Role of yttrium-90 selective internal radiation therapy in the treatment of liver-dominant metastatic colorectal cancer: An evidence-based expert consensus algorithm

Surgical resection of colorectal liver metastases is associated with greater survival compared with non-surgical treatment, and a meaningful possibility of cure. However, the majority of patients are not eligible for resection and may require other non-surgical interventions, such as liver-directed therapies, to be converted to surgical eligibility. Given the number of available therapies, a general framework is needed that outlines the specific roles of chemotherapy, surgery, and locoregional treatments [including selective internal radiation therapy (SIRT) with Y-90 microspheres]. Using a data-driven, modified Delphi process, an expert panel of surgical oncologists, transplant surgeons, and hepatopancreatobiliary (HPB) surgeons convened to create a comprehensive, evidence-based treatment algorithm that includes appropriate treatment options for patients stratified by their eligibility for surgical treatment. The group coined a novel, more inclusive phrase for targeted locoregional tumor treatment (a blanket term for resection, ablation, and other emerging locoregional treatments)

Acquired A amyloidosis from injection drug use presenting with atraumatic splenic rupture in a hospitalized patient: a case report

<p>Abstract</p> <p>Introduction</p> <p>Little is known about splenic rupture in patients who develop systemic acquired A amyloidosis. This is the first report of a case of atraumatic splenic rupture in a patient with acquired A amyloidosis from chronic injection drug use.</p> <p>Case presentation</p> <p>A 58-year-old Caucasian man with a long history of injection drug use, hospitalized for infective endocarditis, experienced atraumatic splenic rupture and underwent splenectomy. Histopathological and microbiological analyses of the splenic tissue were consistent with systemic acquired A amyloidosis, most likely from injection drug use, that led to splenic rupture without any recognized trauma or evidence of bacterial embolization to the spleen.</p> <p>Conclusion</p> <p>In patients with chronic inflammatory conditions, including the use of injection drugs, who experience acute onset of left upper quadrant pain, the diagnosis of atraumatic splenic rupture must be considered.</p

Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts

<p>Abstract</p> <p>Background</p> <p>Accurate tests to diagnose adenocarcinoma and high-grade dysplasia among mucinous pancreatic cysts are clinically needed. This study evaluated the diagnostic utility of amphiregulin (AREG) as a pancreatic cyst fluid biomarker to differentiate non-mucinous, benign mucinous, and malignant mucinous cysts.</p> <p>Methods</p> <p>A single-center retrospective study to evaluate AREG levels in pancreatic cyst fluid by ELISA from 33 patients with a histological gold standard was performed.</p> <p>Results</p> <p>Among the cyst fluid samples, the median (IQR) AREG levels for non-mucinous (n = 6), benign mucinous (n = 15), and cancerous cysts (n = 15) were 85 pg/ml (47-168), 63 pg/ml (30-847), and 986 pg/ml (417-3160), respectively. A significant difference between benign mucinous and malignant mucinous cysts was observed (<it>p </it>= 0.025). AREG levels greater than 300 pg/ml possessed a diagnostic accuracy for cancer or high-grade dysplasia of 78% (sensitivity 83%, specificity 73%).</p> <p>Conclusion</p> <p>Cyst fluid AREG levels are significantly higher in cancerous and high-grade dysplastic cysts compared to benign mucinous cysts. Thus AREG exhibits potential clinical utility in the evaluation of pancreatic cysts.</p

Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer's safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6

Europe-wide expansion and eradication of multidrug-resistant Neisseria gonorrhoeae lineages: a genomic surveillance study

