tbuckley/cabot-search huggingface dataset:
Activity of single-agent gemcitabine in patients (pts) with advanced angiosarcoma: A retrospective study.
Authors: Sarah Watson, Benjamin Verret, Stanislas Ropert, Julien Adam, Rastilav Bahleda, Sylvain Briand, Andrea Cavalcanti, Ali N. Chamseddine, Charles Court, Elie Fadel, Matthieu Faron, Leila Haddag, Clemence Henon, Cecile Le Pechoux, Antonin Levy, Olaf Mercier, Carine Ngo, Charles Honoré, Axel Le Cesne, Olivier Mir
Journal: Journal of Clinical Oncology (2021)

e23547 Background: Gemcitabine has shown clinical activity against angiosarcoma in single cases or small series, as a single agent or in combination with taxanes. We aimed to evaluate its activity in a larger, homogeneous series of pts with advanced angiosarcoma. Methods: We retrospectively reviewed the electronic medical records of consecutive adult pts with advanced angiosarcoma treated with gemcitabine(1000 mg/m2 IV days 1, 8 and 15 of a 28-days cycle) at our institutions from January 2010 to January 2021. All cases were confirmed by an expert pathologist from the French network of Sarcoma pathologists (RRePS). Response was evaluated according to RECIST 1.1, and survival was estimated using the Kaplan-Meier method. Results: Fourty-two pts [median age : 52 years (range : 25-90), median PS : 1 (range : 0-2), 36 women)] were identified. Ten (24%) had locally advanced disease; the median number of metastatic sites was 2 (range : 1-4) in the remaining 32 pts. Primary tumor site was breast/chest wall (12), face/scalp (9), heart (8), other viscera (7) or limbs (7). Eleven (26%) occurred in previously irradiated field. All pts but 4 had received prior anthracyclines (peri-operatively or in the metastatic setting) and weekly paclitaxel, and 9 (21%) had received pazopanib. Gemcitabine was given as second, third and fourth line in 7 (17%), 20 (47%) and 15 (36%) pts, respectively. Best tumor response by RECIST 1.1 was PR (16 pts, 38%), SD (10 pts, 24%) or PD (16 pts, 38%). All pts with cardiac angiosarcoma experienced a PR, as well as 4 of 10 pts with angiosarcoma arising in irradiated field and 3 of the 4 pts with CNS metastases. Median PFS was 5.4 months (95%CI : 3.1-6.5), and median OS was 9.9 months (95%CI : 6.6-13.4). Two febrile neutropenia occurred. No new safety signal was observed. Ongoing studies are exploring whether candidate biomarkers such as hENT1 expression could help predicting the benefit of gemcitabine in pts with angiosarcoma of the heart and large vessels. Conclusions: Single agent gemcitabine has clinically meaningful activity in advanced, heavily pre-treated angiosarcoma (including cardiac angiosarcoma). This series may serve as a benchmark for future clinical trials in angiosarcoma.
Rapid Characterization and Quantification of Extracellular Vesicles by Fluorescence‐Based Microfluidic Diffusion Sizing
Authors: Carolina Paganini, Britta Hettich, Marie R.G. Kopp, Adam Eördögh, Umberto Capasso Palmiero, Giorgia Adamo, Nicolas Touzet, Mauro Manno, Antonella Bongiovanni, Pablo Rivera‐Fuentes, Jean‐Christophe Leroux, Paolo Arosio
Journal: Advanced Healthcare Materials (2021)

Abstract Extracellular vesicles (EVs) are emerging as promising diagnostic and therapeutic tools for a variety of diseases. The characterization of EVs requires a series of orthogonal techniques that are overall time‐ and material‐consuming. Here, a microfluidic device is presented that exploits the combination of diffusion sizing and multiwavelength fluorescence detection to simultaneously provide information on EV size, concentration, and composition. The latter is achieved with the nonspecific staining of lipids and proteins combined with the specific staining of EV markers such as EV‐associated tetraspanins via antibodies. The device can be operated as a single‐step immunoassay thanks to the integrated separation and quantification of free and EV‐bound fluorophores. This microfluidic technique is capable of detecting and quantifying components associated to EV subtypes and impurities and thus to measure EV purity in a time scale of minutes, requiring less than 5 µL of sample and minimal sample handling before the analysis. Moreover, the analysis is performed directly in solution without immobilization steps. Therefore, this method can accelerate screening of EV samples and aid the evaluation of sample reproducibility, representing an important complementary tool to the current array of biophysical methods for EV characterization, particularly valuable for instance for bioprocess development.
