[Management of oxygen delivery and consumption during sepsis]

Maintaining an adequate tissue oxygen delivery (DO(2)) and consumption (VO(2)) is crucial in the treatment of septic patients. A fall in V0(2) is associated with a higher mortality. The early recognition of shock or tissue hypo perfusion impacts on patient prognosis. In occasions, hypovolemia or important regional oxygen debts are not recognized, since macro homodynamic variables have been compensated. In this situation, the use of metabolic hypo perfusion markers such as lactate, central venous oxygen saturation and gastric goniometry, can be helpful. However, interpretation of these markers should be cautious and always considering the overall clinical status of the patient. In the initial stages of sepsis, the dependency of V0(2) on DO(2) predominates as histopathological mechanism of multiple organic failure. In late stages, other factors predominate as determinants of multiple organic failure and mortality, such as hyper or hypo immune response, microcirculatory alterations and cytopathic hypoxia.

Factors influencing age at diagnosis of primary ciliary dyskinesia in European children

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis. Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists. In total, 223 centres from 26 countries reported 1,009 patients aged < 20 yrs. Reported cases per million children (for 5-14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% had situs inversus. Median age at diagnosis was 5.3 yrs, lower in children with situs inversus (3.5 versus 5.8 yrs; p < 0.001) and in children treated in large centres (4.1 versus 4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p < 0.001). This strongly correlated with general government expenditures on health (p < 0.001). This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.

Validation of the DRAGON score in 12 stroke centers in anterior and posterior circulation

BACKGROUND AND PURPOSE The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. METHODS Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. RESULTS Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). CONCLUSIONS The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).

Comprehensive geriatric assessment in patients undergoing transcatheter aortic valve implantation–rationale and design of the European CGA-TAVI registry

Abstract Purpose Aortic stenosis (AS) is the most common valvular abnormality in the elderly population. For inoperable patients or those at high-risk for surgery, transcatheter aortic valve implantation (TAVI) has become an alternative therapeutic option. The aim of the “Comprehensive geriatric assessment for transcatheter aortic valve implantation” (CGA-TAVI) registry is to evaluate the effectiveness of TAVI from the perspective of the geriatrician and to identify patient characteristics and indicators related to complications and clinical benefits for patients with symptomatic severe calcified degenerative AS undergoing TAVI. Materials and methods The CGA-TAVI registry is an international, multi-center, prospective, observational registry across Europe with consecutive patient enrolment. The registry will enrol up to 200 patients with AS undergoing TAVI, starting August 2013. CGA-TAVI has two co-primary objectives: (1) Establish predictive value of Comprehensive geriatric assessment (CGA) for mortality and/or hospitalization in TAVI patients. (2) Demonstrate CGA changes within 3 months after TAVI. Secondary objectives are: (1) Establish predictive value of CGA in TAVI patients for all-cause hospitalization, TAVI-related hospitalization, and nursing home admission. (2) Develop a comprehensive score for the assessment of TAVI patient prognosis. Conclusions The data obtained from the CGA-TAVI registry will supplement previous results to document the potential value of the effectiveness of TAVI from the perspective of geriatricians and will allow the assessment of the predictive value of CGA for mortality and/or hospitalization in elderly TAVI patients. Keywords Aortic stenosis; Transcatheter aortic valve implantation (TAVI); Comprehensive geriatric assessment (CGA); Registry; Predictor

Mandibular implant overdentures followed for over 10 years: patient compliance and prosthetic maintenance

PURPOSE: The mandibular implant overdenture is a popular treatment modality and is well documented in the literature. Follow-up studies with a long observation period are difficult to perform due to the increasing age of patients. The present data summarize a long-term clinical observation of patients with implant overdentures. MATERIALS AND METHODS: Between 1984 and 1997, edentulous patients were consecutively admitted for treatment with an implant overdenture. The dentures were connected to the implants by means of bars or ball anchors. Regular maintenance was provided with at least one or two scheduled visits per year. Recall attendance and reasons for dropout were analyzed based on the specific history of the patient. Denture maintenance service, relining, repair, and fabrication of new dentures were identified, and complications with the retention devices specified separately. RESULTS: In the time period from 1984 to 2008, 147 patients with a total of 314 implants had completed a follow-up period of >10 years. One hundred one patients were still available in 2008, while 46 patients were not reexamined for various reasons. Compliance was high, with a regular recall attendance of >90%. More than 80% of dentures remained in continuous service. Although major prosthetic maintenance was rather low in relation to the long observation period, visits to a dental hygienist and dentist resulted in an annual visit rate of 1.5 and 2.4, respectively. If new dentures became necessary, these were made in student courses, which increased the treatment time and number of appointments needed. Complications with the retention devices consisted mostly of the mounting of new female retainers, the repair of bars, and the changing of ball anchors. The average number of events and the rate of prosthetic service with ball anchors were significantly higher than those with bars. Twenty-two patients changed from ball anchors to bars; 9 patients switched from a clip bar to a rigid U-shaped bar. CONCLUSIONS: This long-term follow-up study demonstrates that implant overdentures are a favorable solution for edentulous patients with regular maintenance. In spite of specific circumstances in an aging population, it is possible to provide long-term care, resulting in a good prognosis and low risk for this treatment modality. For various reasons the dropout rate can be considerable in elderly patients and prosthetic service must be provided regularly.

Chapter I: Definitions, epidemiology, clinical presentation and prognosis

The concept of chronic critical limb ischaemia (CLI) emerged late in the history of peripheral arterial occlusive disease (PAOD). The historical background and changing definitions of CLI over the last decades are important to know in order to understand why epidemiologic data are so difficult to compare between articles and over time. The prevalence of CLI is probably very high and largely underestimated, and significant differences exist between population studies and clinical series. The extremely high costs associated with management of these patients make CLI a real public health issue for the future. In the era of emerging vascular surgery in the 1950s, the initial classification of PAOD by Fontaine, with stages III and IV corresponding to CLI, was based only on clinical symptoms. Later, with increasing access to non-invasive haemodynamic measurements (ankle pressure, toe pressure), the need to prove a causal relationship between PAOD and clinical findings suggestive of CLI became a real concern, and the Rutherford classification published in 1986 included objective haemodynamic criteria. The first consensus document on CLI was published in 1991 and included clinical criteria associated with ankle and toe pressure and transcutaneous oxygen pressure (TcPO(2)) cut-off levels <50 mmHg, <30 mmHg and <10 mmHg respectively). This rigorous definition reflects an arterial insufficiency that is so severe as to cause microcirculatory changes and compromise tissue integrity, with a high rate of major amputation and mortality. The TASC I consensus document published in 2000 used less severe pressure cut-offs (≤ 50-70 mmHg, ≤ 30-50 mmHg and ≤ 30-50 mmHg respectively). The thresholds for toe pressure and especially TcPO(2) (which will be also included in TASC II consensus document) are however just below the lower limit of normality. It is therefore easy to infer that patients qualifying as CLI based on TASC criteria can suffer from far less severe disease than those qualifying as CLI in the initial 1991 consensus document. Furthermore, inclusion criteria of many recent interventional studies have even shifted further from the efforts of definition standardisation with objective criteria, by including patients as CLI based merely on Fontaine classification (stage III and IV) without haemodynamic criteria. The differences in the natural history of patients with CLI, including prognosis of the limb and the patient, are thus difficult to compare between studies in this context. Overall, CLI as defined by clinical and haemodynamic criteria remains a severe condition with poor prognosis, high medical costs and a major impact in terms of public health and patients' loss of functional capacity. The major progresses in best medical therapy of arterial disease and revascularisation procedures will certainly improve the outcome of CLI patients. In the future, an effort to apply a standardised definition with clinical and objective haemodynamic criteria will be needed to better demonstrate and compare the advances in management of these patients.

[How to assess the nutritional status of my patient]

Protein-energy-malnutrition is a growing problem in industrialised countries. Many studies have found malnourishment in 20-60% of hospitalized medical or surgical patients, as well as out-patients. Malnutrition negatively influences patients' prognosis, immune system, muscle strength, and quality of life. As it is a largely treatable co-morbidity, systematic screening for malnutrition and effective management will improve patient outcomes and reduce healthcare costs. Early diagnosis and assessment depends on a simple and standardised screening tool that identifies at-risk patients, allowing the medical team in charge to solve patients' nutritional problems with an interdisciplinary approach.

[Diagnosis and therapy of depression in the heart disease patient]

Even though depressions and depressive symptoms are frequently observed in patients with medical diseases, their psychological problems are often neither diagnosed nor treated. Diagnosis of mood state might be easy in isolated cases yet it often is not since the precise nature of normal mood cannot be expressed in quantitative terms. Furthermore, depression can only be diagnosed based on the doctor's clinical appraisal and the patient's own description of his/her complaints. There is no gold standard on which depressive symptoms can be based on--and further on, depression is not a diagnosis. Instead, it is a syndrome that calls for differential diagnoses before treatment can be offered. Diagnosing depressive comorbidity in patients with medical complaints is even more difficult because of the overlap between symptoms of depression and accompanying symptoms of the somatic illness e.g. lack of energy. Although depressive states have been known to be a risk factor for the prognosis of patients with coronary heart disease for a long time, there is a paucity of research about the therapy these patients undergo due to the fact that tricyclic anti-depressants can have cardiotoxic effects on patients with heart disease. The treatment of depression in these patients has become a much lower risk since the introduction of serotonin reuptake inhibitors. There is widespread evidence that depressive comorbidity has a negative impact on the prognosis of medical disorders. Despite the complex nature of diagnosing depression, proper diagnosis and treatment is increasingly important in internal medicine and especially cardiology.

Prognosis of Children with HIV-1 Infection Starting Antiretroviral Therapy in Southern Africa: A Collaborative Analysis of Treatment Programs

BACKGROUND: Prognostic models for children starting antiretroviral therapy (ART) in Africa are lacking. We developed models to estimate the probability of death during the first year receiving ART in Southern Africa. METHODS: We analyzed data from children ≤10 years old who started ART in Malawi, South Africa, Zambia or Zimbabwe from 2004-2010. Children lost to follow-up or transferred were excluded. The primary outcome was all-cause mortality in the first year of ART. We used Weibull survival models to construct two prognostic models: one with CD4%, age, WHO clinical stage, weight-for-age z-score (WAZ) and anemia and one without CD4%, because it is not routinely measured in many programs. We used multiple imputation to account for missing data. RESULTS: Among 12655 children, 877 (6.9%) died in the first year of ART. 1780 children were lost to follow-up/transferred and excluded from main analyses; 10875 children were included. With the CD4% model probability of death at 1 year ranged from 1.8% (95% CI: 1.5-2.3) in children 5-10 years with CD4% ≥10%, WHO stage I/II, WAZ ≥-2 and without severe anemia to 46.3% (95% CI: 38.2-55.2) in children <1 year with CD4% <5%, stage III/IV, WAZ< -3 and severe anemia. The corresponding range for the model without CD4% was 2.2% (95% CI: 1.8-2.7) to 33.4% (95% CI: 28.2-39.3). Agreement between predicted and observed mortality was good (C-statistics=0.753 and 0.745 for models with and without CD4% respectively). CONCLUSION: These models may be useful to counsel children/caregivers, for program planning and to assess program outcomes after allowing for differences in patient disease severity characteristics.

Interim endoscopy results during neoadjuvant therapy for gastric cancer correlate with histopathological response and prognosis

BACKGROUND Neoadjuvant chemotherapy for locally advanced gastric cancer leads to major histopathological response in less than 30 % of patients. Data on interim endoscopic response assessment do not exist. This exploratory prospective study evaluates early endoscopy after 50 % of the chemotherapy as predictor for later response and prognosis. METHODS Forty-seven consecutive patients were included (45 resected; 33 R0 resections). All patients received baseline endoscopy and CT scans, after 50 % of their chemotherapy (EGD-1, CT-1) and after completion of chemotherapy (EGD-2, CT-2). Interim endoscopic response (EGD-1) was assessed after having received 50 % (6 weeks) of the planned 12 weeks of neoadjuvant chemotherapy. Post-chemotherapy response was clinically assessed by a combination of CT scan (CT-2) and endoscopy (EGD-2). Histopathological response was determined by a standardized scoring system (Becker criteria). Endoscopic response was defined as a reduction of >75 % of the tumor mass. RESULTS Twelve patients were responders at EGD-1 and 13 at EGD-2. Nine patients (19.1 %) were clinical responders and 7 patients (15.6 %) were histopathological responders after chemotherapy. Specificity, accuracy, and negative predictive value of the interim EGD-1 for subsequent histopathological response were 31/38 (82 %), 36/47 (76 %), and 31/33 (93 %); and for recurrence or death, 28/30 (93.3 %), 38/47 (80.9 %), and 28/35 (80.0 %). Response at EGD-1 was significantly associated with histopathological response (p = 0.010), survival (p < 0.001), and recurrence-free survival (p = 0.009). CONCLUSIONS Interim endoscopy after 6 weeks predicts response and prognosis. Therefore, tailoring treatment according to interim endoscopic assessment could be feasible, but the findings of this study should be validated in a larger patient cohort.

