tumorscope to predict response to neoadjuvant chemotherapy (NACT) in early breast cancer (EBC).
Authors: Gong He, Frederick Howard, Tushar Pandey, Hiroyuki Abe, Rita Nanda
Journal: Journal of Clinical Oncology (2021)

582 Background: Despite substantial advances in the understanding of breast cancer biology, the decision to use NACT for EBC is based on tumor size, lymph node status, and subtype. Even with aggressive therapy, the majority of women will not achieve a pathologic complete response (pCR). Investigational treatment regimens, including immunotherapy, can increase pCR rates, but are associated with irreversible immune-related toxicities. Being able to accurately predict pCR could identify candidates for intensification or de-escalation of NACT, allowing for personalized medicine. SimBioSys TumorScope (TS) is a biophysical model that utilizes baseline MRI, receptor status, and planned treatment regimen to simulate response to NACT over time. TS has demonstrated accurate prediction of pCR in prior studies. Here, we describe an independent external validation of TS. Methods: We conducted a retrospective study of University of Chicago patients (pts) who received NACT for EBC from Jan 2010 - March 2020. Pts must have had a pretreatment breast MRI. Tumors were analyzed using TS by investigators who were blinded to response data. TS predicted pCR was predefined as a residual tumor volume &lt; 0.01 cm 3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. Results: 144 tumors from 141 pts were analyzed. Average age was 52 yrs; 65% had stage II and 19% had stage III disease. Sensitivity and specificity of TS for predicting pCR were 90.4% and 92.4%, respectively. Of the 7 patients who were predicted to achieve a pCR but did not, 5 had a tumor cellularity &lt; 5%. With a median follow-up of 4.7 yrs, the 4-yr distant disease free survival (DDFS) was 100% for patients predicted to achieve pCR, versus 81.5% for those predicted to have residual disease. Results were generally robust for all subgroups analyzed (Table). Conclusions: TS accurately predicts pCR and DDFS from baseline MRI and clinicopathologic data. Given the high sensitivity and specificity of this assay across breast cancer subtypes, TS can be used to aid in escalation/de-escalation strategies for EBC.[Table: see text]
Mitochondrial disease in adults: recent advances and future promise
Authors: Yi Shiau Ng, Laurence A Bindoff, Gráinne S Gorman, Thomas Klopstock, Cornelia Kornblum, Michelangelo Mancuso, Robert McFarland, Carolyn M Sue, Anu Suomalainen, Robert W Taylor, David R Thorburn, Doug M Turnbull
Journal: The Lancet Neurology (2021)
Local progenitor cells shape the neoplastic vasculature and promote brain tumor growth.
Authors: Roland Kälin, Linzhi Cai, Dongxu Zhao, Huabin Zhang, Wenlong Zhang, Sabrina Kirchleitner, Sebastian Siller, Wolfgang Enard, Matthias Schiemann, Immanuel Andrä, Claudio Giachino, Verdon Taylor, Michael Synowitz, Joerg Tonn, Louisa von Baumgarten, Ines Hellmann, Rainer Glass
Journal: Journal of Clinical Oncology (2021)

