Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.

BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free and metastatic-free survival with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint disease-free survival (DFS) have been reported for this multicenter, randomized, open-label, phase 3 trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4. Key secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) (RMST difference 5.73 months; 95% CI 0.05-11.41; p=0.048) in the neoadjuvant chemotherapy and the standard of care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard of care group (RMST difference 6.1 months; 95% CI 0.93-11.37; p=0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard of care group (RMST difference 4.37 months; 95% CI 0.35-8.38; p=0.033). The safety profile remained unchanged since the previous analysis. CONCLUSION(S): Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in locally advanced rectal cancer patients and should be considered as a one of the best options of care for these patients.

Physiological variables for the objective detection of nerve block failure in dogs.

OBJECTIVE: To identify physiological variables for objectively detecting nociception indicative of intraoperative peripheral nerve block failure. STUDY DESIGN: A double-blinded randomized clinical study. ANIMALS: A sample of 14 male (40.8 ± 12 kg; mean ± standard deviation) and 16 female (34.3 ± 11.4 kg) client-owned dogs. METHODS: Dogs were randomly assigned to one of three groups for psoas compartment and proximal sciatic nerve blocks (0.2 mL kg-1 per site): guided bupivacaine (GBB), or saline (GSB) block or a blind bupivacaine block (BBB). Guided blocks were performed using an ultrasound-peripheral nerve locator combination. Premedication consisted of medetomidine 0.01 mg kg-1 and morphine 0.3 mg kg-1. General anaesthesia was induced with propofol and maintained with isoflurane in oxygen. Receiver operator characteristic curve analysis was used to compare actual values and change in values of physiological variables between GSB and GBB. The Youden index and associated criterion for each physiological variable were used to determine an objective measure for nociception. Fisher's exact t test, McNemar's test and Cohen's kappa statistical analysis were used to determine association, differences and inter-score reliability between the objective and subjective scoring for BBB. RESULTS: Cardiovascular variables had good discriminating ability to identify a nociceptive response (p < 0.01). The Youden indices for mean (MAP) and diastolic (DAP) arterial pressure were most reliable in detecting nociception. The highest sensitivity was that of ΔMAP (100%) with good agreement between the subjective and objective scores of Δheart rate or systolic arterial pressure (SAP). The use of ΔMAP, ΔSAP, ΔDAP had the best ability in indicating peripheral nerve block failure (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Blood pressure values can detect a response to surgical stimulus in adequately anaesthetized dogs. The use of ΔMAP, ΔSAP or ΔDAP may be considered as objective measures to detect nerve block failure.

SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma.

Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo. We show that EWS/FLI1 promotes SIX1 protein expression, and that the two proteins share genome-wide binding profiles and transcriptional regulatory targets, including many metastasis-associated genes such as integrins, which they co-regulate. We further show that SIX1 downregulation of integrins is critical to its ability to inhibit invasion, a key characteristic of metastatic cells. These data demonstrate an unexpected anti-metastatic function for SIX1, through coordinate gene regulation with the key oncoprotein in ES, EWS/FLI1.

Redistribution of the chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and vascular fibrosis.

Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue-resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and the extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein were upregulated in AdvSca1-SM cells after acute vascular injury, and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-ß1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-ß1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-ß1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data provide insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide antifibrotic clinical benefits.

Crystalline structures of L-cysteine and L-cystine: a combined theoretical and experimental characterization.

It is assumed that genetic diseases affecting the metabolism of cysteine and the kidney function lead to two different kinds of pathologies, namely cystinuria and cystinosis whereby generate L-cystine crystals. Recently, the presence of L-cysteine crystal has been underlined in the case of cystinosis. Interestingly, it can be strikingly seen that cystine ([-S-CH2-CH-(NH2)-COOH]2) consists of two cysteine (C3H7NO2S) molecules connected by a disulfide (S-S) bond. Therefore, the study of cystine and cysteine is important for providing a better understanding of cystinuria and cystinosis. In this paper, we elucidate the discrepancy between L-cystine and L-cysteine by investigating the theoretical and experimental infrared spectra (IR), X-ray diffraction (XRD) as well as Raman spectra aiming to obtain a better characterization of abnormal deposits related to these two genetic pathologies.

