tbuckley/cabot-search huggingface dataset:
Treatment pattern post-osimertinib failure in EGFR mutated NSCLC in India-CRSF202002 study.
Authors: Kushal Gupta, Nirmal Vivek Raut, Gautam Goyal, Avinash Talele, Ashay Karpe, Bhavesh Pradip Poladia, Alok Goel, Ram Abhinav Kannan, Vikas Talreja, Manu Prasad, Trinanjan Basu, Ashish Singh, Rushab Kothari, Arun Chandrasekharan, Deepan Rajamanickam K., Anant Ramaswamy, Joydeep Ghosh, Vipul Doshi, Bharatsinha Baburao Bhosale
Journal: Journal of Clinical Oncology (2021)

e21201 Background: Osimertinib is one of the favoured treatment options in EGFR mutated NSCLC and was established as a treatment option in last 2-3 years. However the treatment pattern post-osimertinib failure is not established. Hence we conducted this audit to study the pattern of treatment post-osimertinib failure in India. Methods: This was a retrospective multi-centric audit of adult (age ≥18 years) EGFR mutated NSCLC patients who were treated with osimertinib and had failed. The treatment pattern of these patients was noted. Descriptive statistics were performed. Median with range was estimated for continuous variables while the percentage with 95% CI were estimated for ordinal and nominal variables. Results: We had 25 patients who had failed on osimertinib. Oligo-progression versus widespread progression was seen in 5 (20%) and 20 (80%) patients respectively. The median age was years 56.5 year (Range-26-71) with 4/25 (16%) of patients were elderly (≥65 years). Male-to-female ratio was 18:7 (72% males, 28% females).The ECOG PS at failure were 0-1 in 12 patients (48%), 2 in 11 patients(44%) and 3-4 in 2 patients (8%) patients. The treatment offered were platinum doublet in 14 patients (56%) with variable combinations with TKIs in 5 patients (20%) and bevacizumab in 4 patients(16%). A repeat NGS for assessing the mechanism of resistance was done in patients revealed new mutations in 6 patients (24%) with EGFR Exon 20 T790M being most common in 3 patients (12%). Conclusions: We conclude that, in real-world practice, platinum-doublet formed the backbone of treatment post-osimertinib progression, with variable combinations, most commonly, along with TKIs or bevacizumab. No standard guidelines for the treatment of patients post-osimertinib progression are available with variable responses and tolerability. Larger and prospective studies are needed to identify the best options of therapies in such patients.
Neuroleptic Malignant Syndrome
Authors: Barry H. Guzé, Lewis R. Baxter
Journal: New England Journal of Medicine (1985)

NEUROLEPTIC drugs, also known as antipsychotic agents and "major" tranquilizers, are among the most commonly prescribed medications in use today. In 1983 six neuroleptic agents were among the 200 most prescribed drugs in the United States.1 Neuroleptic drugs are used extensively in the treatment of psychotic illnesses and are widely employed in general medicine as antiemetics, for dissociative anesthesia, and to treat diseases such as Tourette's syndrome. They have many well-known side effects —e.g., extrapyramidal effects.2 The neuroleptic malignant syndrome (NMS), however, a hyperpyrexic syndrome that is frequently fatal, is not widely recognized. In fact, one popular, authoritative textbook makes . . .
Racial and ethnic disparities among patients with breast cancer and COVID-19.
Authors: Gayathri Nagaraj, Melissa Kate Accordino, Benjamin French, Nicole M. Kuderer, Gary H. Lyman, Daniel G. Stover, Victoria Susana Blinder, Andrew Lachlan Schmidt, Rebecca Arielle Shatsky, Punita Grover, Matthew Puc, Clara Hwang, Elizabeth Marie Wulff-Burchfield, Mark Andrew Lewis, Alvaro G. Menendez, Mehmet Asim Bilen, Jeremy Lyle Warner, Maryam B. Lustberg, Dimpy P Shah
Journal: Journal of Clinical Oncology (2021)