Economic evaluation of crizotinib, alectinib, ceritinib, and brigatinib in treatment naïve anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Briana Choi, Nimer S. Alkhatib, Hala Halawah, Matthias Calamia, Dexter Gulick, AlMothana Manasrah, Odai Alkhdour, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2021)

e21102 Background: Crizotinib was approved by the FDA (2011) as the first ALK inhibitor for ALK+ NSCLC as the first line drug. This was followed by the approval as second line treatment of ceritinib (2014), alectinib (2015) and brigatinib (2017); and, following more data, now also as first line therapies in ALK+ NSCLC. With varying costs and clinical benefits for progression free survival (PFS), cost effectiveness/utility analyses were conducted. Methods: A 3 state Markov model was built including progression free, progression and death. PFS and overall survival curves were digitized and exponential functions were fit the curves for extrapolation beyond trial follow up. A lifetime horizon, US payer perspective, and a discount rate of 3% were applied. Drug costs were based on Redbook Wholesale Acquisition Cost while costs of adverse events, monitoring, disease progression were from literatures (US$ 2020). Adverse events reported at &gt; 5% were included. Crizotinib was used as reference treatment. PFS life years (PFSLY), quality adjusted life years (PFSQALY), incremental cost-effectiveness and utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained (PFSLYG, PFSQALYG) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Results: Crizotinib was the reference drug in the following estimations. For alectinib, at incremental cost of $7,789 (PSA $7,719), the incremental PFSLY of 1.10 (1.10) and PFSQALY 1.07 (1.07) yielded an ICER of $7,109 ($7,030) / PFSLYG and an ICUR of $7,278 ($7.197) / PFSQALYG. For ceritinib, at incremental cost of $88,688 ($88,450), the incremental PFSLY of 1.02 (1.02) and PFSQALY of 1.01 (1.01) resulted in an ICER of $86,970 ($86,729) / PFSLYG and an ICUR of $87,472 / PFSQALYG. For brigatinib, at incremental cost of $84,680 ($83,986), the incremental PFSLY of 1.01 (1.01) and PFSQALY of 1.02 yielded an ICER of $83,774 ($83,073) / PFSLYG and an ICUR of $82,666 ($81,976) / PFSQALYG. Conclusions: Ceritinib had the highest lifetime cost and comparable PFSLY and PFSQALY to brigatinib. However, alectinib reported the highest PFSLY and PFSQALY gained while having lower costs than ceritinib and brigatinib, therefore being the most cost-effective treatment for naïve ALK+ NSCLC.[Table: see text]
A phase 1, multicenter, open-label, dose-escalation, safety, pharmacodynamic, pharmacokinetic study of Q702 with a cohort expansion at the RP2D in patients with advanced solid tumors.
Authors: Angela Tatiana Alistar, Anthony B. El-Khoueiry, Devalingam Mahalingam, Monica M. Mita, Hwankyu Kang, Yeong-In Yang, Jiye Ahn, Jeongjun Kim, Baejung Choi, Yeejin Jeon, Chunwon Jung, Borami Jeon, Jaeseung Kim, Kiyean Nam
Journal: Journal of Clinical Oncology (2021)

TPS2673 Background: Immune checkpoint inhibitors directly targeting T cell activation have been successfully used in the treatment of various malignancies, nevertheless, the durable ORRs are low for certain indications. The low ORRs have been attributed to the immune suppressive tumor microenvironment (TME), composed of innate immune suppressive components such as tumor associated macrophages (TAM) and myeloid-derived suppression cells (MDSC). The potential contributions of innate immune modulation to anti-tumor immunity, suggest the need for the novel strategies to elicit a more efficient/robust immune response against the targeted malignant cells. Axl, Mer and CSF1R receptor tyrosine kinases play vital roles in promoting an immune suppressive TME by affecting TAM and MDSC populations and by decreasing antigen presentation on tumor cells. Q702 is a novel Axl/Mer/CSF1R inhibitor, able to modulate the TAM and MDSC population leading to CD8+ T cell activation and to increase antigen presentation of the tumor cells in syngeneic animal models. Q702, as a monotherapy, shows significant tumor growth inhibition in multiple syngeneic tumor models, and demonstrates synergistic effects with anti-PD-1 treatment particularly in high myeloid containing tumor models. Interestingly, intermittent administration of Q702 monotherapy demonstrates a more favorable immune cell population changes, possibly through preventing immune exhaustion secondary to negative feedback with continuous activation. These results suggest that Q702 monotherapy or in combination with existing therapies have a good potential to become a novel treatment strategy for patients with advanced solid tumors. Methods: “A Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the RP2D in Patients with Advanced Solid Tumors. (NCT04648254)” is open and recruiting patients at 4 US investigative sites. Patients with histologically or cytologically confirmed advanced or metastatic solid tumors, that have progressed following SOC or for which there is no SOC which confers clinical benefit are being enrolled in this study. The study follows a standard dose escalation. The study will enroll up to 78 patients. The primary endpoint is to establish safety, PK profile and define the recommended phase 2 dose. The secondary and exploratory endpoints include establishing pharmacokinetic/pharmacodynamic relationship, potential biomarkers and preliminary anti-tumor activity. Clinical trial information: NCT04648254.
Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study
Authors: Steven E. Kahn, Sharon L. Edelstein, Silva A. Arslanian, Elena Barengolts, Sonia Caprio, David A. Ehrmann, Tamara S. Hannon, Santica Marcovina, Kieren J. Mather, Kristen J. Nadeau, Kristina M. Utzschneider, Anny H. Xiang, Thomas A. Buchanan, David A. Ehrmann, Karla A. Temple, Abby Rue, Elena Barengolts, Babak Mokhlesi, Eve Van Cauter, Susan Sam, M. Annette Miller, Steven E. Kahn, Karen M. Atkinson, Jerry P. Palmer, Kristina M. Utzschneider, Tsige Gebremedhin, Abigail Kernan-Schloss, Alexandra Kozedub, Brenda K. Montgomery, Emily J. Morse, Kieren J. Mather, Tammy Garrett, Tamara S. Hannon, Amale Lteif, Aniket Patel, Robin Chisholm, Karen Moore, Vivian Pirics, Linda Pratt, Kristen J. Nadeau, Susan Gross, Philip S. Zeitler, Jayne Williams, Melanie Cree Green, Yesenia Garcia Reyes, Krista Vissat, Silva A. Arslanian, Kathleen Brown, Nancy Guerra, Kristin Porter, Sonia Caprio, Mary Savoye, Bridget Pierpont, Thomas A. Buchanan, Anny H. Xiang, Enrique Trigo, Elizabeth Beale, Fadi N. Hendee, Namir Katkhouda, Krishan Nayak, Mayra Martinez, Cortney Montgomery, Xinhui Wang, Sharon L. Edelstein, John M. Lachin, Ashley N. Hogan, Santica Marcovina, Jessica Harting, John Albers, Dave Hill, Peter J. Savage, Ellen W. Leschek
Journal: Diabetes Care (2021)

To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols.
