tbuckley/cabot-search huggingface dataset:
Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab in High-Risk Smoldering Multiple Myeloma
Authors: Timothy A. Brighton, Amit Khot, Simon J. Harrison, David Ghez, Brendan M. Weiss, Andres Kirsch, Hila Magen, Mercedes Gironella, Albert Oriol, Matthew Streetly, Britte Kranenburg, Xiang Qin, Rajesh Bandekar, Peter Hu, Mary Guilfoyle, Ming Qi, Sepideh Nemat, Hartmut Goldschmidt
Journal: Clinical Cancer Research (2019)

Abstract Purpose: IL6 is important for the growth and survival of myeloma cells. This study evaluated blocking IL6 with siltuximab to delay the transition from high-risk smoldering multiple myeloma (SMM) to multiple myeloma. Patients and Methods: In a randomized, double-blind, placebo-controlled, multicenter study, 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients). The primary endpoint was 1-year progression-free survival (PFS) rate, based on IMWG CRAB criteria. Secondary endpoints included progressive disease indicator rate, PFS, and safety. Results: Median age was 62 years (range: 21–84); 57% were male and 87% had a baseline Eastern Cooperative Oncology Group score of 0. The 1-year PFS rate was 84.5% (siltuximab) and 74.4% (placebo). After a median follow-up of 29.2 months, 32.6% of PFS events occurred with siltuximab and 42.9% with placebo. Median PFS was not reached with siltuximab but was 23.5 months with placebo [HR 0.50 (95% confidence interval, 0.24–1.04); P = 0.0597]. The safety profile of siltuximab was comparable with placebo. Most adverse events in the siltuximab group were grade 2/3; the most common serious adverse events were infections/infestations, and renal/urinary disorders. Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group). Conclusions: Although this study did not meet the prespecified protocol hypothesis criteria, data suggest that siltuximab may delay the progression of high-risk SMM.
α1ACT Is Essential for Survival and Early Cerebellar Programming in a Critical Neonatal Window
Authors: Xiaofei Du, Cenfu Wei, Daniel Parviz Hejazi Pastor, Eshaan R. Rao, Yan Li, Giorgio Grasselli, Jack Godfrey, Ann C. Palmenberg, Jorge Andrade, Christian Hansel, Christopher M. Gomez
Journal: Neuron (2019)
Creating a Population Model for PK-Tailored Dosing Using Real-World Data from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) Platform
Authors: Pierre Chelle, Cindy Yeung, Santiago Bonanad Boix, Juan Cristobal Morales, Margareth C Ozelo, Juan E. Megias Vericat, Alfonso Iorio, Jeffrey Spears, Roser Mir, Andrea N Edginton
Journal: Blood (2018)
Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study
Authors: Byong Duk Ye, Marina Pesegova, Olga Alexeeva, Marina Osipenko, Adi Lahat, Andriy Dorofeyev, Sigal Fishman, Olena Levchenko, Jae Hee Cheon, Maria Lia Scribano, Radu-Bogdan Mateescu, Kang-Moon Lee, Chang Soo Eun, Sang Joon Lee, Sung Young Lee, HoUng Kim, Stefan Schreiber, Heather Fowler, Raymond Cheung, Young-Ho Kim
Journal: The Lancet (2019)
CLO19-045: Safety of Immune Checkpoint Inhibitors in Cancer Patients With Microsatellite Instability-High (MSI-H) Status: An Experience From Qatar
Authors: Nabil El-Hadi Omar, Sahar Nasser, Mahmoud Gasim, Maneesh Khanna, Abdulqadir J. Nashwan, Jonas W. Feilchenfeldt, Kakil Rasul, Anas Hamad
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Microsatellite instability-high (MSI-H) is shown to predict response to the immune checkpoint inhibitors (ICPi). Recently, the FDA granted an accelerated approval for the use of pembrolizumab in any solid tumor and nivolumab in metastatic colorectal cancer in patients with MSI-H. However, the immune-related adverse events (irAEs) exhibit a unique heterogeneous spectrum than conventional chemotherapy adverse drug reactions (ADRs). Underestimating the irAEs could be potentially lethal. Objectives: To evaluate the irAEs; their management, and outcome in MSI-H patients treated with ICPi at the National Center for Cancer Care and Research (NCCCR) in Qatar. Methods: All patients with MSI-H and treated with ICPi at the NCCCR between January 2015 and June 2018 were reviewed retrospectively. Radiologic assessment of irAEs and Naranjo score were used to estimate and confirm the probability of ADRs. Patient demographics, immunotherapy treatment, reported irAEs, and their management were collected. Results: Of the total cohort of patients receiving ICPIs; 9 patients with MSI-H were identified; all received pembrolizumab. 45% (n=4) of the patients were still actively on treatment; 22% (n=2) received only 1 dose then passed away; 22 % (n=2) discontinued because of disease progression; and 11% (n=1) of the patients received 2 cycles as neoadjuvant treatment. To the best of our knowledge, this is the biggest cohort of cancer patients with MSI-H in the Middle East. Calculated Naranjo score was 7 in 45% of the patients (n=4) and 5 in 22 % of patient (n=2), which indicates a probable ADR. 34% of the patients (n=3) did not experience ADRs till the date of data cutoff. 8 irAEs were seen in 67% (n=6) of the patients (Table 1). Based on laboratory or radiologic confirmation, 87.5% (n=7) were irAEs and 12.5% (n=1) was not related to pembrolizumab. Laboratory findings confirmed 25% of the ADRs and radiologic findings confirmed 75% of the ADRs. Of those who developed irARs, 3 patients required a hold of treatment, 1 needed monitoring, and 2 required pharmacologic interventions. There was one patient who received empirical pharmacologic intervention at which evaluation showed no relation to immunotherapy. Conclusion: irAEs can sometimes be unpredictable, rare, and often missed. Frequent monitoring and early management of these suspected or confirmed adverse effects is life saving and should be done in a multidisciplinary approach.
Functional Characteristics of FAS-L Resistant and IL-2 Deprived Regulatory T Cells (Treg A) in Idiopathic Aplastic Anaemia
Authors: Benedetta Costantini, Syed A Mian, Shok Ping Lim, Frederic Toulza, Stephen Orr, Pilar Perez-Abellan, Ander Abarrategi, Farzin Farzaneh, Dominique Bonnet, Judith Marsh, Shahram Kordasti, Ghulam Mufti
Journal: Blood (2017)
Abstract 19846: Clinical, Symptom, Functional, and QOL Outcomes in a Trial of Prescribed Fluid Restrictions in Persons With Heart Failure
Authors: Carolyn M Reilly, Melinda Higgins, Sandra B Dunbar
Journal: Circulation (2017)

