University Hospital of Heraklion

BACKGROUND: Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established. METHODS: We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction. RESULTS: CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor. CONCLUSIONS: The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours. Genome-wide association studies for breast cancer have identified common genetic variation that influences susceptibility to this disease, but much of the genetic risk remains unexplained. Doug Easton and colleagues report a genome-wide association study for breast cancer in more than 122,000 cases and 105,000 controls. The authors genotyped a subset of these cases using OncoArray, a new, custom genome-wide single-nucleotide polymorphism (SNP) array for cancer genomics. Overall, they identify 65 loci newly associated with breast cancer susceptibility, and estimate that, together with 107 previously identified breast cancer susceptibility loci, these explain about 18 per cent of the familial relative risk of breast cancer. Polygenic risk scores may be used in risk prediction models and may improve early detection and targeted prevention of the disease. Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10−8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

BACKGROUND: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS: We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS: Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS: Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

The technical part of these Guidelines and Recommendations, produced under the auspices of EFSUMB, provides an introduction to the physical principles and technology on which all forms of current commercially available ultrasound elastography are based. A difference in shear modulus is the common underlying physical mechanism that provides tissue contrast in all elastograms. The relationship between the alternative technologies is considered in terms of the method used to take advantage of this. The practical advantages and disadvantages associated with each of the techniques are described, and guidance is provided on optimisation of scanning technique, image display, image interpretation and some of the known image artefacts.

BACKGROUND: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

The clinical part of these Guidelines and Recommendations produced under the auspices of the European Federation of Societies for Ultrasound in Medicine and Biology EFSUMB assesses the clinically used applications of all forms of elastography, stressing the evidence from meta-analyses and giving practical advice for their uses and interpretation. Diffuse liver disease forms the largest section, reflecting the wide experience with transient and shear wave elastography . Then follow the breast, thyroid, gastro-intestinal tract, endoscopic elastography, the prostate and the musculo-skeletal system using strain and shear wave elastography as appropriate. The document is intended to form a reference and to guide clinical users in a practical way.

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed including the assessment of the risk/benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and  2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified …

This is the first European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses extra-intestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. It has been drafted by 21 ECCO members from 13 European countries. Although this is the first ECCO consensus guideline that primarily addresses EIMs, it is partly derived from, updates, and replaces previous ECCO consensus advice on EIMs, contained within the consensus guidelines for Crohn’s disease 1 [CD] and ulcerative colitis 2 [UC]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu ]. Briefly, topics were selected by the ECCO guidelines committee [GuiCom]. ECCO members were selected to form working groups. Provisional ECCO Statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-based Medicine [www.cebm.net]. The ECCO Statements were finalised by the authors at a meeting in Vienna in October 2014 and represent consensus with agreement of at least 80% of participants. Complete consensus [100% agreement] was reached for most statements. The supporting text was then finalised under the direction of each working group leader [VA, SV, FC, MH] before being integrated by the two consensus leaders [MH, FC]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. Up to 50% of patients with inflammatory bowel disease [IBD] experience at least one extra-intestinal manifestation [EIM], which can present before IBD is diagnosed. 34,5,6 EIMs adversely impact upon patients’ quality of life and some, such as primary sclerosing cholangitis [PSC] or venous thromboembolism [VTE], can be life-threatening. The probability of developing EIMs increases with disease duration and in patients who already have one EIM. 7 EIMs are more common in CD than UC, 7,8 particularly in patients with colonic CD; some EIMs, such as iritis/uveitis, are more common in women whereas PSC and ankylosing spondylitis are more common in males. 3 Most EIMs run in parallel with intestinal disease activity, 4 with the exception of ankylosing spondylitis and uveitis and with uncertainty regarding PSC and pyoderma gangrenosum [PG]. 9 The management of complex EIMs should be discussed in a multidisciplinary team meeting. Both peripheral and axial arthropathies occur in UC and CD, and belong to the spondyloarthritis [SpA] group of conditions (evidence level 2 [EL2]). They should be distinguished from arthralgia, which is more common. The prevalence of axial disease is equal between sexes and forms of IBD, but peripheral arthropathies are more common in CD [particularly affecting the colon] and in females [EL3] Diagnosis of axial SpA is based on the clinical feature of inflammatory low back pain associated with magnetic resonance imaging [MRI ]or radiographic features of sacroiliitis [EL 2]. Human leukocyte antigen B27 [HLA-B27] is associated with axial arthritis, but it has a lower prevalence than in idiopathic ankylosing spondylitis, making it unreliable as a diagnostic test in IBD [EL2] Radiological evidence of sacroiliitis occurs in 20–50% of patients with UC and CD, but progressive ankylosing spondylitis occurs in only 1–10% of patients [EL2]. MRI may identify early sacroiliitis in symptomatic patients with normal plain radiology [non-radiographic SpA] [EL2] Arthropathies associated with IBD belong to the SpA group of conditions. According to the Assessment in Spondyloarthritis International Society [ASAS] classification of 2009, 10 SpA are divided into axial and peripheral SpA, depending on the predominant symptoms. Diagnosis of axial SpA is based on magnetic resonance imaging [MRI] or radiographic features of sacroiliitis associated with clinical features of inflammatory low back pain. Radiological evidence of sacroiliitis is common in both UC and CD, occurring in 20–50 % of patients, 11,12,13 but progressive AS with syndesmophytes occurs in only 1–10 % of patients. 14,15,16 Early assessment using T1-weighted spin-echo [TISE], short tau inversion recovery [STIR], and fat-saturated T2-weighted sequences, are recommended for patients aged less than 40 years with inflammatory back pain lasting more than 3 months, to identify non-radiographic sacroiliitis. 17,18 Human leukocyte antigen [HLA]-B27 is found in 25–75% of patients with IBD and AS 11,19,20,21 but only in 7–15% of patients with isolated sacroiliitis. HLA-B27 positive IBD patients seem to be at risk for the development of AS 21 but, due to a lower prevalence than in idiopathic AS, it is unreliable as a diagnostic test in IBD. 22,23 Diagnosis of peripheral arthropathy and/or enthesitis associated with IBD is based on signs of inflammation and exclusion of other specific forms of arthritis [EL3]. Type I is an acute pauciarticular arthritis, affecting large joints, and is usually associated with active IBD. Type II is polyarticular, affecting a larger number of peripheral joints, and is independent of IBD activity [EL4] The peripheral arthritis of IBD is an inflammatory arthropathy but, unlike psoriatic arthritis and other inflammatory arthropathies, it is generally non-erosive. The ASAS guidelines for peripheral SpA included only six patients with IBD, 24 so the clinical classification of IBD-related peripheral arthropathies is usually based on a larger study of IBD patients. 25 On the basis of articular and two have been Type 1 is as pain with evidence of or affecting than joints, the large of the lower The are usually acute and than 10 and usually with IBD Type 2 more than joints, has a and the for or independent of IBD Diagnosis is on clinical based on features of inflammation and exclusion of other specific forms of in to arthritis, and peripheral arthritis has to be from may to and and have been less in IBD. inflammation at the of a to the to and and or is of SpA, with a prevalence of in IBD. arthritis in IBD is usually and and more common in CD, particularly in with colonic may that of bowel it usually with or the of IBD. prevalence in IBD from to in UC and in the of peripheral arthritis is only and in a of patients. The of axial is less and is to the of AS, and the of IBD. AS is a progressive with and affecting patients’ quality of It is to identify early axial SpA, to the to radiographic axial SpA that occurs in % by 2 years in with an or with active inflammation on The of IBD in the of SpA is by the that sacroiliitis and spondylitis occur in to of patients with IBD, whereas to of patients with AS or SpA have evidence of only The of HLA-B27 with AS is in IBD, but to a than in idiopathic AS This may to the between the of AS and IBD. and have more than for IBD in an and in IBD and of for AS were by IBD with a that and to the to the and and to a common the complex with axial SpA should be with and are [EL but with is recommended [EL2]. [EL2] and [EL2] are of early is the for or to [EL2] of inflammation is to peripheral arthritis or symptomatic are [EL but should be as as arthritis, [EL2] and [EL4] may have a is and in [EL2] for the of IBD-related arthropathy are based on in SpA, in IBD have been only or are with axial SpA should be with of the disease the of and in axial but with is in IBD. Although the risk for a larger study CD patients and UC patients that with low of was of was associated with disease activity with Crohn’s but this was by a in disease The of such as and may be with a lower risk of disease than and in are of is the in patients or to on the of on radiographic are less may of early axial SpA, of large are of inflammation is to peripheral is for the of and for symptomatic Although and are or only in ankylosing spondylitis, a 2014 of in patients with peripheral and recommended the for patients with short disease duration and a in that was to study the that be an in SpA patients with peripheral are with seem to can be in has been to be in 35 in patients with disease on quality of pain is common in IBD and may be associated with the of or the of associated with is associated with and usually the first 3 of to is usually Diagnosis of in is from a on radiographic is a risk for and patients who should [EL2] and are common in and patients with IBD disease or low activity, and The of in is based on assessment of by is as a at least lower than the for the between and risk is and to the has been should be as for and the for in the of risk low previous IBD is to and so can be to and peripheral and are and recommended as for IBD patients from for the and are based on risk such as 3 months, of and have been recommended in in the of risk the the for with patients at risk for of the and peripheral should the risk increases for each in the have been in patients with both and normal the that is the risk for in patients with IBD. between and risk The of is a previous by of the is in the of patients with IBD, who are patients aged between and 40 of patients have with a and has been in of IBD patients. of IBD patients can 3 years in a have in with have that in are similar in IBD to in the The of each risk to be has been of the of can be a of IBD. is common in IBD patients, and so may to risk of IBD. study a for in IBD women in a lower risk of CD and UC than in are with previous a in disease to a of and [EL2] are in should and for for the duration of is a for and are recommended the is less than patients, a of should for more [EL4] of disease activity is particularly in the in women or with previous of and other can [EL2] should be in patients with low and/or risk such as which risk in the of a of may be in who has been in IBD in aged to to and/or should be or and and from and/or should be should be in the recommended this usually at a of or should be only is with and increases in patients with IBD. large study in CD that of disease activity and of and were associated with a in of 4 The of and in has been in patients with IBD, in or is common in patients with IBD and should be as should and for that are for the of low in IBD and the risk of but and can be recommended for in IBD patients. to the of a for with is in women or of the is a and should be in patients with or patients, a before be are and have using or as are associated with only increases in and in is evidence that or other peripheral The evidence for and of in patients is patients with active disease should be according to guidelines with to and inflammatory activity, in to or should be in patients with IBD before can be an risk for patients with with more should be to a to an This should be from uveitis and based upon the of and this is or in patients with manifestations and patients should be by an with in inflammatory disease uveitis and are the most common manifestations of IBD. manifestations in IBD can be to and/or of the intestinal disease The classification of uveitis has been in the of guidelines 1 ]. of The most manifestations are or and or uveitis are more to be are occurring in less than but may to of uveitis a of 13 a of features from to to disease activity in the bowel and other extra-intestinal uveitis can be independent of bowel and other EIMs and may the of bowel symptoms. of with to and may be with and and and may as to which is is less common but has more to CD, uveitis is in and acute uveitis with may of a of the features of and The of to of should to an with in the management of and the of and the and the between and pain associated with of the and to be from to or other should for using a to for the of inflammatory and/or both the guidelines and of the International are in disease assessment may be in and of the of manifestations from of IBD in some this to of is to be to of patients in are study of only that patients with IBD are more to of with and and inflammatory disease as EIMs of IBD represent associated with and of both and into the or this may be associated with with and supporting in uveitis with and on I and are by may or or can be for symptomatic