Postinterventional tumor necrosis predicts recurrence-free long-term survival in liver transplant patients with advanced hepatocellular carcinoma.

BACKGROUND: Locoregional interventional bridging treatment (IBT) before liver transplantation (LT) is an accepted neoadjuvant approach in liver transplant patients with hepatocellular carcinoma (HCC). However, the effect of postinterventional tumor necrosis on posttransplantation outcome is known. METHODS: A total of 93 consecutive liver transplant patients with HCC were included in this prospective trial. Fifty-nine patients underwent pretransplantation IBT, by either transarterial chemoembolization (n = 51) or radiofrequency ablation (n = 8). The extent of tumor necrosis assessed at explant pathology (≥50% tumor necrosis rate = extended post-IBT tumor necrosis; <50% tumor necrosis rate = less extended tumor necrosis) and its impact on recurrence-free survival in the context of other prognostic relevant histopathologic variables were analyzed in uni- and multivariate analyses. RESULTS: Extended tumor necrosis was assessed in 44 patients among the IBT population, and tumor necrosis rate was <50% in 15 patients of the IBT and 34 patients of the non-IBT population, respectively. Five-year recurrence-free survival rates were 96% in patients with and 55% in patients without extended tumor necrosis rates (P < .001). Recurrence-free survival rates were similar between patients with HCC meeting the Milan criteria (85%) and those exceeding the Milan criteria but demonstrating extended post-IBT tumor necrosis on explant pathology (80%). On multivariate analysis, only microvascular invasion (odds ratio 6.4) and extended postinterventional tumor necrosis (odds ratio 9.2) were identified as independent histopathologic predictors of recurrence-free outcome (P < .05). CONCLUSIONS: Extended tumor necrosis should be the major objective of neoadjuvant IBT in liver transplant patients with HCC, because it significantly improves posttransplantation outcome. Thereby, even patients with HCC beyond the Milan criteria may achieve excellent survival rates.

Echocardiography versus intracardiac electrocardiography-based optimization for cardiac resynchronization therapy : a comparative clinical long-term trial.

BACKGROUND: Optimization of AV and VV delay programming has been shown to be essential for the success of cardiac resynchronization therapy (CRT). Acute hemodynamic improvement can be obtained by intracardiac electrocardiogram (IEGM)-based optimization. The aim of the present study was to evaluate whether this IEGM-based algorithm is comparable to the current gold standard of echocardiography. METHODS: After device implantation patients with standard criteria for CRT, AV and VV delay programming was either optimized by an IEGM-based algorithm (IEGM group, n = 24) or by echocardiography (echo group, n = 24). Cardiopulmonary exercise capacity was assessed after 3 and 12 months on the basis of NYHA class and the 6-min-walk test. Left ventricular ejection fraction was evaluated by echocardiography. RESULTS: In both groups there was a significant decrease in NYHA class and a significant increase in 6-min-walk distance and ejection fraction after 3 and 12 months. After 12 months there was no significant difference in the proportion of responders, NYHA class and 6-min-walk distance between the IEGM the echo group. CONCLUSION: The present data show that a sustained improvement of cardiopulmonary exercise capacity can be obtained by optimizing CRT patients on the basis of an IEGM algorithm. The comparable results for cardiopulmonary exercise parameters suggest that this new method might become an important tool for adjusting CRT programming in daily practice.

Sustained renal response to mycophenolate mofetil and CNI taper promotes survival in liver transplant patients with CNI-related renal dysfunction.

AIM: The aim of this trial was to evaluate the impact of conversion from a calcineurin-inhibitor (CNI)-based immunosuppressive regimen to mycophenolate mofetil (MMF) and reduced-dose CNI on long-term renal function and survival in a series of 63 liver transplant patients with CNI-induced renal dysfunction. METHODS: CNI dosage was significantly tapered after introduction of 2,000 mg MMF per day. Renal function was assessed by determination of serum creatinine levels and calculated creatinine clearance (CCl). The impact of relevant clinical parameters on renal function and survival post-conversion was analyzed by univariate and multivariate analysis. RESULTS: At 60 months post-conversion, mean creatinine level had significantly declined from 197.2±58.3 µmol/l at baseline to 160.0±76.5 µmol/l, and mean CCl has significantly increased from 38.4±13.4 ml/min at baseline to 47.9±21.1 ml/min (p<0.001), respectively. Forty-six patients (73.1%) demonstrated sustained renal response to modified immunosuppression. Full-dose MMF medication (p=0.006) and the early conversion (p=0.02) were identified as independent predictors of persistent renal function improvement. Sustained renal response to MMF plus reduced-dose CNI was identified as the most relevant independent promoter of long-term survival (hazard ratio 6.9). Five-year survival rate post-conversion was 93.9% in renal responders and 64.3% in renal non-responders (log rank<0.001). CONCLUSIONS: Sustained renal response to MMF and CNI dose reduction promotes long-term survival in liver transplant patients with CNI-induced renal dysfunction.

Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables.

BACKGROUND: The objective of this trial was to analyze the clinical patterns and outcome variables of recurrent hepatocellular carcinoma (HCC) in liver transplant patients. PATIENTS AND METHODS: Sixty patients after liver transplantation (LT) for HCC were analyzed. All of them received initially a calcineurin-inhibitor based immunosuppressive regimen. Recurrent HCC was treated by surgical intervention, if eligible, or adjuvant therapies. Furthermore, patients were converted to a Sirolimus (SRL)-based immunosuppressive regimen after tumor relapse. The impact of clinical and histopathological variables on post-recurrence survival was analyzed in uni- and multivariate analysis. RESULTS: Sixteen liver recipients developed HCC recurrence between 4 and 58 months (median: 23 months) post-LT. Sites of first tumor recurrence were lung (n = 5), liver (n = 4), bone (n = 4), cerebrum (n = 1), adrenal gland (n = 1) and peritoneum (n = 1). Seven patients were amenable for surgical resection, while 9 patients were only suitable for adjuvant treatment (n = 4) or general medical support (n = 5). Median survival rate post-recurrence was 65 months (range: 12-136 months) in patients amenable for surgical therapy, and 5 months (range: 1-52 months) in patients unsuitable for surgical intervention (P = 0.01). Multivariate analysis identified late (>24 months) posttransplant tumor relapse (P = 0.039) and surgical therapy (P = 0.014) as independent predictors of long-term survival after tumor relapse. Five patients are tumour-free alive for a median of 65 months after surgical resection of recurrent HCC and conversion to SRL. CONCLUSION: Liver transplant patients with HCC recurrence should be treated surgically, if eligible, since this is an independent predictor of long-term survival.

Increased 18F-FDG uptake of hepatocellular carcinoma on positron emission tomography independently predicts tumor recurrence in liver transplant patients.

The aim of this retrospective trial was to analyze the value of preoperative (18)F-fluoro-deoxyglucose positron emission tomography ((18)F-FDG PET) to predict parameters of tumor aggressiveness among liver transplant (OLT) patients with hepatocellular carcinoma (HCC). Fifty-five patients with HCC underwent (18)F-FDG-PET during evaluation for OLT. Nineteen patients demonstrated increased (18)F-FDG uptake on PET pre-OLT (PET(+)), and 36 patients revealed negative PET findings (PET(-)). PET(+) patients showed a relative risk of 9.5 and 6.4 for poor differentiation and for microvascular invasion (MVI) in the HCC at explant pathology, respectively. Of the 10 patients (18.2%) who developed HCC recurrences, 9 (90%) revealed increased (18)F-FDG uptake pre-OLT; only 1 (10%) showed a PET(-) status (P < .001). Apart from poor tumor differentiation, PET(+) status was identified as an independent predictor of tumor recurrence post-OLT (odds ratio, 23.9). Our study demonstrated that (18)F-FDG uptake on PET is a reliable preoperative predictor of tumor recurrence after OLT in patients with HCC, triggered by its high association with poor tumor differentiation and MVI.

Recurrence-free long-term survival after liver transplantation in patients with 18F-FDG non-avid hilar cholangiocarcinoma on PET.

