tbuckley/cabot-search huggingface dataset:
Dose-Dependent Effect of Enzyme Replacement Therapy on Neutralizing Antidrug Antibody Titers and Clinical Outcome in Patients with Fabry Disease
Authors: Malte Lenders, Leon Paul Neußer, Michael Rudnicki, Peter Nordbeck, Sima Canaan-Kühl, Albina Nowak, Markus Cybulla, Boris Schmitz, Jan Lukas, Christoph Wanner, Stefan-Martin Brand, Eva Brand
Journal: Journal of the American Society of Nephrology (2018)

Background Use of enzyme replacement therapy (ERT) to treat Fabry disease, caused by deficient lysosomal α -galactosidase A activity, can lead to formation of neutralizing antidrug antibodies (ADAs). These antibodies are associated with increased accumulation of plasma globotriaosylceramide (Gb3) and disease progression. Because agalsidase ERT can saturate ADA-binding sites during infusions (achieving agalsidase/antibody equilibrium), we investigated in this open cohort study whether saturated patients (who have excess agalsidase after infusions) experience better clinical outcomes compared with not saturated patients (who have excess ADAs after infusions). Methods We isolated ADAs from sera of 26 men with Fabry disease receiving ERT (for a median of 94 months) and determined the amount of agalsidase necessary for antibody saturation. Clinical and biochemical outcomes included measurements of eGFR, interventricular septum thickness, and lyso-Gb3. Results ADA titers decreased significantly in all patients during infusion. Agalsidase- α and agalsidase- β had similar ADA-binding capacity and comparable ADA saturation frequency. Fourteen patients with saturated ADAs presented with mild (but significant) loss of eGFR, stable septum thickness, and significantly decreased lyso-Gb3 levels. The 12 not saturated patients had a more pronounced and significant loss of eGFR, increased septum thickness, and a smaller, nonsignificant reduction in lyso-Gb3, over time. In three patients, dose escalation resulted in partially elevated ADA titers, but importantly, also in reduced lyso-Gb3 levels. Conclusions A not saturated ADA status during infusion is associated with progressive loss of eGFR and ongoing cardiac hypertrophy. Dose escalation can result in saturation of ADAs and decreasing lyso-Gb3 levels, but may lead to increased ADA titers.
The Immunobiology of Kidney Cancer
Authors: Charles G. Drake, Mark N. Stein
Journal: Journal of Clinical Oncology (2018)

Although kidney cancer (renal cell carcinoma [RCC]) is susceptible to immunotherapy, the immunologic aspects of the tumor microenvironment (TME) in RCC are relatively unique among tumor types. In RCC, baseline CD8 T-cell infiltration is associated with a worse prognosis. In addition, kidney cancer responds to programmed death-1/programmed death-ligand 1 blockade, despite a relatively low tumor mutation burden. Recent clinical data highlight the efficacy of combined immune checkpoint blockade and demonstrate that combining antiangiogenic agents with programmed death-1/programmed death-ligand 1 blockade has additive activity. Yet an important unanswered question in RCC is the nature of the antigens that are targeted by the immune system when immunotherapy is successful. Ongoing clinical studies are interrogating the multiple suppressive mechanisms in the RCC TME, including metabolic pathways such as those mediated by adenosine and tryptophan as well as cytokine-based therapies. Future regimens are likely to be combinatorial and may eventually be based on a broader understanding of the RCC TME and how it is modulated by both conventional and immune-based therapy.
Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis
Authors: Saifon Chawanpaiboon, Joshua P Vogel, Ann-Beth Moller, Pisake Lumbiganon, Max Petzold, Daniel Hogan, Sihem Landoulsi, Nampet Jampathong, Kiattisak Kongwattanakul, Malinee Laopaiboon, Cameron Lewis, Siwanon Rattanakanokchai, Ditza N Teng, Jadsada Thinkhamrop, Kanokwaroon Watananirun, Jun Zhang, Wei Zhou, A Metin Gülmezoglu
Journal: The Lancet Global Health (2018)

