Search

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents being more specific to cancer cells were expected to be less toxic than cytotoxic agents. Targeted agents have provided clinical benefit in many GI cancer types. For example, antiangiogenics and anti-EGFR therapies have significantly improved survival of patients affected by metastatic colorectal cancer and have deeply changed the therapeutic strategy in this disease. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms (e.g., RAS mutation for anti-EGFR therapies), or to an activity restricted to some tumour settings (e.g., lack of activity in other cancer types, or on the microscopic residual disease in adjuvant setting). Many studies are negative in overall population but positive in some specific patient subgroups (e.g., trastuzumab in HER2-positive gastric cancer), illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this first part, we will focus on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibition is a new therapeutic strategy that has shown promising efficacy in many cancer types. Significant activity associated with mismatch repair (MMR) deficiency has been observed in hypermutated, microsatellite unstable (MSI) metastatic colorectal cancer (CRC). Beyond deficient-MMR tumors, somatic or germline DNA polymerase D1 ( POLD1 ) or DNA polymerase E ( POLE ) alterations cause a hypermutated phenotype in CRC. This recently identified and rare subgroup of proficient-MMR tumors may also benefit from immunotherapy. In this review, we provide a comprehensive overview of recent data on CRC tumors harboring POLD1 or POLE mutations, with a focus on their molecular, histological, and clinical features. We also examine the evidence supporting the development of immune checkpoint inhibitors in this specific subgroup of CRC patients. [ABSTRACT FROM AUTHOR]

Background Sunitinib, pazopanib, sorafenib, axitinib and bevacizumab are the five recommended antiangiogenic agents in first-line therapy for metastatic renal cell carcinoma (mRCC). Because these drugs underwent simultaneous clinical development, no direct efficacy and safety comparison was ever conducted, thus preventing optimal therapy choices. Methods We performed a traditional and network meta-analysis to evaluate the efficacy and safety of mRCC-recommended first-line antiangiogenic agents. After a systematic review of Medline and Embase up to July 2014, we identified randomized clinical trials (RCTs) evaluating the outcomes of mRCC patients treated with sunitinib, pazopanib, sorafenib, axitinib and bevacizumab as first-line treatment. Endpoints of interest were response rate, progression-free survival (PFS), overall survival (OS), and safety. Results We screened 769 abstracts and included nine RCTs with a total of 4282 patients. In the weighted pooled analysis, first-line antiangiogenic agents showed significant improvement in PFS (HR = 0.6; 95% IC, 0.51–0.72) and OS (HR = 0.85; 95% IC, 0.78–0.93) compared to control (placebo or interferon-alpha2a (INF)). Network meta-analysis showed no significant differences among antiangiogenic drugs in 6-month PFS, 1-year OS, disease control rate and drug-related safety for all-grade hypertension, diarrhea, weight-loss, nausea or anorexia. However, pazopanib showed a lower incidence of fatigue, anemia and hand foot skin reaction. Conclusions This meta-analysis confirms the benefits of first-line antiangiogenic therapy in mRCC, with an improvement in OS. Sunitinib, pazopanib, axitinib and bevacizumab + INF offer similar efficacy but different safety profiles which can help clinicians to better personalize treatment decisions in patients with mRCC. [ABSTRACT FROM AUTHOR]

In order to ensure consistency in the decision making process over time, a discrimination testing program must take into account all of five elements: The testing protocol, the sample size, the Type I error ( α ), the Type II error ( β ) (power = 1 − β ) and a measure of the threshold above which the scientist has established that the difference is meaningful to the consumer ( δ R ). Two putatively different products will always be found to be different provided that the sample size is large enough. This fact underscores the need to set δ R . The concept of discriminators is attractive but flawed, as the same underlying sensory difference will result in different proportions of distinguishers depending on the method used. Prescott, Leslie, Kunst, and Kim (2005) proposed the idea of consumer rejection threshold which avoids the pitfalls of the proportion of discriminators concept. However, it is limited to differences that can be linked to a specific compound, such as one responsible for a product defect or off-flavor. In this manuscript two alternative approaches are discussed. The first one uses a special feature of the same-different protocol which permits the estimation of the size of the sensory difference above which consumers would call two products “different”. The second one links the estimate of a standardized measure of sensory difference, d ′, to consumer hedonic response between the product pairs and finds the threshold above which a sensory difference results in a meaningful preference result. Experimental research is needed to study the suitability of these approaches. Ultimately, establishing δ R is essential to ensure that results from a discrimination testing program are actually relevant to the consumers whose behavior it is trying to predict. [ABSTRACT FROM AUTHOR]

In the evaluation of new incarnations of existing products, difference testing is among the most commonly used sensory techniques. However, although difference testing is a classical technique, the science of difference testing continues to evolve. As Thurstonian analysis has gained increased acceptance for its ability to measure sensory differences, recent research advances have provided tools, techniques and theory to view sensory difference tests as measurement instruments. In particular, these advances promise to unite equivalence and difference testing, to help with the determination of consumer-relevant action standards, and to inform business risk calculations. Practical Applications The last 5 years have brought pressure on food and personal-care product companies to provide healthy and cost-effective products without compromising the sensory experience these products provide. In reaction to this pressure, business management has asked sensory and product development to develop and evaluate the feasibility of a large number of modified products. These products can be modified with respect to their ingredients, packaging, production processes, formulation, or as is the case when a complex goal such as sodium reduction is pursued, with respect to many aspects at once. In this article, we review how this business need for more detailed information from difference testing programs has paralleled recent research on the use of sensory difference tests as measurement instruments. [ABSTRACT FROM AUTHOR]

Highlights: [•] The limitations of the Proportion of Discriminators model are highlighted. [•] The need for a meaningful approach to sensory effect size estimation is underscored. [•] Tables are provided to guide the transition to Thurstonian sensory effect size estimation. [ABSTRACT FROM AUTHOR]

Use of the tetrad test has increased recently as both theoretical and experimental results have shown that it is statistically more powerful than the triangle test. In this article, although, we show that this power advantage depends on the choice of instructions. Specifically, we show that if experimenters ask respondents to select the two most similar samples out of four, instead of asking respondents to group the four samples into two groups of two based on similarity, then the resulting test will have approximately the same power as the triangle test. This fact serves as a reminder of the importance of correct test instructions in difference testing, as specific wording can clearly affect a test power and thus the final conclusion of an investigation. Practical Applications Businesses are increasingly considering the tetrad test as an alternative to the triangle test within their difference testing programs. This article clarifies the correct test instructions for the tetrad test, and shows that its power advantage over the triangle test will be compromised if incorrect instructions are given. Thus, it is essential that practitioners provide correct task instructions in order to realize the full potential of the tetrad test. [ABSTRACT FROM AUTHOR]

The role of human intraepithelial Vδ1 γδ T cell cytotoxic effectors in the immune surveillance against metastatic colon cancer has never been addressed, despite their reported capacity to infiltrate colon carcinomas and to kill colonic cancer cells in vitro. We previously showed that Vδ1 γδ T cells are enriched in blood in response to cytomegalovirus (CMV) infection, and that such increase may be protective against epithelial cancers. The objective of the present study was to investigate whether CMV-induced Vδ1 γδ T lymphocytes could inhibit the propagation of human colon tumors in vivo, in order to evaluate their immunotherapeutic potential in this context. Even though metastases are an important cause of death in various cancers including colorectal cancer (CRC), the anti-metastatic effect of immune effectors has been poorly analyzed. To this purpose, we set up a reliable model of metastatic colon cancer through orthotopic implantation of luciferase-expressing human HT29 cells in immunodeficient mice. Using bioluminescence imaging to follow the outcome of colonic cancer cells, we showed that a systemic treatment with CMV-induced Vδ1 γδ T cells could not only inhibit primary colon tumor growth but also the emergence of secondary tumor foci in the lungs and liver. Finally, our data lead to propose that Vδ1 γδ T lymphocytes may directly influence the appearance of metastases independently from their control of primary tumor size. These findings, which extend our previous work, pave the road for the potential manipulation of Vδ1 γδ T lymphocytes in novel anti-CRC immunotherapeutic protocols. [ABSTRACT FROM AUTHOR]

