tbuckley/cabot-search huggingface dataset:
Multiomic, plasma-only ctDNA NGS assay for minimal residual disease (MRD) detection in solid tumors.
Authors: Jessica Kurata, Kristin Sedgwick Price, Kimberly Banks, Elena Zotenko, Dustin Hite, Donavan Cheng, Princy Parsana, Jin Hyun Ju, Tara Dinman, Zong Miao, AmirAli Talasaz
Journal: Journal of Clinical Oncology (2021)

3045 Background: Detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) post-curative intent treatment is predictive of recurrence in many solid tumors. Due to biological challenges with low ctDNA shed in early-stage disease and potential to detect non-tumor derived alterations in plasma (e.g. CHIP), most ctDNA MRD assays are dependent on a priori knowledge of genomic alterations from tumor tissue to achieve high sensitivity and specificity. Tissue-dependent methods limit the clinical application of a MRD assay, especially in cancer types where tissue biopsy is challenging, neoadjuvant therapy (NAT) is standard of care, and/or rapid turnaround times are needed for clinical decision making. We previously validated an assay (Guardant Reveal) that combines somatic and epigenomic analysis to detect ctDNA from early-stage colorectal tumors without tumor tissue or peripheral blood cells. Here we describe the expansion of this assay to detect MRD across multiple tumor types. Methods: Cell-free DNA (cfDNA) fragments are extracted from patient plasma, partitioned based on methylation fraction, enriched using a panel to target informative genomic and epigenomic regions, barcoded, and pooled for sequencing. Methylation status is determined non-destructively and with minimal loss of molecules, allowing sensitive genomic and epigenomic analysis of the same cfDNA fragments. A single assay with a total panel size of 5.3 Mb was developed for MRD analysis in multiple cancer types, including CRC, Lung and Bladder. A “ctDNA detected” result is defined by the de novo identification of tumor-derived somatic variants and/or the observation of a tumor-specific methylation profile exceeding predefined thresholds. Results: The assay performance was tested using 163 pre-treatment clinical samples from patients with early-stage non small cell lung cancer (NSCLC) and bladder cancer and 133 self-declared healthy donors. Sensitivity for pre-treatment detection in NSCLC was 68.9% at 95% specificity (20/42 Stage I: 47.6%, 25/30 Stage II: 83.3%, 19/21 Stage III: 90.5%). Sensitivity for bladder cancer was 44.2% at 95% specificity (13/43 NMIBC: 30.2%, 18/27 MIBC: 66.7%). Additional development from larger cohorts and other tumor types is ongoing and data will be presented as available. Conclusions: Using cancer-specific genomic and epigenomic signals combined with learning-based classifiers, we developed a highly specific method for detecting the presence of ctDNA in early-stage NSCLC and bladder cancer patients from plasma without the need for tumor tissue but with comparable sensitivities to tissue-dependent approaches. A plasma-only MRD assay will allow for greater clinical impact by overcoming the challenges of tissue procurement, particularly following NAT, and enabling faster time to results.
Effect of selenium on melanoma cells
Authors: Pamela Cassidy, Heidi Fain, James Cassidy, Sally Tran, Philip Moos, Sancy Leachman
Journal: Cancer Research (2008)

4677  Selenium shows great promise as a chemopreventive agent for a number of different cancers including those of the prostate, colon and lung. However, the failure of an oral selenium supplement to prevent melanoma and non-melanoma skin cancers in the Nutritional Prevention of Cancer trial of 1996 was particularly disappointing in light of the fact that skin cancer prevention was the primary goal of that trial. In the course of our own studies of potential agents for prevention of melanoma, we found that the sensitivity of melanoma cells in culture to the effects of selenium was comparable to those reported for other tumor types. In our work, we use methylseleninic acid (MSA), a form of selenium that efficiently delivers the selenium metabolite methyl selenol to cells in culture, to study the effects of selenium on cell lines derived from both primary and metastatic melanomas. We have found that as is the case for other tumor types, MSA causes the activation of the unfolded protein response (UPR) in melanoma cells, and we have examined and characterized the major aspects of this response, i.e. increased production of chaperones, attenuation of general protein translation, and activation of IRE-1 and CHOP/Gadd-153. During the course of these examinations, we discovered that MSA treatment results in a decrease in levels of anti-apoptotic proteins. Perturbation of the levels of these proteins activates both the extrinsic and intrinsic apoptotic pathways and causes caspase-dependent apoptosis. We hope to use these observations to guide our efforts to design and evaluate new strategies for the use of selenium for the prevention and treatment of melanoma.
Bridging the gaps between tertiary and community care networks: Results from a southern California survey research analysis.
Authors: Alex Chehrazi-Raffle, Nicholas Salgia, Joann Hsu, Zeynep Busra Zengin, Sabrina Salgia, Neal Chawla, Jasnoor Malhotra, Nazli Dizman, Ramya Muddasani, Luis A Meza, Mary E. Cianfrocca, Jun Gong, Sidharth Anand, Victor Yundeh Chiu, James Jen-Chi Yeh, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2021)