Introduction: Fluid restriction (FR) in heart failure (HF) is controversial and outcomes associated with varying prescribed levels are unknown. Hypothesis: FR groups will demonstrate less congestio...
Biased Receptor Signaling in Drug Discovery
Authors: Terry Kenakin
Journal: Pharmacological Reviews (2019)

A great deal of experimental evidence suggests that ligands can stabilize different receptor active states that go on to interact with cellular signaling proteins to form a range of different complexes in varying quantities. In pleiotropically linked receptor systems, this leads to selective activation of some signaling pathways at the expense of others (biased signaling). This article summarizes the current knowledge about the complex components of receptor systems, the evidence that biased signaling is used in natural physiology to fine-tune signaling, and the current thoughts on how this mechanism may be applied to the design of better drugs. Although this is a fairly newly discovered phenomenon, theoretical and experimental data suggest that it is a ubiquitous behavior of ligands and receptors and to be expected. Biased signaling is simple to detect in vitro and there are numerous methods to quantify the effect with scales that can be used to optimize this activity in structure-activity medicinal chemistry studies. At present, the major hurdle in the application of this mechanism to therapeutics is the translation of in vitro bias to in vivo effect; this is because of the numerous factors that can modify measures of bias in natural physiologic systems. In spite of this, biased signaling still has the potential to justify revisiting of receptor targets previously thought to be intractable and also furnishes the means to pursue targets previously thought to be forbidden due to deleterious physiology (as these may be eliminated through biased signaling).
<i>ALK</i> Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer
Authors: Alice T. Shaw, Benjamin J. Solomon, Benjamin Besse, Todd M. Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Jill S. Clancy, Sherry Li, Antonello Abbattista, Holger Thurm, Miyako Satouchi, D. Ross Camidge, Steven Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Jean-François Martini
Journal: Journal of Clinical Oncology (2019)

Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non-small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients.Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation-focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status.Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47).In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.
Ochronosis Involvement and Extensity With 18F-FDG PET/CT
Authors: Emine Acar, Recep Bekiş, Berin Zengin, Merih Birlik
Journal: Clinical Nuclear Medicine (2019)

