bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous versus subcutaneous route pharmacokinetics of paracetamol (acetaminophen) in palliative care patients: study protocol for a randomized trial (ParaSCIVPallia)
Authors: Vernant Marine , Lepoupet Marie , Creveuil Christian , Alix Antoine , Gourio Charlotte , Peyro-Saint-Paul Laure , Lelong-Boulouard Veronique , Guillaumé Cyril
Published: February 2020

Background

Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data on whether these are equivalent pharmacokinetically are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice. This trial aims to compare the pharmacokinetic (PK) parameters of paracetomol between the IV and SC routes in PC patients.

Methods/design

This is a randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. All adverse events will be reported for a safety analysis. Twenty adult PC patients with an IV device having spontaneous pain not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol as the usual treatment will be included. All patients also have to meet all eligibility criteria.

Conclusion

This is the first study comparing PK parameters for IV paracetamol versus SC paracetamol in PC patients.

Trial registration

ClinicalTrials.gov, NCT03944044. Registered on 4 June 2019.

Committee for the protection of persons (CPP) 18.09.05.58206 approval 4 October 2018.

National Drug Safety Agency (ANSM; Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 29 November 2018.
LUMI-PCR: an Illumina platform ligation-mediated PCR protocol for integration site cloning, provides molecular quantitation of integration sites
Authors: Dawes Joanna C. , Webster Philip , Iadarola Barbara , Garcia-Diaz Claudia , Dore Marian , Bolt Bruce J. , Dewchand Hamlata , Dharmalingam Gopuraja , McLatchie Alex P. , Kaczor Jakub , Caceres Juan J. , Paccanaro Alberto , Game Laurence , Parrinello Simona , Uren Anthony G.
Published: February 2020

Background

Ligation-mediated PCR protocols have diverse uses including the identification of integration sites of insertional mutagens, integrating vectors and naturally occurring mobile genetic elements. For approaches that employ NGS sequencing, the relative abundance of integrations within a complex mixture is typically determined through the use of read counts or unique fragment lengths from a ligation of sheared DNA; however, these estimates may be skewed by PCR amplification biases and saturation of sequencing coverage.

Results

Here we describe a modification of our previous splinkerette based ligation-mediated PCR using a novel Illumina-compatible adapter design that prevents amplification of non-target DNA and incorporates unique molecular identifiers. This design reduces the number of PCR cycles required and improves relative quantitation of integration abundance for saturating sequencing coverage. By inverting the forked adapter strands from a standard orientation, the integration-genome junction can be sequenced without affecting the sequence diversity required for cluster generation on the flow cell. Replicate libraries of murine leukemia virus-infected spleen samples yielded highly reproducible quantitation of clonal integrations as well as a deep coverage of subclonal integrations. A dilution series of DNAs bearing integrations of MuLV or piggyBac transposon shows linearity of the quantitation over a range of concentrations.

Conclusions

Merging ligation and library generation steps can reduce total PCR amplification cycles without sacrificing coverage or fidelity. The protocol is robust enough for use in a 96 well format using an automated liquid handler and we include programs for use of a Beckman Biomek liquid handling workstation. We also include an informatics pipeline that maps reads, builds integration contigs and quantitates integration abundance using both fragment lengths and unique molecular identifiers. Suggestions for optimizing the protocol to other target DNA sequences are included. The reproducible distinction of clonal and subclonal integration sites from each other allows for analysis of populations of cells undergoing selection, such as those found in insertional mutagenesis screens.
Integrating transposable elements in the 3D genome
Authors: Bousios Alexandros , Nützmann Hans-Wilhelm , Buck Dorothy , Michieletto Davide
Published: February 2020

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or “topography”) of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome.
Stability of neuropsychological test performance in older adults serving as normative controls for a study on postoperative cognitive dysfunction
Authors: Feinkohl Insa , Borchers Friedrich , Burkhardt Sarah , Krampe Henning , Kraft Antje , Speidel Saya , Kant Ilse M. J. , van Montfort Simone J. T. , Aarts Ellen , Kruppa Jochen , Slooter Arjen , Winterer Georg , Pischon Tobias , Spies Claudia
Published: February 2020

Objective

Studies of postoperative cognitive dysfunction (POCD) rely on repeat neuropsychological testing. The stability of the applied instruments, which are affected by natural variability in performance and measurement imprecision, is often unclear. We determined the stability of a neuropsychological test battery using a sample of older adults from the general population. Forty-five participants aged 65 to 89 years performed six computerized and non-computerized neuropsychological tests at baseline and again at 7 day and 3 months follow-up sessions. Mean scores on each test were compared across time points using repeated measures analyses of variance (ANOVA) with pairwise comparison. Two-way mixed effects, absolute agreement analyses of variance intra-class correlation coefficients (ICC) determined test–retest reliability.

Results

All tests had moderate to excellent test–retest reliability during 7-day (ICC range 0.63 to 0.94; all p < 0.01) and 3-month intervals (ICC range 0.60 to 0.92; all p < 0.01) though confidence intervals of ICC estimates were large throughout. Practice effects apparent at 7 days eased off by 3 months. No substantial differences between computerized and non-computerized tests were observed. We conclude that the present six-test neuropsychological test battery is appropriate for use in POCD research though small sample size of our study needs to be recognized as a limitation.

Trial registration ClinicalTrials.gov Identifier NCT02265263 (15th October 2014)
Classification of Andrographis paniculata extracts by solvent extraction using HPLC fingerprint and chemometric analysis
Authors: Rafi M. , Devi A. F. , Syafitri U. D. , Heryanto R. , Suparto I. H. , Amran M. B. , Rohman A. , Prajogo B. , Lim L. W.
Published: February 2020

Objective

Andrographis paniculata, widely used as an antidiabetic in Indonesian traditional medicines (jamu), contains chemical compounds whose concentration is related to its therapeutic effects. The concentration of solvents used for extraction will also affect the number of compounds extracted. Therefore, a quality control method is needed to ensure consistency in quantifying these compounds in A. paniculata to improve its therapeutic application. High-performance liquid chromatography fingerprint analysis combined with chemometrics was used to evaluate extracts from different solvent extraction treatments. The content of andrographolide, the main bioactive compound in A. paniculata, and the level of α-glucosidase inhibition activity, an indicator of its antidiabetic activity, were also determined.

Results

Fingerprint chromatograms of A. paniculata extracts from different treatments exhibited a similar pattern with several peaks in common, only differing in area and intensity value. The A. paniculata extracts were classified using HPLC fingerprint and principal component analysis to allow grouping according to their respective solvent extraction treatments. The highest andrographolide content and α-glucosidase inhibition activity occurred in the 50% ethanol extract and the lowest in the water extract. HPLC fingerprint analysis could be used for identifying A. paniculata extracts based on solvent extraction, thus improving quality control for their therapeutic application.
Assessment of levels of asthma control among adult patients with asthma at Chitungwiza Central Hospital, Zimbabwe
Authors: Ndarukwa Pisirai , Chimbari Moses John , Sibanda Elopy
Published: February 2020

Background

The management of the reversible airways obstruction forms the cornerstone of quality asthma management. The aim of this study was to assess the level of control for asthma in adult patients, using a cross sectional study design. The assessment of control for asthma was based on the ACQ.

Methods

We conducted a cross-sectional study to measure the level of control for asthma among patients with asthma who volunteered and were reporting to Chitungwiza Central Hospital. We interviewed and conducted spirometry (lung function testing) on 400 adult patients with asthma. We used the ACQ questions to interview patients. A trained health care provider performed spirometry using the Koko Legend spirometer after meeting all the ambient conditions as outlined in the American Thoracic Society guidelines.

Results

Our study assessed levels of asthma control among 400 adult patients with physician-diagnosed asthma. The results showed that 248 (62%) participants had uncontrolled asthma. The median age of the adult patients who had uncontrolled asthma was 35 years (IQR: 27–44). Using the clinical practice cut-point of 0.75 for controlled asthma, only 152 (38%) were controlled, while 72 (18.8%), 50 (12.5%) and 123 (30.7%) were mildly uncontrolled, moderately uncontrolled and very uncontrolled respectively. Among participants who were widowed had uncontrolled asthma (p = 0.003) while most of the married 103 (67.8%) had controlled asthma (p = 0.018). The findings of the study showed that all the items on the ACQ were significantly different in asthma mean scores (p ≤ 0.0001).

Conclusion

We concluded that most asthma patients that participated in the study were uncontrolled. We therefore, recommend an evaluation of factors associated with poor asthma control in order to improve asthma care and achieve good asthma control outcomes.
A randomized, double-blind, placebo-controlled, parallel-group study of once-daily inhaled fluticasone furoate on the hypothalamic–pituitary–adrenocortical axis of children with asthma
Authors: Bareille Philippe , Tomkins Susan , Imber Varsha , Tayob Mohammed , Dunn Karen , Mehta Rashmi , Khindri Sanjeev
Published: February 2020

Background

To evaluate the effects of fluticasone furoate on the hypothalamic–pituitary–adrenocortical axis, and the safety and tolerability of fluticasone furoate treatment in children with asthma.

Methods

This was a randomized, double-blind, placebo-controlled, multicenter, stratified, parallel-group, non-inferiority study of fluticasone furoate 50 µg inhalation powder administered once daily. The study enrolled children (aged 5–11 years inclusive) with a documented diagnosis of asthma for ≥ 6 months and a Childhood Asthma Control Test score of > 19. After a 7–14-day run-in period, eligible subjects were stratified by age and randomized to fluticasone furoate 50 µg once daily or placebo once daily via ELLIPTA for 6 weeks. The primary endpoint was the change from baseline (expressed as a ratio) in 0–24-h weighted mean serum cortisol at the end of the treatment period.

Results

Fifty-six randomized subjects received fluticasone furoate 50 µg once daily and 55 received placebo. The primary analysis was performed in the serum cortisol population (n = 104) and demonstrated that fluticasone furoate 50 µg once daily was non-inferior to placebo (ratio = 0.93; 95% confidence interval 0.8096, 1.0620), as the lower limit of the 95% confidence interval for the geometric mean treatment ratio of fluticasone furoate 50 µg once daily versus placebo was greater than 0.80. Findings from the intent-to-treat population (n = 111) were similar.

Conclusions

Six weeks of treatment with inhaled fluticasone furoate 50 µg once daily had no clinically relevant effect on the hypothalamic–pituitary–adrenocortical axis function of children, as measured by 24-h serum cortisol profiles. The primary analysis showed that fluticasone furoate 50 µg once daily was non-inferior to placebo. Fluticasone furoate 50 µg once daily was well tolerated and no new safety concerns emerged during the study.

Trial registration

This study is registered in ClinicalTrials.gov (NCT02483975). Date of submission: 25 June 2015.
CEUS LI-RADS: a pictorial review
Authors: Bartolotta Tommaso Vincenzo , Terranova Maria Chiara , Gagliardo Cesare , Taibbi Adele
Published: February 2020

Contrast-enhanced ultrasound (CEUS) greatly improved the diagnostic accuracy of US in the detection and characterization of focal liver lesions (FLLs), and it is suggested and often included in many international guidelines as an important diagnostic tool in the imaging work-up of cirrhotic patients at risk for developing hepatocellular carcinoma (HCC). In particular, CEUS Liver Imaging Reporting and Data System (LI-RADS) provides standardized terminology, interpretation, and reporting for the diagnosis of HCC. The aim of this pictorial essay is to illustrate CEUS features of nodules discovered at US in cirrhotic liver according to LI-RADS categorization.
Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis
Authors: Zhou Tianbiao , Liao Chunling , Li Hong-Yan , Lin Wenshan , Lin Shujun , Zhong Hongzhen
Published: February 2020

Background

Lupus nephritis is usually manifested by proteinuria, active urinary sediment, hypertension, and renal failure and is a serious complication with more than 50% occurrence in systemic lupus erythematosus patients. Mesenchymal stem cells (MSC) present remarkable immunomodulatory ability, and these cells are potential therapeutic agents for autoimmune disorders. In clinical trials, the effectiveness of MSC in the treatment of lupus nephritis is still controversial. A meta-analysis was performed to assess whether MSC can achieve good efficacy in the treatment of lupus nephritis in mice.

Methods

A comprehensive literature search was performed in Cochrane Library, ISI Web of Science, PubMed, and EMBASE from inception to Oct 1, 2019. Two authors independently extracted the data, which were pooled and calculated using RevMan 5.3.

Results

A total of 28 studies met the inclusion criteria. MSC treatment resulted in lower levels of ds-DNA (OR = − 29.58, 95% CI − 29.58, − 17.99; P < 0.00001), ANA (OR = − 70.93, 95% CI − 104.55, − 37.32; P < 0.0001), Scr (OR = − 8.20, 95% CI − 12.71, − 3.69; P = 0.0004), BUN (OR = − 14.57, 95% CI − 20.50, − 8.64; P < 0.00001), proteinuria (OR = − 4.26, 95% CI − 5.15 to − 3.37; P < 0.00001), and renal sclerosis score (OR = − 1.92, 95% CI − 2.66 to − 1.18; P < 0.00001), and MSC treatment could get higher levels of albumin. To detect the potential, the cytokines were also assessed, and the MSC treatment group had lower levels of IL-2, IL-12, IL-17, and IFN-γ when compared with the control group. However, the difference was not notable for IL-4, IL-6, IL-10, TGF-β, MCP-1, TNF-α, Th1, Th17, Foxp3, or Tregs.

Conclusion

Our study confirmed that MSC treatment in an animal model for lupus nephritis in the studies included in the meta-analysis resulted in lower levels of ds-DNA, ANA, Scr, BUN, proteinuria, and renal sclerosis score, and MSC treatment could get higher levels of albumin.
Ventilatory support and mechanical properties of the fibrotic lung acting as a “squishy ball”
Authors: Marchioni Alessandro , Tonelli Roberto , Rossi Giulio , Spagnolo Paolo , Luppi Fabrizio , Cerri Stefania , Cocconcelli Elisabetta , Pellegrino Maria Rosaria , Fantini Riccardo , Tabbì Luca , Castaniere Ivana , Ball Lorenzo , Malbrain Manu L. N. G. , Pelosi Paolo , Clini Enrico
Published: February 2020

Protective ventilation is the cornerstone of treatment of patients with the acute respiratory distress syndrome (ARDS); however, no studies have yet established the best ventilatory strategy to adopt when patients with acute exacerbation of interstitial lung disease (AE-ILD) are admitted to the intensive care unit. Due to the severe impairment of the respiratory mechanics, the fibrotic lung is at high risk of developing ventilator-induced lung injury, regardless of the lung fibrosis etiology. The purpose of this review is to analyze the effects of mechanical ventilation in AE-ILD and to increase the knowledge on the characteristics of fibrotic lung during artificial ventilation, introducing the concept of “squishy ball lung”. The role of positive end-expiratory pressure is discussed, proposing a “lung resting strategy” as opposed to the “open lung approach”. The review also discusses the practical management of AE-ILD patients discussing illustrative clinical cases.
Retraction Note to: Normal families and asymptotic behaviors for solutions of certain Laplace equations
Authors: Yan Zhenhai , Ychussie Beatriz
Published: February 2020