Abstract: Internal preference mapping (IPM) and Landscape Segmentation Analysis® (LSA) are two techniques broadly used to unfold consumers’ overall product liking ratings and create spatial maps that will provide further insights on consumers’ preferences. IPM is based on a vector model while LSA involves an ideal point model. Through a simulation and the analysis of 27 market research data sets, it is shown that IPM consistently creates a hedonic dimension that prevents the identification of satiety prone attributes (intensities higher or lower than a optimal level being disliked by the consumers) on that dimension. As a result, subsequent steps taken upon generating an IPM map such as the investigation of drivers of liking, population segmentation and the estimation of optimal product profiles have also a strong likelihood of resulting in distorted results, the level of distortion being dependent on the actual configuration of the underlying structure that IPM tried to uncover. It is also shown that a technique based on ideal points such as LSA does not exhibit this systematic artifact when unfolding liking data. Consequently, sensory scientists and market researchers should use caution when interpreting and using results issued from an internal preference mapping analysis. [Copyright &y& Elsevier]

This research investigated new paradigms that permit the simultaneous comparison of more than two samples in a discrimination study. Three successive experiments were conducted. All involved noncarbonated orange beverages. In experiment I, Torgerson's method of triads was found to be more discriminating than the multiple dual-pair method and was used in the subsequent two experiments. In experiments II and III, subjects discriminated among stimuli using the Torgerson's method as well as traditional duo–trios. In experiment II, the univariate Thurstonian model with four distributions was found to provide a suitable fit of the data, and the d′ values obtained using the traditional duo–trio methodology were not found to be significantly different from those obtained with Torgerson's method. In experiment III, a multivariate, but not univariate, model provided a good fit of the data. Furthermore, d′ values from the Torgerson's method were not found to be significantly different from those obtained using the traditional duo–trio methodology. PRACTICAL APPLICATIONS This research supported the use of a Thurstonian model for Torgerson's method of triads and uncovered the usefulness of the method when comparing more than two samples using a discrimination methodology, which has applications in situations involving samples with inherent intra-product variations. Flexibility in the models available also permits the estimation of the dimensionality of the differences among the stimuli involved, providing valuable information that can be obtained more efficiently than running multiple pair-wise traditional discrimination trials. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors such as FGF-2 are potent mitogens for endothelial cells and induce their assembly into vascular-like structures in culture and in in vivo assays. However, their putative functions during physiological vascularization are poorly documented. In this study, the eye was used as a model for analyzing the vascular defects caused by targeted FGF inhibition in transgenic mice. Choroidal and retinal vascularizations were studied by immunohistochemistry on whole-mount preparations. Soon after activation of the transgene, angiogenesis that normally occurs during the second half of gestation in the choroid was strongly inhibited resulting in poor capillary density and branching. Later retinas strickingly failed to develop a primary vascular plexus suggesting a defect in induction of vessel assembly. Hyaloid vessels that supply the retina during the fetal period did not regress at birth and later gave rise to unexpected massive neovascularization. This model illustrates major functions of FGFs at different early stages of physiological vascularization. Both the failure in hyaloid regression and the intense angiogenic invasion of endothelial cells into the retina may serve as a model for some related human ocular pathologies. [Copyright &y& Elsevier]

• Replications are routinely used in descriptive analysis. • Authors have argued that replications are not essential. • Meyners et al. disagree and point out weaknesses in the authors' arguments. • Meyners et al.'s arguments are valid and outline the need for power consideration. • Consumer relevance and meaningful difference concepts must also be considered. [ABSTRACT FROM AUTHOR]

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies. [ABSTRACT FROM AUTHOR]