Centre for Genomic Pathogen Surveillance and the Euro-GASP study group: Sonja Pleininger, Alexander Indra, Irith De Baetselier, Wim Vanden Berghe, Blaženka Hunjak, Tatjana Nemeth Blažić, Panayiota Maikanti-Charalambous, Despo Pieridou, Hana Zákoucká, Helena Žemličková, Steen Hoffmann, Susan Cowan, Lasse Jessen Schwartz, Rita Peetso, Jevgenia Epstein, Jelena Viktorova, Ndeindo Ndeikoundam, Beatrice Bercot, Cécile Bébéar, Florence Lot, Susanne Buder, Klaus Jansen, Vivi Miriagou, Georgios Rigakos, Vasilios Raftopoulos, Eszter Balla, Mária Dudás, Lena Rós Ásmundsdóttir, Guðrún Sigmundsdóttir, Guðrún Svanborg Hauksdóttir, Thorolfur Gudnason, Aoife Colgan, Brendan Crowley, Sinéad Saab, Paola Stefanelli, Anna Carannante, Patrizia Parodi, Gatis Pakarna, Raina Nikiforova, Antra Bormane, Elina Dimina, Monique Perrin, Tamir Abdelrahman, Joël Mossong, Jean-Claude Schmit, Friedrich Mühlschlegel, Christopher Barbara, Francesca Mifsud, Alje Van Dam, Birgit Van Benthem, Maartje Visser, Ineke Linde, Hilde Kløvstad, Dominique Caugant, Beata Młynarczyk-Bonikowska, Jacinta Azevedo, Maria-José Borrego, Marina Lurdes Ramos Nascimento, Peter Pavlik, Irena Klavs, Andreja Murnik, Samo Jeverica, Tanja Kustec, Julio Vázquez Moreno, Asuncion Diaz, Raquel Abad, Inga Velicko, Magnus Unemo, Helen Fifer, Jill Shepherd, Lynsey PattersonBackground: Genomic surveillance using quality-assured whole-genome sequencing (WGS) together with epidemiological and antimicrobial resistance (AMR) data is essential to characterise the circulating Neisseria gonorrhoeae lineages and their association to patient groups (defined by demographic and epidemiological factors). In 2013, the European gonococcal population was characterised genomically for the first time. We describe the European gonococcal population in 2018 and identify emerging or vanishing lineages associated with AMR and epidemiological characteristics of patients, to elucidate recent changes in AMR and gonorrhoea epidemiology in Europe. Methods: We did WGS on 2375 gonococcal isolates from 2018 (mainly Sept 1-Nov 30) in 26 EU and EEA countries. Molecular typing and AMR determinants were extracted from quality-checked genomic data. Association analyses identified links between genomic lineages, AMR, and epidemiological data. Findings: Azithromycin-resistant N gonorrhoeae (8·0% [191/2375] in 2018) is rising in Europe due to the introduction or emergence and subsequent expansion of a novel N gonorrhoeae multi-antigen sequence typing (NG-MAST) genogroup, G12302 (132 [5·6%] of 2375; N gonorrhoeae sequence typing for antimicrobial resistance [NG-STAR] clonal complex [CC]168/63), carrying a mosaic mtrR promoter and mtrD sequence and found in 24 countries in 2018. CC63 was associated with pharyngeal infections in men who have sex with men. Susceptibility to ceftriaxone and cefixime is increasing, as the resistance-associated lineage, NG-MAST G1407 (51 [2·1%] of 2375), is progressively vanishing since 2009-10. Interpretation: Enhanced gonococcal AMR surveillance is imperative worldwide. WGS, linked to epidemiological and AMR data, is essential to elucidate the dynamics in gonorrhoea epidemiology and gonococcal populations as well as to predict AMR. When feasible, WGS should supplement the national and international AMR surveillance programmes to elucidate AMR changes over time. In the EU and EEA, increasing low-level azithromycin resistance could threaten the recommended ceftriaxone-azithromycin dual therapy, and an evidence-based clinical azithromycin resistance breakpoint is needed. Nevertheless, increasing ceftriaxone susceptibility, declining cefixime resistance, and absence of known resistance mutations for new treatments (zoliflodacin, gepotidacin) are promising.This study was supported by the European Centre for Disease Prevention and Control, the Centre for Genomic Pathogen Surveillance, the Li Ka Shing Foundation (Big Data Institute, University of Oxford), the Wellcome Genome Campus, the Foundation for Medical Research at Örebro University Hospital, and grants from Wellcome (098051 and 099202). LSB was funded by Conselleria de Sanitat Universal i Salut Pública, Generalitat Valenciana (Plan GenT CDEI-06/20-B), Valencia, Spain, and Ministry of Science, Innovation and Universities (PID2020–120113RA-I00), Spain, at the time of analysing and writing this manuscript.info:eu-repo/semantics/publishedVersio

Indo-Pacific Warm Pool convection and ENSO since 1867 derived from Cambodian pine tree cellulose oxygen isotopes

The Indo-Pacific Warm Pool (IPWP) is a major source of heat and moisture to the atmosphere and thus strongly influences the global climate. In this study, we investigate how moisture fluxes from the IPWP influence the stable isotope signature of precipitation over Southeast Asia by analyzing the oxygen isotopic composition (δ^18O) of tree cellulose from southern Cambodia. The cellulose δ^18O record, spanning AD 1867-2006, documents a regular seasonal cycle with an average amplitude of ~4‰ that is primarily controlled by seasonal differences in the isotopic composition of precipitation. Using the outputs from an isotope-enabled atmospheric model, we illustrate how the δ^18O of precipitation at our site is predominantly controlled by the amount of rainout that occurs over the moisture source region, the IPWP. This is verified by strong correlations of our cellulose δ^18O record with instrumental measurements of precipitation and outgoing longwave radiation over the IPWP, suggesting that the cellulose δ^18O could be used to reconstruct the convection intensity over the IPWP. Spectral analysis of the cellulose δ^18O reveals significant peaks at 2-7 years corresponding to ENSO frequencies. The variability of the cellulose δ^18O record on the ENSO band exhibits characteristics that match existing coral δ^18O records from the tropical Pacific, with reduced amplitude of variability in the 1920s through the 1960s, a period of weak ENSO activity

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe