Hôpital Européen

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

BACKGROUND: Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. METHODS: We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. RESULTS: The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001). CONCLUSIONS: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).

BACKGROUND: Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease. METHODS: From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. RESULTS: As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. CONCLUSIONS: When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.

BACKGROUND: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma. METHODS: From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. RESULTS: At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo. CONCLUSIONS: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).

Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.

Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626

Ventilator-associated pneumonia (VAP) continues to complicate the course of 8 to 28% of patients receiving mechanical ventilation (MV). In contrast to infections of more frequently involved organs (e.g., urinary tract and skin), for which mortality is low, ranging from 1 to 4%, the mortality rate for VAP ranges from 24 to 50% and can reach 76% in some specific settings or when lung infection is caused by high-risk pathogens. The predominant organisms responsible for infection are Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae, but etiologic agents widely differ according to the population of patients in an intensive care unit, duration of hospital stay, and prior antimicrobial therapy. Because appropriate antimicrobial treatment of patients with VAP significantly improves outcome, more rapid identification of infected patients and accurate selection of antimicrobial agents represent important clinical goals. Our personal bias is that using bronchoscopic techniques to obtain protected brush and bronchoalveolar lavage specimens from the affected area in the lung permits physicians to devise a therapeutic strategy that is superior to one based only on clinical evaluation. When fiberoptic bronchoscopy is not available to physicians treating patients clinically suspected of having VAP, we recommend using either a simplified nonbronchoscopic diagnostic procedure or following a strategy in which decisions regarding antibiotic therapy are based on a clinical score constructed from seven variables. Selection of the initial antimicrobial therapy should be based on predominant flora responsible for VAP at each institution, clinical setting, information provided by direct examination of pulmonary secretions, and intrinsic antibacterial activities of antimicrobial agents and their pharmacokinetic characteristics. Further trials will be needed to clarify the optimal duration of treatment and the circumstances in which monotherapy can be safely used.

: Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

OBJECTIVE: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. CONCLUSIONS: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by a Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential con?ict of interest is reported on the websites of the ESH and the ESC

BACKGROUND: In patients who have chronic heart failure with reduced left ventricular ejection fraction, severe secondary mitral-valve regurgitation is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown. METHODS: or a regurgitant volume of >30 ml per beat), a left ventricular ejection fraction between 15 and 40%, and symptomatic heart failure, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months. RESULTS: At 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the intervention group and 51.3% (78 of 152 patients) in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53). The rate of death from any cause was 24.3% (37 of 152 patients) in the intervention group and 22.4% (34 of 152 patients) in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77). The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the intervention group and 47.4% (72 of 152 patients) in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56). CONCLUSIONS: Among patients with severe secondary mitral regurgitation, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone. (Funded by the French Ministry of Health and Research National Program and Abbott Vascular; MITRA-FR ClinicalTrials.gov number, NCT01920698 .).

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Committee; LVH: left ventricular hypertrophy; LVM: left ventricular mass; PDE-5: phosphodiesterase-5; PPAR-γ: peroxisome proliferators-activated receptor-γ; PWV: pulse wave velocity; SBP: systolic blood pressure; WHO: World Health Organization. Introduction In the 2 years since the publication of the 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) [1], research on hypertension has actively been pursued and the results of new important studies (including several large randomized trials of antihypertensive therapy) have been published. Some of these studies have reinforced the evidence on which the recommendations of the 2007 ESH/ESC guidelines were based. However, other studies have widened the information available in 2007, modifying some of the previous concepts, and suggesting that new evidence-based recommendations could be appropriate. The aim of this document of the ESH is to address a number of studies on hypertension published in the last 2 years in order to assess their contribution to our expanding knowledge of hypertension. Furthermore, some critical appraisal of the current recommendations of the ESH/ESC, as well as of other guidelines, might be a useful step toward the preparation of a third version of the European guidelines in the future. The most important conclusions are summarized in boxes. The points that will be discussed are reported in Box 1.Box. 1Assessment of subclinical organ damage for stratification of total cardiovascular risk The 2007 ESH/ESC guidelines recommend total cardiovascular risk be evaluated in each patient to decide about important aspects of treatment: the blood pressure (BP) threshold at which to commence drug administration, the target BP to be reached by treatment, the use of two-drug combinations as the initial treatment step, and the possible addition to the antihypertensive treatment regimen of lipid-lowering and antiplatelet agents [1]. Among the criteria to assess total cardiovascular risk, the European guidelines consider subclinical organ damage to be a very important component, because asymptomatic alterations of the cardiovascular system and the kidney are crucial intermediate stages in the disease continuum that links risk factors such as hypertension to cardiovascular events and death. On the basis of a number of criteria (prognostic importance, prevalence in the population, availability and cost of the assessment procedures, etc.), the 2007 European guidelines considered detection of organ damage as important for the diagnostic and prognostic evaluation of hypertensive patients. They further subdivided the different types of organ damage into (1) those that can be identified by relatively simple and cheap procedures [electrocardiogram, serum creatinine, estimated glomerular filtration rate (eGFR), and measurement of urinary protein excretion in order to detect microalbuminuria or proteinuria], which were thus regarded as suitable for routine search in the whole hypertensive population, and (2) those that require more complex procedures or instrumentations (echocardiogram, carotid ultrasonography, pulse wave velocity), which were for this reason only recommended for a more in-depth characterization of the hypertensive patient. Since then, other studies have added useful information on the importance of detecting subclinical organ damage in the hypertensive population, strengthening the recommendation to use the most easily available and the least costly procedures in the routine examination of individuals with hypertension. Heart A few recent papers have revived interest in the of the to the risk of cardiovascular In a a new of left ventricular the of left ventricular that is on and has been reported to be to cardiovascular The for and Furthermore, in the the have reported that in hypertensive with left individuals at risk of cardiovascular cardiovascular and for a very recent on the in as with left ventricular and of cardiovascular events hypertension is by risk for each evidence is available on the of as by of interest because of to more and and A has information more and hypertensive with left ventricular left ventricular left ventricular in of the left ventricular and and the risk of as large as that of with left ventricular in on population, the left ventricular and for and only in the risk with has been by other In a on a of hypertensive for with a of and cardiovascular events and with for cardiovascular risk factors Furthermore, a of hypertensive in the that cardiovascular events about more in with a or more with those with a this in the population, with a to in cardiovascular and were for a large number of and BP A in the risk more risk the The of carotid and with cardiovascular discussed in the 2007 guidelines, has been further by which have that carotid cardiovascular events of BP and and this for the at the carotid and for the at the of the carotid that by the at the and by the carotid prognostic in addition to that of prognostic of carotid has been reported in a of of the of cardiovascular which for about years has on the prognostic of arterial In the population, pulse wave with a in the risk of a cardiovascular Furthermore, of for cardiovascular events has been in for years of and wave such as BP and have been as of cardiovascular events in recent studies In in of these studies of and hypertensive only and cardiovascular for cardiovascular risk and carotid However, be that in most available the of BP pressure which the BP be considered in the of hypertensive in of further new the evidence on the prognostic of that available at the of the 2007 guidelines [1]. 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Supplementary data with additional supplementary tables complementing the full text, as well as section 11 on non-thrombotic PE, are available from erj.ersjournals

BACKGROUND: Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. METHODS: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).