tbuckley/cabot-search huggingface dataset:
Reply
Authors: Silvia Nardelli, Stefania Gioia, Lorenzo Ridola, Alessio Farcomeni, Manuela Merli, Oliviero Riggio
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We thank Chen et al. and Moon et al. for their interest in our study.1 Their comments are extremely stimulating and appropriate. Both groups pointed out that some variables, including infections, smoking, obesity, nonsteroidal anti‐inflammatory drug (NSAID) use, and vascular diseases, have not been taken into account as potential risk factors for mortality in our multivariate analysis. As far as the relationship between proton pump inhibitor (PPI) use and infections, our group has already demonstrated that PPI use is an independent risk factor for the development of infections in patients with cirrhosis,2 which is in turn associated with higher mortality.3 Following the suggestion of Moon et al., we examined the causes of death stratified according to PPI use, and we confirm that the deaths due to an infection were more frequent in PPI users (49% versus 19%, P < 0.01). Moreover, in our series this result could be underestimated by the fact that some patients considered deceased for hepatic encephalopathy (HE) or liver failure may also have had an infection as the precipitating event. As far as the other confounding variables, we strongly agree with the possibility that PPI use may merely be a marker of patient comorbidities such as smoking, obesity, NSAID use, and vascular disease. However, this possibility is probably more relevant in cirrhosis related to nonalcoholic steatohepatitis and metabolic syndrome, which was uncommonly represented in our series (only 5% of patients). A very interesting suggestion of both letters was to compare separately the mortality among “inappropriate” and “appropriate” PPI users versus PPI nonusers. Even separating the two groups, PPI users were found to have significantly lower survival than PPI nonusers: in fact, mortality rate was significantly higher compared to nonusers both in “appropriate” PPI users (75% versus 19%, P < 0.001) and in “inappropriate” PPI users (46% versus 19%, P < 0.001). These results, as suggested by Chen et al., support a cause–effect relationship between mortality and PPI usage, which would be further sustained by studies aimed at investigating the effect of PPI withdrawal on minimal and overt HE as well as on mortality. All of these findings further support the need for particular caution in prescribing PPIs in patients with cirrhosis.
Detection of Local Relapse of Prostate Cancer With 18F-PSMA-1007
Authors: Robert Seifert, Darius Schafigh, Martin Bögemann, Matthias Weckesser, Kambiz Rahbar
Journal: Clinical Nuclear Medicine (2019)

Abstract Prostate-specific membrane antigen (PSMA)–targeted PET/CT has become a fundamental tool in the management of patients with prostate cancer, especially to rule out local recurrence after surgery or radiation. However, the assessment of the prostatic fossa is difficult due to the renal excretion of PSMA-targeted radionuclides. PET/CT studies using 68 Ga-PSMA-11 PET/CT and 18 F-PSMA-1007 of a 61-year-old man after radical prostatectomy are presented. This case illustrates that 18 F-PSMA-1007 is an ideal radionuclide for the detection of local recurrence of prostate cancer and is superior to 68 Ga-PSMA-11, especially in case of pelvic lesions.
Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases
Authors: V.A. Kinsler, O. Boccara, S. Fraitag, A. Torrelo, P. Vabres, A. Diociaiuti
Journal: British Journal of Dermatology (2019)

Cutaneous mosaicism is an area of dermatology in which there has been an explosion of knowledge within the current decade. This has led to fundamental changes in the understanding of the conditions in this field, and to an ongoing paradigm shift in the approach to management of mosaic skin disorders. To lay out the general principles of mosaicism as they are currently understood, summarize the known cutaneous mosaic abnormalities of the skin with associated phenotypic and genotypic information, review the latest trials on targeted therapies and propose guidelines for the general approach to a patient with suspected mosaicism. This was a consensus expert review as part of the European Reference Network project (ERN‐Skin). This study provides clinicians with a practical approach to the patient with suspected mosaicism, redefines mosaicism for the modern genetic era, and proposes a new classification system based on genetic mechanism. What's already known about this topic? Cutaneous mosaicism is a complex field of dermatology that encompasses most birthmarks, and many rare syndromes. Some cutaneous patterns are known to be seen in mosaicism. Very few treatment options are available for most mosaic abnormalities of the skin. Recent high‐sensitivity genetic techniques have led to an explosion of knowledge about genotype and phenotype in the literature. What does this study add? Expert consensus from the European Reference Network project. Review of knowledge of confirmed mosaic abnormalities of the skin, including cutaneous phenotype, extracutaneous associated features and genotype. Proposed new classification of mosaic abnormalities of the skin by genetic mechanism and therefore inheritance potential. Practical tips on correct sample collection and genetic investigation. Review of trials of targeted therapies. Guidelines for a practical clinical approach to the patient with suspected mosaicism.
CSF1R and BTK inhibitions as novel strategies to disrupt the dialog between mantle cell lymphoma and macrophages
Authors: Antonin Papin, Benoit Tessoulin, Céline Bellanger, Anne Moreau, Yannick Le Bris, Hervé Maisonneuve, Philippe Moreau, Cyrille Touzeau, Martine Amiot, Catherine Pellat-Deceunynck, Steven Le Gouill, David Chiron
Journal: Leukemia (2019)
Should this systematic review and meta-analysis change my practice? Part 1: exploring treatment effect and trustworthiness
Authors: Mervyn J Travers, Myles Calder Murphy, James Robert Debenham, Paola Chivers, Max K Bulsara, Matthew K Bagg, Thorvaldur Skulli Palsson, William Gibson
Journal: British Journal of Sports Medicine (2019)