Preterm birth is the leading cause of death in children younger than 5 years worldwide. Although preterm survival rates have increased in high-income countries, preterm newborns still die because of a lack of adequate newborn care in many low-income and middle-income countries. We estimated global, regional, and national rates of preterm birth in 2014, with trends over time for some selected countries.
End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma
Authors: Caron A. Jacobson, Frederick L. Locke, David B. Miklos, Alex F. Herrera, Jason R. Westin, Jennifer Lee, John M. Rossi, Lianqing Zheng, Mauro P. Avanzi, Zachary J. Roberts, Jennifer Sun
Journal: Blood (2018)
Association of Aspirin and Nonsteroidal Anti-Inflammatory Drugs With Colorectal Cancer Risk by Molecular Subtypes
Authors: Efrat L Amitay, Prudence R Carr, Lina Jansen, Viola Walter, Wilfried Roth, Esther Herpel, Matthias Kloor, Hendrik Bläker, Jenny Chang-Claude, Hermann Brenner, Michael Hoffmeister
Journal: JNCI Journal of the National Cancer Institute (2018)

Regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) for a longer period has been inversely associated with colorectal cancer (CRC) risk. However, CRC is a heterogenic disease, and little is known regarding the associations with molecular pathological subtypes.Analyses included 2444 cases with a first diagnosis of CRC and 3130 healthy controls from a German population-based case control study. Tumor tissue samples were analyzed for major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Information on past and current use of NSAIDs, including aspirin, was obtained by standardized interviews. Multinomial logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided.Regular use of NSAIDs was associated with a reduced CRC risk if tumors were MSS (OR = 0.66, 95% CI = 0.57 to 0.77), BRAF wildtype (OR = 0.67, 95% CI = 0.58 to 0.78), or KRAS wildtype (OR = 0.68, 95% CI = 0.58 to 0.80). Regular NSAID use was less clearly and mostly not statistically significantly associated with CRC risk reduction for MSI-high, BRAF-mutated, or KRAS-mutated CRC. In more specific analyses on MSI-high CRC, regular use of NSAIDs was associated with much stronger risk reduction in the absence of BRAF or KRAS mutations (OR = 0.34, 95% CI = 0.18 to 0.65) but not with KRAS- or BRAF-mutated MSI-high CRC (Pheterogeneity < .001). Results for just aspirin use were similar.Our study suggests variation in risk reduction of CRC subtypes following regular use of NSAIDs and aspirin. Regular use of NSAIDs and aspirin may be more strongly associated with risk reduction of MSI-high CRC without KRAS or BRAF mutation.
Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies
Authors: James J. Harding, Subhiksha Nandakumar, Joshua Armenia, Danny N. Khalil, Melanie Albano, Michele Ly, Jinru Shia, Jaclyn F. Hechtman, Ritika Kundra, Imane El Dika, Richard K. Do, Yichao Sun, T. Peter Kingham, Michael I. D'Angelica, Michael F. Berger, David M. Hyman, William Jarnagin, David S. Klimstra, Yelena Y. Janjigian, David B. Solit, Nikolaus Schultz, Ghassan K. Abou-Alfa
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Experimental Design: Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture–based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: WNT/β-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K–mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (&amp;lt;1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics. Conclusions: Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies. See related commentary by Pinyol et al., p. 2021
Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study
Authors: Joseph M. Connors, Anas Younes, Andrea Gallamini, Stephen M. Ansell, Won-Seog Kim, Ranjana H Advani, Nancy L. Bartlett, David J. Straus, Anna Sureda, Martin Hutchings, Monika Dlugosz-Danecka, Gerald Engley, Keenan Fenton, Rachael Liu, Harry Miao, Hina Jolin, Ashish Gautam, John Radford
Journal: Blood (2018)
Abstract 18082: Perk Inhibition Improves Pulmonary Arterial Hypertension in Mice
Authors: Takashi Shimizu, Eiki Takimoto, Tomokazu Sumida, Atsuhiko T Naito, Issei Komuro
Journal: Circulation (2016)