1538 Background: Although many tertiary cancer centers offer access to myriad research protocols, the majority of patients nevertheless receive treatment at community practices. We sought to examine the barriers that hamper clinical collaboration between tertiary and community practice environments in Southern California. Methods: A 31-item survey was distributed to community and tertiary oncologists using REDCap, a browser-based electronic data capture system. Survey questions assessed the following attributes: demographics and features of clinical practice, referral patterns, availability and knowledge pertaining to clinical trials, strategies for knowledge acquisition, and integration of community and tertiary practices. Results: The survey was distributed to 98 oncologists, 85 (87%) of whom completed it in full. The most common institutional affiliations were City of Hope Comprehensive Cancer Center (58%), University of California, Los Angeles (10%), and Cedars Sinai Medical Center (8%). In total, 52 (61%) respondents were community practitioners and 33 (38%) were tertiary oncologists. A majority (56%) of community oncologists defined themselves as general oncologists whereas almost all (97%) tertiary oncologists reported a subspecialty. Clinical trial availability was the most common reason for pt referrals to tertiary centers (73%). The most frequent barrier to tertiary referral was financial considerations (59%). Clinical trials were offered by 97% of tertiary practitioners as compared to 67% of community oncologists (p = 0.001). Of note, while a majority of tertiary center providers (52%) described the primary value of community practices to be a source of referrals for clinical trials, most community oncologists (82%) reported only a minimal-to-moderate understanding of clinical trials available at regional tertiary centers. Conclusions: Community oncologists refer patients to tertiary centers primarily with the intent of clinical trial enrollment; however, significant gaps exist in their knowledge of trial availability. Our results identify the need for enhanced communication and collaboration between community and tertiary providers to expand patients’ access to clinical trials.
LGG-07. IS BRAF ALTERATION OR A HISTOLOGIC ‘QUALIFIER’ A PREDICTOR OF OUTCOME IN PEDIATRIC PILOCYTIC ASTROCYTOMA?
Authors: Samuel J Cler, Alexander Skidmore, Alexander T Yahanda, Ali Mian, Kimberly Mackey, Sonika Dahiya, Jennifer Strahle
Journal: Neuro-Oncology (2021)

Abstract Introduction Pediatric pilocytic astrocytomas (PA) are the most common pediatric central nervous system tumor. Surgical resection is the primary treatment for PA with five-year survival rates up to 95%. Despite a favorable prognosis, our understanding about the prognostic value of histopathological findings, such as histopathologic qualifier* or BRAF alterations is evolving. Methods Patients treated for a WHO grade 1 PA at Washington University in St. Louis/St. Louis Children’s Hospital were analyzed for clinical details, including pathology diagnosis (*histopathologic qualifier refers to designations in the diagnosis such as “WHO Grade I pilocytic astrocytoma with increased proliferative index”). BRAF alterations include gene fusions and point mutations. Results 224 patients were analyzed (51% female, mean age 9.6 years). Tumors were located in the cerebellum/fourth ventricle (50%), optic pathway/hypothalamus (15%), brainstem (12%), and cerebral cortex (11%). BRAF alterations were identified in 55/77 patients (71.4%) and additional histopathologic qualifiers were present in 27/220 patients (12.3%). 196 patients (87.5%) underwent surgical treatment and 22 (9.8%) had biopsy alone. 45 patients (22%) displayed tumor progression or recurrence after resection. The presence of a histopathologic ‘qualifier’ in the topline or BRAF alteration was not associated with tumor progression or recurrence (p=0.36, p=0.77). Ki-67 proliferative indices were not predictive of progression or recurrence (p=0.94), including when controlling for extent of resection and adjuvant therapy. BRAF alterations, specifically KIAA1549 fusions, were associated with cerebellar/fourth ventricular tumor location (p&amp;lt;0.001) and younger patient age (p=0.03). Extent of resection was the only predictor of outcome identified in this study; patients with gross total resection had significantly lower rates of progression and recurrence (p&amp;lt;0.0001). Conclusion BRAF alterations and histopathologic qualifiers were not associated with tumor progression or recurrence in pediatric PA, although BRAF fusions were more common in tumors located in the cerebellum/fourth ventricle and in younger patients.
Bioinspired therapeutic platform based on extracellular vesicles for prevention of arterial wall remodeling in hypertension
Authors: Chen Wang, Changyang Xing, Zhelong Li, Yunnan Liu, Qiaoying Li, Yixiao Wang, Jiao Hu, Lijun Yuan, Guodong Yang
Journal: Bioactive Materials (2021)

Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure, and its physiopathologic mechanism is still not fully understood. We here aimed to explore whether extracellular vesicle (EV) mediated intercellular communication between endothelium and smooth muscle cell contribute to the blood vessel remodeling under hypertension. We here revealed that the arterial endothelial cells robustly secreted EV, which in turn could be circulated and/or directly taken up by the subendothelial smooth muscle cells (SMC). Under hypertension, the EV secretion increased and the miRNA profile changed significantly mainly due to the raised mechanical force and subsequent enhanced reactive oxygen species generation. Among the miRNA cargos in the EV, miR-320d/423-5p were found increased most significantly. In vivo delivery of miR-320d/423-5p mimics via engineered EV increased their expression in arterial vessels, recapitulating the phenotype in hypertension. In contrast, therapeutic delivery of miR-320d/423-5p inhibitors via engineered EV alleviated the phenotype in spontaneous hypertension rat model. Together, we have found that the injured endothelium due to the raised mechanical force in hypertension contributes to the arterial wall remodeling via the secreted EV. Our study has not only provided novel insights on the mechanism of hypertension associated blood vessel wall remodeling, but also shed light on therapeutic intervention of hypertension associated vascular diseases.
Rajinder Prasad Bhutiani
Authors: Nidhi Bhutiani, Akshay Bhutiani, Aleka Bhutiani
Journal: BMJ (2021)

It is with our deepest sorrow that our family informs you of the peaceful passing of Rajinder Prasad Bhutiani (“Raj”) at the Royal Brompton Hospital. Having contracted covid-19 in the course of his NHS duties caring for patients, Raj was admitted to Northwick Park Hospital on 31 March 2020 and later to Harefield Hospital and then the Royal Brompton Hospital.

Raj showed tremendous and relentless strength, courage, and determination to overcome covid-19 successfully and make a full recovery. On countless occasions, he defied the challenging odds that he faced and the modern understanding of medicine. A senior consultant who had a pivotal role in Raj’s battle for recovery said that Raj was an incredibly strong man, an inspiration …
Palliative radiotherapy referrals in the last days of cancer patients' life: Could we do better?
Authors: Leora Brazg Ferro, Eliya Shachar, Orit Gutfeld, Ido Wolf, Yasmin Natan Oz
Journal: Journal of Clinical Oncology (2021)