The aim of this retrospective study was to assess the value of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) for predicting biological tumor behavior and outcome after liver transplantation (LT) in patients with otherwise unresectable hilar cholangiocarcinoma (HC). Preoperative (18)F-FDG-PET scanning was performed in 13 patients with type IV Klatskin tumor before LT. PET+ status indicated patients with an increased pretransplant (18)F-FDG uptake, whereas PET- recipients had no increased preoperative (18)F-FDG uptake on PET. Pretransplant PET findings were correlated with histopathological tumor characteristics and patient outcome after LT. Eight patients demonstrated positive preoperative PET findings (61.5%), whereas five patients had no increased preoperative (18)F-FDG tumor uptake (38.5%) on PET. One PET+ patient died after 1 month due to liver allograft dysfunction. Seven PET+ liver recipients developed tumor recurrence, whereas five PET- patients were tumor-free alive after a median of 76 months post-LT (p = 0.001). The 2-year recurrence-free survival rate after LT was 100% in PET- patients and 28.6% in the PET+ population (log-rank = 0.008). Our results suggest that patients with (18)F-FDG non-avid HC on PET may achieve recurrence-free long-term survival after LT.

Oral tacrolimus bioavailability is increased after right split liver transplantation.

OBJECTIVE: Tacrolimus (Tac) is mainly metabolized in the liver. The aim of this trial was to analyze Tac bioavailability after partial liver transplantation. PATIENTS AND METHODS: A total of 33 patients after right split liver grafting (n=8 living related, LRLT; n=8 cadaver split, CS) or full-size liver transplantation (n=17, FS) were included in this trial. All of them received Tac perorally with an initial dose of 2x5 mg/d. Dose adjustment was performed according to the Tac trough level (T0) with an initial target T0 levels of 12 to 15 ng/mL. RESULTS: The time to reach target T0 levels tended to be lower (P=.05) in the split liver groups (LRLT: 2.8+/-1.6 days; CS: 2.1+/-0.9 days; FS: 4.5+/-3.2 days). In addition, mean Tac dose to maintain the target T0 level was significantly decreased (P=.01) in the split liver cohorts (LRLT: 5.8+/-1.1 mg/d; CS: 5.5+/-2.5 mg/d; FS: 9.8+/-3.9 mg/d). Only graft weight/standard liver volume ratio (r=.566, P=.02) and graft weight/body weight ratio (r=.709, P=.002) showed significant correlations with Tac maintenance doses in the split liver group. CONCLUSIONS: Peroral Tac bioavailability was significantly higher after partial liver transplantation using the right hepatic lobe compared with full-size transplants. The volume of the split liver graft highly correlated with Tac maintenance therapy and should be used to calculate the most appropriate initial posttransplantation Tac dose.

Conversion to mycophenolate mofetil for modulating recurrent hepatitis C in liver transplant recipients.

BACKGROUND: The aim of this study was to analyze the influence of cyclosporine A (CsA) taper in conjunction with mycophenolate mofetil (MMF) therapy on recurrent hepatitis C virus (HCV) in liver transplant patients. PATIENTS AND METHODS: Nineteen liver recipients with serologically and morphologically confirmed recurrent HCV were included in this study. After MMF introduction up to a maximum dose of 2000 mg/day, CsA dose was significantly tapered. In the control group immunosuppression remained unchanged. Allograft function and morphology, viral loads, and renal function were analyzed continuously. RESULTS: MMF treatment was well tolerated without risk of rejection. Allograft fibrosis progressed in 6 patients of the MMF group (66.6%) and none (0%) of the controls at 12-month biopsy (P=0.005). Moreover, aminotransferases and viral loads increased slightly in the MMF-treated patients. Renal function improved significantly (serum creatinine: 239.3+/-90.2 micromol/L vs. 175.8+/-46.0 micromol/L; P=0.008) in the treatment group, while deteriorating (serum creatinine: 156.8+/-44.6 micromol/L vs. 214.8+/-120.1 micromol/L; P=0.06) in the controls. CONCLUSION: MMF introduction allows a safe CsA taper in HCV-positive liver transplant patients and results in significant improvement of renal function. However, there seems to be a risk of marked progression of HCV-induced allograft injury.

Prevention of early loss of bone mineral density after liver transplantation by prostaglandin E1.