for or uveitis should be by an and or and [EL4] a is the of most is may be with following management of the bowel and to the of and uveitis should be with and uveitis and other the level of evidence with the evidence for of being in patients with uveitis but IBD. of and or have been from 3 or 4 the of and in uveitis and but is based upon evidence from the of only a IBD. and have each been to be in CD and or It is associated with disease and has a CD of and associated with UC, have been has been described in with IBD, particularly in patients with UC, and may be due to by T2-weighted is a disease that in and that to It can be associated with IBD. Diagnosis of is on clinical a be [EL3]. is usually based on that of the IBD. are in and forms can be with or [EL4] is and by or of in It the of the particularly the and usually occurs at of IBD in with and The CD, which may at as or or with present can the or 9 clinical can be and is usually the a The prevalence of in IBD from to in CD than UC and more common IBD patients. The of is that it be a the can be in of patients. is associated with IBD but with it is to disease activity, is based on that of the IBD. may be in or are with or may be gangrenosum can occur on the the but the are the and to 9 the form of or or but of the to the development of that that is on has is by the of a that a with with a between and in It can and is usually based on the of the following exclusion of other or venous is a of it can be in a of some a from the of the can in are but can be to other of UC patients a than that in The is but has been to and are by regarding the between and IBD activity, as it may parallel IBD activity or run an independent has a to following in more than of in the as the gangrenosum can be with or or or [EL4] The should be as it can be a is evidence that the of for between IBD and patients. is the of the most were and were with and or for the management of in patients with was first in The study on the of with was a of patients, patients with IBD. or was at 2 primary more patients in the group with in both were patients with the at The was with short duration of less than a of IBD patients with with to has the of should be a to be have the of in the of patients with of the to of the The of or is an but the advice of a should be should be in with a is of the group of acute that but can be distinguished by and It is by inflammatory or usually affecting the or can be It can be by It has only been as an IBD It is more common in women and in patients with colonic or other The is associated with active or prevalence are The have been such as a or an with are and have been to be should be in or and may such as and inflammation 2 ]. have the development of psoriatic and in patients with CD and UC an which seem to to the of the or the duration of and were the most of have been and have been are in of patients with clinical risk and of disease in patients with IBD that with psoriatic and by of patients psoriatic and of whereas and were were associated with IBD activity, but were more females and with of or were associated with for and 1 and has been can inflammation of the which is a and is usually upon to a is Most are with and can usually be [EL3] should be with the advice of a with and or in or in 50% of patients. with psoriatic that with and who a has been to be in the of the of have of to with The is derived from the and the is based on Up to of patients with IBD have and disease independent of IBD should be PSC is the most common disease specific to IBD, and may to of patients in some have been in IBD patients with normal of European of patients with PSC have IBD. According to and IBD in PSC is as UC and less as of sclerosing cholangitis such as or conditions have to be sclerosing cholangitis has similar and/or but usually in the of IBD. of PSC and pain. are and may be by of IBD. patients with IBD, a clinical for PSC is as this disease patients with in of sclerosing cholangitis have been a of PSC can be magnetic resonance Although common at some it has been that is of to a of PSC the of is and clinical of PSC is The ECCO consensus group that should be to is and/or is patients with should be as is recommended for an or independent of of sclerosing cholangitis should be PSC is normal in a with IBD and a should be to PSC [EL2] of patients, is normal with This group is as a disease which is associated with a of PSC are and may be a is only in patients and features of or PSC is is recommended in PSC patients with features of of and/or an should of sclerosing cholangitis [EL4] should the of PSC in an IBD are normal in of PSC patients. are usually is in of PSC patients and should the of which is found in to of PSC patients. features of are should be but have a low are in of PSC but are found in and IBD patients sclerosing cholangitis be is of sclerosing cholangitis is according to the other and to and is as sclerosing cholangitis in of to may be in PSC patients the for sclerosing patients may a more disease but specific management are The of PSC in an IBD It is to that from is lower than that of The of clinical the risk for at the level is and is a for in and in of PSC and PSC may be associated with such as 1 and PSC to and development in the and affecting and large inflammation the in and with an risk of with IBD have a of with IBD patients PSC or normal patients with PSC and IBD, present with is in in and features that PSC is associated with UC, IBD has specific disease is or the as inflammation This is by the of This be by It that IBD has a that may PSC has a Early that PSC is associated with as in other have The first study in and has been to IBD in to which is in and are in a in and The study was in the authors PSC of European using the and the the number of PSC risk to of a with PSC than with IBD, the of disease in PSC that are from of IBD. has been to to or in PSC or PSC Although should be and/or should be in patients with features of [EL3] the evidence for in PSC is in based on is to clinical has been by most an study to most be should be in patients with and such as or have been is an for and are under PSC patients with clinical or of or an is recommended to that may be to or and for [EL2]. is recommended The and early of such as and are to the management of patients with assessment for the of is are the and imaging may between and in should be in patients with as this may the risk of and particularly in patients in is most is a for in selected of that and PSC patients with disease or with of should be for may be in selected patients with on is the only that can are with to PSC patients with disease should be for according to with and selected with cholangitis can be for The and in PSC patients is due to the disease and the risk of PSC patients with to from this has been is a for that can the diagnostic of in in PSC patients with IBD is recommended 1 to 2 years of PSC with is the recommended strategy [EL2]. PSC patients evidence of IBD, is recommended years PSC is associated with a risk of and in patients with associated IBD, both before and may IBD and PSC have been diagnosed. with is recommended at and 1 to 2 years This should be is to in to is recommended imaging should be is for and in an of antigen and has been but are associated with a risk to of in PSC patients. On this to has been recommended or but from patients with IBD can and and [EL The prevalence of disease between to in ulcerative colitis and to in Crohn’s disease prevalence are of the and that colitis and or IBD patients, so of may be is and usually with but has been are in of IBD patients on risk for disease and the risk of of of is may occur in patients with and can be using and It has been in of patients with The of and to Most occur within the first of The may be and usually with and/or that to normal of the Up to of patients who have may to the and should be in the of an and a and by and that of and disease have been is a of IBD. It is more in the to thromboembolism or IBD are for both conditions and are with in with guidelines is is a of IBD, with a of in CD and in UC patients. active inflammation of the bowel may in in and is specific other than of the active IBD, a of on has been in IBD may be an CD, an associated inflammatory disease such as primary or are in IBD patients. an with inflammation has been of or to is usually associated with and and CD [EL3]. of have been due to is in IBD patients. and are more [EL3] The for acute is 4 in CD and in The clinical and of acute in IBD are similar to the Diagnosis is based on the of at least two of level the of and are to in IBD, as pain due to can be to from that by active IBD. an is found in of IBD patients. forms of acute The first is to and idiopathic and associated with The is due to the management of IBD or due to associated which to CD; and or The most common by of and has been described in IBD. or is It occurs in of IBD patients. is evidence that can disease which occurs within the first 3 to 4 of and has a The risk to be in who the are more to The risk of is evidence for a are an both within the and IBD The risk of is in CD but in of in IBD is in with in IBD is by the of a in most of The prevalence of such as or or been found to be and in patients with CD and UC, using and to of patients with PSC have the are found in of CD and of UC patients. are with is associated with IBD [EL and to be manifestations may be more common in IBD patients than in the [EL to be venous and The may and is a [EL and IBD patients with peripheral from a with of and pain. was more common in with and and and were present in IBD patients. was to disease activity in only of patients. was associated with in the other of and affecting the with due to affecting the and have been the IBD patients have been described with and of an by and on have been in CD patients who and have been as as acute have been described that are independent of disease activity and may the of IBD. venous should be in patients with a a of IBD, with or or IBD-related peripheral can be risk have been such as and and and and to but 3 should to and MRI are manifestations due to IBD are and a should first be the progressive peripheral for the prevalence of manifestations in IBD, from to but is by and study using the an for developing or of for CD and for UC, with a prevalence of a of study more than IBD an for or diagnostic for an risk of in with UC that may have represented a of IBD patients, between and at the the of peripheral as 10 and and years of IBD, that is in IBD. are to the of peripheral have been described with and and and of manifestations thromboembolism and to and peripheral is usually to IBD activity, of the bowel activity the are to and have been in may be have been is a to the of which have been associated with with a or as by the the are by the most manifestation in IBD patients. of is in 3 The of and are in IBD [EL particularly in women [EL inflammation to [EL has been to be in IBD [EL of and in a risk of thromboembolism in particularly and The risk of disease in IBD was by both and whereas the risk of and of were each by one were between CD and The by only two of patients, IBD patients, and one large of that may be to the IBD patients. primarily for the risk of and disease was a risk of in IBD patients years was in one only two This in patients to with a risk of to be risk of peripheral based on from two one large study and The of peripheral disease is low in IBD, affecting only of patients. have an in IBD, in to This is due to in the of and low prevalence in IBD The of risk or the risk in IBD patients a low This the risk in IBD patients who have inflammation to an between IBD activity and and was in a the risk of and was similar to the in patients with the risk was

Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.

This report summarizes current physiological and technical knowledge on esophageal pressure (Pes) measurements in patients receiving mechanical ventilation. The respiratory changes in Pes are representative of changes in pleural pressure. The difference between airway pressure (Paw) and Pes is a valid estimate of transpulmonary pressure. Pes helps determine what fraction of Paw is applied to overcome lung and chest wall elastance. Pes is usually measured via a catheter with an air-filled thin-walled latex balloon inserted nasally or orally. To validate Pes measurement, a dynamic occlusion test measures the ratio of change in Pes to change in Paw during inspiratory efforts against a closed airway. A ratio close to unity indicates that the system provides a valid measurement. Provided transpulmonary pressure is the lung-distending pressure, and that chest wall elastance may vary among individuals, a physiologically based ventilator strategy should take the transpulmonary pressure into account. For monitoring purposes, clinicians rely mostly on Paw and flow waveforms. However, these measurements may mask profound patient-ventilator asynchrony and do not allow respiratory muscle effort assessment. Pes also permits the measurement of transmural vascular pressures during both passive and active breathing. Pes measurements have enhanced our understanding of the pathophysiology of acute lung injury, patient-ventilator interaction, and weaning failure. The use of Pes for positive end-expiratory pressure titration may help improve oxygenation and compliance. Pes measurements make it feasible to individualize the level of muscle effort during mechanical ventilation and weaning. The time is now right to apply the knowledge obtained with Pes to improve the management of critically ill and ventilator-dependent patients.

The current article is an integrative and analytical literature review on the concept and meaning of empathy in health and social care professionals. Empathy, i.e., the ability to understand the personal experience of the patient without bonding with them, constitutes an important communication skill for a health professional, one that includes three dimensions: the emotional, cognitive, and behavioral. It has been proven that health professionals with high levels of empathy operate more efficiently as to the fulfillment of their role in eliciting therapeutic change. The empathetic professional comprehends the needs of the health care users, as the latter feel safe to express the thoughts and problems that concern them. Although the importance of empathy is undeniable, a significantly high percentage of health professionals seem to find it difficult to adopt a model of empathetic communication in their everyday practice. Some of the factors that negatively influence the development of empathy are the high number of patients that professionals have to manage, the lack of adequate time, the focus on therapy within the existing academic culture, but also the lack of education in empathy. Developing empathetic skills should not only be the underlying objective in the teaching process of health and social care undergraduate students, but also the subject of the lifelong and continuous education of professionals.

INTRODUCTION: Central venous cannulation is crucial in the management of the critical care patient. This study was designed to evaluate whether real-time ultrasound-guided cannulation of the internal jugular vein is superior to the standard landmark method. METHODS: In this randomised study, 450 critical care patients who underwent real-time ultrasound-guided cannulation of the internal jugular vein were prospectively compared with 450 critical care patients in whom the landmark technique was used. Randomisation was performed by means of a computer-generated random-numbers table, and patients were stratified with regard to age, gender, and body mass index. RESULTS: There were no significant differences in gender, age, body mass index, or side of cannulation (left or right) or in the presence of risk factors for difficult venous cannulation such as prior catheterisation, limited sites for access attempts, previous difficulties during catheterisation, previous mechanical complication, known vascular abnormality, untreated coagulopathy, skeletal deformity, and cannulation during cardiac arrest between the two groups of patients. Furthermore, the physicians who performed the procedures had comparable experience in the placement of central venous catheters (p = non-significant). Cannulation of the internal jugular vein was achieved in all patients by using ultrasound and in 425 of the patients (94.4%) by using the landmark technique (p < 0.001). Average access time (skin to vein) and number of attempts were significantly reduced in the ultrasound group of patients compared with the landmark group (p < 0.001). In the landmark group, puncture of the carotid artery occurred in 10.6% of patients, haematoma in 8.4%, haemothorax in 1.7%, pneumothorax in 2.4%, and central venous catheter-associated blood stream infection in 16%, which were all significantly increased compared with the ultrasound group (p < 0.001). CONCLUSION: The present data suggest that ultrasound-guided catheterisation of the internal jugular vein in critical care patients is superior to the landmark technique and therefore should be the method of choice in these patients.