Molecular Modelling of Human Red Blood Cell Pyruvate Kinase: Structural Implications of a Novel G1091 to A Mutation Causing Severe Nonspherocytic Hemolytic Anemia
Authors: Wouter W. van Solinge, Rob J. Kraaijenhagen, Gert Rijksen, Richard van Wijk, Bjarne B. Stoffer, Michael Gajhede, Finn C. Nielsen
Journal: Blood (1997)
Prognostic pathological and clinical factors associated with overall survival in metastatic melanoma undergoing anti PD-1 treatment.
Authors: Kim Koczka, Rodrigo Rigo, Aleksi Suo, Mohammad Asad, Edwin Wang, Eugene Batuyong, Tina Cheng
Journal: Journal of Clinical Oncology (2021)

e21531 Background: Anti-PD-1 immunotherapy has revolutionized metastatic melanoma treatment, as first-line monotherapy or in combination with Ipilimumab. Up to 40% of patients will progress within 3 months, with limited evidence on who derives benefit from immunotherapy. We report clinical and pathological predictive and prognostic factors from a multi-institutional cohort. Methods: Patients between 2014-2017 treated with Nivolumab and Pembrolizumab were identified from a provincial pharmacy database in Alberta, Canada. All patients had unresectable stage III or IV melanoma. Patient characteristics, investigations, treatment and clinical outcomes were obtained from electronic medical records. We utilized Cox regression and Kaplan-Meier methods to analyze progression free survival (PFS) and overall survival (OS). Results: 143 patients with either cutaneous (115) or primary unknown (28) melanoma were identified. Immunotherapy was median second line treatment and patients received a median of 7 doses. The median age was 64, and 144 (80%) were either ECOG 0 or 1 at treatment initiation. The overall response rate was 33%, with median follow up of 25 months. Ulcerated primary tumors had a lower mOS of 30 months vs. 49 months (p=0.042). Other pathologic factors (including Breslow Depth, tumor infiltrating lymphocytes, mitosis) were not associated with PFS or OS. Clinical factors associated with worsened mPFS and mOS were liver metastases, &gt;3 sites of disease, and any visceral disease. Elevated LDH, platelets, neutrophils, and lower hemoglobin, lymphocytes, and a neutrophil/lymphocyte ratio were associated with worse mPFS and mOS. We identified 4 prognostic subgroups using LDH and number of visceral sites (Table) which was statistically significant for mPFS and mOS. Conclusions: Ulcerated primary tumors, liver metastasis, and more sites of disease had worse mPFS and mOS. We also identified 4 novel prognostic subgroups strongly associated with survival outcomes.[Table: see text]
Increased mortality among smokers with myelodysplastic syndrome (MDS).
Authors: Phaedon D. Zavras, Prateek Pophali, Aditi Shastri, Lizamarie Bachier-Rodriguez, Alejandro R. Sica, Mendel Goldfinger, Noah Kornblum, Ira Braunschweig, Amit K. Verma, Ioannis Mantzaris
Journal: Journal of Clinical Oncology (2021)

e19036 Background: Recent studies have shown smoking to be an independent risk factor for MDS. We aimed to assess whether smoking is associated with worse outcomes among patients (pts) with MDS at Montefiore Medical Center, Bronx, NY. Methods: Pts with MDS and chronic myelomonocytic leukemia (CMML) diagnosed between June 16, 2000 and November 13, 2020 were analyzed. Those without available tissue diagnosis or smoking history data were excluded. Descriptive statistics compared ever-smokers to non-smokers. Cox PH regression was used to analyze the risk of transformation to acute myeloid leukemia (AML) and mortality in the 2 groups and multivariable analysis (MVA) adjusted for age, sex, de novo disease and R-IPSS. Results: A total of 147 pts were identified, 109 (74.1%) had a diagnosis of de novo MDS, 89 (60.5%) had history of active or former smoking and 58 (39.5%) were non-smokers. Smokers were predominantly males (66.3%) in contrast to non-smokers (37.9%) (p=0.001). Smokers were diagnosed more frequently with high or very high risk MDS, although the difference was not statistically significant (38.1% vs 28.6%, respectively; p=0.28). TP53 mutations were numerically more frequent among smokers (24.4%), compared to non-smokers (12.8%) (p=0.16). Median follow-up time for smokers and non-smokers was 19.4 and 31.4 months, respectively. In MVA, there was a trend for increased risk of AML transformation in smokers vs non-smokers (HR 2.03, 95% CI 0.99 – 4.15; p=0.052). Smokers with MDS were found to have significantly greater mortality compared to non-smokers (HR 2.08, 95% CI, 1.22 – 3.54; p=0.007). Conclusions: Smoking was associated with worse survival among MDS pts in our cohort. Although not significantly different, the prevalence of TP53 mutations was higher among smokers. Larger studies are warranted to confirm our findings.