6500 Background: Racial/ethnic minorities have disproportionately increased risk of contracting COVID-19 and experiencing severe illness; they also have worse breast cancer (BC) outcomes. COVID-19 outcomes among racial/ethnic minorities with BC are currently unknown. We sought to compare clinicopathologic characteristics and COVID-19 outcomes stratified by race/ethnicity. Methods: The COVID-19 and Cancer Consortium registry (NCT04354701) was used to identify patients with invasive BC and laboratory-confirmed SARS-CoV-2 diagnosed in the U.S. between 2020-03-06 and 2021-02-04. The primary analysis was restricted to women who self-identified as non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic (H). Demographic, cancer characteristics, and COVID-19 outcomes were evaluated. COVID-19 outcomes included: hospital admission, intensive care unit (ICU) admission, mechanical ventilation, death within 30 days of COVID-19 diagnosis and death from any cause during follow-up. Descriptive statistics were used to compare clinicopathologic characteristics and Fisher exact tests were used to compare COVID-19 outcomes across the 3 racial/ethnic groups. Results: A total of 1133 patients were identified of which 1111 (98%) were women; of which 575 (52%) NHW, 243 (22%) NHB, 183 (16%) H, and 110 (10%) other/unknown. Baseline characteristics differed among racial/ethnic groups. H were younger (median age: NHW 63y; NHB 62y; H 54y) and more likely to be never smokers (NHW 62%; NHB 62%; H 78%). NHB had higher rates of obesity (NHW 40%; NHB 54%; H 46%), diabetes (NHW 16 %; NHB 32%; H 20%) and combined moderate and severe baseline COVID-19 at presentation (NHW 28%; NHB 42%; H 28%). Cancer characteristics are as shown (Table). Significant differences were observed in outcomes across racial/ethnic groups including higher rates of hospital admission (NHW 34%; NHB 49%; H 34%; P &lt;0.001), mechanical ventilation (NHW 3%; NHB 9%; H 5%; P=0.002), 30-day mortality (NHW 6%; NHB 9%; H 4%; P=0.043) and total mortality (NHW 8%; NHB 12%; H 5%; P=0.05) among NHB compared to NHW and H. Conclusions: This is the largest study to show significant differences in COVID-19 outcomes by racial/ethnic groups of women with BC. The adverse outcomes in NHB could be due to higher moderate to severe COVID-19 at presentation and preexisting co-morbidities. H did not have worse outcomes despite having more active disease and recent anti-cancer therapy, including with cytotoxic chemotherapy – potentially due to younger age and nonsmoking status.[Table: see text]
O-Fucose and Fringe-Modified Recombinant Notch Peptides As Decoy Molecules to Promote Hematopoietic Progenitor Mobilization
Authors: Lan Zhou, Shuiliang Yu, Weihuan Wang, Marwah Albakri, Seunghwan Lim, Chris Siebel, Hillard M Lazarus, John Letterio, Wei Xin
Journal: Blood (2017)
Germinal center–dependent and –independent memory B cells produced throughout the immune response
Authors: Charlotte Viant, Tobias Wirthmiller, Mohamed A. ElTanbouly, Spencer T. Chen, Ervin E. Kara, Melissa Cipolla, Victor Ramos, Thiago Y. Oliveira, Leonidas Stamatatos, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2021)

Memory B cells comprise a heterogenous group of cells that differ in origin and phenotype. During the early phases of the immune response, activated B cells can differentiate into IgM-expressing memory cells, short-lived plasma cells, or seed germinal centers (GCs). The memory compartment is subsequently enriched by B cells that have been through several rounds of division and selection in the GC. Here, we report on the use of an unbiased lineage-tracking approach to explore the origins and properties of memory B cell subsets in mice with an intact immune system. We find that activated B cells continue to differentiate into memory B cells throughout the immune response. When defined on the basis of their origins, the memory B cells originating from activated B cells or GCs differ in isotype and overall gene expression, somatic hypermutation, and their affinity for antigen.
Cancer care during COVID-19: Data from 157 patient organizations.
Authors: Lorna Warwick, Elisabeth Baugh, Fatima Cardoso, Rachel H. Giles, Alex Filicevas, Jesme Fox, Kathy Rose Oliver, Frances Reid, Jenny Isaacson, Andrew Spiegel, Roberta Ventura, Nicole Sheahan, Clara MacKay
Journal: Journal of Clinical Oncology (2021)

