PURPOSEAnaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a... Show morePURPOSEAnaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor.METHODSWe enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1.RESULTSForty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1-positive (8/28; 29%) versus PD-L1-negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 >= 50% (6/17; 35%). Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1-positive population.CONCLUSIONTo our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade. Show less
Pillay, P.; Downs, J.A.; Changalucha, J.M.; Brienen, E.A.T.; Ramarokoto, C.E.; Leutscher, P.D.C.; ... ; Lieshout, L. van 2020
Female Genital Schistosomiasis (FGS) is a neglected disease affecting millions, however challenging to diagnose. This explorative descriptive study compares Schistosoma real-time PCR analysis of... Show moreFemale Genital Schistosomiasis (FGS) is a neglected disease affecting millions, however challenging to diagnose. This explorative descriptive study compares Schistosoma real-time PCR analysis of cervico-vaginal lavages (CVL) with corresponding urine and stool samples of 933 women from five different previously described study populations. Sampling included 310 women from an S. mansoni endemic region in Mwanza, Tanzania and 112 women from a nearby S. haematobium endemic region. Findings were compared with samples collected from S. haematobium endemic regions in South Africa from 394 women and from 117 women from Madagascar of which 79 were urine pre-selected microscopy positive cases from highly-endemic communities and 38 were urine microscopy negatives from a low-endemic community. As anticipated, urine and stool microscopy and gynecological investigations varied substantially between study populations; however, the same Schistosoma real-time PCR was performed in one reference laboratory. Schistosoma DNA was detected in 13% (120/933) of the CVL, ranging from 3% in the S. mansoni Tanzanian endemic region to 61% in the pre-selected Malagasy urine microscopy positive cases. Detectable Schistosoma DNA in CVL was associated with Schistosoma DNA in urine but not with microscopic detection of eggs in urine or by cytological examination. This study confirmed real-time PCR for the detection of Schistosoma DNA in gynecological samples to be a valuable diagnostic tool to study the distribution of FGS within schistosomiasis endemic areas. Show less
BackgroundSpartalizumab is a humanized IgG4 kappa monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to... Show moreBackgroundSpartalizumab is a humanized IgG4 kappa monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in <= 3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types. Show less
Altmetric’s mission is to help others understand the influence of research online.We collate what people are saying about published research in sources such as the mainstream media, policy... Show moreAltmetric’s mission is to help others understand the influence of research online.We collate what people are saying about published research in sources such as the mainstream media, policy documents, social networks, blogs, and other scholarly and non-scholarly forums to provide a more robust picture of the influence and reach of scholarly work. Altmetric works with some of the biggest publishers, funders, businesses and institutions around the world to deliver this data in an accessible and reliable format.ContentsAltmetrics, Ten Years Later, Euan Adie (Altmetric (founder) & Overton)Reflections on Altmetrics, Gemma Derrick (University of Lancaster), Fereshteh Didegah (Karolinska Institutet & Simon Fraser University), Paul Groth (University of Amsterdam), Cameron Neylon (Curtin University), Jason Priem (Our Research), Shenmeng Xu (University of North Carolina at Chapel Hill), Zohreh Zahedi (Leiden University)Worldwide Awareness and Use of Altmetrics, Yin-Leng Theng (Nanyang Technological University)Leveraging Machine Learning on Altmetrics Big Data, Saeed-Ul Hassan (Information Technology University), Naif R. Aljohani (King Abdulaziz University), Timothy D. Bowman (Wayne State University)Altmetrics as Social-Spatial Sensors, Vanash M. Patel (West Hertfordshire Hospitals NHS Trust), Robin Haunschild (Max Planck Institute for Solid State Research), Lutz Bornmann (Administrative Headquarters of the Max Planck Society)Altmetric’s Fable of the Hare and the Tortoise, Mike Taylor (Digital Science)The Future of Altmetrics: A Community Vision, Liesa Ross (Altmetric), Stacy Konkiel (Altmetric)https://digitalcommons.unl.edu/scholcom/170 Show less
A central issue with many interpretations of radicalization remains their tendency to overemphasize the role of extremist beliefs in motivating involvement in terrorism. A er elaborating on... Show moreA central issue with many interpretations of radicalization remains their tendency to overemphasize the role of extremist beliefs in motivating involvement in terrorism. A er elaborating on this critique, the authors propose that ‘fanaticism’, a concept developed by Taylor in the early 1990s, o ers a way of overcoming this de ciency in radicalization-based approaches through its conditional understanding of when radical beliefs can lead to violent behavior. Primary-sources driven empirical analysis supports both the critique of radicalization and the discussion of fanaticism’s bene ts. Results are relevant to both academics and counterterrorism practitioners working to understand the role of extremist beliefs in motivating involvement in terrorist violence. Show less
To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four... Show moreTo identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 x 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 x 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 x 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 x 10(-50)). These data provide new insight into the pathogenesis of cHL. Show less
