tbuckley/cabot-search huggingface dataset:
Camrelizumab combined with ablation and chemotherapy for pancreatic cancer with liver metastases: A single-arm, phase II, prospective clinical study.
Authors: Zhiwei Li, Qingwei Li, Zhigang Ma, Yue Ma, Dan Su, Changjie Lou, Guangyu Wang, Chao Liu, Yanqiao Zhang
Journal: Journal of Clinical Oncology (2021)

TPS4169 Background: Pancreatic cancer represents one of the most aggressive tumors and the majority of patients receive a diagnosis of metastatic disease, mainly in the liver, leading to poor prognosis and survival. Currently, chemotherapy has been the treatment of choice for fit patients with pancreatic cancer liver metastases (PCLM), reaching a median survival of about 5 to 7 months. In addition, local ablation of the metastatic tumors, by increasing neoantigen exposure and transforming the immune microenvironment to reduce the progression of liver metastases, might increase the survival benefit of patients. Camrelizumab, an anti-PD-1 monoclonal antibody, has obtained preliminary results in metastatic pancreatic cancer. Therefore, this study aims to explore the effectiveness and safety of camrelizumab combined with ablation and chemotherapy in the treatment of PCLM. Methods: In this single-arm, prospective, phase II study, 34 patients with histological or cytological diagnosis of PCLM, ECOG performance score of 0-1, no prior chemotherapy or the interval of adjuvant chemotherapy ≥6 months, plan to be enrolled. The enrolled patients first received ablation surgery of liver metastases, then chemotherapy (the standard regimen for advanced pancreatic cancer, determined by the investigator) combined with camrelizumab (200 mg, iv, q3w) is administered 1 week after ablation. If the patient has multiple metastatic tumors, the ablation needs to be performed in stages. The treatment regimens will continue until the disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint is 6-month progress-free survival (6-month PFS) rate (per RECIST v1.1 by researcher). Secondary endpoints are objective response rate, disease control rate, progression-free survival, overall survival and safety. On the basis of a threshold 6-month PFS rate of 25%, targeting an expected 6-month PFS rate of 44% and assuming 18 months follow-up, 80% power and a one-sided α = 0.05, this design requires 34 evaluable patients to be accrued over 2 years. Clinical trial information: NCT04420130.
HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens
Authors: Will Fischer, Elena E. Giorgi, Srirupa Chakraborty, Kien Nguyen, Tanmoy Bhattacharya, James Theiler, Pablo A. Goloboff, Hyejin Yoon, Werner Abfalterer, Brian T. Foley, Houriiyah Tegally, James Emmanuel San, Tulio de Oliveira, Sandrasegaram Gnanakaran, Bette Korber, Eduan Wilkinson, Nokukhanya Msomi, Arash Iranzadeh, Vagner Fonseca, Deelan Doolabh, Koleka Mlisana, Anne von Gottberg, Sibongile Walaza, Mushal Allam, Arshad Ismail, Thabo Mohale, Allison J. Glass, Susan Engelbrecht, Gert Van Zyl, Wolfgang Preiser, Francesco Petruccione, Alex Sigal, Diana Hardie, Gert Marais, Marvin Hsiao, Stephen Korsman, Mary-Ann Davies, Lynn Tyers, Innocent Mudau, Denis York, Caroline Maslo, Dominique Goedhals, Shareef Abrahams, Oluwakemi Laguda-Akingba, Arghavan Alisoltani-Dehkordi, Adam Godzik, Constantinos Kurt Wibmer, Bryan Trevor Sewell, José Lourenço, Sergei L. Kosakovsky Pond, Steven Weaver, Marta Giovanetti, Luiz Carlos Junior Alcantara, Darren Martin, Jinal N. Bhiman, Carolyn Williamson
Journal: Cell Host & Microbe (2021)
Correction: Allogeneic transplantation in elderly patients ≥65 years with non-Hodgkin lymphoma: a time-trend analysis
Authors: Nirav N. Shah, Kwang Woo Ahn, Carlos Litovich, Anna Sureda, Mohamed A. Kharfan-Dabaja, Farrukh T. Awan, Siddhartha Ganguly, Usama Gergis, David Inwards, Reem Karmali, Alexsandr Lazaryan, Lazaros Lekakis, Pashna Munshi, Sunita Nathan, Ayman A. Saad, Melhem Solh, Amir Steinberg, Ravi Vij, William A. Wood, Timothy S. Fenske, Sonali Smith, Mehdi Hamadani
Journal: Blood Cancer Journal (2021)
Primary pancreatic adenocarcinoma (PPDA) and metastatic pancreatic adenocarcinoma (MPDA): Are they genomically distinct?
Authors: Sunny R. K. Singh, Shravan Leonard-Murali, Ruicong She, Chun-Hui Lin, Jonathan Freaney, Laila Poisson, Gazala Khan
Journal: Journal of Clinical Oncology (2021)