The Editors-in-Chief have retracted this article [1] because it shows significant overlap with an article by different authors that was simultaneously under consideration with another journal [2] and with a previously published article by another group of different authors [3]. In addition, the identity of the corresponding author could not be verified: Roskilde University confirmed that Beatriz Ychussie was never affiliated to this institution. The authors have not responded to any correspondence about this retraction.
Flow cytometric micronucleus assay and TGx-DDI transcriptomic biomarker analysis of ten genotoxic and non-genotoxic chemicals in human HepaRG™ cells
Authors: Buick Julie K. , Williams Andrew , Gagné Rémi , Swartz Carol D. , Recio Leslie , Ferguson Stephen S. , Yauk Carole L.
Published: February 2020

Background

Modern testing paradigms seek to apply human-relevant cell culture models and integrate data from multiple test systems to accurately inform potential hazards and modes of action for chemical toxicology. In genetic toxicology, the use of metabolically competent human hepatocyte cell culture models provides clear advantages over other more commonly used cell lines that require the use of external metabolic activation systems, such as rat liver S9. HepaRG™ cells are metabolically competent cells that express Phase I and II metabolic enzymes and differentiate into mature hepatocyte-like cells, making them ideal for toxicity testing. We assessed the performance of the flow cytometry in vitro micronucleus (MN) test and the TGx-DDI transcriptomic biomarker to detect DNA damage-inducing (DDI) chemicals in human HepaRG™ cells after a 3-day repeat exposure. The biomarker, developed for use in human TK6 cells, is a panel of 64 genes that accurately classifies chemicals as DDI or non-DDI. Herein, the TGx-DDI biomarker was analyzed by Ion AmpliSeq whole transcriptome sequencing to assess its classification accuracy using this more modern gene expression technology as a secondary objective.

Methods

HepaRG™ cells were exposed to increasing concentrations of 10 test chemicals (six genotoxic chemicals, including one aneugen, and four non-genotoxic chemicals). Cytotoxicity and genotoxicity were measured using the In Vitro MicroFlow® kit, which was run in parallel with the TGx-DDI biomarker.

Results

A concentration-related decrease in relative survival and a concomitant increase in MN frequency were observed for genotoxic chemicals in HepaRG™ cells. All five DDI and five non-DDI agents were correctly classified (as genotoxic/non-genotoxic and DDI/non-DDI) by pairing the test methods. The aneugenic agent (colchicine) yielded the expected positive result in the MN test and negative (non-DDI) result by TGx-DDI.

Conclusions

This next generation genotoxicity testing strategy is aligned with the paradigm shift occurring in the field of genetic toxicology. It provides mechanistic insight in a human-relevant cell-model, paired with measurement of a conventional endpoint, to inform the potential for adverse health effects. This work provides support for combining these assays in an integrated test strategy for accurate, higher throughput genetic toxicology testing in this metabolically competent human progenitor cell line.
MRI measurement of optic nerve sheath diameter using 3D driven equilibrium sequence as a non-invasive tool for the diagnosis of idiopathic intracranial hypertension
Authors: Abdelrahman Ahmed S. , Barakat Mai M. K.
Published: February 2020

Background

The idiopathic intracranial hypertension is a disease that is represented by high intracranial pressure of unknown reason. The visual disturbance presents the main medical problem of this syndrome. This study was conducted to assess the diagnostic value of the optic nerve sheath diameter (ONSD) measured using MRI 3D DRIVE in the diagnosis of idiopathic intracranial hypertension.

Results

The mean value of the ONSD measured using 3D DRIVE sequence in the patient group (5.81 ± 0.33) was significantly higher than the mean value of the normal control group (4.95 ± 0.45) (p < 0.001). The optimal optic nerve sheath diameter cut-off value for diagnosing idiopathic intracranial hypertension was > 5.31 mm, with 94.12% sensitivity and 93.3% negative predictive value.

Conclusion

The high resolution of 3D DRIVE provides an accurate measurement of ONSD which correlated with elevated cerebrospinal fluid pressure and hence the diagnosis of idiopathic intracranial hypertension.
Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): Results from the multicohort, phase II KEYNOTE-158 study.
Authors: Marabelle Aurelien , Cassier Philippe Alexandre , Fakih Marwan , Guren Tormod Kyrre , Italiano Antoine , Kao Steven Chuan-Hao , Nielsen Dorte , Ascierto Paolo Antonio , Bariani Giovanni M. , Santoro Armando , Shah Manisha H. , Asselah Jamil , El-Khoueiry Anthony B. , Spencer Kristen Renee , Takahashi Shunji , Chatterjee Arkendu , Jin Fan , Norwood Kevin , Delord Jean-Pierre
Published: February 2020