SIX1 reprograms myogenic transcription factors to maintain the rhabdomyosarcoma undifferentiated state.

Rhabdomyosarcoma (RMS) is a pediatric muscle sarcoma characterized by expression of the myogenic lineage transcription factors (TFs) MYOD1 and MYOG. Despite high expression of these TFs, RMS cells fail to terminally differentiate, suggesting the presence of factors that alter their functions. Here, we demonstrate that the developmental TF SIX1 is highly expressed in RMS and critical for maintaining a muscle progenitor-like state. SIX1 loss induces differentiation of RMS cells into myotube-like cells and impedes tumor growth in vivo. We show that SIX1 maintains the RMS undifferentiated state by controlling enhancer activity and MYOD1 occupancy at loci more permissive to tumor growth over muscle differentiation. Finally, we demonstrate that a gene signature derived from SIX1 loss correlates with differentiation status and predicts RMS progression in human disease. Our findings demonstrate a master regulatory role of SIX1 in repression of RMS differentiation via genome-wide alterations in MYOD1 and MYOG-mediated transcription.

Adsorption of Toluene and Water over Cationic-Exchanged Y Zeolites: A DFT Exploration.

In this study, density functional theory (DFT) calculations have been performed to investigate the adsorption mechanisms of toluene and water onto various cationic forms of Y zeolite (LiY, NaY, KY, CsY, CuY and AgY). Our computational investigation revealed that toluene is mainly adsorbed via π-interactions on alkalis exchanged Y zeolites, where the adsorbed toluene moiety interacts with a single cation for all cases with the exception of CsY, where two cations can simultaneously contribute to the adsorption of the toluene, hence leading to the highest interaction observed among the series. Furthermore, we find that the interaction energies of toluene increase while moving down in the alkaline series where interaction energies are 87.8, 105.5, 97.8, and 114.4 kJ/mol for LiY, NaY, KY and CsY, respectively. For zeolites based on transition metals (CuY and AgY), our calculations reveal a different adsorption mode where only one cation interacts with toluene through two carbon atoms of the aromatic ring with interaction energies of 147.0 and 131.5 kJ/mol for CuY and AgY, respectively. More importantly, we show that water presents no inhibitory effect on the adsorption of toluene, where interaction energies of this latter were 10 kJ/mol (LiY) to 47 kJ/mol (CsY) higher than those of water. Our results point out that LiY would be less efficient for the toluene/water separation while CuY, AgY and CsY would be the ideal candidates for this application.

Use of blood colour for assessment of arterial oxygen saturation in immobilized impala (Aepyceros melampus).

OBJECTIVE: To determine the relationship between arterial blood colour [as defined by the International Commission on Illumination (CIE) L∗a∗b∗ colour space] and haemoglobin oxygen saturation [functional saturation (SaO2) and fractional saturation (FO2Hb)], and if arterial blood colour can be used to predict arterial haemoglobin oxygen saturation. STUDY DESIGN: Descriptive study as an adjunct to two prospective randomized crossover studies. ANIMALS: A group of 10 wild caught adult female impala (Aepyceros melampus) weighing 34.1 ± 5.2 kg (mean ± standard deviation). METHODS: Impala were immobilized with potent opioids (0.09 mg kg-1 of etorphine or thiafentanil). A total of 163 arterial blood samples were collected anaerobically into heparinized syringes from arterial cannulae and analysed immediately using spectrocolourimetry and co-oximetry. Data were analysed by modelling the relationship between predicted arterial blood colour CIE L∗a∗b∗ components and SaO2 and FO2Hb. The models were then used to predict values for L∗, a∗ and b∗ to produce a colour palette for the range of SaO2 and FO2Hb used. The modified version of the Farnsworth-Munsell hue test was used to assess the subjective ordering of the resulting colour palette by 20 observers. RESULTS: The second-order polynomial (quadratic) model produced the best fit for all three arterial blood colour CIE L∗a∗b∗ components for both SaO2 and FO2Hb. The regression models were used to generate predicted arterial blood colour CIE L∗a∗b∗ components for the midpoint of each decile over a range of SaO2 and FO2Hb percentages (15% to 95%). The resulting colour palettes were correctly ordered by all observers in the SaO2 range of 45-95% saturation. CONCLUSIONS AND CLINICAL RELEVANCE: An association between arterial blood colour (as defined by CIE L∗a∗b∗ components) and SaO2 and FO2Hb exists, and arterial blood colour can be used to give a clinically useful estimate of arterial haemoglobin oxygen saturation in impala.