INTRODUCTION: As a result of preexisting chronic liver disease and immunosuppression, the majority of liver transplant patients develop bone mineral density (BMD) loss in the first 3 to 6 months posttransplantation, leading to an increased fracture risk. Using basic prophylaxis and treatment by administration of vitamin D, calcium, and bisphosphonates, BMD loss may be controlled in the long term. In contrast, there is no established medical concept for prevention of early posttransplant BMD loss. MATERIAL AND METHODS: The aim of this trial was to evaluate the effect of prostaglandin E1 on BMD after liver transplantation. Between 1998 and 2004, 29 patients were enrolled in this study. BMD measurement was performed at lumbar spine and femoral neck using dual energy x-ray absorptometry pretransplant, and 3, 6, 12, and 24 months posttransplant. All patients received calcium and vitamin D as basic prophylaxis. In 13 patients, prostaglandin E1 (PGE) was additionally administered for 12 days posttransplant. RESULTS: BMD loss was significantly lower at 3 and 6 months posttransplant in the PGE group (lumbar spine, P < .03; femoral neck, P < .009). Development of BMD loss was comparable between both groups during further follow-up. In the PGE group there was a significantly lower fracture rate compared with the controls (P < .02). CONCLUSION: The application of PGE 1 proved to be beneficial in compensating the early posttransplant BMD loss and in subsequently reducing fracture rate. These positive effects of PGE 1 could be demonstrated in both the femoral neck and lumbar spine.

Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation.

The aim of this study was to evaluate the impact of mycophenolate mofetil (MMF) on incidence, delay, severity and clinical course of early recurrent hepatitis C after liver transplantation (LT). A total of 21 hepatitis C virus (HCV)-positive patients after LT were prospectively enrolled in this study. All of them received a quadruple induction cyclosporine A (CsA)-based immunosuppression, augmented by MMF (n=12) or by azathioprine (n=9, AZA). MMF tended to delay recurrent disease (50+/-35 versus 35+/-35 weeks, P=0.5) with significantly lower levels of aminotransferases (P<0.05). Furthermore, patients under MMF revealed less severe allograft fibrosis at disease recurrence (stage of fibrosis: 1.5+/-0.5 versus 2.2+/-1.2; P=0.07). But stage of fibrosis significantly increased in the MMF-group (P<0.05) during 6 months of antiviral treatment. Three patients in the MMF-group and none of the controls suffered from severe fibrosing cholestatic recurrent hepatitis C. Initial post-LT administration of MMF tended to delay recurrent hepatitis C and to limit initial HCV-related biochemical and morphological graft dysfunction. But during clinical follow-up, its immunosuppressive capabilities exceeded possible antiviral properties, finally leading to significant progression of graft fibrosis. Thus, concomitant dose reduction of other basic immunosuppressants might be useful in this clinical setting.

Recognition and management of overweight and obesity in primary care in Germany.

BACKGROUND: In contrast to the well-documented high prevalence of overweight and obesity in the general population, the prevalence, recognition rates and management by primary care physicians--as the core gatekeeper in the health care system--remains poorly studied. PURPOSE OF THE STUDY: To examine (1) the point prevalence of overweight (BMI 25.0-29.9 kg/m(2)) and obesity (BMI> or =30 kg/m(2)) in primary care patients, (2) prevalence patterns in patients with high-risk constellations (diabetes, hypertension, cardiovascular disease, etc.), (3) doctors' recognition and interventions, as well as patients' use and perceived effectiveness of weight-loss interventions and (4) factors associated with non-treatment. METHODS: Cross-sectional point prevalence study of 45 125 unselected consecutive primary care attendees recruited from a representative nationwide sample of 1912 primary care practices. MEASURES: (1) standardized clinical appraisal of each patient by the physician (diagnostic status and recognition, severity, comorbidity, current and past interventions). (2) Patient self-report questionnaire: height and weight, illness history, past and current treatments and their perceived effectiveness, health attitudes and behaviors. RESULTS: (1) In all, 37.9% of all primary care attendees were overweight, 19.4% obese. (2) Rates for overweight and obesity were highest in patients with diabetes (43.6 and 36.7%) and hypertension (46.1 and 31.3%), followed by patients with cardiovascular disorders. Rates of overweight/obesity increased steadily by the number of comorbid conditions. (3) Doctors' recognition of overweight (20-30%) and obesity (50-65%) was low, patients' actual use of weight control interventions even lower (past 12 months: 8-11%, lifetime: 32-39%). Patient success rates were quite limited. (4) Co- and multimorbidity in particular as well as other patient and illness variables were identified as predictors for recognition, but prediction of patients' actual use of weight loss interventions was limited. CONCLUSIONS: Primary care management of overweight and obesity is largely deficient, predominantly due to four interrelated factors: doctors' poor recognition of patients' weight status, doctors' inefficient efforts at intervention, patients' poor acceptance of such interventions and dissatisfaction with existing life-style modification strategies.

[How do risk patients with overweight/obesity differ in their health knowledge and behaviour from patients with normal weight? A study in primary medical care]. / Wie unterscheiden sich Risikopatienten mit Ubergewicht/Adipositas in ihrem Gesundheitswissen und Verhalten von normalgewichtigen Patienten? Eine Untersuchung im primärärztlichen Bereich.

OBJECTIVES AND METHODS: Individual health-related behaviour patterns and lifestyles are strongly associated with the risk of suffering from cardiovascular diseases. Overweight (BMI 25 to 30 kg/m(2)) and obese patients (BMI > or = 30 kg/m(2)) are at particular risk to develop these diseases. Therefore, we investigated whether these patients are more aware of health-related issues and problems than normal-weight patient with data from the HYDRA study on 45,000 subjects. RESULTS: Health knowledge, problem awareness and health behaviour differed significantly among the examined patient groups (normal weight/overweight/obesity). The overweight and obese patients were aware of potential risk factors for various diseases (e. g. hypertension, diabetes); they recognized their own health-related problems and attended courses to change their problematic health behaviours more frequently. According to the patients' evaluations, however, these offers of courses are not very helpful. CONCLUSION: Changing the contents and implementations of health courses seems necessary to decrease costs and improve quality in the health care system on a long-term basis.

Impact of selective prostaglandin E1 treatment on graft perfusion and function after liver transplantation.

BACKGROUND/AIMS: In several clinical trials, the prophylactic application of prostaglandin E1 did not demonstrate a significant effect on incidence of primary graft nonfunction after liver transplantation. The aim of this study was to evaluate the effect of a selective prostaglandin E1 treatment in liver transplant patients with initially compromised perfusion and thereby depressed early posttransplant graft function. METHODOLOGY: A total of 142 patients were enrolled in this study. In all of them, duplexsonography was performed daily to generally assess patency of allograft vessels and to specifically calculate the resistive index of the hepatic artery. Intravenous therapy with a prostaglandin E1 analogue (Alprostadil, 0.5 microg/kg/h) was initiated in 67 patients after determination of a primarily elevated (>0.75) and posttransplant increasing resistive index of the hepatic artery that was associated with continuously elevating aminotransferases. RESULTS: After initiation of treatment, the arterial resistive index decreased significantly from 0.83+/-0.1 to 0.72+/-0.1 on the first day of application (P<0.05). Primarily elevated serum levels of aspartate aminotransferase (AST: Alprostadil: 890+/-180 IU/L: CONTROL: 375+/-98 IU/L) and alanine aminotransferase (ALT: Alprostadil: 850+/-178 IU/L, CONTROL: 310+/-79 IU/L) decreased significantly and reached values comparable to the control group after three days of therapy (AST: Alprostadil: 190+/-40 IU/L, CONTROL: 150+/-45 IU/L ALT: Alprostadil: 280+/-57 IU/L, CONTROL: 180+/-50 IU/L) (P<0.05). Only 2 grafts with initial compromised perfusion and function (3%) developed primary graft nonfunction. CONCLUSIONS: Prostaglandin E1 seems to be effective in ameliorating ischemia-reperfusion injury to the liver in patients with elevated arterial vascular resistance and early depressed graft function after liver transplantation. Duplexsonography in combination with graft function are useful tools for indicating and monitoring treatment.

[Aim, design and methods of the "Hypertension and diabetes screening and awareness" -- (HYDRA) study]. / Ziel, Design und Methodik der "Hypertension and Diabetes Risk Screening and Awareness"-(HYDRA)-Studie.