BACKGROUND: Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES: The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS: Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS: A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS: FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Anaemia is the most common systemic complication and extraintestinal manifestation of inflammatory bowel disease [IBD].1–3 In the majority of cases, IBD-associated anaemia is a unique example of the combination of chronic iron deficiency and anaemia of chronic disease [ACD].4,5 Other more rare causes of anaemia in IBD include vitamin B12 and folate deficiency, toxic effects of medications, and others. The impact of anaemia on the quality of life of IBD patients is substantial. It affects various aspects of quality of life such as physical, emotional, and cognitive functions, the ability to work, hospitalization, and healthcare costs.6 Anaemia in IBD is not just a laboratory marker; it is a complication of IBD that needs appropriate diagnostic and therapeutic approaches.3 Despite the broad use of anti-inflammatory therapy, anaemia may recur fast after successful therapy. As anaemia is a serious medical condition that may become life threatening [if blood transfusions are not available or compatible], preventive measures should be considered. Prevention of anaemia and maintenance of iron and vitamin stores are therefore warranted. The goal of this consensus initiated by the European Crohn’s and Colitis Organisation [ECCO] was to establish European consensus guidelines for the diagnosis, treatment and prevention of iron deficiency and iron deficiency anaemia [IDA], but also for non-iron deficiency anaemia and associated conditions. The consensus is based in parts on a previous evidence-based consensus publication on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases.7 The strategy to reach the consensus involved several steps and follows the standard operating procedures for consensus guidelines of ECCO. An open call for chairs and participants for this consensus was made [see acknowledgements and www.ecco-ibd]. Participants were selected by the Guidelines Committee of ECCO [GuiCom] on the basis of their publication record and a personal statement. Four working groups [WGs] were formed: WG 1 on Diagnosis of anaemia, WG 2 on Treatment of iron deficiency anaemia, WG 3 on Prevention of iron deficiency anaemia, and WG 4 on Management of non-iron deficiency anaemia. Participants were asked to answer relevant questions on current practise and areas of controversy related to the diagnosis and management of anaemia in IBD based on their experience as well as evidence from the literature [Delphi procedure].8 In parallel, the WG members performed a systematic literature search of their topic with the appropriate key words using Medline/PubMed/ISI/Scopus and the Cochrane database, as well as their own files. The evidence level [EL] was graded according to the Oxford Centre for Evidence-Based Medicine.9 Provisional guideline statements [with supporting text] were then written by the WG chairs, based upon answers to the questionnaire, and were circulated among the WG members, prompting discussions and exchange of literature evidence. The proposed statements and the supporting text were submitted to an online platform for online discussion and two online voting procedures, among all consensus participants for the first voting procedure and also for all national representatives of ECCO for the second voting procedure. The WGs finally met in Frankfurt on June 28, 2013 for a face-to-face discussion and to vote and consent on the statements. Technically this was done by projecting the statements and revising them on screen until a consensus was reached. Consensus was defined as agreement by more than 80% of participants, termed a Consensus Statement and numbered for convenience in the document. The final manuscript was written by the WG chairs in conjunction with the WG members and was revised for consistency by CG and AD. An update of this current consensus guideline is planned in about 4 years. The currently used WHO definition of anaemia [Table 1] applies also to patients with IBD. All patients with IBD should be assessed for the presence of anaemia. The major forms of anaemia in IBD are iron deficiency anaemia, anaemia of chronic disease and anaemia of mixed origin [EL 5] Minimum hemoglobin and hematocrit levels used to define anaemia in people living at sea level. 10 Minimum hemoglobin and hematocrit levels used to define anaemia in people living at sea level. 10 Normal hemoglobin varies with age and gender. Also other factors influence hemoglobin levels such as pregnancy, high altitudes, smoking, and ethnicity.11,12 The lower limits of normal hemoglobin concentration are even lower in African Americans [11.5g/dL for women, 12.9g/dL for men] and in the elderly. Interpretation of hemoglobin and hematocrit levels needs to consider such modulating factors. The definitions of anaemia in IBD is indifferent to other conditions and it is reasonable that WHO cut-offs apply.10 IBD patients should be regularly assessed for the presence of anaemia because of its high prevalence, its impact on quality of life, and comorbidity.13 About two-thirds of such patients have anaemia at diagnosis. During follow-up the prevalence and causes of anaemia may change.14 In children anaemia is even more common [about 70%] than in adults [about 30–40%].15 For laboratory screening, complete blood count, serum ferritin, and C-reactive protein [CRP] should be used. For patients in remission or mild disease, measurements should be performed every 6 to 12 months. In outpatients with active disease such measurements should be performed at least every 3 months [EL 5]. Patients at risk for vitamin B12 or folic acid deficiency [eg small bowel disease or resection] need proper surveillance. Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is present in the absence of thiopurine use [EL 4] The risk of developing anaemia relates to disease activity, because both blood loss and ACD are triggered by intestinal inflammation. Complete [or full] blood count, CRP, and serum ferritin are minimum requirements to detect anaemia, an inflammatory flare, or iron deficiency at an early stage. Diagnostic measurement of complete blood counts and CRP has been part of previous recommendations in IBD.7,16 The recommended timelines are based on expert opinion and reflect common clinical practice, but do not apply to hospitalized patients. In patients with extensive small bowel resection, extensive ileal Crohn’s disease, ileal-anal pouch, evidence of vitamin B12 or folic acid deficiency should be assessed more frequently than once a year.17 Anaemia workup should be initiated if the hemoglobin is below normal. The minimum workup includes red blood cell indices such as red cell distribution width [RDW] and mean corpuscular volume [MCV], reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation [TfS], and CRP concentration. More extensive workup includes serum concentrations of vitamin B12, folic acid, haptoglobin, the percentage of hypochromic red cells, reticulocyte hemoglobin, lactate dehydrogenase, soluble transferrin receptor, creatinine, and urea [EL 4]. Advice from a hematologist is appropriate if the cause of anaemia remains unclear after more extensive workup [EL 5] The purpose of these recommendations is to set an appropriate threshold to trigger action, and to advise on necessary tests. The initial workup of anaemia should follow a simple algorithm widely used in hematology [Figure 1]. Starting from the evaluation of MCV, the most common causes of anaemia in IBD may be recognized: microcytosis indicates iron-restricted anaemia [true or functional iron deficiency], macrocytosis may indicate B12 or folate deficiency, and normocytosis anaemia of chronic disease [ACD]. Thus, the MCV and mean corpuscular hemoglobin [MCH] are useful variables and available within the complete blood count. In ACD, they may be normal or low.18 Macrocytosis is indicative of vitamin deficiency, but also arises from thiopurine treatment [azathioprine or 6-mercaptopurine], other medications, alcohol abuse, hypothyroidism, or reticulocytosis. Anaemia classification based on MCV and reticulocytes. Anaemia can be effectively classified by using a combination of MCV and reticulocytes. Micro-, normo- and macrocytic anaemias cover all forms of anaemia, and the reticulocyte count tells whether the bone marrow can respond by increasing erythropoiesis, which gives early and important information on the direction of the investigation. All deficiency states are excluded by increased reticulocytes. Retic, reticulocyte count; N, normal; Tsat, transferrin saturation; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; DAT, direct antibody test; Hb, hemoglobin; IDA, iron deficiency anaemia; FID, functional iron deficiency; MDS, myelodysplastic syndrome; N, normal; S-ferritin, serum ferritin; Tsat, transferrin saturation; *anaemia secondary to malignancy, infection, kidney disease etc. In the next step, reticulocyte count is considered. Low or ‘normal’ reticulocytes indicate inability to respond properly to anaemia, either because of deficiencies that result in inappropriate erythropoiesis or primary bone marrow disease. Increased reticulocytes indicate increased red cell formation and therefore exclude deficiencies. Instead, hemolysis should be sought after by estimation of serum concentrations of haptoglobin, lactate dehydrogenase, and bilirubin. The minimum workup should include complete blood count with MCV, reticulocytes, serum ferritin, transferrin saturation, and CRP. In accordance with the algorithm in Figure 1, more extensive workup may include vitamin B12, folic acid, haptoglobin, a differential white blood cell count, and bone marrow smear.19 A comprehensive list of anaemias classified with MCV and reticulocytes is given in Table 2. In some situations microcytosis and macrocytosis co-exist, so that the two may other and result in a normal A of the red can in this as is an of iron of anaemia by MCV and reticulocytes from of anaemia by MCV and reticulocytes from and white blood cell counts are also available within the complete blood count and to anaemia from A soluble of the transferrin in the and its concentration is to the of transferrin It is in in situations the bone marrow needs more both in and in iron deficiency [true or An soluble transferrin is a of erythropoiesis, in the of iron deficiency in the presence of [with normal or even serum The percentage of hypochromic red cells, the hemoglobin concentration of reticulocytes, and the red blood cell are also useful for the diagnosis of iron-restricted blood cell is a which the volume of and the volume of reticulocytes. disease is not associated with an in in and may not be by clinical may be to disease in patients with a or CRP. Diagnostic for iron deficiency on the level of inflammation. In patients or evidence of active disease, serum ferritin is an appropriate [EL In the presence of a serum ferritin to may be with iron deficiency [EL 4] In the iron deficiency anaemia and ACD is both conditions In the management of IBD patients with anaemia, the of the appropriate treatment is based on this deficiency may be by blood loss from the of the with iron or iron the In the absence of or clinical evidence of iron deficiency is if the serum ferritin is In the presence of serum ferritin levels can be high iron In such cases, is an appropriate to after iron therapy, serum ferritin levels well with iron iron ferritin and levels deficiency anaemia may cause an of or The concentration of in the serum is an of the iron available for erythropoiesis ferritin, chronic has on a that the and ferritin are to iron deficiency anaemia and ACD with a high diagnostic The measurement of percentage of hypochromic red and reticulocyte hemoglobin two measurements useful in the diagnosis of functional iron deficiency, can be in In the presence of or clinical evidence of the diagnostic for ACD are a serum ferritin and the serum ferritin level is and a combination of iron deficiency and ACD is [EL The ACD