A randomised controlled trial of regular early specialist palliative care on quality of life in malignant pleural mesothelioma – ‘RESPECT-Meso’
Authors: Fraser J H Brims, Samal Gunatilake, Iain Lawrie, Laura Marshall, Carole Fogg, Cathy Qi, Lorraine Creech, Nicola Holtom, Stephanie Killick, Bernard Yung, David Cooper, Louise Stadon, Peter Cook, Elizabeth Fuller, Julie Walther, Claire Plunkett, Andrew Bates, Carolyn Mackinlay, Anil Tandon, Nick Maskell, Karen Forbes, Najib M Rahman, Stephen Gerry, Anoop Chauhan
Journal: Thorax (2018)
<i>MGMT</i> gene polymorphisms in patients with severe hematological toxicity treated with temozolomide for adult diffuse gliomas: Results from a tertiary-care comprehensive cancer center.
Authors: Prithwijit Moitra, Abhishek Chatterjee, Priti Khatri Kota, Pradnya Kowtal, Archya Dasgupta, Jayant Sastri, Ayushi Sahay, Epari Shridhar, Vijay Maruti Patil, Aliasgar Moiyadi, Rajiv Sarin, Tejpal Gupta
Journal: Journal of Clinical Oncology (2021)

e14032 Background: Polymorphisms in MGMT gene have been implicated in temozolomide (TMZ)-induced hematological toxicity in patients with adult diffuse gliomas. We aimed to investigate the association of three single nucleotide polymorphisms (SNPs) in the MGMT gene viz. L84F, I143V/K178R with severe hematological toxicity in patients of adult diffuse glioma treated with TMZ at an academic neuro-oncology unit of a tertiary-care comprehensive cancer centre from India. Methods: Thirty-three patients of adult diffuse glioma treated with multi-modality adjuvant therapy including TMZ who developed CTCAE V5.0 grade 2-4 hematological toxicity were included after written informed consent. Genomic DNA was extracted from peripheral blood mononuclear cells for SNP analysis. Correlation of MGMT SNP with patient demographics and hematological toxicity was assessed using the Chi-square and Fisher’s exact test. Results: Twenty-four patients (72.7%) developed grade 3-4 hematological toxicity with TMZ with a distinct female predilection. The variant T allele of L84F was expressed in 28.7% of the total 66 analyzed alleles which was markedly higher than previously reported in the general population of South Asian ancestry. The variant G allele of I43V/K178R was expressed in 9.3% (6/64) of 64 analyzed alleles. Persistent myelosuppression lasting beyond 2 months after cessation of TMZ correlated with I143V/K178R hetero/homozygous compared to wild type allele (p = 0.03). However, no significant correlation could be seen between any of the tested MGMT SNPs and grade of hematological toxicity. Conclusions: There is a higher prevalence of the L84F polymorphism in Indian patients with severe hematological toxicity than previously reported in the literature. The variant G allele of I143V/K178R is associated with prolonged and persistent myelosuppression induced by TMZ. A larger case-control is being planned to further elucidate the causal relationship between MGMT gene polymorphisms and TMZ-induced severe hematological toxicity.