Cross-Sectional Variations in Structure and Function of Coral Reef Microbiome With Local Anthropogenic Impacts on the Kenyan Coast of the Indian Ocean.

Coral reefs face an increased number of environmental threats from anthropomorphic climate change and pollution from agriculture, industries and sewage. Because environmental changes lead to their compositional and functional shifts, coral reef microbial communities can serve as indicators of ecosystem impacts through development of rapid and inexpensive molecular monitoring tools. Little is known about coral reef microbial communities of the Western Indian Ocean (WIO). We compared taxonomic and functional diversity of microbial communities inhabiting near-coral seawater and sediments from Kenyan reefs exposed to varying impacts of human activities. Over 19,000 species (bacterial, viral and archaeal combined) and 4,500 clusters of orthologous groups of proteins (COGs) were annotated. The coral reefs showed variations in the relative abundances of ecologically significant taxa, especially copiotrophic bacteria and coliphages, corresponding to the magnitude of the neighboring human impacts in the respective sites. Furthermore, the near-coral seawater and sediment metagenomes had an overrepresentation of COGs for functions related to adaptation to diverse environments. Malindi and Mombasa marine parks, the coral reef sites closest to densely populated settlements were significantly enriched with genes for functions suggestive of mitigation of environment perturbations including the capacity to reduce intracellular levels of environmental contaminants and repair of DNA damage. Our study is the first metagenomic assessment of WIO coral reef microbial diversity which provides a much-needed baseline for the region, and points to a potential area for future research toward establishing indicators of environmental perturbations.

The utility of Escherichia coli as a contamination indicator for rural drinking water: Evidence from whole genome sequencing.

Across the water sector, Escherichia coli is the preferred microbial water quality indicator and current guidance upholds that it indicates recent faecal contamination. This has been challenged, however, by research demonstrating growth of E. coli in the environment. In this study, we used whole genome sequencing to investigate the links between E. coli and recent faecal contamination in drinking water. We sequenced 103 E. coli isolates sampled from 9 water supplies in rural Kitui County, Kenya, including points of collection (n = 14) and use (n = 30). Biomarkers for definitive source tracking remain elusive, so we analysed the phylogenetic grouping, multi-locus sequence types (MLSTs), allelic diversity, and virulence and antimicrobial resistance (AMR) genes of the isolates for insight into their likely source. Phylogroup B1, which is generally better adapted to water environments, is dominant in our samples (n = 69) and allelic diversity differences (z = 2.12, p = 0.03) suggest that naturalised populations may be particularly relevant at collection points with lower E. coli concentrations (<50 / 100mL). The strains that are more likely to have originated from human and/or recent faecal contamination (n = 50), were found at poorly protected collection points (4 sites) or at points of use (12 sites). We discuss the difficulty of interpreting health risk from E. coli grab samples, especially at household level, and our findings support the use of E. coli risk categories and encourage monitoring that accounts for sanitary conditions and temporal variability.

A Citrus Based Sensory Functional Food Ingredient Induces Antidepressant-like Effects: Possible Involvement of an Interplay between the Olfactory and the Serotonergic Systems.