includes all anaemia associated with and by chronic disease. the of on to anaemia as well as the direct of in the bone More has also that has a on iron In patients with active various the of in the which iron from the of transferrin saturation and iron to the a of functional iron deficiency for erythropoiesis and also and The in also iron from the The may to ACD with functional iron deficiency and are common for with and others. iron deficiency is defined as a with normal or iron a of iron from the a transferrin saturation in and iron in the bone which ACD with is if the serum ferritin is and the is below An in hypochromic red a of reticulocyte hemoglobin indicate FID, but as these measurements are not available in the diagnosis of is made from the combination of and normal or In the serum ferritin may be useful to exclude iron deficiency [if the is MCV may be or normal in is not MCV is but this may also be the with ACD gives reticulocyte not all IBD patients with anaemia of In an may be all the involved in anaemia, but is or not anaemia of chronic disease may with or The definitions are useful in this Anaemia of chronic disease anaemia chronic disease and by inflammatory ACD with functional iron ACD can be by and normal or [or increased levels of hypochromic red in ACD anaemia of chronic inflammatory disease of anaemia this definition is widely used for anaemia the is to a of iron in the bone either by iron deficiency or is recommended in all IBD patients iron deficiency anaemia is present [EL 1] of life with of anaemia, and this is of clinical The to iron in patients anaemia is more and on the and is evidence of in iron deficiency anaemia in other conditions such as chronic and such evidence is not available in the of The goal of iron is to hemoglobin levels and iron stores [EL 1] The lower the hemoglobin, the is the to of An in hemoglobin of at least within 4 of treatment is an of iron should be as first treatment in patients with active with previous to with hemoglobin below and in patients need [EL 1] The treatment of iron deficiency anaemia with iron has relevant in IBD patients. iron is more a and is than Thus, iron are in the of IBD-associated anaemia and were recommended also in previous iron is and well both in the of and maintenance of iron stores in patients with iron are currently available for treatment of by and can be and iron in IBD patients are available from iron and iron of to iron have been is to treatment For iron are to The can be within are also available for which is for use in chronic kidney disease and is currently in a of other conditions associated with iron deficiency, IBD and The currently available iron are not and has been direct Thus, a direct of the currently available with to and other not as and other in various are not A is for iron as they a risk for serious The risk of iron in patients are as in is a transferrin saturation and serum ferritin should be used as limits for iron is as are to and are associated with The estimation of iron need is based on hemoglobin and and this is more for the treatment of in IBD patients than based on the [EL the iron in in hemoglobin in the is to used in clinical practice, and iron The a and simple [Table with the in patients with The simple and as well as a with the iron In this clinical the simple has been used for of In clinical practice, it is also used for of other iron of this include patients with hemoglobin below need an the estimation of iron needs in iron deficiency anaemia is not A minimum of should be for estimation of iron for estimation of iron iron is in patients with IBD and may be used in patients with mild anaemia, disease is and have not been to iron anaemia has been defined by the WHO as hemoglobin in and in indicate that iron may be as as iron in a has a in ferritin and hemoglobin in of the effects from iron are of iron from the is and iron is to the intestinal has been in in of IBD indicate that iron may disease and intestinal In a in African iron and increased on iron were done with on as indicate with a even in IBD patients with a of to more than iron is recommended in patients with IBD [EL The of iron from is in can to iron stores are and iron is In and women, iron treatment is in in IBD is as are associated with more effects and lower Patients with IBD should be for iron deficiency every 3 months for at least a after and 6 and 12 months [EL 4] iron anaemia by within 10 patients with IBD should be for iron deficiency every 3 months using a combination of hemoglobin, ferritin, transferrin saturation, and CRP. anaemia may be indicative of intestinal disease even if is clinical remission and inflammatory are normal [EL 5] A intestinal disease and on and the of blood loss and of anaemia on the other important for prevention of anaemia is the treatment of the this is in clinical the to anaemia on the ability to bowel A of iron deficiency in patients should the of a on inflammatory The goal of preventive treatment is to hemoglobin and serum ferritin levels within the normal [EL deficiency can cause and quality of life even anaemia is not In it is common in clinical to iron deficiency as the of disease in IBD patients. The to iron in patients with but anaemia may on the clinical and the The for are based on the that iron is for all of the of iron deficiency may anaemia. and cognitive loss of or may be present anaemia and may upon iron Also and can be IBD-associated iron deficiency and anaemia recur frequently and even after treatment with of iron deficiency is lower in patients with ferritin levels [EL Anaemia to recur frequently and fast after iron The of relates to the of iron stores by serum serum ferritin levels of of iron deficiency within the than levels below this it was that iron at ferritin levels of to successful treatment of iron deficiency anaemia with with iron should be initiated as as serum ferritin below or hemoglobin below 12 or to As iron deficiency anaemia frequently and iron maintenance may anaemia The whether can anaemia in patients been for IBD-associated was a patients Serum ferritin was assessed every 2 months and patients of ferritin levels below of patients lower in with patients the of the to until the of the a from is and of IBD were in the and were and the was not to detect a treatment on quality of life, a in of was in of The that of anaemia in patients with IBD. In to the and the such a to anaemia management the healthcare are more than as high for with IBD patients The of non-iron deficiency anaemia by MCV and reticulocytes is recommended [EL 5] The WHO for the hemoglobin are widely and should be used also for factors pregnancy, high and age be considered. Anaemia in IBD may have causes iron The causes of in IBD are indifferent to other conditions and can be classified according to MCV and reticulocytes [Table The initial of anaemia should follow the algorithm in Figure The classification of anaemia is in Table 2. It is not that more than cause of anaemia in a may the initial diagnosis of The risk of developing anaemia relates to disease activity, because both blood loss and anaemia of chronic disease are triggered by intestinal inflammation. For differential diagnosis it should be that the causes of in IBD can be or [Table 4]. of non-iron deficiency anaemia in from of non-iron deficiency anaemia in from Anaemia of chronic disease is the most anaemia in hospitalized patients and in from that are associated with chronic of such as chronic inflammatory or ACD is by a normal or MCV and or normal reticulocyte clinical are also causes of related to IBD to to and to B12 or folic acid deficiencies. Treatment of may include of IBD folic treatment of other causes of such as or use of in cases, such as or kidney secondary or bone marrow Patients with anaemia of chronic disease with an to iron and IBD may be for treatment [EL 1] with a hemoglobin level not [EL 5] The presence of anaemia of chronic disease is a of active disease. of IBD treatment should In two the of on hemoglobin and in patients with or it was that treatment hemoglobin levels with even after for disease In IBD patients to has been to by increasing serum and has been the to anaemia in some IBD As anaemia of chronic disease from erythropoiesis secondary to increased levels of as may bone marrow It is that the of than its effects on the bone marrow the The to iron can be by reticulocyte counts after iron Patients with a diagnosis of anaemia of chronic disease, anaemia or to and may be for indicate that a majority of patients with IBD respond to treatment with an in hemoglobin and of quality of treatment is to hemoglobin of in or is in therefore the measures iron should functional iron deficiency and ferritin levels should be Low transferrin and levels are associated with to iron and may be used for of of B12 and folate should be to anaemia [EL 5] and folate may in after ileal and deficiency to and serum levels should be measured in patients with high In cases, measurement of or can be Increased indicates deficiency of either B12 or folate with a than serum B12 is for B12 deficiency and has a Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is Patients at risk for vitamin B12 or folic acid deficiency [eg small bowel disease or resection] need surveillance. The recommended timelines are based on expert and reflect common clinical practice, but do not apply to patients with extensive small bowel resection, extensive ileal Crohn’s disease, or ileal-anal used may erythropoiesis, both such as the of folate and as in the of or from folate deficiency, or acid have been related to a of hemolysis or In the treatment of anaemia, red blood cell may be hemoglobin concentration is below or if or risk factors are present [EL 4]. transfusions should be by iron [EL 4] In the transfusions of red blood were common in the treatment of anaemia in IBD. requirements with the of iron and transfusions to such as anaemia with anaemia, of all other The trigger to is and The to blood transfusions is not based on the hemoglobin but and blood transfusions and whether they are to in patients or in remains transfusions are widely used as an for of or anaemia. transfusions do not the and have Other iron with or should be of and after transfusions as these are a which not normal Management of in IBD should exclude other such as and effects of Patients with of anaemia of chronic disease should be also for the of an may be by and may be based on clinical and laboratory tests. In intestinal or extraintestinal with anaemia may the of macrocytosis and may cause mild In of of chronic disease, treatment of IBD should be in combination with treatment In active inflammatory may iron erythropoiesis, and to the anaemia of chronic disease. this of anaemia, the most important is to complete disease is not associated with an in and may not be by clinical may be also to disease in patients with a cause anaemia. other causes of anaemia are the should be or of should be and are for inflammatory bowel disease but they are associated with a of The of from to and bone marrow is of the most serious In has been associated with anaemia, and red cell have an of in in bone marrow The thiopurine and the majority of with In a with Crohn’s disease patients developing or treatment of be by these most In measurement is not and is by and blood can be by the presence of rare In an increased may result from of or ECCO has a of of The of is based on a used by the Committee of The is not at the ECCO and the of but also is open to on the ECCO a comprehensive of of of The ECCO Consensus Guidelines are based on an Consensus treatment are a for the and should not be based on the of the ECCO Consensus The European Crohn’s and Colitis Organisation of its members consensus may not be for information in in the ECCO Consensus of working groups for the ECCO Anaemia Consensus chairs are Diagnosis of A Treatment of iron deficiency Prevention of iron deficiency Management of non-iron deficiency The national representatives and in the online voting are to from the ECCO for to and the are to all an in and to the ECCO Consensus procedures on are also to as in this guideline in to this guideline an and to the of this guideline in clinical

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after cardiac and major non-cardiac surgery with general anaesthesia in the elderly. We hypothesized that the incidence of POCD would be less with regional anaesthesia rather than general. METHODS: We included patients aged over 60 years undergoing major non-cardiac surgery. After giving written informed consent, patients were randomly allocated to general or regional anaesthesia. Cognitive function was assessed using four neuropsychological tests undertaken preoperatively and at 7 days and 3 months postoperatively. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in two or more test parameters. RESULTS: At 7 days, POCD was found in 37/188 patients (19.7%, [14.3-26.1%]) after general anaesthesia and in 22/176 (12.5%, [8.0-18.3%]) after regional anaesthesia, P = 0.06. After 3 months, POCD was present in 25/175 patients (14.3%, [9.5-20.4%]) after general anaesthesia vs. 23/165 (13.9%, [9.0-20.2%]) after regional anaesthesia, P = 0.93. The incidence of POCD after 1 week was significantly greater after general anaesthesia when we excluded patients who did not receive the allocated anaesthetic: 33/156 (21.2%[15.0-28.4%]) vs. 20/158 (12.7%[7.9-18.9%]) (P = 0.04). Mortality was significantly greater after general anaesthesia (4/217 vs. 0/211 (P < 0.05)). CONCLUSION: No significant difference was found in the incidence of cognitive dysfunction 3 months after either general or regional anaesthesia in elderly patients. Thus, there seems to be no causative relationship between general anaesthesia and long-term POCD. Regional anaesthesia may decrease mortality and the incidence of POCD early after surgery.