e14044 Background: Aggressive brain tumors like glioblastoma depend on support by their local environment. While the role of tumor-associated myeloid cells on glioblastoma progression is well-documented, we have only partial knowledge of the pathological impact of glioblastoma -parenchymal progenitor cells. Methods: We investigated the glioblastoma microenvironment with transgenic lineage-tracing models ( nestin-creER2, R26-tdTomato and sox2-creER2,R26-tdTomato), intravital imaging, single-cell transcriptomics, immunofluorescence and flow-cytometry as well as histopathology and characterized a previously unknown tumor-associated progenitor cell. In functional experiments, we studied the knockout of the transcription factor SOX2 in these tumor-associated cells. Results: Lineage-traced cells from mouse glioblastoma were obtained by flow-cytometry and single cell transcriptomes compared to established gene expression data from brain tumor parenchymal cells. The traced tumor-associated cells had a transcriptomic profile largely resembling myeloid cells and expressed microglia-/macrophage-markers on the protein-level. However, transgenic models and bone-marrow chimera revealed that the traced cells were clearly distinct from microglia or macrophages. The traced tumor associated cells with a myeloid expression profile derived from a SOX2-dependent progenitor cell. Consequently, conditional Sox2-knockout ablated the entire myeloid-like cell population. Remarkably, this tumor-associated cell population had a large impact on disease-progression causing significant reduction of glioblastoma –vascularization to 53%, changing vascular function and leading to a decrease in tumor volume to 42% as compared to controls. The myeloid-like progenitor cells were identified in human brain tumors by immunofluorescence and in scRNA-seq data. Conclusions: We identified a previously unacknowledged population of tumor-associated progenitor cells with a myeloid-like expression profile that transiently appeared during glioblastoma growth. These progenitors have strong impact on glioblastoma progression and point towards a new and promising therapeutic target in order to support anti-angiogenic regimen in glioblastoma.
Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia
Authors: Jan A. Deprest, Alexandra Benachi, Eduard Gratacos, Kypros H. Nicolaides, Christoph Berg, Nicola Persico, Michael Belfort, Glenn J. Gardener, Yves Ville, Anthony Johnson, Francesco Morini, Mirosław Wielgoś, Ben Van Calster, Philip L.J. DeKoninck
Journal: New England Journal of Medicine (2021)

Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease.
Attitudes and Factors Associated With COVID-19 Vaccine Hesitancy Among Patients With Breast Cancer
Authors: Cynthia Villarreal-Garza, Bryan F. Vaca-Cartagena, Andrea Becerril-Gaitan, Ana S. Ferrigno, Fernanda Mesa-Chavez, Alejandra Platas, Ana Platas
Journal: JAMA Oncology (2021)

dose.In this cohort, ipsilateral axillary nodal activity was much less common after the first vaccine dose, and women were more likely to develop reactive nodes, an important implication for breast cancer imaging concordant with the statement issued by the Society of Breast Imaging. 6 Limitations.This was a single institutional study with limited sample size and follow-up, comparing 2 COVID-19 vaccines available at Yale School of Medicine in early vaccination stage.However, the study was conducted by strict and reproducible PET and CT criteria, and provides a framework for the future studies in this field.Conclusions | Ipsilateral axillary nodal reactivity is commonly seen after the intramuscular administration of the COVID-19 mRNA vaccines, more so after the second dose than after the first, and more commonly with the Moderna than the Pfizer vaccine.
Effect of Medicaid expansion on incidence of early-onset colorectal cancer incidence among Hispanics.
Authors: Shafia Rahman, Riya Jayesh Patel, Jianyou Liu, Ana Acuna-Villaorduna, Mimi Kim, Sanjay Goel
Journal: Journal of Clinical Oncology (2021)

3547 Background: Early onset colorectal cancer (EO-CRC, age &lt; 50 years) is an emerging public health crisis; especially in Hispanics. Access to healthcare is critical for timely detection and is tied to medical insurance. In 2010, the Affordable Care Act allowed for expansion of Medicaid eligibility across the country, however, states were permitted to opt out by the US Supreme Court ruling of 2012, which created an unintended experiment in the healthcare market. We evaluated the effects of Medicaid expansion on the incidence of EO-CRC among Hispanics with the hypothesis that it would lead to an increase in incidence and early detection EO-CRC. Methods: The National Cancer Data Base was used to collect data on newly diagnosed Hispanics with EO-CRC (40-49 years), across all stages, from 2010-2017. Data for 21 expansion states (ES) that expanded Medicaid in 2014, and 16 non expansion (NES) states was analyzed. The yearly state-wise Hispanic population was collected from U.S Census Bureau for 2010-17. Incidence was computed as number of new cases of CRC divided by size of the state’s Hispanic population. Segmented Poisson generalized linear mixed effects model was used to analyze rate of change in yearly incidence of EOCRC before and after 2014, in ES and NES. Results: Average annual incidence (AI) of EO-CRC in Hispanics was 6/100,000 and 8/100,000 pre and post expansion, in ES, and 8/100,000 and 9/100,000 pre and post 2014 in the NES, respectively. Increase in AI of EO-CRC was 3.6% per year (2010-14) (95% CI: -0.1% to 7.4%), and 9.8% (2014-17) (95% CI: 5.2% to 14.7%) for ES states; and 6.4% (2010-14) (95% CI: 2.1% to 10.8%), and 1% (2014-17) (95% CI: -3.8% to 6.1%) in NES. ES showed greater change in EO-CRC incidence post expansion (2014) vs. pre-expansion, as compared to NES (p=0.078) table. There was no difference in stage at diagnosis between pre- and pos- expansion periods between ES and NES. Conclusions: Increase in incidence of EO-CRC in ES is likely due to greater access to health care due to Medicaid coverage as compared to NES. Other potential factor is migration of Medicaid eligible persons from NES to ES. However we need data past 2017 to confirm the current trend.[Table: see text]
Cytoprotective effects of spirulina extract against doxorubicin‐induced cardiotoxicity: Biochemical evidences and translational perspectives in cardio-oncology.
Authors: Nicola Maurea, Vincenzo Quagliariello, Andrea Paccone, Michelino De Laurentiis, Simona Buccolo, Martina Iovine, Gerardo Botti
Journal: Journal of Clinical Oncology (2021)

e15042 Background: Spirulina, a blue-green algae used in the daily diet of natives of Africa and America, has antioxidant, anticancer, antiviral, hepatoprotective, immune enhancing and lipid-lowering effects. Considering that doxorubicin-induced cardiotoxicity involves myocardial inflammation, ferroptosis and overexpression of several cytokines involved in cell dead and apoptosis, the use of spirulina during exposure to doxorubicin could be an intriguing method to reduces myocardial injuries in cancer patients undergoing treatment with anthracyclines. Methods: Human fetal cardiomyocytes (HFC cell line) were exposed to doxorubicin (from 10 to 500 nM), alone or in combination with spirulina extract (from 10 to 100 µg/ml) for 24 and 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca 2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Spirulina extract, co-incubated with doxorubicin exerts cardioprotective effects, enhancing cell viability of 20-36.7 % compared to untreated cells (p&lt;0,01 for all); spirulina extract reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms and reduces oxidative damages of doxorubicin resulting in lower intracellular calcium content. Conclusions: For the first time, it was demonstrated that spirulina extract exert anti-inflammatory and cytoprotective properties in myocardial cells exposed to growing concentration of doxorubicin leading to preclinical studies in mice analyzing any effects on cardiac strain and left ventricular ejection function.
A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage
Authors: Jay R. Laver, Diane Gbesemete, Adam P. Dale, Zoe C. Pounce, Carl N. Webb, Eleanor F. Roche, Jonathan M. Guy, Graham Berreen, Konstantinos Belogiannis, Alison R. Hill, Muktar M. Ibrahim, Muhammad Ahmed, David W. Cleary, Anish K. Pandey, Holly E. Humphries, Lauren Allen, Hans de Graaf, Martin C. Maiden, Saul N. Faust, Andrew R. Gorringe, Robert C. Read
Journal: Science Translational Medicine (2021)