Aim of the study is a comprehensive clinical-epidemiological description of the prevalence of arterial hypertension and diabetes among primary care patients along with an assessment of doctor's recognition rates and prescription behaviour. The paper describes methods and design of the study and provides background information on the sampling process, instruments used as well as characteristics of doctors and patients. The study is based on a nationally representative sample of 1,912 primary care doctors and 45,000 patients that attended the doctors' office on the target days. The patients were also characterized by laboratory tests. The first stage of study consisted of a comprehensive description of the doctors' characteristics in terms of psychosocial, qualification- and provider aspects as well as attitudes towards hypertension and diabetes and their management. In the second stage all patients completed a questionnaire to describe their health behaviour and attitudes as well as the treatment history and therapy. In the third stage all patients were characterized by their doctors in terms of their diagnostic status and their past and current interventions.

[Management of diabetes and hypertension: how do primary care physicians judge their performance?]. / Wie beurteilen Arzte ihre Versorgungspraxis bei Diabetes mellitus und arterieller Hypertonie? Die "Hypertension and Diabetes Risk Screening and Awareness-(HYDRA)"-Vorstudie.

With regard to the management of hypertension and diabetes, HYDRA reveals that doctors report multiple problems in their everyday practice. Being confronted with an average of 73 patients a day, with almost every second having either diabetes or hypertension, frequently associated with multiple comorbid conditions, the core obstacle is the time factor. Doctors do not have sufficient time to perform diagnostic tests and especially no time for non-drug interventions of any type. Further available treatment guidelines are only used in 1 out of 2 doctors. Further they seem not to affect doctors performance significantly.

[Hypertension, diabetes mellitus and comorbidity in primary care]. / Arterielle Hypertonie, Diabetes mellitus und assoziierte Erkrankungen in der Allgemeinarztpraxis. Grössenordnung und Indikatoren der Belastung und der Versorgungsqualität.

Almost every second patient seeing a primary care doctor suffers from arterial hypertension and about every fifth has diabetes mellitus. These diseases often occur at the same time. They are associated in more than 80% of the cases with other severe concomitant and subsequent diseases (heart attack, stroke, renal failure, neuropathy etc.). The magnitude especially of subsequent and concomitant diseases, the dimension of the personal suffering and the immense diagnostic and therapeutic challenges for the doctors have been massively underestimated so far. The article informs about the prevalence of the above disease, and structure of the problem. Before the background of an extremely high patient load seen by German General Physicians, the mainstay challenge is highlighted how to achieve further improvements of the quality of care on the basis of scientific guidelines alone, without a concomitant change in the system structure.

Inactivation of interleukin-6 by neutrophil proteases at sites of inflammation. Protective effects of soluble IL-6 receptor chains.

In contrast to the excessively elevated immunochemically detectable concentrations of interleukin-6 (IL-6) in inflammatory exudates, the IL-6 bioactivities are significantly reduced, suggesting an inactivation of IL-6 at sites of inflammation. Since high amounts of proteases are released by invading neutrophils (PMN) in close temporal correlation to elevated IL-6 concentrations at sites of inflammation, this study focused on effects of the PMN-derived proteases elastase (NE), proteinase 3 (PR 3) and cathepsin G (Cat G) on the bioactivity and molecular integrity of IL-6. Here, we demonstrate that these enzymes play a crucial role in the initiation of the degradation and subsequent inactivation of IL-6 at sites of inflammation. Soluble IL-6 receptor subunits elicit a protective effect against the IL-6 inactivation by Cat G, only. Possible consequences of the proteolytical IL-6 inactivation for local inflammatory processes will be discussed.

Evidence for a crucial role of neutrophil-derived serine proteases in the inactivation of interleukin-6 at sites of inflammation.

The bioactivity of interleukin-6 (IL-6) was found to be dramatically reduced in fluids from sites of inflammation. Here, we provide evidence that the neutrophil-derived serine proteases elastase, proteinase 3 and cathepsin G are mainly involved in its degradation and subsequent inactivation. The initially hydrolyzed peptide bonds were detected to be Val(11)-Ala(12) and Leu(19)-Thr(20) (elastase), Phe(78)-Asn(79) (cathepsin G) and Ala(145)-Ser(146) (proteinase 3). The soluble IL-6 receptor elicits a protective effect against the IL-6 inactivation by cathepsin G only. The inactivation of IL-6 by neutrophil-derived serine proteases might act as a feedback mechanism terminating the IL-6-induced activation of neutrophils.