In the present study, we examined the neurobehavioral effects of a sensory functional food ingredient mainly based on Citrus sinensis extracts (D11399) using a battery of tests recapitulating various endophenotypes of depression such as anxiety in the open field (OF), the elevated plus-maze (EPM), and the novelty suppressed feeding (NSF), self-care in the splash test (ST), despair in the forced swimming task (FST) but also anhedonia in the sucrose preference test (SPT) in mice. A one-week oral administration of D11399 promoted anxiolytic- and antidepressant-like responses in naïve mice subjected to the NSF and FST. In a marked contrast, the administration of D11399 by oral gavage or the inhibition of olfaction by methimazole prevented such beneficial effects. We further investigated the neurobehavioral properties of a ten-week oral administration of D11399 in the corticosterone (CORT) mouse model of depression. Interestingly, D11399 also elicited anxiolytic- and antidepressant-like effects in various paradigms. To characterize the putative underpinning neurobiological mechanisms in CORT mice, we investigated whether cellular and molecular processes commonly associated with antidepressant responses such as monoaminergic neurotransmission and neuronal maturation in the hippocampus were impacted. Although D11399 did not modify the hippocampal extracellular levels of monoamines (i.e. serotonin and norepinephrine), it reversed the ability of CORT to decrease serotonin neurons firing rate in the dorsal raphe and neuronal maturation in the hippocampus. These findings suggest that the anxiolytic- and antidepressant-like effects of this sensory functional food ingredient are closely related with olfaction and likely a concomitant change in the activity of the central serotonergic system. Further experiments are warranted to precise the neuronal circuits linking sensorial and emotional modalities and identify innovative therapeutic strategies aimed to relieve depressive endophenotypes.

Whole genome sequences of multi-drug resistant Escherichia coli isolated in a Pastoralist Community of Western Uganda: Phylogenomic changes, virulence and resistant genes.

BACKGROUND: The crisis of antimicrobial resistance is already here with us, affecting both humans and animals alike and very soon, small cuts and surgeries will become life threatening. This study aimed at determine the whole genome sequences of multi-drug resistant Escherichia coli isolated in a Pastoralist Community of Western Uganda: phylogenomic changes, virulence and resistant genes. METHODS: This was a laboratory based cross sectional study. Bacterial isolates analyzed in this study were 42 multidrug resistant E. coli isolated from stool samples from both humans (n = 30) and cattle (n = 12) in pastoralist communities collected between January 2018-March 2019. Most of the isolates (41/42) were resistant to three or more antibiotics (multi-drug resistant) and 21/42 isolates were ESBL producers; 13/30 from human and 8/12 from cattle. Whole Genome Sequencing (WGS) was carried out at the facilities of Kenya Medical Research Institute-Wellcome trust, Kilifi, to determine the phylogenomic changes, virulence and resistant genes. RESULTS: At household level, the genomes from both human and animals clustered away from one another except for one instance where two human isolates from the same household clustered together. However, 67% of the E. coli isolated from cattle were closely related to those found in humans. The E. coli isolates were assigned to eight different phylogroups: A, B1, B2, Cladel, D, E, F and G, with a majority being assigned to phylogroup A; while most of the animal isolates were assigned to phylogroup B1. The carriage of multiple AMR genes was higher from the E. coli population from humans than those from cattle. Among these were Beta-lactamase; blaOXA-1: Class D beta-lactamases; blaTEM-1, blaTEM-235: Beta-lactamase; catA1: chloramphenicol acetyl transferase; cmlA1: chloramphenicol efflux transporter; dfrA1, dfrA12, dfrA14, dfrA15, dfrA17, dfrA5, dfrA7, dfrA8: macrolide phosphotransferase; oqxB11: RND efflux pump conferring resistance to fluoroquinolone; qacL, qacEdelta1: quinolone efflux pump; qnrS1: quinolone resistance gene; sul1, sul2, sul3: sulfonamide resistant; tet(A), tet(B): tetracycline efflux pump. A high variation of virulence genes was registered among the E. coli genomes from humans than those of cattle origin. CONCLUSION: From the analysis of the core genome and phenotypic resistance, this study has demonstrated that the E. coli of human origin and those of cattle origin may have a common ancestry. Limited sharing of virulence genes presents a challenge to the notion that AMR in humans is as a result of antibiotic use in the farm and distorts the picture of the directionality of transmission of AMR at a human-animal interface and presents a task of exploring alternative routes of transmission of AMR.