e18564 Background: Representatives from 8 global cancer coalitions/alliances, representing 650 cancer patient groups and the interests of over 14 million patients have come together during the pandemic to review and evaluate the patient-perspective impact. Cancer services have faced challenges as a result of COVID-19, including suspension of screening and diagnostic services; delays in diagnosis leading to higher mortality rates; cancellation/deferral of life-saving treatments; changes in treatment regimens and suspension of vital research. For organisations that provide support to cancer patients, declining income, the need to reduce staff and move to virtual working practices has put extra strain while demand for support due to the pandemic has increased. Methods: 5 coalitions surveyed their member organisations. A number of coalitions consulted their members by individual surveys or consultations. Results: A survey of 157 organisations representing advanced breast, bladder, lymphoma, ovarian and pancreatic cancer patient groups from 56 countries found that 57% experienced an average increase of 44% in patient calls and emails. 45% reported that their future viability may be under threat because of the impact of COVID-19 on income. Examples of good practice were reported where healthcare systems have acted to protect patients and cancer services. These include the introduction of COVID-free centres, separation of cancer patients from those who may have COVID-19, and the introduction of virtual and telemedicine services. Organisations have also introduced new ways of working including virtual psychological support services and app-based support groups. These best practices should form part of a global plan of action for future health crisis. Conclusions: Collaboration between patient advocacy organisations, governments and health services is needed to ensure the ground lost to the COVID-19 pandemic is regained. Action is required to restore cancer services safely and effectively without delay. Additional resources for organisations that support cancer patients are required to ensure that they continue to provide vital services. Finally, a global plan of action for cancer is required to meet the challenges of any future health crisis.
SARS-CoV-2 vaccines elicit durable immune responses in infant rhesus macaques
Authors: Carolina Garrido, Alan D. Curtis, Maria Dennis, Sachi H. Pathak, Hongmei Gao, David Montefiori, Mark Tomai, Christopher B. Fox, Pamela A. Kozlowski, Trevor Scobey, Jennifer E. Munt, Michael L. Mallory, Pooja T. Saha, Michael G. Hudgens, Lisa C. Lindesmith, Ralph S. Baric, Olubukola M. Abiona, Barney S. Graham, Kizzmekia S. Corbett, Darin Edwards, Andrea Carfi, Genevieve Fouda, Koen K. A. Van Rompay, Kristina De Paris, Sallie R. Permar
Journal: Science Immunology (2021)

The inclusion of infants in the SARS-CoV-2 vaccine roll-out is important to prevent severe complications of pediatric SARS-CoV-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. However, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. Toward this goal, we assessed the safety and immunogenicity of two SARS-CoV-2 vaccines. Two groups of 8 infant rhesus macaques (RMs) were immunized intramuscularly at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. Both vaccines elicited high magnitude IgG binding to RBD, N terminus domain, S1, and S2, ACE2 blocking activity, and high neutralizing antibody titers, all peaking at week 6. S-specific memory B cells were detected by week 4 and S-specific T cell responses were dominated by the production of IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The immune responses for the mRNA-LNP vaccine were of a similar magnitude to those elicited by the Moderna mRNA-1273 vaccine in adults. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines were well-tolerated and highly immunogenic in infant RMs, providing proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity that might decrease the transmission of SARS-CoV-2 and mitigate the ongoing health and socioeconomic impacts of COVID-19.
Disparities in government and nonprofit organization funding may hinder clinical trial development for underfunded cancers.
Authors: Suneel Deepak Kamath
Journal: Journal of Clinical Oncology (2021)

1573 Background: National Cancer Institute (NCI) and nonprofit organization (NPO) funding is critical for research and advocacy, but may not be equitable across cancers. This could negatively impact clinical trial development for underfunded cancers. Methods: This study evaluated funding from the NCI and NPOs with &gt; $5 million in annual revenue supporting leukemia, lymphoma, melanoma, lung, breast, colorectal, pancreatic, hepatobiliary, prostate, ovarian, cervical and endometrial cancers from 2015-2018 based on publically available reports and tax records. The primary objectives were to assess for disparities in NCI and NPO funding across different cancers compared to their median incidence and mortality from 2015-2018, and to determine if underfunding correlates with fewer clinical trials found in clinicaltrials.gov. Correlations between combined NCI and NPO funding for each cancer and its incidence, mortality and number of clinical trials were evaluated using descriptive statistics and Pearson correlation coefficients. Results: Diseases with the largest combined NCI+NPO funding were breast ($3.75 billion), leukemia ($1.99 billion) and lung cancer ($1.56 billion). Those with the least funding were endometrial ($94 million), cervical ($292 million), and hepatobiliary cancers ($348 million). These data are summarized in the Table. Disease-specific NCI+NPO funding correlated well with incidence, but less so with mortality (Pearson correlation coefficients: 0.74 and 0.63, respectively). Disease-specific NPO funding correlated moderately well with incidence, but was poorly correlated with mortality (Pearson correlation coefficients: 0.54 and 0.39, respectively). Breast cancer, leukemia and lymphoma were consistently well-funded compared to their incidence and mortality, while colorectal, lung, hepatobiliary and uterine cancers were consistently underfunded. The amount of NCI funding, NPO funding and combined NCI+NPO funding for a particular cancer each correlated strongly with the number of clinical trials for that disease (Pearson correlation coefficients: 0.88, 0.87 and 0.91, respectively). Conclusions: Many cancers with high incidence and mortality are underfunded. Cancers with higher mortality rates receive less funding, particularly from NPOs. Underfunding strongly correlates with fewer clinical trials, which could impede future advances in underfunded cancers.[Table: see text]
Financial impact of tepotinib for the treatment of adult patients with metastatic non-small cell lung cancer bearing <i>MET</i>ex14 skipping in the United States.
Authors: Matthew Stargardter, Mo Yang, Jon Tosh, Apoorva Ambavane, Madhav Mittal, Helene Vioix, Frank Xiaoqing Liu, Ali McBride
Journal: Journal of Clinical Oncology (2021)