Udgivelsesdato: 2008-May

Lead is a metal which has been associated with human activities for the last 6000 years. In ancient civilizations, uses of lead included the manufacture of kitchen utensils, trays, and other decorative articles. However, lead is also toxic to humans, with the most deleterious effects on the hemopoietic, nervous, reproductive systems and the urinary tract. The main sources of lead exposure are paints, water, food, dust, soil, kitchen utensils, and leaded gasoline. The majority of cases of lead poisoning are due to oral ingestion and absorption through the gut. Lead poisoning in adults occurs more frequently during exposure in the workplace and primarily involves the central nervous system. Symptoms of hemopoietic system involvement include microcytic, hypochromic anemia with basophilic stippling of the erythrocytes. Hyperactivity, anorexia, decreased play activity, low intelligence quotient, and poor school performance have been observed in children with high lead levels. Lead crosses the placenta during pregnancy and has been associated with intrauterine death, prematurity, and low birth weight. In 1991, the Centers for Disease Control and Prevention in the USA redefined elevated blood lead levels as those > or = 10 microg/dl and recommended a new set of guidelines for the treatment of lead levels > or =15 microg/dl.

Kupffer cells, the resident liver macrophages have long been considered as mostly scavenger cells responsible for removing particulate material from the portal circulation. However, evidence derived mostly from animal models, indicates that Kupffer cells may be implicated in the pathogenesis of various liver diseases including viral hepatitis, steatohepatitis, alcoholic liver disease, intrahepatic cholostasis, activation or rejection of the liver during liver transplantation and liver fibrosis. There is accumulating evidence, reviewed in this paper, suggesting that Kupffer cells may act both as effector cells in the destruction of hepatocytes by producing harmful soluble mediators as well as antigen presenting cells during viral infections of the liver. Moreover they may represent a significant source of chemoattractant molecules for cytotoxic CD8 and regulatory T cells. Their role in fibrosis is well established as they are one of the main sources of TGFbeta1 production, which leads to the transformation of stellate cells into myofibroblasts. Whether all these variable functions in the liver are mediated by different Kupffer cell subpopulations remains to be evaluated. In this review we propose a model that demonstrates the role of Kupffer cells in the pathogenesis of liver disease.

Effective leadership of healthcare professionals is critical for strengthening quality and integration of care. This study aimed to assess whether there exist an association between different leadership styles and healthcare quality measures. The search was performed in the Medline (National Library of Medicine, PubMed interface) and EMBASE databases for the time period 2004-2015. The research question that guided this review was posed as: "Is there any relationship between leadership style in healthcare settings and quality of care?" Eighteen articles were found relevant to our research question. Leadership styles were found to be strongly correlated with quality care and associated measures. Leadership was considered a core element for a well-coordinated and integrated provision of care, both from the patients and healthcare professionals.

Unequivocal international guidelines regarding the diagnosis and management of patients with acute appendicitis are lacking. The aim of the consensus meeting 2015 of the EAES was to generate a European guideline based on best available evidence and expert opinions of a panel of EAES members. After a systematic review of the literature by an international group of surgical research fellows, an expert panel with extensive clinical experience in the management of appendicitis discussed statements and recommendations. Statements and recommendations with more than 70 % agreement by the experts were selected for a web survey and the consensus meeting of the EAES in Bucharest in June 2015. EAES members and attendees at the EAES meeting in Bucharest could vote on these statements and recommendations. In the case of more than 70 % agreement, the statement or recommendation was defined as supported by the scientific community. Results from both the web survey and the consensus meeting in Bucharest are presented as percentages. In total, 46 statements and recommendations were selected for the web survey and consensus meeting. More than 232 members and attendees voted on them. In 41 of 46 statements and recommendations, more than 70 % agreement was reached. All 46 statements and recommendations are presented in this paper. They comprise topics regarding the diagnostic work-up, treatment indications, procedural aspects and post-operative care. The consensus meeting produced 46 statements and recommendations on the diagnostic work-up and management of appendicitis. The majority of the EAES members supported these statements. These consensus proceedings provide additional guidance to surgeons and surgical residents providing care to patients with appendicitis.