Introduction: Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling, characterized by endothelial dysfunction and pulmonary artery smooth muscle cell (PASM...
THU0256 High disease activity, reduced physical function, long disease duration, fatigue and living without a partner are factors related to worse health related quality of life in ankylosing spondylitis
Authors: H. Forsblad-D’elia, L. Law, J. Beckman Rehnman, A. Deminger, E. Klingberg, L. T. H. Jacobsson
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ankylosing spondylitis (AS) begins early in life. The disease often leads to reduced physical function and also reduced health related quality of life (HRQoL). Knowledge is limited about factors related to HRQoL and how it develops over time. <h3>Objectives</h3> To assess HRQoL by SF-36 in a cohort of patients with AS compared with controls and to explore associations between HRQoL and spinal radiographic damage, physical function, disease activity and demographic data. <h3>Methods</h3> A cohort of patients with AS from Western Sweden were assessed at baseline and after 5 years with; x-ray of the spine for mSASSS, clinical examination and questionnaires, including BASMI, BASFI, ASDAS, BASDAI and SF-36. In this abstract we report the baseline results. Each patient's SF-36 results were compared with 5 age- and sex matched persons (n=1055) from the SF-36 Swedish normative population database. Associations between SF-36 mental component summary (MCS) and physical component summary (PCS) scores and disease related and demographic factors were investigated. Univariate logistic regression analyses were assessed with PCS and MCS below/above their respective median values (below median=1 and above median=0) as dependent variables and disease related and demographic variables as covariates. Variables with p<i>-</i>values≤0.2 in the univariate analyses were entered as covariates in multivariate models after checking for multicollinearity. <h3>Results</h3> 210 patients, age (median, IQR) 49.0 (40.0, 61.2) years, symptom duration 24.0 (13.0, 34.0) years, men 58%, HLAB27 87% were included. AS patients scored significantly lower (p&lt;0.001) compared to controls in all SF-36 domains and component summaries. AS women scored significantly lower compared to AS men in three domains, Physical Function, Vitality and Mental Health. Both men and women scored significantly lower in PCS compared with MCS. The results of the multiple logistic regressions are shown in the table 1. <h3>Conclusions</h3> Patients with AS had significantly lower HRQoL compared with controls. Women with AS scored lower in some domains compared to men and PCS was more affected compared to MCS in both sexes. Both demographic and disease related factors were associated with HRQoL, partly overlapping for PCS and MCS. By modifying factors, such as ASDAS and fatigue, HRQoL may potentially be improved. The development of SF-36 over 5 years will be investigated. <h3>Disclosure of Interest</h3> H. Forsblad-D'elia Grant/research support from: Advisory Board Fees from Sandoz, Novartis and Abbvie and an unrestricted grant from Novartis, L. Law: None declared, J. Beckman Rehnman: None declared, A. Deminger: None declared, E. Klingberg: None declared, L. T.H. Jacobsson: None declared
Selective expression of the Sp17/AKAP4/PTTG1 in NSCLC for detection and therapy.
Authors: Saba Radhi, Charles Saadeh, Raymond Wade, Jesse Mer, Yuefei Yu, Leonardo Mirandola, Venu Konala, Amardeep Aulakh, Raffaella Chiaramonte, Natalia Platonova, Kristopher Zepeda, Michela Colombo, Marjorie Jenkins, Jose A. Figueroa, Everardo Cobos, Cynthia A. Jumper, Raed Alalawi, Maurizio Chiriva-Internati
Journal: Journal of Clinical Oncology (2013)

e18527 Background: Cancer testis antigens (CTA) are a class of tumor associated antigens, showing a restricted expression in cancer, strong immunogenicity, and weak expression in normal tissues. Sp17/AKAP4/PTTG1 have been previously investigated, showing promising results as a target antigens. Our aim was to investigate the expression of Sp17/AKAP4/PTTG1 in lung cancer patients. Methods: We analyzed two lung cancer cell lines, one normal bronchus cell line, a panel of normal tissues and patient’s cells by RT-PCR, flow-cytometry, immunocytochemistry (ICC), and immunofluorescence (IF). CTA immunogenicity was investigated by measuring circulating specific antibodies in the sera of lung cancer patients. Results: ELISA analyses show the presence of circulating CTA-specific antibodies in the sera of lung cancer patients, indicating the immunogenicity of Sp17, AKAP-4 and PTTG-1. We showed that CTA, Sp17, AKAP-4 and PTTG-1 can be detected in both sera and tissue of patients with NSCLC. Furthermore, CTA can elicit an immunogenic response in patients affected with this disease. Conclusions: Our results provide the first evidence that the CTAs SP17/AKAP4/PTTG1 are expressed in both non-small cell lung cancer cell lines and primary tumor tissues and can elicit an immunogenic response in patients afflicted with this disease. Based on our findings we believe further studies are warranted to explore the feasibility of developing CTA-tailored immunotherapeutic strategies for non-small cell lung cancer.
Evaluation of a micro-spectrometer for the real-time assessment of liver graft with mild-to-moderate macrosteatosis: A proof of concept study
Authors: Nicolas Golse, Cyril Cosse, Marc-Antoine Allard, Andrea Laurenzi, Michele Tedeschi, Nicola Guglielmo, Elena Fernandez-Sevilla, Maud Robert, Boris Tréchot, Daniel Pietrasz, Gabriella Pittau, Oriana Ciacio, Antonio Sa Cunha, Denis Castaing, Daniel Cherqui, René Adam, Didier Samuel, Mylene Sebagh, Eric Vibert
Journal: Journal of Hepatology (2018)
Cost of narrowband ultraviolet B for psoriasis
Authors: K. Boswell, H. Cameron, J. West, C. Fleming, S. Ibbotson, R. Dawe, J. Foerster
Journal: British Journal of Dermatology (2018)