e21108 Background: MET exon 14 ( METex14) skipping is found in approximately 3% of the non-small cell lung cancer (NSCLC) population and is associated with poor prognoses. We estimated the financial impact to US Medicare and commercial plans of reimbursing the receptor tyrosine kinase inhibitor (TKI) tepotinib for adult patients with metastatic NSCLC bearing METex14 skipping. Methods: We developed an Excel-based economic model to project plan financial outlays with or without tepotinib from 2021-2023. The number of patients eligible for treatment with MET TKIs was estimated from epidemiological data, real-world evidence, and forecasted biomarker testing rates. It was assumed this population has access to other TKIs (capmatinib and crizotinib) and non-targeted standards of care, including immune checkpoint inhibitors, anti–vascular endothelial growth factor (VEGF) medications, and chemotherapy. It was also assumed most patients receiving tepotinib would otherwise be treated with another TKI. Efficacy and safety inputs were obtained from the Phase II VISION study (July 2020 data cut-off), published literature and prescribing information. Resource utilization and costs (2020 US dollars) were informed by online pricing databases, CMS fee schedules, Healthcare Cost and Utilization Project (HCUP) and trial data, expert opinion, and publicly available sources. Results: In hypothetical Medicare and commercial plans with one million members each, an estimated 160 and 32 adult patients with metastatic NSCLC would test positive for METex14 skipping between 2021-2023, respectively. Of these, 26 Medicare and 5 commercial plan members would receive tepotinib. Introducing tepotinib reduced cumulative financial outlays by $661,379 and $151,700 for Medicare and commercial payers respectively, or $0.0061 and $0.0014 per patient per month, primarily due to lower overall drug acquisition and disease management costs relative to a treatment mix without tepotinib. Results are most sensitive to the clinical efficacy of tepotinib and capmatinib. Conclusions: Using tepotinib in adult patients with metastatic NSCLC bearing METex14 skipping is expected to have minimal financial impact on Medicare and commercial payers in the US.[Table: see text]
Aesthetic outcome and patient’s quality of life in breast cancer patients undergoing mastectomy with or without immediate reconstruction.
Authors: Sidra Afzal, Asad Parvaiz, Nida Javed
Journal: Journal of Clinical Oncology (2021)

e12587 Background: : Although post mastectomy Immediate breast reconstruction has shown to improve physical and psychosocial well-being of breast cancer patients, this is not a usual procedure in Pakistan due to limited resources and lack of awareness. The aim of our study is to evaluate patient’s satisfaction/ aesthetic outcomes between the patients undergoing mastectomy alone (Group A) and the ones undergoing mastectomy followed by immediate reconstruction (Group B). Methods: This is a prospective study conducted at Shaukat Khanum Hospital Pakistan comparing aesthetic outcome, patient’s satisfaction and Quality of life between two groups using Breast Q module. All patients undergoing mastectomy with and without reconstruction between April 2017 to July 2019 are included. Sample size of 84 was calculated (42 in each group). Results: The mean Q score of satisfaction with the breast in group B is 82.64 and in group A is 35.82 (P = 0.001). The mean Q score of Psychosocial well-being in group B is 89 vs 44.95 in group A (P = 0.001). The mean Q score of Physical well-being in group B is 98.23 vs 90.41 in group A (P = 0.002). The mean Q score of sexual well-being in group B is 81.93 vs 43 in Group A (P = 0.001). [Mean difference in score of 5-10 - little change, 10-20 - moderate change, &gt; 20 - significant change].The mean difference between two groups in satisfaction with breast , psychosocial well-being and sexual well-being is more than 20 with a statistically significant p-value, while in physical well-being the mean difference is 7.8 which falls in little change group. Conclusions: Our study shows that reconstruction helps breast cancer patients in providing comprehensive care in a manner that they achieve a higher satisfaction with their appearance, psychological and sexual well-being without compromising oncological safety and this should be practiced more in our country. Also patients education about these procedures should be raised to help them fighting against this disease
Treatment of direct oral anticoagulants in patients with liver cirrhosis and portal vein thrombosis
Authors: Ho Soo Chun, A Reum Choe, Minjong Lee, Yuri Cho, Hwi Young Kim, Kwon Yoo, Tae Hun Kim
Journal: Clinical and Molecular Hepatology (2021)

Although patients with cirrhosis are known to be in a state of "rebalance" in that pro- and anticoagulant factors increase the risk for both bleeding and thrombosis, the prevalence of portal vein thrombosis (PVT) in patients with cirrhosis can be up to 26%. Therefore, physicians should consider anticoagulation for the prevention and management of PVT in patients with cirrhosis who are at high risk of PVT. Vitamin K antagonist or low molecular weight heparin is suggested as the standard treatment for PVT in cirrhosis. With the advent of new direct-acting oral anticoagulants (DOACs), there is a paradigm shift of switching to DOACs for the treatment of PVT in patients with cirrhosis. However, the safety and efficacy of DOACs in the treatment of PVT was not well-known in patients with cirrhosis. Therefore, this review focused on the current knowledge about the efficacy, safety concerns, and hepatic metabolism of DOACs in patients with cirrhosis and PVT.
HGG-30. BRAIN PENETRANT HDAC INHIBITOR RG2833 SYNERGIZES WITH LOMUSTINE AND RADIATION TO INDUCE DIPG CELL DEATH
Authors: Katherine Barnett, Orlandi Novak, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is driven by epigenetic dysregulation. The pan-HDAC inhibitor panobinostat showed pre-clinical efficacy against DIPG, but was limited by toxicity in clinical trials. RG2833 (RGFP109) is a selective HDAC1/3 inhibitor with established brain penetration. RG2833 reverses temozolomide-resistance in glioblastoma through downregulation of the NFĸB pathway. As this pathway is upregulated in DIPG and may contribute to tumorigenesis, we hypothesized that RG2833 would kill DIPG cells. We found that RG2833 treatment inhibits cell growth in the 4 to 9μM range in both autopsy and biopsy-derived DIPG cell lines (MTS assay for HSJD007 p=0.0004, JHH-DIPG1 p=0.001, SF-7761 p=0.04, SU-DIPG13 p=0.01 by t-test). Western blot confirmed on target activity by increased histone 3 acetylation at IC50 doses. RG2833 induces apoptosis (cPARP Western blot, cleaved caspase 3 immunofluorescence HSJD007 p&amp;lt;0.003, JHH-DIPG1 p=0.0026 by t-test) and slows cell proliferation (phospho-Rb Western blot, BrdU immunofluorescence HSJD007 p=0.008, JHH-DIPG1 p=0.0002 by t-test) in multiple DIPG cell lines. RG2833 disrupts the NFĸB pathway through acetylation of p65, resulting in decreased expression of NFĸB regulated pro-survival genes (Western blot for BCL2, BCL-xL, and XIAP). In a DIPG flank tumor mouse model, treatment with RG2833 alone for 1 week suppresses flank tumor growth (p&amp;lt; 0.005 by t-test) and induces apoptosis (Western blot for cPARP). We next assessed whether RG2833 combines synergistically with conventional therapies. We found that RG2833 has strong synergism with both lomustine and radiation to slow DIPG cell growth in vitro (ZIP synergy scores by SynergyFinder for RG2833+lomustine in JHH-DIPG1 17.8 and HSJD007 17.7, RG2833+radiation in JHH-DIPG1 9.7 and JHH-DIPG16A 10.9). Evaluation of combination treatment for apoptotic effects in vitro and in vivo are ongoing. This data identifies selective HDAC inhibitor RG2833 as a promising therapy for DIPG that combines synergistically with conventional therapies.