The Causes of Kidney Allograft Failure: More Than Alloimmunity. A Viewpoint Article

Kidney allograft failure is a serious condition as it implies the need for re-initiation of dialysis with associated morbidity and mortality, reduced quality of life and higher economic cost. Despite improvements in short-term survival of kidney allografts, this progress was not matched in long-term graft survival. In this viewpoint paper, we summarize the available literature on the causes of kidney allograft failure, both early and late, both nonimmune and allo-immune, to gain better insight in the causes of graft failure. Such insight is necessary to better target therapies or take preventative measures, that improve long-term outcome after kidney transplantation.status: publishe

Hemodynamic monitoring: To calibrate or not to calibrate? Part 2 — Non-calibrated techniques

  There is much evidence that fluid overload leads to adverse outcomes in perioperative and critically ill patients. Cardiac output monitoring can help us guiding initial and ongoing fluid resuscitation and can help us to assess whether a patient will be responsive to fluids when hypotensive. In recent years, many sophisticated devices that measure a variety of hemodynamic parameters have evolved on the market. We wanted to provide an overview of the different techniques available today, including their validation in different patient populations. In this second part of the review, we focus on non-calibrated techniques, both invasive and non-invasive. For each technique a short overview of the working principle, together with the advantages, disadvantages and the available validation literature is listed. Many promising minimal invasive monitoring devices can help us to further optimize our hemodynamic treatment in both the perioperative and critical care setting. However, the validation data are scarce for many of these techniques, especially in complex circumstances with changing hemodynamics (preload, afterload and contractility), as with the use of fluids and vasoactive medication. The measurements made by these devices, therefore, need to be interpreted with caution. Further improvements and more validation data are needed before these techniques can be implemented in common day practice. Moreover, in severely shocked hemodynamic unstable patients, calibrated techniques are to be preferred over those which are uncalibrated. Hence, the new techniques not only need to be accurate, but also need to be precise in order to keep track of changes.    There is much evidence that fluid overload leads to adverse outcomes in perioperative and critically ill patients. Cardiac output monitoring can help us guiding initial and ongoing fluid resuscitation and can help us to assess whether a patient will be responsive to fluids when hypotensive. In recent years, many sophisticated devices that measure a variety of hemodynamic parameters have evolved on the market. We wanted to provide an overview of the different techniques available today, including their validation in different patient populations. In this second part of the review, we focus on non-calibrated techniques, both invasive and non-invasive. For each technique a short overview of the working principle, together with the advantages, disadvantages and the available validation literature is listed. Many promising minimal invasive monitoring devices can help us to further optimize our hemodynamic treatment in both the perioperative and critical care setting. However, the validation data are scarce for many of these techniques, especially in complex circumstances with changing hemodynamics (preload, afterload and contractility), as with the use of fluids and vasoactive medication. The measurements made by these devices, therefore, need to be interpreted with caution. Further improvements and more validation data are needed before these techniques can be implemented in common day practice. Moreover, in severely shocked hemodynamic unstable patients, calibrated techniques are to be preferred over those which are uncalibrated. Hence, the new techniques not only need to be accurate, but also need to be precise in order to keep track of changes.

Hemodynamic monitoring: To calibrate or not to calibrate? Part 1 – Calibrated techniques

  Over recent decades, hemodynamic monitoring has evolved from basic cardiac output monitoring techniques to a broad variety of sophisticated monitoring devices with extra parameters. In order to reduce morbidity and mortality and optimize therapeutic strategies, different monitoring techniques can be used to guide fluid resuscitation and other medical management. Generally, they can be divided in calibrated and non-calibrated techniques. In the first part of this review, the available calibrated techniques, ranging from invasive to non-invasive, will be discussed. We performed a review of the literature in order to give an overview of the current hemodynamic monitoring devices. For each monitoring system, a short overview of the physical principles, the advantages and disadvantages and the available literature with regard to validation is given. Currently, many promising hemodynamic monitoring devices are readily available in order to optimize therapeutic management in both perioperative and ICU settings. Although several of these calibrated techniques have been validated in the literature, not all techniques have been shown to reduce morbidity and mortality. Many new techniques, especially some non-calibrated devices, lack good validation data in different clinical settings (sepsis, trauma, burns, etc.). The cardiac output values obtained with these techniques need therefore to be interpreted with caution as will be discussed in the second part of this concise review. Transthoracic echocardiography forms a good initial choice to assess hemodynamics in critically ill patients after initial stabilisation. However in complex situations or in patients not responding to fluid resuscitation alone, advanced hemodynamic monitoring is recommended with the use of calibrated techniques like transpulmonary thermodilution. Calibrated techniques are preferred in patients with severe shock and changing conditions of preload, afterload and contractility. The use of the pulmonary artery catheter should be reserved for patients with right ventricular failure in order to assess the effect of medical treatment.  Over recent decades, hemodynamic monitoring has evolved from basic cardiac output monitoring techniques to abroad variety of sophisticated monitoring devices with extra parameters. In order to reduce morbidity and mortalityand optimize therapeutic strategies, different monitoring techniques can be used to guide fluid resuscitation andother medical management. Generally, they can be divided in calibrated and non-calibrated techniques. In the firstpart of this review, the available calibrated techniques, ranging from invasive to non-invasive, will be discussed. Weperformed a review of the literature in order to give an overview of the current hemodynamic monitoring devices.For each monitoring system, a short overview of the physical principles, the advantages and disadvantages and theavailable literature with regard to validation is given. Currently, many promising hemodynamic monitoring devicesare readily available in order to optimize therapeutic management in both perioperative and ICU settings. Althoughseveral of these calibrated techniques have been validated in the literature, not all techniques have been shown toreduce morbidity and mortality. Many new techniques, especially some non-calibrated devices, lack good validationdata in different clinical settings (sepsis, trauma, burns, etc.). The cardiac output values obtained with these techniquesneed therefore to be interpreted with caution as will be discussed in the second part of this concise review.Transthoracic echocardiography forms a good initial choice to assess hemodynamics in critically ill patients afterinitial stabilisation. However in complex situations or in patients not responding to fluid resuscitation alone, advancedhemodynamic monitoring is recommended with the use of calibrated techniques like transpulmonary thermodilution.Calibrated techniques are preferred in patients with severe shock and changing conditions of preload, afterload andcontractility. The use of the pulmonary artery catheter should be reserved for patients with right ventricular failurein order to assess the effect of medical treatment