Psoriasis is a very common disease, affecting around 2% of people worldwide and 1.5 million in the UK. Many patients are affected throughout their lives. Psoriasis can often be treated with creams. However, when this is not enough patients can be treated by specially filtered ultraviolet light called “narrowband‐UVB”. This treatment is very effective in 3 out of 4 people, safe, and does not require blood testing. However, in many regions it is not readily available. One reason for this is that it is regarded as expensive since patients have to attend 3 times per week for a few minutes for several weeks, and staff administer the treatment. In this study, the authors extracted all the treatment cost that one large provider in the UK, NHS Tayside, has incurred over six years for this treatment. Including even all indirect costs such as pension contribution, estate etc., NHS Tayside spent an average of only £257 per person for a complete treatment. This result suggests that offering this treatment to more patients would be very cost effective and might avoid or delay the need to use immunosuppressive drugs in many patients.
AMV564, a Bivalent Bispecific (2×2) CD33/CD3 T-Cell Engager, Is Active and Improves Survival in a Mouse Model of Acute Myeloid Leukemia
Authors: Linda G Eissenberg, Julie Ritchey, Michael P. Rettig, Judith A. Fox, Jeanmarie Guenot, John F. DiPersio
Journal: Blood (2018)
ADTH-02 Trans-anal submucosal endoscopic resection (taser) for complex rectal polyps
Authors: Ioannis Stasinos, ZP Tsiamoulos, Vasilios Papastergiou, Rajaratnam Rameshshanker, Adel Polecina, Joseph Sebastian, Aurelia Wawszczak, Omar Faiz, Janindra Warusavitarne, BP Saunders
Journal: Endoscopy (2018)

<h3>Introduction</h3> Trans-Anal Submucosal Endoscopic Resection (TASER) is a novel instrumental platform for resection of large (≥5 cm) and/or complex rectal polyps (CRPs). It involves a multi-port trans-anal access, enabling dynamic tissue retraction to assist endoscopic submucosal dissection (ESD), used alone or in conjunction with supplementary techniques [Endoscopic Mucosal Resection (EMR) or Ablation (EMA), Trans-Anal Excision (TAE)]. <h3>Methods</h3> A prospective database (Jan 2013–October 2017) was analysed including consecutive patients undergoing TASER for CRPs in two UK centres. <h3>Results</h3> Sixty-four CRPs (median size 7.5 cm; range: 5–18) were resected in 64 patients (36 males, mean 67.1 years): 33 by ESD and 31 by hybrid procedures (ESD+EMR=14, ESD+EMR+EMA=6, ESD+TAE=4, ESD+EMR+TAE=3, ESD+EMR+EMA+TAE=4). Forty-seven (73.4%) lesions were granular-type laterally spreading tumors, 9 (14.1%) were recurrences, 13 (20.3%) had severe submucosal fibrosis, and 7 (10.9%) involved the dentate line. Histology showed low-grade adenoma/dysplasia in 35 (54.7%), high-grade adenoma/dysplasia in 21 (32.8%), T1&lt;1000 µm in 5 (7.8%), and T1≥1000 µm in 4 (6.2%). In 10 cases a full-thickness dissection was required due to severe submucosal fibrosis (n=8) or T1 cancer (n=2); the defect was closed in 6/10, by using endoclips (n=2) or surgical sutures/endoclips (n=4). All patients were admitted for overnight observation and intravenous antibiotic cover; the median hospital stay was 1 day (range 1–6). Complete endoscopic excision was achieved in a single session in 60 (93.8%), and 2 sessions in 4 (6.2%) cases. Thirty-eight (59.4%) resections were en-bloc, and 36(56.3%) were histologically complete. Delayed bleeding and post-polypectomy syndrome occurred in 3 (4.7%) and 7 (10.9%) respectively, with no surgical intervention required. One patient underwent a defunctioning ileostomy due to intra-peritoneal perforation. Of the 9 malignant cases: 4 with T1≥1000 µm cancer (2/4 full thickness) were subject to radical surgery, and 5 with T1&lt;1000 µm underwent endoscopic surveillance. Endoscopic surveillance data were available for 44 (68.8%) patients, with a median (range) follow-up of 9.2 (3–43.5) months. The local recurrence was 13.6%; in all cases treated endoscopically. To date, the overall rate of patients spared from radical surgery is 60/64 (93.7%). <h3>Conclusions</h3> The current study demonstrates favorable clinical outcomes of TASER, offering surgery-sparing cure in &gt;90% of patients with CRPs. The use of a transanal platform to allow a flexible resection approach, enabling both endoscopic and trans-anal resection techniques, appears to be advantageous.
Proposal of a new scoring formula for the DLQI in psoriasis
Authors: F. Rencz, L. Gulácsi, M. Péntek, A.K. Poór, M. Sárdy, P. Holló, A. Szegedi, É. Remenyik, V. Brodszky
Journal: British Journal of Dermatology (2018)

Psoriasis is a common skin disease affecting approximately 2% of the population. Psoriasis can have a negative impact on patients’ everyday activities and wellbeing. Dermatology Life Quality Index (DLQI) is a widely used measure to assess quality of life in patients with psoriasis. It consists of 10 questions covering symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. Each question is scored as follows: ‘not at all’=0, ‘a little’=1, ‘a lot’=2 and ‘very much’=3. However, certain questions of the DLQI such as sports, sexual difficulties and working/studying are not relevant to every patient. As ‘not relevant’ responses are scored as if the item of the questionnaire had no impact on patients’ life at all (=0), they may artificially improve patients’ quality of life scores. For these patients, despite having severe psoriasis, it is more difficult to fulfil the DLQI threshold required by clinical guidelines to become candidates for stronger, systemic treatments such as biologics. This study, from Hungary, involved 242 patients with psoriasis. The authors developed a new scoring for the DLQI questionnaire, namely the DLQI‐R that corrects for the bias in the ‘not relevant’ response option, and proved its validity (i.e. that it works). The DLQI‐R scoring formula eliminates the items marked as ‘not relevant’ while increasing the weight of the relevant items in the total score of the questionnaire. It primarily strives to provide fair access to systemic treatments for psoriasis patients who cannot comply with the DLQI criteria in treatment guidelines because certain items of the questionnaire are simply not relevant to them.
Osteopontin controls immunosuppression in the tumor microenvironment
Authors: Michael R. Shurin
Journal: Journal of Clinical Investigation (2018)

Cancer cells evade the immune system through a variety of different mechanisms, including the inhibition of antitumor effector T cells via checkpoint ligand-receptor interaction. Moreover, studies have shown that blocking these checkpoint pathways can reinvigorate the antitumor immunity, thereby prompting the development of numerous checkpoint immunotherapies, several of which are now being approved to treat multiple types of cancer. However, only a fraction of patients achieves promising long-term outcomes in response to checkpoint inhibition, suggesting the existence of additional unknown tumor-induced immunosuppressive pathways. In this issue of the JCI, Klement and colleagues describe an additional pathway of T cell inhibition in cancer. Specifically, the authors demonstrate that downregulation of IRF8, a molecular determinant of apoptotic resistance, in tumor cells aborts repression of osteopontin, which in turn binds to its physiological receptor CD44 on activated T cells and suppresses their activation. These results suggest that osteopontin may act as another immune checkpoint and may serve as a target to expand the number of patients who respond to immune checkpoint inhibitor therapy.