Pelvic lymph node dissection in the context of radical cystectomy: a thorough insight into the connection between patient, surgeon, pathologist and treating institution

Pelvic lymph node dissection (PLND) in patients with bladder cancer varies widely in extent, technique employed, and pathological workup of specimens. The present paper provides an overview of the existing evidence regarding the effectiveness of PLND and elucidates the interactions between patient, surgeon, pathologist, and treating institution as well as their cumulative impact on the final postoperative lymph node (LN) staging. Bladder cancer patients undergoing radical cystectomy with extended PLND appear to have better oncologic outcomes compared to patients undergoing radical cystectomy and limited PLND. Attempts have been made to define and assess the quality of PLND according to the number of lymph nodes identified. However, lymph node counts depend on multiple factors such as patient characteristics, surgical template, pathological workup, and institutional policies; hence, meticulous PLND within a defined and uniformly applied extended template appears to be a better assurance of quality than absolute lymph node counts. Nevertheless, the prognosis of the patients can be partially predicted with findings from the histopathological evaluation of the PLND specimen, such as the number of positive lymph nodes, extracapsular extension, and size of the largest LN metastases. Therefore, particular prognostic parameters should be addressed within the pathological report to guide the urologist in terms of patient counseling.

Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials

OBJECTIVE To investigate the long-term prognostic implications of coronary calcification in patients undergoing percutaneous coronary intervention for obstructive coronary artery disease. METHODS Patient-level data from 6296 patients enrolled in seven clinical drug-eluting stents trials were analysed to identify in angiographic images the presence of severe coronary calcification by an independent academic research organisation (Cardialysis, Rotterdam, The Netherlands). Clinical outcomes at 3-years follow-up including all-cause mortality, death-myocardial infarction (MI), and the composite end-point of all-cause death-MI-any revascularisation were compared between patients with and without severe calcification. RESULTS Severe calcification was detected in 20% of the studied population. Patients with severe lesion calcification were less likely to have undergone complete revascularisation (48% vs 55.6%, p<0.001) and had an increased mortality compared with those without severely calcified arteries (10.8% vs 4.4%, p<0.001). The event rate was also high in patients with severely calcified lesions for the combined end-point death-MI (22.9% vs 10.9%; p<0.001) and death-MI- any revascularisation (31.8% vs 22.4%; p<0.001). On multivariate Cox regression analysis, including the Syntax score, the presence of severe coronary calcification was an independent predictor of poor prognosis (HR: 1.33 95% CI 1.00 to 1.77, p=0.047 for death; 1.23, 95% CI 1.02 to 1.49, p=0.031 for death-MI, and 1.18, 95% CI 1.01 to 1.39, p=0.042 for death-MI- any revascularisation), but it was not associated with an increased risk of stent thrombosis. CONCLUSIONS Patients with severely calcified lesions have worse clinical outcomes compared to those without severe coronary calcification. Severe coronary calcification appears as an independent predictor of worse prognosis, and should be considered as a marker of advanced atherosclerosis.

Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 (MACC1) for survival prognosis of colorectal cancer patients: a retrospective cohort study.