1

Background: For patients (pts) with ASCC, second-line or later treatment options have been limited. Pembrolizumab (pembro), an anti-PD-1 monoclonal antibody, has demonstrated antitumor activity in several tumor types (including ASCC) in the multicohort phase 1b KEYNOTE-028 study. KEYNOTE-158 (NCT02628067) is an open-label, phase 2, multicohort study that evaluates antitumor activity and safety of pembro in pts with previously treated advanced cancer. Results from the ASCC cohort are presented. Methods: Eligible pts were ≥18 y with histologically/cytologically documented metastatic and/or unresectable ASCC with prior treatment failure on or intolerance to standard first-line therapy, measurable disease per RECIST v1.1, ECOG PS of ≤1, and evaluable tissue sample for PD-L1 and biomarker analysis. PD-L1 expression was assessed by the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). Pts received pembro 200 mg Q3W until disease progression, unacceptable AE, or completion of 35 cycles. The primary endpoint was ORR per RECIST v1.1 (assessed every 9 wk for 12 mo, then every 12 wk thereafter) by independent central review. Secondary endpoints were DOR, OS, PFS and safety. Results: 112 pts with ASCC were enrolled (81.3% women; median age, 61 y [range 32–79]; ≥2 prior therapies, 73.2%). At database cutoff (Dec 6, 2018) 10 pts (8.9%) had completed 35 cycles and 102 discontinued; median follow-up was 12.0 mo (range, 0.8–33.0) Five pts had CR and 8 had PR; ORR was 11.6% (95% CI, 6.3–19.0). Median DOR was not reached (range, 6.0+ to 29.1+ mo). Responses occurred in 11/75 pts (14.7%) with PD-L1 combined positive score (CPS) ≥1 and 2/30 pts (6.7%) with PD-L1 CPS < 1. Among all pts, median OS was 12.0 mo (95% CI, 9.1–15.4), and median PFS was 2.0 mo (95% CI, 2.0–2.1). 68 (60.7%) pts had treatment-related AEs, including 21 (18.8%) who had grade 3–5 events; there were no treatment-related deaths. 4 pts (3.6%) discontinued due to treatment-related AEs. 27 pts (24.1%) had immune-mediated AEs/infusion reactions. Conclusions: Pembro demonstrated antitumor activity and manageable toxicity in pts with heavily pretreated advanced ASCC, regardless of PD-L1 status. Clinical trial information: NCT02628067.
Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with mFOLFOX6 (three versus six months) in the prospective IDEA France cohort study (PRODIGE-GERCOR).
Authors: Pages Franck , Andre Thierry , Taieb Julien , Vernerey Dewi , Henriques Julie , Borg Christophe , Marliot Florence , Ben Jannet Rim , Louvet Christophe , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Faroux Roger , Duval Alex , Laurent-Puig Pierre , Svrcek Magali , Hermitte Fabienne , Catteau Aurelie , Galon Jerome , Emile Jean-François
Published: February 2020

10

Background: In stage III colon cancer patients treated with CAPOX, 3 months of therapy was as effective as 6 months. It was not the case for those receiving mFOLFOX6. We assessed the prognostic and predictive value of the Immunoscore (IS) in the mFOLFOX6 subgroup (90% of patients enrolled) of the IDEA France cohort study. Methods: 1200 patients randomly assigned to 3 months (n = 593) or 6 months (n = 607) of mFOLFOX6, with available tumor sample, were included. Densities of CD3+ and cytotoxic CD8+ T-cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS using the pre-defined cut-off. The IS performance to predict disease-free survival (DFS) was assessed in each arm and adjusted in multivariate Cox models. Results: In a two-category IS analysis, Low and (Int+High) IS were observed in 423 (43.5%) and 550 (56.5%) patients, respectively. Low IS identified patients with higher-risk of relapse or death (HR = 1.60; 95% CI 1.27-2.01, P < 0.0001). The 3-year DFS was 66.34% (95% CI 61.54-70.69) and 77.66% (95% CI 73.86-80.97) for Low and (Int+High) IS, respectively. In multivariate analysis, IS remained independently associated with DFS (P = 0.0007) when combined with T/N stage. A statistically significant interaction was observed for the IS predictive value for treatment duration (3 vs 6 months) in term of DFS in the whole population (P = 0.0566) and TN subgroups (Low-risk T1-3, N1 vs High-risk T4 and/or N2; P = 0.0015). The 3-year DFS of patients with (Int+High) IS in the 3-month arm was 71.5% (95% CI 65.7-76.6) versus 83.8% (95% CI, 78.8-87.8) in the 6-month arm (HR = 0.528; 95% CI 0.372-0.750; log-rank P = 0.0004); the benefit retained in low-risk and high-risk patients (all P≤0.010). 6-month mFOLFOX6 showed no significant benefit for patients with Low IS (HR = 0.836, log-rank P = 0.269). Conclusions: The IS prognostic value in patients treated with mFOLFOX6 was confirmed. Its predictive value for benefit of longer duration treatment, despite a strong statistical signal, needs to be confirmed in an external validation cohort. Clinical trial information: NCT03422601.
Irinotecan, cetuximab, and bevacizumab (CBI) versus irinotecan, cetuximab, and placebo (CI) in irinotecan-refractory metastatic colorectal cancer (mCRC): Results from an ACCRU network randomized phase II trial.
Authors: Lipsyc-Sharf Marla , Ou Fang-Shu , Yurgelun Matthew B. , Rubinson Douglas Adam , Schrag Deborah , Dakhil Shaker R. , Stella Philip J. , Weckstein Douglas Jay , Wender Donald B. , Faggen Meredith Gail , Zemla Tyler , Heying Erica N. , Schuetz Samantha R , Noble Stephanie , Meyerhardt Jeffrey A. , Bekaii-Saab Tanios S. , Fuchs Charles S. , Ng Kimmie
Published: February 2020

102

Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.
A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer.
Authors: Monge B. M. Cecilia , Xie Changqing , Steinberg Seth M. , Fioraventi Suzanne , Walker Melissa , Mabry-Hrones Donna , Wood Bradford J. , Kleiner David E , Greten Tim F.
Published: February 2020

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Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 108 plaque forming units (pfu) (DL1) or at 109 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.
Oligometastatic colorectal cancer: Prognostic implications of tumor load, role of locoregional treatments, and of first-line therapy intensification—A pooled analysis of TRIBE and TRIBE2 studies by GONO.
Authors: Zucchelli Gemma , Moretto Roberto , Rossini Daniele , Lonardi Sara , Murgioni Sabina , Tonini Giuseppe , Cupini Samanta , Ratti Margherita , Urbano Federica , Libertini Michela , Antoniotti Carlotta , Corallo Salvatore , Buonadonna Angela , Bordonaro Roberto , Ricci Vincenzo , Tamburini Emiliano , Grande Roberta , Aprile Giuseppe , Falcone Alfredo , Cremolini Chiara
Published: February 2020

12

Background: According to the ESMO guidelines a metastatic spread involving up to 2 or occasionally 3 sites with 5 or sometimes more metastases (mts) is defined as oligometastatic disease (OMD) and the possibility to offer locoregional treatments (LRTs) should be carefully considered. Tumor load and treatment’s objective (cytoreduction vs disease control) are included among factors affecting the choice of the intensity of the upfront chemotherapy (CT). Nevertheless, no data from clinical trials adopting this definition are currently available, so that the prognostic effect of tumor load, the impact of LRTs and the magnitude of benefit from the CT-intensification in OMD remain unclear. Here we assess the effect of FOLFOXIRI/bev compared to doublets (FOLFOX or FOLFIRI)/bev and the impact of LRTs according to tumor load (OMD vs non-OMD) in a pooled analysis of two randomized phase III studies (TRIBE and TRIBE2). Methods: Subgroup analyses for ORR, PFS and OS were performed according to tumor load at baseline. OMD was defined as up to 5 mts, up to 3 mts in one organ, up to 3 affected organs, mts size ≤ 3 cm, absence of ascites and peritoneal, bone and central nervous system mts. Results: Among 1187 patients (pts) enrolled, 1158 were classifiable: 126 as OMD (11%) and 1032 as non-OMD (89%). Pts with OMD had longer PFS (14.3 vs 10.5 months (mos); p < 0.01) and OS (44.3 vs 24.0 mos; p < 0.01) compared with those with non-OMD. These results were confirmed in multivariable models (p < 0.01). Also among pts who underwent LRTs with curative intent during first line (N = 202), those with OMD at baseline (N = 35) reported longer OS than those with non-OMD (59.6 vs 50.6 mos; p = 0.04). The benefit provided by FOLFOXIRI/bev compared to doublets/bev was confirmed in the OMD subgroup with no interaction effect between treatment arm and tumor load in terms of ORR, PFS and OS (p for interaction = 0.10, 0.58 and 0.23, respectively). Conclusions: OMD is confirmed as a positive prognostic factor and is associated with a higher magnitude of long-term benefit from LRTs than non-OMD. The positive impact of the intensification of the upfront CT is independent of tumor load.
First-line durvalumab + monalizumab, mFOLFOX6, and bevacizumab or cetuximab for metastatic microsatellite-stable colorectal cancer (MSS-CRC).
Authors: Wainberg Zev A. , Diamond Jennifer Robinson , Curigliano Giuseppe , Deva Sanjeev , Bendell Johanna C. , Han Sae-Won , Kalyan Aparna , Naidoo Jarushka , Kim Richard D. , Patel Sandip Pravin , Kourtesis Panagiotis , Li Xia , Ascierto Maria , Song Xuyang , Das Mayukh , Segal Neil Howard
Published: February 2020

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Background: Targeting multiple immune checkpoint pathways and combining checkpoint inhibition with chemotherapy may enhance response in MSS-CRC. In a Phase 1/2, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was added to monalizumab (M; an anti-NKG2A antibody). In dose-exploration cohorts, D+M was added to chemotherapy and a biologic agent (bevacizumab [DMCB] or cetuximab [DMCC]) for first-line treatment of advanced/metastatic MSS-CRC. Initial data showed DMCB was well tolerated and clinically active. Here we report updated efficacy and safety of DMCB and initial safety of DMCC. Methods: Eligible patients (pts) had MSS-CRC ( RAS/BRAF wt with a left-sided colon primary tumor in the DMCC cohort) and ECOG PS 0–1. They received D 1500 mg Q4W, M 750 mg Q2W, mFOLFOX6 Q2W and bevacizumab 5 mg/kg Q2W or cetuximab 250/400 mg/m2 QW (up to 500 mg/m2 Q2W) for up to 3 yr. The primary endpoint was safety and tolerability; secondary endpoints included antitumor activity. Results: As of Aug 26, 2019, 18 pts received DMCB and 17 pts received DMCC. Treatment-emergent adverse events (AEs) occurred in 100.0% of the DMCB cohort (most commonly fatigue, nausea and peripheral neuropathy) and 94.1% of the DMCC cohort (most commonly peripheral neuropathy, rash and dermatitis acneiform). The AEs were grade 3/4 in 77.8% of pts receiving DMCB and 70.6% of pts receiving DMCC, and were serious in 38.9% and 47.1%, respectively. Response was evaluable in 17 pts receiving DMCB; objective response rate was 41.2% (all PRs; Table). Responses occurred early and the median duration of response has not yet been reached. Conclusions: In advanced/metastatic MSS-CRC, first-line DMCB and DMCC had a manageable safety profile and DMCB showed promising preliminary activity. Clinical trial information: NCT02671435.

[Table: see text]
Started dose of regorafenib and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): A systematic review and meta-analysis.
Authors: Fedyanin Mikhail , Polyanskaya Elizaveta , Pokataev Ilya , Tryakin Alexey , Tjulandin Sergei
Published: February 2020

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Background: Regorafenib is one of the standards of care in pts with chemorefractory mCRC. However, high toxicity is a common reason of treatment discontinuation, interruption and dose reduction. There are conflicting results how started dose of regorafenib influence OS (REBECCA, ReDOS and ARRANGE trials). Therefore, we performed systemic review and meta-analysis to evaluate association between started dose of regorafenib and OS in pts with mCRC. Methods: We performed a search of all retrospective and prospective studies in PubMed, Embase, and Cochrane library. The search criteria included all articles and abstracts for all years before 20.08.2019. We compared the pts with standard dose (160 mg) and <160 mg at the first cycle. Primary outcome was hazard ratio (HR) for OS and 95% confidence interval (CI). Random effects were used for analysis due to potential heterogeneity of the studies. Meta-analysis was conducted by "Review Manager" Ver. 5.3. Results: We identified 6 trials – 3 prospective and 3 retrospective ones, which included 1955 pts (160 mg – 1584 and <160 mg – 571 pts). Two trials showed worsening OS in pts with dose <160 mg (Adenis et al., 2016 – HR 1.26, 95%CI 1.01-1.56 and Aljubran et al., 2019 – HR 2.25, 95%CI 0.93-5.43). Two studies showed improving OS in pts with dose <160 mg (Bekaii-Saab et al., 2018 – HR 0.72, 95%CI 0.47-1.11; Gotfrit et al., 2017 – HR 0.46, 95%CI 0.17-1.22). And two studies didn’t show any difference (Yamaguchi et al., HR 0.95, 95%CI 0.82-1.1 and Argiles et al., 2019 - HR 0.86, 95%CI 0.65-1.13). According to results of the meta-analysis there was not any difference in OS between groups with the dose 160 mg and <160 mg at the first cycle: HR 0.97, 95% CI 0.78-1.21; p = 0.79; I2 = 64. Conclusions: Started dose of regorafenib <160 mg in the pts with chemorefractory mCRC does not worsen the OS and this approach can be safely used in the daily clinical practice.
Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603).
Authors: Shitara Kohei , Hara Hiroki , Takahashi Naoki , Kojima Takashi , Kawazoe Akihito , Asayama Masako , Yoshii Takako , Kotani Daisuke , Tamura Hitomi , Mikamoto Yuichi , Hirano Nami , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Nishikawa Hiroyoshi , Fukuoka Shota
Published: February 2020

135

Background: In the phase 1 REGONIVO study, regorafenib of 80 mg/day plus nivolumab showed manageable safety profiles and encouraging anti-tumor activity for advanced colorectal cancer (CRC) or gastric cancer (GC) with objective response rate (ORR) of 36% in CRC and 44% in GC (Fukuoka, et al. ASCO 2019). Updated efficacy results are presented. Methods: Enrolled patients (pts) received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one to estimate the MTD and the recommended dose. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 28-8 antibody. Tumor mutation burden (TMB) was measured using Oncomine tumor mutation load assay. Results: Fifty pts were enrolled (25 CRC; 25 GC) until October 2018 with median prior treatment line of 3. Efficacy results were updated as of September 1st 2019. One CRC pt was with MSI-high but all other pts were with MSS or MMR-proficient. Among the 20 pts (9 CRC and 11 GC) with objective response (40%), responses are still ongoing in 13 pts (7 CRC and 6 GC) and the median duration of response was not reached (NR). Median progression free survival (PFS) was 7.8 months in CRC (95% CI, 2.8- NR) and 5.5 months (95% CI, 2.6-10.2 months) in GC. One-year PFS rate was 41.7% in CRC and 22.4% in GC. Median overall survival (OS) was not reached in CRC (95% CI, 9.7-NR) and 12.1 months (95% CI, 5.2-NR) in GC. One-year OS rate was 68% in CRC and 55.3% in GC. No significant difference of PFS and ORR was observed in CRC according to PD-L1 and TMB. Conclusions: Encouraging anti-tumor activity of the combination of regorafenib plus nivolumab had been maintained with long-term follow-up. A randomized study for MSS CRC is under planning. Clinical trial information: NCT03406871.
Factors associated with effectiveness of trifluridine/tipiracil versus regorafenib in patients with pretreated metastatic colorectal cancer (mCRC).
Authors: Grell Peter , Borilova Simona , Schwanzerova Renata , Kukolikova Sabina , Dvorak Josef , Vocka Michal , John Stanislav , Buchler Tomas , Selingerova Iveta , Petruzelka Lubos B. , Vyzula Rostislav , Kiss Igor , Obermannova Radka
Published: February 2020

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Background: Trifluridine/tipiracil (T) and regorafenib (R) are indicated for patients with refractory mCRC. Currently, no biomarkers are used to select which patient will benefit from which treatment. Methods: We retrospectively evaluated 212 patients who received T and/or R. Different factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. Results: T received 132, R 52, both drugs 28 patients. Median age was 64 (range 28-83), male 64%, PS 0 37%, median line of treatment 3, characteristic was similar between treatment groups. Median follow-up was 16.5 months. Median OS for T was 10.2, for R 6.9 months, P = 0.03. Factors significantly associated with OS were: ≥ 24 months from diagnosis of mCRC (0.49, P < 0.001), PS 0 (HR 1.54, P = 0.007), baseline WBC < 8 × 109/L (HR 0.47, P < 0.001), normal baseline CRP (HR 0.47, P < 0.001), ≥ 3 months from last therapy (fluoropyrimidine for T, anti-VEGF for R) (HR 0.66, P = 0.006). We developed a scoring system TASREG from these factors, 1 point for each factor, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS for all patients according to risk group was 4.6 for high risk, 7.9 intermediate, 11.8 months favorable risk (P < 0.001). Score was also significant for T and R group evaluated separately. Score was also significant for PFS. Factors associated with OS specific for T were neutropenia G≥2 (HR 0.34, P < 0.001); for R normal baseline LDH (HR 0,40. P < 0.001), no liver metastases (HR 0.45, P = 0.002), non-synchronous disease (HR 0,40, P < 0.001). Conclusions: We could find factors associated with better outcomes for both treatment groups and factors specific for T or R. TASREG is simple prognostic tool for patients with refractory mCRC.
The impact of body mass index (BMI) on the safety and outcomes of small molecule inhibitors (SMI) in gastrointestinal cancer.
Authors: McCabe Colleen , Patel Urvi , Beardslee Tyler , Caulfield Sarah , Lee Christin , Pruitt Rosie , Chen Zhengjia , Goyal Subir , Draper Amber , Shaib Walid Labib
Published: February 2020

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Background: A number of studies have demonstrated that overweight and early obese states are associated with improved survival in renal and melanoma cancer patients. The purpose of this study was to investigate the impact of BMI on outcomes of GI cancers treated with SMIs. Methods: A retrospective chart review was conducted to compare outcomes between patients with BMIs ≥ 25 and < 25 who received treatment at Winship between 1/2010-8/2019. The primary objective was to determine the PFS, OS, and ADR rates of patients with BMI ≥ 25 treated with SMIs compared to patients with BMIs < 25. PFS and OS rates were estimated with the Kaplan-Meier method and compared between the groups using the log-rank test. The incidence of adverse events was estimated as frequency and percentage and logistic regression was used to estimate the impact of BMI on adverse effects. Results: 269 patients were included in analysis for PFS, 61 for OS and 281 for ADR rate analysis. Diagnoses included HCC (n = 123, 44%) and CRC (n = 158, 56%). There was no significant difference seen in PFS and OS between the BMI < 25 and BMI ≥ 25 groups (HR 1.17 (0.87-1.56), p = 0.291, HR 1.10 (0.66-1.84), p = 0.713, respectively). A significant difference was demonstrated in the rates of adverse reactions between the two groups (OR 0.31 (0.19-0.52), p<.001) with BMI < 25 having a lower rate of ADRs. After adjusting for covariates, HCC vs CRC diagnosis (p = 0.002) and not requiring dose reduction or delay due to toxicity (p<0.001) were significantly associated with better PFS. Conclusions: Based on the multiple regression analysis, patients with a BMI ≥ 25 do not have improved outcomes over those with a BMI < 25 when taking SMIs for their GI malignancies. Patients with BMI < 25 experienced less drug toxicity that required dose reduction, discontinuation, or treatment delays.

[Table: see text]