e16226 Background: PDA is an aggressive disease with a dismal prognosis. Advances in next-generation sequencing (NGS) have enabled targeted therapies, revolutionizing treatments of several solid tumors. Their role in the management of PDA is limited, in part due to the paucity in our understanding of targetable genomic events. We sought to evaluate genomic differences between PPDA and MPDA in the tumor and tumor immune microenvironment (TIME). The genomic changes after chemotherapy (CTX) administration were also evaluated. Methods: NGS data derived from tumor samples of 150 unique patients was analyzed. Targeted 648 gene DNA sequencing was performed using the Tempus xT and xO assays. Patients were allocated into 2 cohorts: PPDA (n = 75) and MPDA (n = 75), which were overall similar in terms of their demographics. The frequencies of somatic mutations were compared. The immune infiltrate was imputed from RNAseq. Proportions of immune cells (IC), and the tumor mutational burden (TMB) relative to the proportion of IC in the TIME, were also analyzed. Kaplan Meier Survival estimates for most frequent mutations and TMB were calculated. Results: The most frequently mutated genes amongst the 150 study subjects were: KRAS (92.7%), TP53 (76.7%), CDKN2A (45.3%), SMAD4 (31.3%), ATM (12.7%) and ARID1A (10.7%). Patients in the MPDA cohort had a higher rate of mutation in several genes when compared to PPDA, most notably in TP53 (85.3% vs 68.0%, p = 0.010), ARID1A (16.0 vs 5.3%, p = 0.037) CDKN2A (49.3 vs. 41.3%, p = 0.3) and SMAD4 (33.3 vs. 29.3 p = 0.7). We also evaluated if the genetic changes between PPDA and MPDA are associated with alterations in the TMB and differences in the TIME. A higher TMB was seen amongst patients in the MPDA vs PPDA cohort (2.73 vs 1.73 Mut/Mb, p = 0.008). TMB was also significantly increased after CTX (2.22 vs 1.63 Mut/Mb p = 0.049). TMB ≥ 3 was associated with decreased odds of progression free survival ≥ 12 months (OR 0.26 95% CI 0.078-0.822, p = 0.023). Regarding immune infiltrate, the proportion of CD4 and CD8 T cells were higher in the PPDA cohort. Macrophages and NK cells were more prevalent the MPDA cohort. TMB had a positive correlation with the degree of macrophage infiltration in the TIME (Multivariate estimate: 1.70, p value 0.01). Conclusions: PPDA and MPDA are biologically dissimilar entities with genomic disparity. Associated differences were observed in TMB and TIME. There is a differential increase in the spectrum of mutations in MPDA as compared to PPDA, specifically in p53, ARID1A, CDKN2A and SMAD4. The burden of increased mutations in MPDA is associated with an increase in the TMB and tumor associated macrophages. The role of serial NGS in the management of PDA both in early and late disease should be investigated further to identify evolving genomic changes that correlate with outcome.
Monocyte metabolic transcriptional programs associate with resistance to tuberculin skin test/interferon-γ release assay conversion
Authors: Jason D. Simmons, Phu T. Van, Catherine M. Stein, Violet Chihota, Thobani Ntshiqa, Pholo Maenetje, Glenna J. Peterson, Anthony Reynolds, Penelope Benchek, Kavindhran Velen, Katherine L. Fielding, Alison D. Grant, Andrew D. Graustein, Felicia K. Nguyen, Chetan Seshadri, Raphael Gottardo, Harriet Mayanja-Kizza, Robert S. Wallis, Gavin Churchyard, W. Henry Boom, Thomas R. Hawn
Journal: Journal of Clinical Investigation (2021)

