Summary Background For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of ...nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. Methods We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1–10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov , number NCT01658878. Findings Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase. Interpretation Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Funding Bristol-Myers Squibb.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.
Systematic review and network meta-analysis.
...Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.
Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.
36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.
Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.
PROSPERO CRD42017082553.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Reducing Salmonella enterica association with plants during crop production could reduce risks of fresh produce-borne salmonellosis. Plant growth-promoting rhizobacteria (PGPR) colonizing plant roots ...are capable of promoting plant growth and boosting resistance to disease, but the effects of PGPR on human pathogen-plant associations are not known. Two root-colonizing Pseudomonas strains S2 and S4 were investigated in spinach, lettuce and tomato for their plant growth-promoting properties and their influence on leaf populations of S. enterica serovar Newport. Plant roots were inoculated with Pseudomonas in the seedling stage. At four (tomato) and six (spinach and lettuce) weeks post-germination, plant growth promotion was assessed by shoot dry weight (SDW) and leaf chlorophyll content measurements. Leaf populations of S. Newport were measured after 24h of leaf inoculation with this pathogen by direct plate counts on Tryptic Soy Agar. Root inoculation of spinach cv. ‘Tyee’, with Pseudomonas strain S2 or S4 resulted in a 69% and 63% increase in SDW compared to non-inoculated controls (p<0.005 and p<0.01, respectively). Similarly, Romaine lettuce cv. ‘Parris Island Cos’ responded positively to S2 and S4 inoculation (53% and 48% SDW increase, respectively; p<0.05), and an increase in leaf chlorophyll content (p<0.001), compared to controls. Tomato cv. ‘Nyagous’ yielded significantly greater SDW (74%, p<0.01 and 54%, p<0.05 for S2 and S4, respectively), and also higher leaf chlorophyll content (19% and 29%, p<0.001, respectively) relative to controls. Leaf chlorophyll content only increased in S4-inoculated tomato cv. ‘Moneymaker’ plants (27%, p<0.001), although both S2 and S4 promoted plant growth by over 40% compared to controls (p<0.01 and p<0.05, respectively). No significant growth promotion was detected in tomato cv. ‘BHN602’, but S2-inoculated plants had elevated leaf chlorophyll content (13%, p<0.01). Root inoculation with Pseudomonas S4 restricted S. Newport populations inoculated on leaves of spinach (p<0.001) and all three tomato cultivars (p<0.05), compared to controls, 24h post Salmonella inoculation. Impairment of S. Newport leaf populations was also observed on spinach when plant roots were inoculated with S2 (p<0.01). With an initial leaf inoculum of approximately 6.0logCFU of S. Newport/plant, the significantly greater reduction of S. Newport populations on Pseudomonas-treated plants than those on non-inoculated control plants after 24h was modest with differences of one log or less. By contrast, the survival of S. Newport on the leaves of Romaine lettuce was not influenced by Pseudomonas root colonization. These findings provide evidence that root inoculation of certain specialty crops with beneficial Pseudomonas strains exhibiting PGPR properties may not only promote plant growth, but also reduce the fitness of epiphytic S. enterica in the phyllosphere. Plant-mediated effects induced by PGPR may be an effective strategy to minimize contamination of crops with S. enterica during cultivation.
•Pseudomonas S2, S4 act as plant growth-promoting rhizobacteria (PGPR) on produce.•Rhizosphere S2 and S4 promoted biomass accumulation in spinach, lettuce and tomato.•S2 or S4 root inoculation boosted chlorophyll content in lettuce and tomato leaves.•Spinach and tomato colonized with S4 restricted Salmonella populations on leaves.•PGPR-induced effects could prime plants against human enteric pathogens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cold-smoked salmon is a ready-to-eat seafood product of high commercial importance. The processing and storage steps facilitate the introduction, growth, and persistence of foodborne pathogens and ...spoilage bacteria. The growth of commensal bacteria during storage and once the product is opened also influence the quality and safety of cold-smoked salmon. Here we investigated the microbial community through targeted 16S rRNA gene and shotgun metagenomic sequencing as means to better understand the interactions among bacteria in cold-smoked salmon. Cold-smoked salmon samples were tested over 30 days of aerobic storage at 4°C and cultured at each time point in a buffered Listeria enrichment broth (BLEB) commonly used to detect Listeria in foods. The microbiomes were composed of Firmicutes and Proteobacteria, namely, Carnobacterium, Brochothrix, Pseudomonas, Serratia, and Psychrobacter. Pseudomonas species were the most diverse species, with 181 taxa identified. In addition, we identified potential homologs to 10 classes of bacteriocins in microbiomes of cold-smoked salmon stored at 4°C and corresponding BLEB culture enrichments. The findings presented here contribute to our understanding of microbiome population dynamics in cold-smoked salmon, including changes in bacterial taxa during aerobic cold storage and after culture enrichment. This may facilitate improvements to pathogen detection and quality preservation of this food.
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CEKLJ, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Translational research plays a key role in drug development and biomarker discovery for hepatocellular carcinoma (HCC). However, unique challenges exist in this field because of the limited ...availability of human tumor samples from surgery, the lack of homogenous oncogenic driver mutations, and the paucity of adequate experimental models. In this review, we provide insights into these challenges and review recent advancements, with a particular focus on the two main agents currently used as mainstream therapies for HCC: anti-angiogenic agents and immunotherapy. First, we examine the pre-clinical and clinical studies to highlight the challenges of determining the optimal therapeutic combinations with biologically effective dosage for HCC. Second, we discuss biomarker studies focusing on anti-PD1/anti-PD-L1-based combination therapy. Finally, we discuss the progress made in our collective understanding of tumor immunology and in multi-omics analysis technology, which enhance our understanding of the mechanisms underlying immunotherapy, characterize different patient subgroups, and facilitate the development of novel combination approaches to improve treatment efficacy. In summary, this review provides a comprehensive overview of efforts in translational research aiming at advancing our understanding of and improving the treatment of HCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A number of APETALA2 (API)/ETHYLENE RESPONSE FACTOR (ERF) genes have been shown to function in abiotic and biotic stress responses, and these genes are often induced by multiple stresses. We report ...here the characterization of an AP2/ERF gene in Arabidopsis (Arabidopsis thaliana) that is specifically induced during hypoxia. We show that under normoxic conditions, the expression of AOERF73/HRE1 can be induced by exogenous addition of 1-aminocyclopropane-1-carboxylic acid and that a combination of hypoxia and 1-aminocyclopropane-1-carboxylic acid results in hyperinduction of AOERF73/HRE1 expression. In addition, hypoxic induction of AOERF73/HRE1 is reduced but not completely abolished in ethylene-insensitive mutants and in the presence of inhibitors of ethylene biosynthesis and responses. These results suggest that, in addition to ethylene, an ethylene-independent signal is also required to mediate hypoxic induction of AtERF73/HRE1. To assess the role of AtERF73/HRE1, we generated three independent RNA interference (RNAi) knockdown lines of AtERF73/HRE1. Under normoxic conditions, the AtERF73/HREl-RNAi seedlings displayed increased ethylene sensitivity and exaggerated triple responses, indicating that AtERF73/HRE1 might play a negative regulatory role in modulating ethylene responses. Gas chromatography analyses showed that the production of ethylene was similar between wild-type and RNAi lines under hypoxia. Quantitative reverse transcription-polymerase chain reaction analyses showed that hypoxia-inducible genes could be affected by AtERF73/HREl-RNAi lines in two different ways: hypoxic induction of glycolytic and fermentative genes was reduced, whereas induction of a number of peroxidase and cytochrome P450 genes was increased. Taken together, our results show that AtERF73/HRE1 is involved in modulating ethylene responses under both normoxia and hypoxia.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background
Despite a protracted disease course and multiple available therapies, patients with well‐differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed ...death–ligand 1 (PD‐L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE‐028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti–programmed cell death protein 1 immunotherapy pembrolizumab in patients with well‐differentiated or moderately‐differentiated NETs.
Methods
Patients with PD‐L1–positive, locally advanced or metastatic carcinoid or well–differentiated or moderately‐differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint.
Results
Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD‐L1–positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow‐up was 20 months (range, 2‐35 months) and 21 months (range, 5‐32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%‐31.2%) and 6.3% (95% CI, 0.2%‐30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9‐11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment‐related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune‐mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort).
Conclusions
Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well‐tolerated.
The multicohort, phase 1 KEYNOTE‐028 study evaluated the antitumor activity and safety of pembrolizumab in patients with neuroendocrine tumors (NETs). Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs (objective response rate of 12.0% and 6.3%, respectively, in patients with carcinoid and pancreatic NETs) and was well‐tolerated.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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