e24008 Background: The role of active cancer therapy towards the end of life (EOL) is debatable and may even be considered harmful. While palliative radiotherapy may be highly effective in reducing cancer-related symptoms of advanced disease, the beneficial effects are usually at least 2-4 weeks from completion of treatment. Thus, radiotherapy administered at the end of life is often ineffective, and may actually impair quality of life and be associated with an unnecessary burden to the health care system. The universal Israeli health care system enables the administration of radiotherapy without financial or regulatory barriers, even at EOL. We aimed to assess the use radiotherapy towards EOL in a tertiary care Israeli cancer center. Methods: We retrospectively analyzed data of patients receiving palliative radiation and died within 30 days of their simulation from March 2019 until September 2020. Results: Out of approximately 2,000 patients treated with radiotherapy during the study period, 148 (8%) patients were referred for palliative radiation and died within 30 days of their simulation. The majority (88, 59.5%) were male, the median age was 67.3 years and the most common malignancies patients suffered from were lung cancer (49, 33.1%), gastrointestinal tumors (28, 18.9%), genito-urinary malignancies (23, 15.5%) or breast cancer (15, 10.1%). The median ECOG PS was 3. Nineteen patients (12.8%) did not initiate radiation treatment plan, 24 patients (16.2%) completed less than half of the planned treatment and 89 patients (60.1%) completed the entire duration of treatment. Of the patients who completed the planned therapy, 34 patients (38.2%) received a single fraction protocol. The majority of patients (89, 60.1%) were referred to the radiation unit by their treating medical oncologists or hemato-oncologist. None of the patients were referred by palliative care team members at our center. Most (105, 70.9%) received previous systemic therapies; but less than half (48, 45.7%) were under active treatments within a month prior to the radiation simulation. Conclusions: Relatively large number of patients with advanced malignancies are referred for futile palliative radiotherapy during the last 30 days of their life, thus impairing their quality of life and creating an unnecessary burden on public health services. These patients are often being referred by their treating oncologists who are familiar with their oncological history. These findings call for the implementation of collaborative multi-disciplinary teams, primarily directed at optimizing care at the end of life, setting achievable treatment goals, and improving quality of life.
Notch Signaling Controls Drug Response in B-Cell Acute Lymphoblastic Leukemia (B-ALL)
Authors: Paul Takam Kamga, Giada Dal Collo, Martina Midolo, Annalisa Adamo, Alessandro Gatti, Roberta Carusone, Elda Mimiola, Angela Mercuri, Massimiliano Bonifacio, Mauro Krampera
Journal: Blood (2017)
Recurrence rate according to Oncotype Dx recurrence score (RS) in women with estrogen receptor (ER) positive, Her2 negative and 1 to 3 positive nodes: Real-world data in a Mexican private institution.
Authors: Geovani Amador, Raul Alejandro Andrade Moreno, José Fabián Martínez-Herrera, Raquel Gerson, Juan Alberto Serrano
Journal: Journal of Clinical Oncology (2021)

e12536 Background: Oncotype Dx is a 21 gene assay that evaluates de expression of 21 genes associated with recurrence in early breast cancer (EBC). In women with ER positive, HER2 negative and no lymph node involvement, it has demonstrated it prognostic value and has shown to predict the benefit of adjuvant chemotherapy in high-risk patients, sparing toxicity to patients with low risk of recurrence. Nevertheless, in women with ER positive, HER2 negative and 1 to 3 nodes, the role of de 21 gene assay was not clear until recently. Methods: Retrospective review of medical records of patients with ER +, HER2 negative and 1 to 3 positive nodes breast cancer treated at our institution. Clinicopathological characteristics and 21 gene recurrence score (RS) were collected and a survival analysis by the Kaplan-Meier method was performed in patients with RS &lt; 25 and according to menopausal status as in RxPONDER in SPSS v 25.0 IBM. Results: From January 2008 to December 2018, data from 136 patients with EBC clinical stage (IA-IIB), HR +/ HER2-, N0-1 with Oncotype Dx performed were collected, of which only 25 patients had 1-3 nodal involvement and were included in the statistical analysis. Mean age at diagnosis was 54 years (35-73), the most frequent histology in the general population was invasive ductal carcinoma (92.0%), followed by lobular carcinoma (8.0%), 72.0% of patients presented in stage IIA, followed by stage IB in 20.0%. RE were positive in all patients and progesterone receptors were positive in 72.0%, none of the patients had HER2 overexpression, mean Ki-67 expression was 17.4% (4.0-50.0%). Most tumors were modemoderately differentiated (72.0%). Lymphovascular and perineural invasion were present in 44.0% and 24.0% respectively. Follow up data was available for 17 patients of which 12 had a RS of 25 or less. Recurrence was present in only 3 patients in this group of patients representing 25%. During the first 5 years only 1 patient recurred, which represents a 5-year Recurrence rate (RR) of 8.3% with a 5-year RFS of 91.7%. 10-year Recurrence free survival (RFS) was 75.0% with a median RFS that has not been reached. RFS was 80.0% in postmenopausal women compared 71.4% for those premenopausal at 10 years follow-up (p=0.735). None of the patients in this group received adjuvant chemotherapy. Conclusions: We report our experience at a comprehensive cancer center in a time lapse of 10 years. RFS at 5 years was 91.7% and at 10 years of follow up was 75%. This in accordance with the results of RxPONDER trial that reported a 5-year progression free survival of 92.4% in patients with chemo-endocrine adjuvant therapy and 91.0% in patients in the endocrine therapy only arm. This supports the use of this trial for decision making outside of the controlled clinical trials setting.
Early impact of lung cancer screening program.
Authors: Isabel M. Emmerick, Feiran Lou, Maggie M. Powers, Keren Guiab, Bryce Bludevich, Poliana Lin, Mark Maxfield, Karl Uy
Journal: Journal of Clinical Oncology (2021)