L'Écho : grand quotidien d'information du Centre Ouest

30 décembre 19351935/12/30 (A64).Appartient à l’ensemble documentaire : PoitouCh

Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response

Introduction: In triple negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. In the current study we deep sequenced DNA of tumors prior to chemotherapy to search for predictors of response or resistance. Methods: Next generation sequencing (NGS) was performed for 1,977 genes involved in tumorigenesis. DNA from 56 pre-treatment TNBC-biopsies was sequenced, as well as matched normal DNA. Following their tumor biopsy, patients started neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. We studied associations between genetic alterations and three clinical variables: chemotherapy response, relapse-free survival and BRCA proficiency. Results: The mutations observed were diverse and few recurrent mutations were detected. Most mutations were in TP53, TTN, and PIK3CA (55 %, 14 %, and 9 %, respectively). The mutation rates were similar between responders and non-responders (average mutation rate 9 vs 8 mutations). No recurrent mutations were associated with chemotherapy response or relapse. Interestingly, PIK3CA mutations were exclusively observed in patients proficient for BRCA1. Samples with a relapse had a higher copy number alteration rate, and amplifications of TTK and TP53BP2 were associated with a poor chemotherapy response. Conclusions: In this homogenous cohort of TNBCs few recurrent mutations were found. However, PIK3CA mutations were associated with BRCA proficiency, which can have clinical consequences in the near future

La Croix du Nord : supplément régional à la Croix de Paris ["puis" grand journal quotidien du Nord de la France]

10 septembre 19111911/09/10 (A22,N7617).Appartient à l’ensemble documentaire : NordPdeC

Additional file 4: Table S3. of Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response

List of all mutations. This file shows all mutations passing thresholds as explained in “Methods”. The column “confirmed” shows mutations that have been confirmed by either Sanger Sequencing or deep whole exome sequencing in another research project (unpublished data). The column “included in analysis” shows the mutations that passed our threshold for putative driver mutations, based on effect, SIFT, polyphen scores and COSMIC (see “Methods”). The column “dubious” shows the mutations that might be dubious based on gene length, expression or replication time [20]. (XLSX 64 kb

Additional file 9: Figure S3. of Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response

Validation of TTK, TP53BP2 and genome-wide copy number profiles with Nimblegen 135 K aCGH arrays. aCGH and exome data, for the samples for which aCGH data were available (three cases for TTK, five cases for TP53BP2). Arrow indicates respectively the TTK and TP53BP2 locus. From page 3 on we show all 14 samples for which we have both exome and aCGH data, irrespective of TTK and TP53BP2 status. In these rainbow plots, the samples containing a TTK or TP53BP2 gain are indicated with an arrow at the respective genomic location. (PDF 1639 kb

Additional file 2: Table S1. of Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response

1977 Cancer Gene Panel. This file lists all 1,977 genes in the Cancer Gene Panel, used in this study. (XLS 111 kb

EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature (BRCA1-like) and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors. Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. Weclassified 370 tumors by copy-number profiles as BRCA1-like or non-BRCA1-like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinumbased chemotherapy compared with standard anthracyclinebased chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a Brca1-deficient mouse model. Results: The highest EZH2 expression was found in BRCA1associated tumors harboring a BRCA1 mutation, BRCA1-promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1-like and non-BRCA1-like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1-deficient mice in comparison with single agents. Conclusions: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo