Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. Methods/Design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 degrees C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival

Sex differences modulating serotonergic polymorphisms implicated in the mechanistic pathways of risk for depression and related disorders:

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137310/1/jnr23877.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137310/2/jnr23877_am.pd

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry. © 2022 The AuthorsImmuno-Génétique, Inflammation, retro-Virus, Environnement : de l'étiopathogénie des troubles psychotiques aux modèles animauxRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

Establishment and relief of CpG-dependent transgene repression during germ line passage and mouse development

Methylation of genomic DNA at CpG sequences has a repressive effect on gene expression in vertebrates. The level of methylation of the genome varies widely during development in mammals. The DNA of early germ cells and blastocysts is largely hypomethylated but that of implantation embryos is hypermethylated. To test whether these variations might affect gene expression, we have studied the pattern of expression of a CpG-rich and of a CpG-poor LacZ transgene driven by a strong promotor of an ubiquitous gene. We find that the changes of the expression of the CpG-rich LacZ gene directly correlate with variations of methylation and that lowering the level of CpG in the reporter gene decreases dramatically its susceptibility to these variations. Therefore, in association with fluctuations in genome methylation a CpG-dependent system of repression must control positively and negatively gene expression during development and gametogenesis. We also find that the repression of the CpG-rich LacZ reporter can be abolished in 2-cell embryo by inhibitors of histone deacetylases suggesting that, at least at this stage, this CpG-dependent repression acts through histone deacetylation. In addition, we show that the β-globin locus control region and other genomic elements completely reverse the repression established at implantation in embryonic cells. The complex patterns of expression of the CpG-rich and poor LacZ reporter genes during gametogenesis and development-including a sex-dependent expression in the zygotic nucleus before the morula stage-are described. The possible implication of the constraints imposed on gene expression by DNA methylation revealed by this study are discussed

Les stratégies d'adaptation des ménages et des entreprises face à la transition énergétique : une comparaison entre les métropoles de Lille et de Lyon

L'objectif du projet TransEnergy financé par l'ANR Villes Durables 2010 était d'apporter des éléments de connaissance sur les stratégies d'adaptation des ménages et des entreprises à la transition énergétique en comparant les choix de localisation des ménages et des entreprises des métropoles de Lille et de Lyon. La recherche, conçue sur une analyse systémique, s'est appuyée sur une analyse des différentes échelles du territoire, des secteurs d'activités industriels et des contraintes des ménages. Elle a été produite grâce à une complémentarité disciplinaire (ont été mobilisées la sociologie, l'anthropologie, l'aménagement et les sciences de l'ingénieur) et des modes d'investigation du réel comprenant l'usage de méthodologies tant quantitatives que qualitatives

Les stratégies d'adaptation des ménages et des entreprises face à la transition énergétique : une comparaison entre les métropoles de Lille et de Lyon

L'objectif du projet TransEnergy financé par l'ANR Villes Durables 2010 était d'apporter des éléments de connaissance sur les stratégies d'adaptation des ménages et des entreprises à la transition énergétique en comparant les choix de localisation des ménages et des entreprises des métropoles de Lille et de Lyon. La recherche, conçue sur une analyse systémique, s'est appuyée sur une analyse des différentes échelles du territoire, des secteurs d'activités industriels et des contraintes des ménages. Elle a été produite grâce à une complémentarité disciplinaire (ont été mobilisées la sociologie, l'anthropologie, l'aménagement et les sciences de l'ingénieur) et des modes d'investigation du réel comprenant l'usage de méthodologies tant quantitatives que qualitatives

Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials.

Item does not contain fulltextDisease-free survival is increasingly being used as the primary endpoint of most trials testing adjuvant treatments in cancer. Other frequently used endpoints include overall survival, recurrence-free survival, and time to recurrence. These endpoints are often defined differently in different trials in the same type of cancer, leading to a lack of comparability among trials. In this Commentary, we used adjuvant studies in colon cancer as a model to address this issue. In a systematic review of the literature, we identified 52 studies of adjuvant treatment in colon cancer published in 1997-2006 that used eight other endpoints in addition to overall survival. Both the definition of these endpoints and the starting point for measuring time to the events that constituted these endpoints varied widely. A panel of experts on clinical research on colorectal cancer then reached consensus on the definition of each endpoint. Disease-free survival--defined as the time from randomization to any event, irrespective of cause--was considered to be the most informative endpoint for assessing the effect of treatment and therefore the most relevant to clinical practice. The proposed guidelines may add to the quality and cross-comparability of future studies of adjuvant treatments for cancer