A new liquid chromatography-tandem mass spectrometry (LC–MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold ® column using a gradient elution of 10 mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3 mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000 ng/mL for REGO and its metabolites and 80 to 5 000 ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this research was twofold: first, the performance of the tetrad protocol was compared to that of the triangle test under conditions that could possibly lower its sensitivity, consequently resulting in the loss of its theoretical power advantage. Second, the same samples were compared with a preference test to investigate whether a no difference conclusion obtained with a discrimination test would consistently result in a non-significant preference (consumer relevance). The investigation involved sensory differences that could be deemed small (d′ values less than 1.0) as well as the comparison of resampling vs. no resampling conditions. 456 consumers performed tests using apple and orange juices for which slight sensory differences were created through dilution. In all conditions, the tetrad always exhibited a greater number of correct answers than the triangle, confirming its greater statistical power. Therefore, it was concluded that even for small sensory differences, and in conditions where sensory fatigue could play a greater role (resampling allowed), the tetrad test sill appears like a good alternative to the triangle. Also, the theoretical increase in performance predicted when allowing sample resampling was confirmed. For the preference study, the same stimuli were evaluated by 208 subjects. Consumer relevance was defined as a significant result between two products in a preference test (assuming no population segmentation). Such significant preferences were found for three out of the four conditions, including the one with the smallest difference for which a significant result had not been found with either the tetrad or triangle. The non-significant preference in the fourth condition was attributed to segmentation in the population. Therefore, this investigation confirmed further that the tetrad test is a viable alternative to the triangle test, as it exhibits a greater statistical power even in conditions that could potentially affect it negatively. Also, it was shown that a non-significant sensory difference can still result in a significant preference test, outlining the necessity to go beyond the simple use of a ‘more powerful’ discrimination test when making decisions and to define the actual consumer relevance of an underlying sensory difference. [Copyright &y& Elsevier]

Aims: Lung cancer is the leading cause of cancer death worldwide, and tobacco smoking is a recognized major risk factor for lung tumor development. We analyzed the effect of tobacco-specific nitrosamines (TSNAs) on human lung adenocarcinoma metabolic reprogramming, an emergent hallmark of carcinogenesis. Results: A series of in vitro and in vivo bioenergetic, proteomic, metabolomic, and tumor biology studies were performed to analyze changes in lung cancer cell metabolism and the consequences for hallmarks of cancer, including tumor growth, cancer cell invasion, and redox signaling. The findings revealed that nicotine-derived nitrosamine ketone (NNK) stimulates mitochondrial function and promotes lung tumor growth in vivo. These malignant properties were acquired from the induction of mitochondrial biogenesis induced by the upregulation and activation of the beta-2 adrenergic receptors (β2-AR)-cholinergic receptor nicotinic alpha 7 subunit (CHRNAα7)-dependent nitrosamine canonical signaling pathway. The observed NNK metabolic effects were mediated by TFAM overexpression and revealed a key role for mitochondrial reactive oxygen species and Annexin A1 in tumor growth promotion. Conversely, ectopic expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase rescued the reprogramming and malignant metabolic effects of exposure to NNK and overexpression of TFAM, underlining the link between NNK and mitochondrial redox signaling in lung cancer. Innovation: Our findings describe the metabolic changes caused by NNK in a mechanistic framework for understanding how cigarette smoking causes lung cancer. Conclusion: Mitochondria play a role in the promotion of lung cancer induced by tobacco-specific nitrosamines. Antioxid. Redox Signal. 36, 525–549. [ABSTRACT FROM AUTHOR]

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of betablocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs. [ABSTRACT FROM AUTHOR]

The IMMUNOBIL PRODIGE 57 trial is a non-comparative randomized phase II study assessing the efficacy and safety of the durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) combination with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy. Taxanes have already been safely combined with immune checkpoint inhibitors in other tumors. We report results of the 20-patient safety run-in. Patients received durvalumab (1500 mg at day 1 [D1] of each cycle)/tremelimumab (75 mg at D1 for 4 cycles; Arm A) or durvalumab/tremelimumab with paclitaxel (80 mg/m2 at D1, D8, D15; Arm B) every 28 days. Twenty patients were enrolled (Arm A/B: 10/10). There were no dose-limiting toxicities (DLTs) in Arm A. Six DLTs were observed in five patients (50%) in Arm B, meeting a stopping rule for the trial inclusions. DLTs included three serious anaphylactic reactions (with one cardiac arrest), two enterocolitis, and one infectious pneumopathy with septic shock. There were no patients with history of personal or familial auto-immune disease. The safety run-in part of IMMUNOBIL PRODIGE 57 raised concerns regarding co-administration of paclitaxel with durvalumab and tremelimumab in BTC, with an unexpected increase in anaphylactic adverse events. Phase II of the study will only evaluate the durvalumab and tremelimumab combination arm. NCT03704480. • IMMUNOBIL phase II trial enrolls patients with advanced biliary tract cancers (BTC). • Patients received durvalumab and tremelimumab with or without paclitaxel. • With six dose-limiting toxicities in Arm B, a stopping rule was met. • An unexpected increase in anaphylactic adverse events was observed. • It raised concerns for durvalumab/tremelimumab combined with paclitaxel in BTC. [ABSTRACT FROM AUTHOR]

Aims: REDOX signaling from reactive oxygen species (ROS) generated by the mitochondria (mitochondrial reactive oxygen species [mtROS]) has been implicated in cancer growth and survival. Here, we investigated the effect of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo. Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies. [ABSTRACT FROM AUTHOR]

The variability of definitions for time-to-event (TTE) end-points impacts the conclusions of randomised clinical trials (RCTs). The Definition for the Assessment of Time-to-event Endpoints in CANcer (DATECAN) initiative aims to provide consensus definitions for TTE end-points used in RCTs. Here, we formulate guidelines for adjuvant colon cancer RCTs. We performed a literature review to identify TTE end-points and events included in their definition in RCT publications. Then, a consensus was reached among a panel of international experts, using a formal modified Delphi method, with 2 rounds of questionnaires and an in-person meeting. Twenty-four experts scored 72 events involved in 6 TTE end-points. Consensus was reached for 24%, 57% and 100% events after the first round, second round and in-person meeting. For RCTs not using overall survival as their primary end-point, the experts recommend using disease-free survival (DFS) rather than recurrence-free survival (RFS) or time to recurrence (TTR) as the primary end-point. The consensus definition of DFS includes all causes of death, second primary colorectal cancers (CRCs), anastomotic relapse and metastatic relapse as an event, but not second primary non-CRCs. Events included in the RFS definition are the same as for DFS with the exception of second primary CRCs. The consensus definition of TTR includes anastomotic or metastatic relapse, death with evidence of recurrence and death from CC cause. Standardised definitions of TTE end-points ensure the reproducibility of the end-points between RCTs and facilitate cross-trial comparisons. These definitions should be integrated in standard practice for the design, reporting and interpretation of adjuvant CC RCTs. • Randomised trials for adjuvant therapy in colon cancer (CC) use multiple time-to-event (TTE) end-points that lack standardised definitions. • Recommendations for the definition of TTE end-point in adjuvant CC randomised trials were established. • These guidelines should become standard practice because they would facilitate data interpretation and across-trial comparisons. [ABSTRACT FROM AUTHOR]

Abstract Background The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. Methods We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. Results The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). Conclusion We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design. Highlights • We analysed nearly 800 patients with advanced biliary tract cancer treated with second-line chemotherapy (L2) for factors predictive of overall survival (OS). • We validated some previously reported independent prognostic factors: performance status, first-line efficacy, primary tumour surgery, and carbohydrate antigen 19-9. • We identified peritoneal carcinomatosis as a new pejorative prognostic factor. • We developed and validated a prognostic model and score (CT2BIL score) which allow the identification of patients with poor OS who are unlikely to benefit from L2. • The CT2BIL score may be useful to guide clinicians' decision and in clinical trials for the stratification of patient randomisation and pre-planned subgroup analyses. [ABSTRACT FROM AUTHOR]

SiC-based materials are good candidates for the application as solar receivers except concerning their optical properties. Indeed, considering the use at high temperature, materials used as solar receivers have to efficiently absorb the visible-near infrared waves (corresponding to solar spectral range) and simultaneously reflect the mid and far-infrared rays but SiC is absorbent in all the whole visible-infrared spectral domain. In this challenging work, a suitable YBa 2 Cu 3 O 7-δ oxide which can present appropriate optical properties is studied. It was synthesized following a sol–gel route and it was obtained with a high level of purity. YBa 2 Cu 3 O 7-δ pellets were realized and heat treated at different temperatures revealing that the higher the heat treatment is, the better the oxygen stoichiometry (7-δ) is and the smoothest the surface is. This directly acts on the YBa 2 Cu 3 O 7-δ optical properties. Considering these results, an YBa 2 Cu 3 O 7-δ coating was realized on SiC pellets by dip-coating. A homogenous and covering layer of about 10 μm was obtained presenting very promising optical properties which were predominant in the FIR-MIR range whereas absorptance was increased in NIR-visible range. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αβ and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αβ T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε−/− mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27− γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag−/−γc−/− mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients. [ABSTRACT FROM AUTHOR]

Congenital erythropoietic porphyria (CEP) is due to a deficiency in the enzymatic activity of uroporphyrinogen III synthase (UROS); such a deficiency leads to porphyrin accumulation and results in skin lesions and hemolytic anemia. CEP is a candidate for retrolentivirus-mediated gene therapy, but recent reports of insertional leukemogenesis underscore the need for safer methods. The discovery of induced pluripotent stem cells (iPSCs) has opened up new horizons in gene therapy because it might overcome the difficulty of obtaining sufficient amounts of autologous hematopoietic stem cells for transplantation and the risk of genotoxicity. In this study, we isolated keratinocytes from a CEP-affected individual and generated iPSCs with two excisable lentiviral vectors. Gene correction of CEP-derived iPSCs was obtained by lentiviral transduction of a therapeutic vector containing UROS cDNA under the control of an erythroid-specific promoter shielded by insulators. One iPSC clone, free of reprogramming genes, was obtained with a single proviral integration of the therapeutic vector in a genomic safe region. Metabolic correction of erythroblasts derived from iPSC clones was demonstrated by the disappearance of fluorocytes. This study reports the feasibility of porphyria gene therapy with the use of iPSCs. [Copyright &y& Elsevier]

The normal spectral emittance of a partially yttria-stabilized hafnia (YSH) ceramic has been measured by infrared emittance spectroscopy in a spectral range going from 60 to 17 500 cm-1 (0.075-2.2 eV), and up to 2350 K. Using these experimental data, the temperature dependence of the absorption coefficient and the total emittance have been calculated. The physical mechanisms explaining the spectral features of the whole set of spectra are exposed qualitatively. The spectral weight of each contribution is then discussed for interpreting the influence of temperature on the total normal emittance in the range of temperatures (1200-2500 K) where YSH ceramics can be used for their refractory properties (thermal barrier coating, nuclear reactor, thermal protection systems, etc.). [ABSTRACT FROM AUTHOR]

Background & Aims: We previously showed that Reptin is overexpressed in hepatocellular carcinoma (HCC), and that in vitro depletion of Reptin with siRNAs led to HCC cell growth arrest and apoptosis. Here, we asked whether in vivo targeting of Reptin in established tumours had a therapeutic effect. Methods: We used lentiviral vectors to construct HuH7 and Hep3B cell lines with doxycycline (Dox)-dependent expression of Reptin (R2) or control shRNA (GL2). Cells were injected subcutaneously into immunodeficient mice, and Dox was given when tumours reached a volume of 250mm3. Results: In vitro, the growth of GL2−Dox, GL2+Dox, and R2−Dox cells was undistinguishable whereas that of R2+Dox cells stopped 4days after Dox treatment. The growth decrease was associated with increased apoptosis, and evidence of replicative senescence, as shown by staining for acid β-galactosidase and the presence of senescence-associated heterochromatin foci. In xenografted mice, R2+Dox tumour growth stagnated or even regressed with prolonged treatment in contrast with the GL2−Dox, GL2+Dox, and R2−Dox tumours that progressed steadily. The blockage of tumour progression was associated with the induction of senescence and reduced cell proliferation. Conclusions: In vivo Reptin depletion leads to tumour growth arrest. Reptin may prove a valuable target in HCC. [Copyright &y& Elsevier]

Two experiments were conducted to investigate the suitability of the Thurstonian models for the 2-AFC (2-alternative forced choice) and 2-AC protocols (2-AFC test with a “no difference” option). The Thurstonian approach predicts that if the same subjects and products are used, the degree of difference measured between the products (d′) should be the same. Experiment I tested this prediction using solutions with different salt concentration. The average d′ values for the 2-AFC and 2-AC were found to be 1.66 and 1.54, respectively, and were not significantly different (t-test, p=0.46). This indicated the suitability of the models for a taste stimulus. Experiment II used a trigeminal stimulus: sparkling water with different CO2 levels as a food system. Three levels of carbonation were used and all three possible pairs of samples were compared. The d′ values measured for the 2-AFC and 2-AC for each pair of products were: pair 1––1.7 and 1.7; pair 2––0.8 and 0.7; pair 3––1.2 and 1.0. For each pair of products, no significant difference was observed between the d′ of each protocol (t-tests, p=0.65, 0.20, 0.30, respectively), giving further support to the Thurstonian models of these paradigms and indicating their robustness. [Copyright &y& Elsevier]

This research examined potential biases associated with paired preference tests and how these biases might differ between Japanese and American cultures. The three biases that were investigated were the potential differential use of the no preference option, a predisposition in choosing the first stimulus in a pair, and finally a potential tendency of picking the stimulus with the numerically higher code in the pair. In this investigation, 96 American and 192 Japanese subjects performed six paired preference tests involving three types of grapefruit juices, three of the pairs involving identical samples. Of the three biases, only the differential use of the "no preference" option was significantly observed, with American subjects exhibiting higher "no preference" frequencies than Japanese for identical pairs (24% and 9%, respectively). Interestingly, no clear position or code bias effects were uncovered, a result possibly driven by the experimental approach used in this research. Potential explanations are discussed. Practical applications: Biases when executing paired preference tests have been documented. Addressing them, if not controlling them, is necessary to ensure reliable interpretation of test results. One important bias involves the use of the "no preference" option for identical samples. This use directly impacts how an identicality norm can be utilized to interpret test results. Assuming the wrong identicality norm will increase the likelihood of reaching an incorrect conclusion. This research establishes the identicality norm for Japanese subjects and confirms that such norm would be different from that of American subjects and more like that of Korean consumers. This will be of value for companies conducting research across cultures to ensure that more reliable conclusions are reached. No clear position or code biases were found in this research. Nevertheless, sample position balancing and the use of two sets of labeling codes in any paired preference test design are recommended since these effects have been previously reported elsewhere. [ABSTRACT FROM AUTHOR]

Background: In advanced pancreatic ductal adenocarcinoma (aPDAC), there is no consensual strategy for second-line chemotherapy (L2). Better discrimination of overall survival (OS) may help clinical decision-making. We aimed to predict OS from the beginning of L2 and to assess the benefit from chemotherapy among the identified risk groups.Methods: Analyses were derived from all consecutive aPDAC patients treated at Besancon University Hospital, Besancon, France, between January 2003 and December 2013 (n = 462). The association of 50 parameters with OS was evaluated using univariate and multivariable Cox analyses. Based on the final model, a prognostic nomogram and score were developed and externally validated. Patients in the external validation cohort who received L2 (n = 163) were treated at three French institutions between January 2010 and April 2016. All statistical tests were two-sided.Results: In the development cohort, 395 patients (85.5%) were eligible for L2, of which 261 (66.1%) were treated. Age, smoking status, liver metastases, performance status, pain, jaundice, ascites, duration of first-line, and type of L2 regimen were identified as independent prognostic factors for OS in L2. The score determined three groups with median OS of 11.3 months (95% confidence interval [CI] = 9.1 to 12.9 months), 3.6 months (95% CI = 2.6 to 4.7 months), and 1.4 months (95% CI = 1.2 to 1.7 months), for low-, intermediate-, and high-risk groups, respectively ( P < .001). By applying the score in the population eligible for L2 but untreated, the chemotherapy benefit was statistically significant across all groups, but with a magnitude of the effect decreased statistically significantly from low- to high-risk groups ( P = .001 for treatment and risk groups interaction term). The ability of the score to discriminate OS was confirmed in the external validation cohort.Conclusions: This prognostic nomogram and score in patients with aPDAC can accurately predict OS before administration of L2 and may help clinicians in their therapeutic decisions. [ABSTRACT FROM AUTHOR]