Comparative analysis of the vaginal microbiome of pregnant women with either Trichomonas vaginalis or Chlamydia trachomatis.

BACKGROUND: Although the significance of the human vaginal microbiome for health and disease is increasingly acknowledged, there is paucity of data on the differences in the composition of the vaginal microbiome upon infection with different sexually transmitted pathogens. METHOD: The composition of the vaginal bacterial community of women with Trichomonas vaginalis (TV, N = 18) was compared to that of women with Chlamydia trachomatis (CT, N = 14), and to that of controls (N = 21) (women negative for TV, CT and bacterial vaginosis). The vaginal bacterial composition was determined using high throughput sequencing with the Ion 16S metagenomics kit of the variable regions 2, 4 and 8 of the bacterial 16S ribosomal RNA gene from the vaginal swab DNA extract of the women. QIIME and R package "Phyloseq" were used to assess the α- and ß-diversity and absolute abundance of the 16S rRNA gene per sample in the three groups. Differences in taxa at various levels were determined using the independent T-test. RESULTS: A total of 545 operational taxonomic units (OTUs) were identified in all the three groups of which 488 occurred in all three groups (core OTUs). Bacterial α-diversity, by both Simpson's and Shannon's indices, was significantly higher, (p = 0.056) and (p = 0.001) respectively, among women with either TV or CT than among controls (mean α-diversity TV-infected > CT-infected > Controls). At the genus level, women infected with TV had a significantly (p < 0.01) higher abundance of Parvimonas and Prevotella species compared to both controls and CT-infected women, whereas women infected with CT had a significantly (p < 0.05) higher abundance of Anaerococcus, Collinsella, Corynebacterium and Dialister. CONCLUSION: The vaginal microbiomes of TV and CT-infected women were markedly different from each other and from women without TV and CT. Future studies should determine whether the altered microbiomes are merely markers of disease, or whether they actively contribute to the pathology of the two genital infections.

Infestation mechanisms of two woodborer species in the mangrove Sonneratia alba J. Smith in Kenya and co-occurring endophytic fungi.

Insect damage on trees can severely affect the quality of timber, reduce the fecundity of the host and render it susceptible to fungal infestation and disease. Such pathology weakens or eventually kills the host. Infestation by two insect woodborer species (a moth and a beetle) is causing mortality of Sonneratia alba, a wide-ranging pioneer mangrove species of the Indo-Pacific. Establishing the infestation mechanism of the two insect woodborer species is an initial and essential step towards understanding their ecological role in the mangroves and in determining sustainable management priorities and options. Our main objectives were to investigate the infestation mechanism employed by the two insect woodborers which infest S. alba trees, to establish the occurrence of secondary infestation by endophytic fungi in the infested S. alba branches, and to explore a control management option to the woodborer infestation. We conducted an external inspection of infested branches in two large embayments in Kenya, Gazi Bay and Mida Creek, and by splitting infested branches we determined the respective internal infestation mechanisms. Infested wood samples from Gazi Bay and Mida Creek were incubated at 28±1°C for 3-5 days to establish the presence of fungi. A survey was conducted in both Gazi Bay and Mida Creek to ascertain the presence of ants on S. alba. The infestation characteristics of the two insect woodborer species were different. It took 6-8 months for the beetle to kill a branch of 150 cm-200 cm long. For the moth to kill a branch, it depended upon several factors including the contribution by multiple species, other than the moth infestation alone. A total of 15 endophytic fungal species were identified. Two ant species Oecophylla longipoda and a Pheidole sp. inhabited 62% and 69% respectively of sampled S. alba trees in Gazi Bay whereas only Pheidole sp. inhabited 17% of the sampled S. alba trees in Mida Creek. In summary, we have documented the time it takes each woodborer species to kill a branch, the infestation mechanism of the two insect woodborers, and we hypothesized on the role of two ant species. The presence of several different fungal species was ascertained, and we discussed their possible role in the infested wood. Our results cannot unambiguously associate the woodborers and identified fungi. We recommend further studies to investigate the presence or absence, and if present, the nature of fungi in the gut of the woodborers.

Repeated clinical malaria episodes are associated with modification of the immune system in children.

BACKGROUND: There are over 200 million reported cases of malaria each year, and most children living in endemic areas will experience multiple episodes of clinical disease before puberty. We set out to understand how frequent clinical malaria, which elicits a strong inflammatory response, affects the immune system and whether these modifications are observable in the absence of detectable parasitaemia. METHODS: We used a multi-dimensional approach comprising whole blood transcriptomic, cellular and plasma cytokine analyses on a cohort of children living with endemic malaria, but uninfected at sampling, who had been under active surveillance for malaria for 8 years. Children were categorised into two groups depending on the cumulative number of episodes experienced: high (≥ 8) or low (< 5). RESULTS: We observe that multiple episodes of malaria are associated with modification of the immune system. Children who had experienced a large number of episodes demonstrated upregulation of interferon-inducible genes, a clear increase in circulating levels of the immunoregulatory cytokine IL-10 and enhanced activation of neutrophils, B cells and CD8+ T cells. CONCLUSION: Transcriptomic analysis together with cytokine and immune cell profiling of peripheral blood can robustly detect immune differences between children with different numbers of prior malaria episodes. Multiple episodes of malaria are associated with modification of the immune system in children. Such immune modifications may have implications for the initiation of subsequent immune responses and the induction of vaccine-mediated protection.

Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS).

PURPOSE: The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). PATIENTS AND METHODS: E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. RESULTS: Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37-62%) and 48% (85% CI: 35-60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3-12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9-6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82-2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. CONCLUSION: CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

Prognostic factors in patients treated with second-line chemotherapy for advanced gastric cancer: results from the randomized prospective phase III FFCD-0307 trial.

AIM: The aim of this study was to determine prognostic factors in patients treated with second-line therapy (L2) for locally advanced or metastatic gastric and gastro-esophageal junction (GEJ) adenocarcinoma in a randomized phase III study with predefined L2. METHODS: In the FFCD-0307 study, patients were randomly assigned to receive in L1 either epirubicin, cisplatin, and capecitabine (ECX arm) or fluorouracil, leucovorin, and irinotecan (FOLFIRI arm). L2 treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). Chi square tests were used to compare the characteristics of patients treated in L2 with those of patients who did not receive L2. Prognostic factors in L2 for progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox model. RESULTS: Among 416 patients included, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) patients in the FOLFIRI arm received ECX in L2. Patients treated in L2, compared with those who only received L1 had : a better ECOG score (0-1: 90.4% versus 79.7%; p = 0.0002), more frequent GEJ localization (40.8% versus 27.6%; p = 0.005), and lower platelet count (median: 298000 versus 335000/mm3; p = 0.02). In multivariate analyses, age < 60 years at diagnosis (HR 1.49, 95% CI 1.09-2.03, p = 0.013) and ECOG score 2 before L2 (HR 2.62, 95% CI 1.41-4.84, p = 0.005) were the only significant poor prognostic factors for OS. CONCLUSION: Age ≥ 60 years at diagnosis and ECOG score 0/1 before L2 were the only favorable prognostic factors for OS.

FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases: Results of the FFCD 1102 phase II trial.

AIM OF THE STUDY: The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting. PATIENTS AND METHODS: Chemotherapy-naïve patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0-1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%. RESULTS: Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3-97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3-43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8-12.9) and 33.4 m (95% CI, 22.6-38.2), respectively. CONCLUSION: Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01674309.