As a service to its readership, BJSM publishes educational editorials in order to provide methodological guidance and direction to clinicians and researchers.1 For example, a recent BJSM invited commentary outlined important methodological aspects of randomised controlled trials ( RCTs ) in order to help readers better understand and interpret findings.2 Similarly, a recent BJSM editorial written for clinicians has outlined five essential methodological considerations or ‘hacks’ to consider when reading a systematic review (SR), while another editorial has outlined common pitfalls for authors conducting a SR.3 4 In light of recent suggestions of untrustworthiness of systematic review and meta-analyses (SRMA) findings,5–7 researchers are encouraged to maximise the transparency of their work. Similarly, clinicians and policymakers are encouraged to scrutinise SRMA in order to decide if the findings should influence clinical decisions or policies. The purpose of our two-part educational editorial series is to highlight important methodological aspects of SRMA of the effects of interventions and thus help clinicians make judicious choices when considering whether to accept the findings. By using a worked example, we hope this resource serves as a guide for clinicians when critically appraising SRMA findings and deciding whether (or not) to accept the reported findings or the interpretation of the authors.

A SR attempts to collate all empirical evidence that fits prespecified eligibility criteria in order to answer a specific research question.8 An interventional SR specifically assesses the benefits and harms of an intervention and should provide an unbiased, robust, transparent and reproducible overview of the effect of an intervention and the quality of the evidence from identified clinical studies.9 Should the SR contain sufficient and appropriate quantitative data from the included studies, a meta-analysis (MA) can be conducted to provide a pooled estimate of effect, and to examine variation among individual study …
PI3K-dependent motility of prostate cancer cells is mediated through post-transcriptional control of the p35 regulatory subunit of CDK5
Authors: Anjali Mishra, Christopher Strock, Douglas Ball, Barry Nelkin
Journal: Cancer Research (2008)

LB-92  We have previously shown that CDK5 activity is required for prostate cancer motility and metastasis (Strock et al, Cancer Res. 66:7509, 2006). Activity of CDK5, a kinase involved in cell motility, is cell type specific, tightly controlled by the restricted expression of the CDK5R1 (Cyclin-dependent kinase 5 regulatory subunit 1) gene, which encodes p35, a protein strictly required for activity of CDK5. We have observed high levels of CDK5R1 expression across a panel of prostate cancer (DU145, LNCaP, PC3, AT6.3) cell lines and in primary prostate cancers; blocking CDK5 activity in these cells resulted in loss of motility, invasion, and metastasis. Since PI3K promotes motility and invasion in cancer, it was important to determine the relationship between PI3K signaling and CDK5 activity. Here, we demonstrate that PI3K-dependent motility of DU145 prostate cancer cells is mediated substantially through control of CDK5 activity, by post-transcriptional modulation of the CDK5 positive regulatory subunit p35. Using western blot analysis, we found that inhibitors of PI3 kinase (LY294002; 25µM) and EGFR (AG1478, 1µM) substantially inhibited p35 protein levels in prostate cancer cell lines DU145 and PC3. LY294002 inhibited p35 protein level as early as 1 hour, and AG1478 at 2 hours. Nevertheless, real time analysis indicated 2-4 fold increase in the mRNA levels of CDK5R1 in DU145 cells after treatment with these inhibitors, indicating that the decrease in CDK5R1 protein levels was regulated at a post-transcriptional level. Boyden chamber analysis showed that LY294002 substantially inhibited the migration of DU145 cells. To determine whether the decrease in CDK5R1 was responsible for the LY294002-mediated loss of motility, we enforced expression of exogenous CDK5R1 in DU145 cells, using a lentiviral vector. This construct, containing only the coding region of CDK5R1, without the 5’ and 3’ UTRs, resulted in CDK5R1 protein expression levels similar to those in parental DU145 cells, and these levels were not decreased upon LY294002 treatment. Migration of these cells, with enforced CDK5R1 expression, was assessed by Boyden chamber analysis, in the presence or absence of LY294002. These experiments demonstrated that continued expression of CDK5R1 prevented LY294002-mediated inhibition of cell migration. Our results indicate that PI3K controls cell migration in prostate cancer cells by post-transcriptional modulation of CDK5 activity. These results, suggesting that CDK5 may be an important effector of the PI3K pathway, further suggest that CDK5 may be a potential therapeutic target in prostate and other cancers.
Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline
Authors: Gianpiero Manes, Gregorios Paspatis, Lars Aabakken, Andrea Anderloni, Marianna Arvanitakis, Philippe Ah-Soune, Marc Barthet, Dirk Domagk, Jean-Marc Dumonceau, Jean-Francois Gigot, Istvan Hritz, George Karamanolis, Andrea Laghi, Alberto Mariani, Konstantina Paraskeva, Jürgen Pohl, Thierry Ponchon, Fredrik Swahn, Rinze W. F. ter Steege, Andrea Tringali, Antonios Vezakis, Earl J. Williams, Jeanin E. van Hooft
Journal: Endoscopy (2019)

Main Recommendations ESGE recommends offering stone extraction to all patients with common bile duct stones, symptomatic or not, who are fit enough to tolerate the intervention. Strong recommendation, low quality evidence. ESGE recommends liver function tests and abdominal ultrasonography as the initial diagnostic steps for suspected common bile duct stones. Combining these tests defines the probability of having common bile duct stones. Strong recommendation, moderate quality evidence. ESGE recommends endoscopic ultrasonography or magnetic resonance cholangiopancreatography to diagnose common bile duct stones in patients with persistent clinical suspicion but insufficient evidence of stones on abdominal ultrasonography. Strong recommendation, moderate quality evidence. ESGE recommends the following timing for biliary drainage, preferably endoscopic, in patients with acute cholangitis, classified according to the 2018 revision of the Tokyo Guidelines: – severe, as soon as possible and within 12 hours for patients with septic shock – moderate, within 48 – 72 hours – mild, elective. Strong recommendation, low quality evidence. ESGE recommends endoscopic placement of a temporary biliary plastic stent in patients with irretrievable biliary stones that warrant biliary drainage. Strong recommendation, moderate quality of evidence. ESGE recommends limited sphincterotomy combined with endoscopic papillary large-balloon dilation as the first-line approach to remove difficult common bile duct stones. Strong recommendation, high quality evidence. ESGE recommends the use of cholangioscopy-assisted intraluminal lithotripsy (electrohydraulic or laser) as an effective and safe treatment of difficult bile duct stones. Strong recommendation, moderate quality evidence. ESGE recommends performing a laparoscopic cholecystectomy within 2 weeks from ERCP for patients treated for choledocholithiasis to reduce the conversion rate and the risk of recurrent biliary events. Strong recommendation, moderate quality evidence.
A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma
Authors: Mark A. Schroeder, Mark A. Fiala, Eric Huselton, Michael H. Cardone, Savina Jaeger, Sae Rin Jean, Kathryn Shea, Armin Ghobadi, Tanya Wildes, Keith E. Stockerl-Goldstein, Ravi Vij
Journal: Clinical Cancer Research (2019)

Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients.We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the MTD of carfilzomib was determined to be 56 mg/m2 (days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m2 on day 8) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Seventeen additional patients were enrolled in the phase II portion.KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0-21.7).This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.
Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry
Authors: M. Fishman, J. P. Dutcher, J. I. Clark, A. Alva, G. P. Miletello, B. Curti, Neeraj Agarwal, R. Hauke, K. M. Mahoney, H. Moon, J. Treisman, S. S. Tykodi, G. Daniels, M. A. Morse, M. K. K. Wong, H. Kaufman, N. Gregory, D. F. McDermott
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. <h3>Methods</h3> Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIM<sup>SM</sup> registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2–124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. <h3>Results</h3> Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. <h3>Conclusions</h3> Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. <h3>Trial registration</h3> PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.
Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa
Authors: K. Twaroski, C. Eide, M.J. Riddle, L. Xia, C.J. Lees, W. Chen, W. Mathews, D.R. Keene, J.A. McGrath, J. Tolar
Journal: British Journal of Dermatology (2019)