After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid (FFA) transcriptional responses enriched across 2 independent cohorts suggesting RSTR and LTBI monocytes have distinct activation states. We compared intracellular Mtb replication in macrophages treated with FFAs and found that palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth. This PA activity correlated with its inhibition of proinflammatory cytokines in Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was restored by activation of AMP kinase (AMPK), a central host metabolic regulator known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7 SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA transcriptional programs and by genetic variation in a central metabolic regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion.
Optic glioma in children: Turkish experience.
Authors: Inci Yaman Bajin, David Nathan Korones, Burca Aydin, Kader Karli Oguz, Nilgun Kurucu, Bilgehan Yalcin, Ali Varan, Tezer Kutluk
Journal: Journal of Clinical Oncology (2021)

e14042 Background: Optic gliomas are the most common tumors of the optic pathway, comprising about 1% of all intracranial tumours. Here we present the clinical characteristics and the outcome of patients with optic glioma at our institution. Methods: Seventy two patients diagnosed and followed up at a pediatric cancer center in Ankara, Turkey between January 1, 2008 and December 31, 2020 were included in this analysis. The clinical features and outcome of patients were recorded from patient files and hospital information system retrospectively. Results: The median age at the time of diagnosis was 3.5 years (4-157 months), the female/male ratio was 1.3. Fourteen children (19%) were asymptomatic and tumors were detected with routine surveillance, and 58 (81%) had symptoms (the most common being proptosis in 16 patients (22%)). The most common site of optic glioma was the intraorbital region (31%). Fourty patients (55%) had neurofibromatosis type 1 (NF-1). Five patients had histopathological diagnoses; 3 pilomyxoid astrocytoma, 2 pilocytic astrocytoma. Children were treated if they had tumor progression on MRI and/or worsening visual acuity. Twenty seven (38%) children were observed without any therapy, 6 patients (8%) received radiation and chemotherapy, 4 patients (5%) received radiation only, and 35 patients (49%) received chemotherapy only. Treatment regimens for the 41 children who received chemotherapy included carboplatin/etoposide (17), cisplatin/etoposide (18), carboplatin/vincristine (5), and temozolomide (1). The 5-year progression-free survival (PFS) and overall survival (OS) were 64% and 90%, respectively with a 31 month median follow-up. The 5 year PFS was significantly lower in patients with optic tract-hypothalamic-chiasmatic involvement (34%) than orbital involvement (83%) (p=0.013). Five year PFS was significantly higher in patients with NF-1 (80%) than patients without NF-1(46%) (p=0.027) and significantly lower in patients diagnosed at &lt;3 years old (37%) (p=0.05). Five patients died of disease, and one died of infection after chemotherapy. Two patients treated with platin (1 carboplatin, 1 cisplatin) developed ototoxicity. One patient with NF-1 developed Moya-Moya disease. Two patients developed multiple pituitary hormone deficiencies and one patient developed precocious puberty during follow-up. No secondary malignancy was observed. Conclusions: The management of optic glioma remains challenging. Although the overall survival for children with this disease is excellent, progression of disease is frequent, particularly in those children without NF-1, younger children and non-orbital tumors. This study from Turkey showed comparable results with high-income countries. Further studies with longer follow-up periods are needed to find appropriate treatment strategies.
The national impact of the COVID-19 pandemic on U.S. prostate cancer community care.
Authors: Matthew R. Cooperberg, Paul Brendel, Daniel J. Lee, Rahul Doraiswami, Hariesh Rajasekar, Danil V. Makarov, William Meeks, Raymond Fang, Matthew T Roe, Jeremy B. Shelton
Journal: Journal of Clinical Oncology (2021)

5061 Background: We used data from a specialty-wide, community-based urology registry to determine trends in outpatient prostate cancer (PCa) care during the COVID-19 pandemic. Methods: 3,165 (̃ 25%) of US urology providers, representing 48 states and territories, participate in the American Urological Association Quality (AQUA) Registry, which collects data via automated extraction from electronic health record systems. We analyzed trends in PCa care delivery from 156 practices contributing data in 2019 and 2020. Risk stratification was based on prostate-specific antigen (PSA) at diagnosis, biopsy Gleason, and clinical T-stage, and we used a natural language processing algorithm to determine Gleason and T-stage from unstructured clinical notes. The primary outcome was mean weekly visit volume by PCa patients per practice (visits defined as all MD and mid-level visits, telehealth and face-to-face), and we compared each week in 2020 through week 44 (November 1) to the corresponding week in 2019. Results: There were 267,691 PCa patients in AQUA who received care between 2019 and 2020. From mid-March to early November, 2020 (week 10 – week 44) the magnitude of the decline and recovery varied by risk stratum, with the steepest drops for low-risk PCa (Table). For 2020, overall mean visits per day (averaged weekly) were similar to 2019 for the first 9 weeks (̃25). Visits declined to week 14 (18.19; a 31% drop from 2019), recovered to 2019 levels by week 23, and declined steadily to 11.89 (a 58% drop from 2019) as of week 44, the cut off of this analysis. Conclusions: Access to care for men with PCa was sharply curtailed by the COVID-19 pandemic, and while the impact was less for men with high-risk disease compared to those with low-risk disease, visits even for high-risk individuals were down nearly one-third and continued to fall through November. This study provides real-world evidence on the magnitude of decline in PCa care across risk groups. The impact of this decline on cancer outcomes should be followed closely.[Table: see text]
Impact of COVID-19 in the screening and treatment of breast cancer in the Brazilian public health system: Data from a healthcare data warehouse.
Authors: Alessandra Menezes Morelle, Fernando Castilho Venero, Rafael Dal Ponte Ferreira, Pedro Tofani Santanna, Rommel Fabricio Pereira da Silva, Patrícia Zieguelmann
Journal: Journal of Clinical Oncology (2021)

e18807 Background:Since December 2019, the world is facing a pandemic caused by a novel coronavirus (SARS-CoV-2). We sought to analyze the behavior of cancer treatments and procedures in breast cancer in Brazil after the beginning of the COVID-19 pandemic through an artificial intelligence platform with real life data. Methods:Data evaluation was performed using the TechTrials platform. This platform created a unique healthcare data warehouse containing hundreds of different publicly available data sources about Brazilian Public Health System and with proprietary technology, developed several analytics products that explore and release real-world data (RWD) insights. For this analysis data were extracted from DATASUS – SIA (outpatients information system). For each outcome, data from January 2011 to February 2020 were used to adjust a time series to predict values for March to November 2020. Those values were compared with the observed ones. Results: Biopsies, mammograms and procedures showed a sharp decrease (41.9%, 73.7% and 31.1%, respectively), in April 2020 (following month of the first COVID-19 case in Brazil) with some recovering in the following months. All observed values of biopsies, the number of mammograms from March to October and the number of procedures in April and May were significantly smaller than the predicted ones. Number of women undergoing chemotherapy began to decline in August and remained falling until the last month of available data.(Table). Conclusions: This study is the first one that analyzes RWD of breast cancer screening, diagnosis and treatment in Brazil as a result of the COVID-19 pandemic. The impact of the decrease observed in screening and diagnosis is already evident in the number of women undergoing chemotherapy. These data will continue to be monitored in the coming months when only then will data be available for staging at diagnosis.[Table: see text]
2-deoxy-D-glucose (2-DG) inhibits angiogenesis by interfering with N-linked glycosylation
Authors: Jaclyn Walbroehl, Metin Kurtoglu, Theodore J. Lampidis, Jaime R. Merchan
Journal: Cancer Research (2008)