The human nasopharynx contains a stable microbial ecosystem of commensal and potentially pathogenic bacteria, which can elicit protective primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica produced safe, sustained pharyngeal colonization. This has potential utility as a vehicle for sustained release of antigen to the human mucosa, but commensals in general are thought to be immunologically tolerated. Here, we show that engineered N. lactamica, chromosomally transformed to express a heterologous vaccine antigen, safely induces systemic, antigen-specific immune responses during carriage in humans. When the N. lactamica expressing the meningococcal antigen Neisseria Adhesin A (NadA) was inoculated intranasally into human volunteers, all colonized participants carried the bacteria asymptomatically for at least 28 days, with most (86%) still carrying the bacteria at 90 days. Compared to an otherwise isogenic but phenotypically wild-type strain, colonization with NadA-expressing N. lactamica generated NadA-specific immunoglobulin G (IgG)- and IgA-secreting plasma cells within 14 days of colonization and NadA-specific IgG memory B cells within 28 days of colonization. NadA-specific IgG memory B cells were detected in peripheral blood of colonized participants for at least 90 days. Over the same period, there was seroconversion against NadA and generation of serum bactericidal antibody activity against a NadA-expressing meningococcus. The controlled infection was safe, and there was no transmission to adult bedroom sharers during the 90-day period. Genetically modified N. lactamica could therefore be used to generate beneficial immune responses to heterologous antigens during sustained pharyngeal carriage.
A 10-item frailty index based on a comprehensive geriatric assessment (FI-CGA-10) in older adults with cancer: Development and construct validation.
Authors: Tomohiro F. Nishijima, Mototsugu Shimokawa, Taito Esaki, Masaru Morita, Yasushi Toh, Hyman B. Muss
Journal: Journal of Clinical Oncology (2021)

e24011 Background: A frailty index based on domain-level deficits in a comprehensive geriatric assessment (FI-CGA) has been previously developed and validated in general geriatric patients (Jones D, Aging Clin Exp Res 2005). Our objectives were to construct an FI-CGA and to assess its construct validity in geriatric oncology setting. Methods: Consecutive older adults with cancer who underwent a CGA on a geriatric oncology service were included. We developed a 10-item frailty index based on deficits in 10 domains (FI-CGA-10): cognition, mood, communication, mobility, balance, nutrition, basic and instrumental activities of daily living, social support and comorbidity. Deficits in each domain were scored as 0 (no problem), 0.5 (minor problem) and 1.0 (major problem). Scores were calculated by dividing the sum of the score of each domain by 10, and categorized as fit ( &lt; 0.2), pre-frail (0.2–0.35), and frail ( &gt; 0.35). Construct validity was tested by comparing the FI-CGA-10 with the following established frailty measures: the Canadian Study of Health and Aging (CSHA) Clinical Frailty Scale (CFS), CSHA rules-based frailty definition and CSHA Function Scale. To evaluate the ability to predict mortality, we tested association between the FI-CGA-10 and validated prognostic indices for mortality: the Lee index and Schonberg index (higher scores reflect a higher risk of mortality). We also examined associations between the FI-CGA-10 and several features commonly seen in frail older adults such as function (Timed Up &amp; Go (TUG) test), cognitive impairment (Mini-Cog), and high comorbidity burden (Charlson Comorbidity Index (CCI)). Results: Of 540 patients (median age 80 years, range 66–96 years), common cancer types were gastrointestinal tract in 37%, hepatobiliary and pancreatic in 22%, and head and neck in 12%. 406 (75%) patients had ECOG PS 0 to 1. The FI-CGA-10 had a right-skewed distribution and was well approximated by the gamma distribution. Overall, 20% of patients were fit, 41% were pre-frail, and 39% were frail. The FI-CGA-10 was highly correlated with CSHA CFS (Pearson's r = 0.83), CSHA rules-based frailty definition (r = 0.67) and CSHA Function Score (r = 0.77). People who were more frail had higher scores on the Lee index (fit: 7.3, prefrail: 8.8, frail: 12.0; p &lt; .0001) and Schonberg index (fit: 10.1, prefrail: 13.1, frail: 15.7; p &lt; .0001), suggesting an increased probability of death. Increasing levels of frailty were significantly associated with a longer TUG (seconds), fit: 11.3, prefrail: 13.0, frail: 26.3; p &lt; .0001, poorer cognitive function (Mini-Cog score, fit: 4.7, prefrail: 4.0, frail: 3.1; p &lt; .0001), and higher comorbidity burden (CCI, fit: 0.8, prefrail: 1.4, frail: 1.9; p &lt; .0001). Conclusions: The FI-CGA-10 is a clinically sensible and construct-validated measure of quantifying frailty from a CGA.