Revertant mosaicism has been described previously in recessive dystrophic epidermolysis bullosa (RDEB), manifesting as regions of skin with normal mechanical and biological characteristics. Here we report the discovery of revertant dermal fibroblasts, unique in that all other documented cases of revertant mosaicism occur in epidermal keratinocytes. To determine the cause of revertant mosaicism found in a patient with RDEB from isolated epidermal keratinocytes and dermal fibroblasts in blister and mosaic skin regions. Skin biopsies were taken from blister and mosaic skin regions of a patient with RDEB. Allele identification was confirmed and the type VII collagen (C7) content and COL7A1 expression profile of isolated keratinocytes and fibroblasts was determined. Keratinocytes isolated from the mosaic area had a slight increase in C7, although overall expression of COL7A1 was unchanged between blister and mosaic fibroblasts. Differential allele expression was identified in blister and mosaic fibroblasts using targeted RNA sequencing (TREx), where the allele harbouring a point mutation was preferentially expressed over that containing a frameshift mutation. A crossing over event was identified in mosaic fibroblasts that was not present in blister fibroblasts, yielding a functional COL7A1 allele in a subset of cells. In documenting a novel case of revertant mosaicism in RDEB, we have identified dermal fibroblasts as having the capacity to correct blistering functionally. We have also pioneered the use of TREx in quantifying allele‐specific expression. Using fibroblasts instead of keratinocytes for RDEB therapies offers advantages in the local and systemic therapy of RDEB. What's already known about this topic? Revertant mosaicism has been previously documented in patients with recessive dystrophic epidermolysis bullosa (RDEB), however, it has only been found in epidermal keratinocytes. What does this study add? We have demonstrated that COL7A1 gene reversion in dermal fibroblasts occurs and is able to form functional skin in a patient with RDEB. Additionally, we have pioneered a new application for targeted RNA sequencing in quantifying allele‐specific expression in fibroblasts and keratinocytes. What is the translational message? This opens up possibilities for using fibroblasts as local and systemic therapy for patients with RDEB.
B- Cell Maturation Antigen Is Exclusively Expressed in a Wide Range of B-Cell and Plasma Cell Neoplasm and in a Potential Therapeutic Target for Bcma Directed Therapies
Authors: Pallavi Khattar, Janine Pichardo, Achim Jungbluth, Qi Gao, Eric L Smith, Mikhail Roshal, Ahmet Dogan
Journal: Blood (2017)
PET-guided, BEACOPPescalated therapy in advanced Hodgkin lymphoma – Authors' reply
Authors: René-Olivier Casasnovas, Reda Bouabdallah, Pauline Brice, Julien Lazarovici, Hervé Ghesquieres, Aspasia Stamatoullas, Alina Berriolo-Riedinger, Luc-Matthieu Fornecker, Marc André, Michel Meignan
Journal: The Lancet Oncology (2019)
Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia
Authors: S. Weis, M. Kesselmeier, J.S. Davis, A.M. Morris, S. Lee, A. Scherag, S. Hagel, M.W. Pletz
Journal: Clinical Microbiology and Infection (2019)

BackgroundFor patients with bacteraemia caused by methicillin-sensitive Staphylococcus aureus anti-staphylococcal penicillins (ASPs) or cefazolin are agents of choice. While ASPs are potentially nephrotoxic, cefazolin may be less effective in some S. aureus strains due to an inoculum effect.ObjectivesTo perform a systematic literature review and meta-analysis assessing current evidence comparing cefazolin with ASPs for patients with S. aureus bacteraemia (SAB).MethodsWe searched MEDLINE, ISI Web of Science (Science Citation Index Expanded) and the Cochrane Database as well as clinicaltrials.gov from inception to 26 June 2018. All studies investigating the effects of cefazolin versus ASP in patients with methicillin-sensitive SAB were eligible for inclusion regardless of study design, publication status or language. Additional information was requested by direct author contact. A meta-analysis to estimate relative risks (RRs) with the corresponding 95% confidence intervals (CIs) was performed. Statistical heterogeneity was estimated using I2. The primary endpoint was 90-day all-cause mortality. The Newcastle–Ottawa Scale (NOS) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) were used for study and data quality assessment.ResultsFourteen non-randomized studies were included. Seven reported the primary endpoint (RR 0.71 (0.50, 1.02), low quality of evidence). Cefazolin treatment may be associated with lower 30-day mortality rates (RR 0.70 (0.54, 0.91), low quality of evidence) and less nephrotoxicity (RR 0.36 (0.21, 0.59), (low quality of evidence)). We are uncertain whether cefazolin and ASP differ regarding treatment failure/relapse as the quality of the evidence has been assessed as very low (RR of 0.84 (0.59, 1.18)). For patients with endocarditis (RR 0.71 (0.12, 4.05)) or abscesses (RR 1.17 (0.30, 4.63)), cefazolin treatment may be associated with equal 30-day and 90-day mortality (low quality of evidence).ConclusionsCefazolin seemed to be at least equally as effective as ASPs while being associated with less nephrotoxicity.