Total neoadjuvant treatment versus standard chemoradiation to increase the sphincter preservation rate for distal locally advanced rectal cancer (TESS).
Authors: Weiwei Xiao, Xiaojun Wu, Peiqiang Cai, YeZhong Zhuang, Xiaozhong Wang, Shoumin Bai, Qiaoxuan Wang, YiJing Ye, Qing Liu, Min Liu, Shuang Liu, ZhiFan Zeng, Zhi-Zhong Pan, Yuanhong Gao, Gong Chen
Journal: Journal of Clinical Oncology (2021)

TPS3615 Background: Standard treatment of rectal cancer is neoadjuvant capecitabine chemotherapy with radiotherapy, followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, suggests organ preservation as an alternative to rectal excision in good responders after neoadjuvant chemoradiotherapy to decrease surgical morbidity and increase quality of life. RAPIDO and PRODIGE-23 trials showed that TNT strategy could improve the pathological complete response (pCR) rateand reduce the risk of distant metastasis. The objective of this trial is to increase the proportion of sphincter preservation rate for distal rectal cancer patients by optimizing tumor response, by using TNT regimen as compared to conventional chemoradiotherapy. TESS (clinicalTrials.gov, NCT03840239), a prospective, open label, multicenter, randomized phase 2 study, is underway. Methods: Main inclusion criteria include: cT3-4aNany or cTanyN+ rectal adenocarcinoma aged 18-70y; ECOG performance 0-1; distance≤5cm from anal verge. 168 patients will be randomized 1:1. Patients in the TNT group will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplation) before, during and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as watch and wait) and adjuvant chemotherapy capecitabine 2 cycles. Patients in the standard treatment group will receive neoadjuvant radiotherapy 50Gy/25 fractions combined with capecitabine 5 weeks before TME (or other treatment decisions, such as watch and wait), and adjuvant chemotherapy Capeox 6 cycles. Primary endpoint is the rate of sphincter preservation rate (absence of stoma). Secondary endpoints include: Ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; acute toxicity; surgical complications; long-term anal function; late toxicity; ECOG standard score; disease-free survival; overall survival. First site opened in January 24, 2019. Clinical trial information: NCT03840239.
Persistent Racial/Ethnic Disparities in Fatal Unintentional Drowning Rates Among Persons Aged ≤29 Years — United States, 1999–2019
Authors: Tessa Clemens, Briana Moreland, Robin Lee
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

During 1999-2019, a total of 81,947 unintentional drowning deaths occurred in the United States (1). Drowning is one of the three leading causes of unintentional injury death among persons aged ≤29 years and results in more deaths among children aged 1-4 years than any other cause except birth defects (2). Drowning death rates have decreased since 1990 (declining by 57% worldwide and by 32% in the United States) (3). However, because of racial/ethnic disparities in drowning risk, rates remain high among certain racial/ethnic groups, particularly American Indian or Alaska Native (AI/AN) persons and Black or African-American (Black) persons (4). To assess whether decreasing drowning death rates have been accompanied by reductions in racial/ethnic disparities, and to further describe these disparities by age group and setting, CDC analyzed U.S. mortality data during 1999-2019. The drowning death rate among persons aged ≤29 years was 1.3 per 100,000 population. The rate per 100,000 among AI/AN persons (2.5) and Black persons (1.8) was higher than among all other racial/ethnic groups and was 2.0 and 1.5 times higher than among White persons (1.2). Racial/ethnic disparities in drowning death rates did not significantly decline for most groups, and the disparity in rates among Black persons compared with White persons increased significantly from 2005-2019. Drowning death rates are associated with persistent and concerning racial/ethnic disparities. A better understanding of the factors that contribute to drowning disparities is needed. Implementing and evaluating community-based interventions, including those promoting basic swimming and water safety skills, among disproportionately affected racial/ethnic groups could help reduce drowning disparities.