Abstract Ochronosis (alkaptonuria) is an autosomal recessive inherited metabolic disease that causes pigmentation by accumulation of homogenous acid in the connective tissue. The most important causes of morbidity are ochronotic arthropathy and cardiovascular involvement seen in fourth and sixth decades, respectively. In this case report, we report the prevalence of 18 F-FDG PET/BT findings in a 48-year-old man with ochronosis who underwent 18 F-FDG PET/BT imaging for the evaluation of mediastinal lymphadenopathy.
Comparison of Cost Center–Specific vs Hospital-wide Cost-to-Charge Ratios for Operating Room Services at Various Hospital Types
Authors: Christopher P. Childers, Jill Q. Dworsky, Marcia M. Russell, Melinda Maggard-Gibbons
Journal: JAMA Surgery (2019)

This analysis estimates differences associated with using general hospital-wide cost-to-charge ratios vs cost center–specific cost-to-charge ratios for operating room services and discusses whether this bias varies by hospital type.
Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia
Authors: Nolwenn Lucas, Matthieu Duchmann, Philippe Rameau, Floriane Noël, Paula Michea, Véronique Saada, Olivier Kosmider, Gérard Pierron, Martin E Fernandez-Zapico, Matthew T. Howard, Rebecca L. King, Sandrine Niyongere, M’boyba Khadija Diop, Pierre Fenaux, Raphael Itzykson, Christophe Willekens, Vincent Ribrag, Michaela Fontenay, Eric Padron, Vassili Soumelis, Nathalie Droin, Mrinal M Patnaik, Eric Solary
Journal: Leukemia (2019)
Kentucky’s governor boasts of bringing his children to a “pox party”
Authors: Owen Dyer
Journal: BMJ (2019)

Matt Bevin, the Republican governor of Kentucky, has told a radio show that he brought all nine of his children to a “pox party” in order to deliberately infect them with chickenpox.

“We found a neighbour that had it,” Bevin told local radio station Talk 104.1 . “And I went and made sure every one of my kids was exposed to it and they got it. And they had it as children, they were miserable for a few days, and they all turned out fine.” …
Abstract A06: MicroRNA-195 acts as a tumor suppressor miRNA in human melanoma cells by targeting Prohibitin 1
Authors: Priscila D. R. Cirilo, Bruna R. S. Côrrea, Mei Qiao, Luciana N. S. Andrade, Roger Chammas, Luiz O. F. Penalva
Journal: Clinical Cancer Research (2018)

Abstract Melanoma is the most lethal type of skin cancer. Since chemo-resistance is a significant barrier, identification of regulators affecting chemo-sensitivity is necessary in order to create new forms of intervention. Here, we investigate the role of miR-195, its impact on Prohibitin 1 (PHB1) expression, and on chemo-sensitivity in melanoma cells. TCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by qRT-PCR and Western blot, luciferase reporter, and rescue experiments. Cell proliferation, hypodiploid, and caspase 3/7 assays were performed to investigate the potential action of miR-195 as chemo-sensitizer in melanoma cells treated with cisplatin and temozolomide. Analysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, qRT-PCR data showed that miR-195 is downregulated while PHB1 is upregulated in a collection of melanoma lines. We demonstrated that miR-195 regulates PHB1 directly by qRT-PCR and Western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect of miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as a tumor suppressor and potential chemo-sensitivity agent. Citation Format: Priscila D. R. Cirilo, Bruna R. S. Côrrea, Mei Qiao, Luciana N. S. Andrade, Roger Chammas, Luiz O. F. Penalva. MicroRNA-195 acts as a tumor suppressor miRNA in human melanoma cells by targeting Prohibitin 1 [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A06.
BPI19-010: Febrile Neutropenia Induced by Chemotherapy: Impact of Risk Re-Stratification
Authors: David da Silva Dias, Catarina Jorge, Mafalda Baptista, Ana Júlia Arede, Paulo Luz, Tânia Madureira, Beatriz Gosalbez
Journal: Journal of the National Comprehensive Cancer Network (2019)

Introduction: Febrile neutropenia (FN) induced by chemotherapy (ChT) arises until 6 weeks after the last cycle, usually between 5 and 10 days post-ChT. Infection risk is 20%–30%. It is difficult to stratify patients with low risk of complications due to FN. MASCC index is useful but has limitations. This correlates with unnecessary hospital admissions, complications, and costs. Methods: Retrospective study of patients with diagnosis of FN induced by ChT, admitted to our center between 2012 and 2016. Primary goal was to describe this population. Secondary goal was to re-stratify the risk of FN using MASCC and CISNE indexes, clinical judgement, and social/logistic factors. SPSS v23 was used for statistical analysis. Results: 211 patients were included; median age, 66 years. Median hospital stay was 6 days (1–89). 25% were nosocomial admissions. At admission 46% of patients presented with stage IV cancer. 75% were solid neoplasms and 25% were hematologic. Profound neutropenia was observed in 43% and severe neutropenia in 36%. Overall mortality rate was 13%. Sepsis was diagnosed in 24 patients (11%), with a mortality rate of 54%. Only 12.3% of patients had prophylaxis with granulocyte-colony stimulating factor. At admission, 64% of patients had no obvious focal infection; 20% had probable focus; and in 16% a microorganism was identified, most commonly gram-negative Enterobacteriaceae . Most used antibiotics were piperacillin/tazobactam (44%) and its combination with aminoglycoside (34%). This combination showed benefit against some extended-spectrum beta-lactamase (ESBL)–producing strains and multiresistant (MR) Pseudomonas aeruginosa (2.8%). MASCC index identified 31% of patients with low risk FN. After applying the CISNE index, clinical judgement, and social/logistic factors, only 11% were identified as low-risk FN and did not benefit from admission. This translates to an avoidable cost of €48,000 according to the center’s annual report. Conclusion: The combination of β-lactam and aminoglycoside is overused in our practice. It is not recommended in hemodynamically stable patients and contradictory in unstable ones; still it shows some effect versus MR and ESBL strains. A study to evaluate their incidence in our center is now in progress. Low risk FN was observed in 11% of admitted patients. Our center has an internal protocol and has been able to provide a good overall response.
The Effect of the Proteasome Inhibitor Ixazomib (MLN9708) and UPR Mediated Therapy in Multiple Myeloma Cells and Bone Marrow Niche
Authors: Azam Salimi, Kema Marlen Schroeder, Margherita Vieri, Tim H. Brümmendorf, Iris Appelmann, Behzad Kharabi
Journal: Blood (2017)
Pulmonary fibrosis: “idiopathic” is not “cryptogenic”
Authors: Athol U. Wells, Kevin K. Brown, Kevin R. Flaherty, Martin Kolb, Victor J. Thannickal
Journal: European Respiratory Journal (2019)

The writer makes a powerful plea for clarity of thought based on clarity of language, arguing from the Socratic maxim that "the beginning of wisdom is the definition of terms". This etymological perspective is extremely apposite because the distinction between "cryptogenic" and "idiopathic" disease is seminal in the ongoing idiopathic pulmonary fibrosis (IPF) terminology debate. The additional argument advanced by Professor Cottin for retention of the term "idiopathic pulmonary fibrosis" is highly persuasive <http://ow.ly/n05630nVCZd>
Tissue hypoxia, inflammation, and loss of glomerular filtration rate in human atherosclerotic renovascular disease
Authors: Abdelrhman Abumoawad, Ahmed Saad, Christopher M. Ferguson, Alfonso Eirin, John R. Woollard, Sandra M. Herrmann, LaTonya J. Hickson, Emily C. Bendel, Sanjay Misra, James Glockner, Lilach O. Lerman, Stephen C. Textor
Journal: Kidney International (2019)
CLO19-035: Safety Profile and Adverse Events of Sunitinib as a First-Line Treatment for Advanced/Metastatic Clear-Cell Renal Cell Carcinoma: Pooled Analysis of Randomized Controlled Trials
Authors: Tarek Haykal, Babikir Kheiri, Varun Samji, Yazan Zayed, Ragheed Al-Dulaimi, Inderdeep Gakhal, Areeg Bala, Jason Sotzen, Ahmed Abdalla, Ghassan Bachuwa
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact prevalence of all sunitinib-related AEs in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled prevalence of the most common reported side effects of sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4,106 patients. The mean age was 62, with 66.44% males. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue, 44%; diarrhea, 38%; nausea, 31%; hand-foot syndrome, 30%; hypertension, 27%; dysgeusia, 25%; hypothyroidism, 25%; cconstipation, 20%; stomatitis, 20%; inflammation of the mucosa, 18%; dyspepsia, 16%; vomiting, 14%; rash, 12%; asthenia, 11%; and epistaxis, 10%. Grade 3 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension, 9%; fatigue, 8%; hand-foot syndrome, 5%; asthenia, 5%; diarrhea, 4%; and inflammation of the mucosa, 2%. Laboratory abnormalities were also reported as follows: increased AST, 7%; increased lipase, 6%; neutropenia, 6%; thrombocytopenia, 6%; hypophosphatemia, 5%; lymphocytopenia, 5%; anemia, 4%; and leukopenia, 3%. Conclusion: Despite s unitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, its safety profile is concerning, with a high prevalence of reported dangerous side effects. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the burden of adverse events.