BACKGROUND Metastasis of colorectal cancer (CRC) is directly linked to patient survival. We previously identified the novel gene Metastasis Associated in Colon Cancer 1 (MACC1) in CRC and demonstrated its importance as metastasis inducer and prognostic biomarker. Here, we investigate the geographic expression pattern of MACC1 in colorectal adenocarcinoma and tumor buds in correlation with clinicopathological and molecular features for improvement of survival prognosis. METHODS We performed geographic MACC1 expression analysis in tumor center, invasive front and tumor buds on whole tissue sections of 187 well-characterized CRCs by immunohistochemistry. MACC1 expression in each geographic zone was analyzed with Mismatch repair (MMR)-status, BRAF/KRAS-mutations and CpG-island methylation. RESULTS MACC1 was significantly overexpressed in tumor tissue as compared to normal mucosa (p < 0.001). Within colorectal adenocarcinomas, a significant increase of MACC1 from tumor center to front (p = 0.0012) was detected. MACC1 was highly overexpressed in 55% tumor budding cells. Independent of geographic location, MACC1 predicted advanced pT and pN-stages, high grade tumor budding, venous and lymphatic invasion (p < 0.05). High MACC1 expression at the invasive front was decisive for prediction of metastasis (p = 0.0223) and poor survival (p = 0.0217). The geographic pattern of MACC1 did not correlate with MMR-status, BRAF/KRAS-mutations or CpG-island methylation. CONCLUSION MACC1 is differentially expressed in CRC. At the invasive front, MACC1 expression predicts best aggressive clinicopathological features, tumor budding, metastasis formation and poor survival outcome.

Loss of tapasin correlates with diminished CD8(+) T-cell immunity and prognosis in colorectal cancer.

BACKGROUND Tapasin is a crucial component of the major histocompatibility (MHC) class I antigen presentation pathway. Defects in this pathway can lead to tumor immune evasion. The aim of this study was to test whether tapasin expression correlates with CD8(+) cytotoxic T lymphocyte (CTL) infiltration of colorectal cancer (CRC) and overall survival. METHODS A next-generation tissue microarray (ngTMA) of 198 CRC patients with full clinicopathological information was included in this study. TMA slides were immunostained for tapasin, MHC I and CD8. Marker expression was analyzed with immune-cell infiltration, patient survival and TNM-staging. RESULTS A reduction of tapasin expression strongly correlated with venous invasion (AUC 0.682, OR 2.7, p = 0.002; 95% CI 1.7-5.0), lymphatic invasion (AUC 0.620, OR 2.0, p = 0.005; 95 % CI 1.3-3.3), distant metastasis (AUC 0.727, OR 2.9, p = 0.004; 95% CI 1.4-5.9) and an infiltrative tumor border configuration (AUC 0.621, OR 2.2, p = 0.017; 95% CI 1.2-4.4). Further, tapasin expression was associated with CD8(+) CTL infiltration (AUC 0.729, OR 5.4, p < 0.001; 95% CI 2.6-11), and favorable overall survival (p = 0.004, HR 0.6, 95% CI 0.42-0.85). CONCLUSIONS Consistent with published functional data showing that tapasin promotes antigen presentation, as well as tumor immune recognition and destruction by CD8(+) CTLs, a reduction in tapasin expression is associated with tumor progression in CRC.

Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment.

While coronary atherosclerosis is a leading cause of mortality, evaluation of coronary lesions was previously limited to either indirect angiographic assessment of the lumen silhouette or post mortem investigations. Intracoronary (IC) imaging modalities have been developed that allow for visualization and characterization of coronary atheroma in living patients. Used alone or in combination, these modalities have enhanced our understanding of pathobiological mechanisms of atherosclerosis, identified factors responsible for disease progression, and documented the ability of various medications to reverse the processes of plaque growth and destabilization. These methodologies have established a link between in vivo plaque characteristics and subsequent coronary events, thereby improving individual risk stratification, paving the way for risk-tailored systemic therapies and raising the option for pre-emptive interventions. Moreover, IC imaging is increasingly used during coronary interventions to support therapeutic decision-making in angiographically inconclusive disease, guide and optimize procedural results in selected lesion and patient subsets, and unravel mechanisms underlying stent failure. This review aims to summarize current evidence regarding the role of IC imaging for diagnosis and risk stratification of coronary atherosclerosis, and to describe its clinical role for guiding percutaneous coronary interventions. Future perspectives for in-depth plaque characterization using novel techniques and multimodality imaging approaches are also discussed.