e18677 Background: Lung cancer has the highest mortality among the leading cancers in the U.S. Its detection in the early stages is one of the strategies to increase survival. This study aims to identify whether the implementation of a structured Lung Cancer Screening Program impacted the percentage of Early Stage Lung Cancer Diagnosis (ESLCD). Methods: Retrospective cohort study aiming to identify changes over time considering the following indicators: a) percentage of ESLCD; b) the percentage of lung resections for ESLCD. In October 2019, there was a restructuring of our institutional Lung Cancer Screening Program (LCSP). We analyzed quarterly incident lung cancer cases at our institution between October 2017 and December 2019. Descriptive, bivariate, and multivariate analyses were performed. Results: Our cohort comprised 736 patients. The age average was 69.3 years, 54.6% female, 96.5% white. Clinical Stage 1A to 2B corresponded to 43.3% of patients. 71.9% had their diagnosis and treatment in the institution. Factors associated with ESLCD were being in the LCSP (OR 4.4 [95%CI 2.3-8.1]); diagnosis and treatment in the institution (OR 2.2 [95%CI 1.6-3.2]); having 3 or less comorbidities (OR 1.6 [95%CI 1.2-2.1]) and female (OR 1.4 [95%CI 1.1-1.9]). In the last Quarter of 2017, the percentage of ESLCD through LCSP was 2.6%, and in the last Quarter of 2019 (2019Q4), 28.8%, representing a 1025% growth. Also, in 2019Q4, 44.8 % of the ESLCD cases that had surgery came through the LCSP, which is a significant increase from prior quarters. Conclusions: The restructuring of our LCSP may have resulted in an increase in ESLCD and the number of curative surgeries for Lung Cancer. Identification of opportunities for improvement of health care delivery can help to increase ESLCD; a longer time for follow-up is needed to observe if the upward trend is sustained and its effects on patient survival. Selected indicators by quarter, 2017 to 2019.[Table: see text]
Electric fan use for cooling during hot weather: a biophysical modelling study
Authors: Nathan B Morris, Georgia K Chaseling, Timothy English, Fabian Gruss, Mohammad Fauzan Bin Maideen, Anthony Capon, Ollie Jay
Journal: The Lancet Planetary Health (2021)

BackgroundIn hot weather, electric fans can potentially provide effective cooling for people, with lower greenhouse gas emissions and cost than air conditioning. However, international public health organisations regularly discourage fan use in temperatures higher than 35°C, despite little evidence. We aimed to determine humidity-dependent temperature thresholds at which electric fans would become detrimental in different age groups.MethodsWe used biophysical modelling to determine the upper humidity-dependent temperature thresholds at which fan use would become detrimental (ie, worsen heat stress) for healthy young adults (aged 18–40 years), healthy older adults (aged ≥65 years), and older adults taking anticholinergic medication. We also obtained hourly environmental data for the period Jan 1, 2007, to Dec 31, 2019, for 108 populous cities to determine the number of days fan use would be effective for cooling, standardised to a 31-day hot weather month. We established simplified temperature thresholds for future fan use recommendations on the basis of temperatures below which fan use would never have been detrimental between Jan 1, 2007, and Dec 31, 2019, across all prevailing levels of ambient humidity.FindingsAccording to our model, fan use would have been beneficial on 30·0 (96·6%) of 31 hot weather days for healthy young adults and 29·4 (94·9%) of 31 hot weather days for both older adults and older adults taking anticholinergic medication between Jan 1, 2007, and Dec 31, 2019. Adherence to the current WHO recommendation of fan use below temperatures of 35°C only, fan use would have been recommended on 27·2 days (87·7%) of 31 hot weather days. According to our simplified thresholds for fan use (at temperatures <39·0°C for healthy young adults, <38·0°C for healthy older adults, and <37·0°C for older adults taking anticholinergic medication), fan use would have been recommended on 29·6 (95·5%) of 31 hot weather days in healthy young adults, 29·4 (94·8%) days in healthy older adults, and 28·8 (93·0%) days in older adults taking anticholinergic medication between Jan 1, 2007, and Dec 31, 2019.InterpretationElectric fan use, particularly for healthy young adults, would not have worsened heat stress on the majority of study days between 2007 and 2019. Our newly proposed thresholds for fan use provide simple guidelines that improve future heatwave fan use recommendations.FundingNone.