367  Aims: Interference with endothelial glucose metabolism with regard to angiogenesis inhibition has rarely been explored. The aim of this study was to determine the effects of blocking glucose metabolism on angiogenesis, and to characterize glucose dependent molecular pathways critical to tumor neovascularization, specifically N-linked glycosylation. Methods: The effects of 2-DG and other glycolytic inhibitors on human umbilical vein endothelial cells (HUVEC) proliferation, cytotoxicity, and capillary formation in vitro were assessed. Sensitivity of endothelial cells (ECs) and tumor cells to 2-DG was compared. To assess if the inhibitory effects were due to 2-DG’s interference with N-linked glycosylation, mannose rescue experiments were performed. Western blotting for the molecular chaperone proteins Grp78/Bip, Grp94 and GADD153/C/EBP homologous protein (GADD153/CHOP) and caspase-3 cleavage were done from HUVEC lysates treated with 2DG and mannose to detect 2-DG induced unfolded protein response (UPR) and activation of UPR dependent apoptotic pathways, respectively. Results:2-DG inhibited HUVEC proliferation and induced EC cytotoxicity in a dose dependent manner and at lower concentrations than those required to cause cytotoxicity in selected cancer cells. EC tube formation was also significantly inhibited. Importantly, 2-DG treatment did not result in damage of established capillaries in vitro. The EC inhibitory effects of 2-DG were significantly higher than those of other glycolytic inhibitors (2-fluorodeoxy-D-glucose and oxamate) at equimolar concentrations, and were reversed by mannose, the predominant sugar molecule involved in N-linked glycosylation of glycoproteins. Western blot analysis on HUVEC lysates treated with 2-DG demonstrated induction of endoplasmic reticulum (ER) stress through activation of UPR, resulting in upregulation of GADD153/CHOP and caspase-3 cleavage. Those effects were reversed by mannose treatment, confirming N-linked glycosylation as the predominant mechanism of UPR-mediated apoptosis. Conclusion:2-DG significantly inhibits EC proliferation, in vitro angiogenesis, and induces cytotoxicity at concentrations below those required to affect tumor cells. The inhibitory effects appear to be due to the following sequence: Interference with N-linked glycosylation, induction of UPR, and activation of the UPR specific apoptotic pathway GADD153/CHOP. Our data underscore the importance of glucose metabolism in general and N-linked glycosylation, in particular on neovascularization, and provide a novel strategy for angiogenesis inhibition for the treatment of cancer. Studies assessing the effects of 2-DG on in vivo angiogenesis models are underway.
3-Year Follow-Up of Radiation-Associated Changes in Diastolic Function by Speckle Tracking Echocardiography
Authors: Suvi Sirkku Tuohinen, Tanja Skyttä, Heini Huhtala, Tuija Poutanen, Vesa Virtanen, Pirkko-Liisa Kellokumpu-Lehtinen, Pekka Raatikainen
Journal: JACC CardioOncology (2021)

Radiation therapy (RT) results in myocardial changes consisting of diffuse fibrosis, which may result in changes in diastolic function.The aim of this study was to explore RT-associated changes in left ventricular (LV) diastolic function.Sixty chemotherapy-naive patients with left-sided, early-stage breast cancer were studied with speckle tracking echocardiography at 3 time points: prior to, immediately after, and 3 years after RT. Global and regional early diastolic strain rate (SRe) were quantified, as were parameters of systolic function.Regional changes in SRe, particularly the apical and anteroseptal segments, were observed over time and were more evident than global changes. The apical SRe declined from a median of 1.24 (interquartile range: 1.01 to 1.39) s-1 at baseline to 1.02 (interquartile range: 0.79 to 1.15) s-1 at 3 years of follow-up (p < 0.001). This decline was associated with the left ventricular maximal radiation dose (β = 0.36, p = 0.007). The global SRe was <1.00 s-1 (SRedep) in 11 (18.3%) patients at baseline, 21 (35%) patients (p = 0.013) post-RT, and 17 (28.3%) patients (p = 0.051) at 3 years. SRedep post-RT was independently associated with baseline cardiac abnormalities (odds ratio: 0.26; 95% confidence interval: 0.08 to 0.84; p = 0.025); SRedep at 3 years of follow-up was associated with the baseline Charlson comorbidity index (odds ratio: 2.36; 95% confidence interval: 1.17 to 4.77; p = 0.017). Diastolic function abnormalities were evident even in patients with preserved global longitudinal strain at 3 years.RT resulted in changes in the SRe in the apical and anteroseptal segments over 3 years of follow-up. Changes in SRe apical segments were present even in patients with preserved systolic function and were independently associated with RT dose and cardiovascular comorbidities.
Dying at home during the pandemic
Authors: Irene J Higginson, David Brooks, Stephen Barclay
Journal: BMJ (2021)

Data from the Office for National Statistics show that covid-19 was responsible for most of the 76 000 excess deaths during 2020 in England and Wales, with only around 2000 attributable to other causes. 1 The number of deaths from all causes in private homes increased by about one third to 167 000 in 2020, compared with an average of 125 000 between 2015 and 2019.Around 41 000 more people died in private homes than in a normal year (which is more than half of the total number of excess deaths) but only a small number (just over 3000 or 7%) were recorded as being due to covid-19. 1 Most of these deaths at home were from underlying causes seen every year: dementias (which increased by 65%), heart and lung diseases, cancers, and neurological diseases. 2Some covid-19 deaths that occurred at home may have been wrongly attributed to these conditions, especially early in the pandemic when symptoms were poorly understood and testing scarce.Nevertheless, this is still likely to represent a significant shift of people dying of causes other than covid-19 from hospital to home.