Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Accuracy of Parathyroid Adenoma Localization by Preoperative Ultrasound and Sestamibi in 1089 Patients with Primary Hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (pHPT) is well treatable surgically. Sonography (US) and sestamibi scintigraphy (MIBI) are used routinely, but it is unclear how valuable they are in determining Parathyroid glands' different locations. This study aimed to evaluate the prognostic value of US and MIBI in relation to the different localization of parathyroid adenomas in one of the largest study populations analyzed to date. METHODS: 1089 patients with pHPT who had treatment in one tertiary referral center between 2007 and 2016 were analyzed. Preoperative US and MIBI reports were compared with the parathyroid adenoma's intraoperative localization. All parathyroid glands were confirmed by histological diagnosis. RESULTS: No gland was detectable in 22.5% and 27.7% of all patients, by US or by MIBI, respectively. In relation to the different adenoma locations, the sensitivity of US ranged from 21.3% (upper right) to 68.9% (lower left) and of MIBI ranged from 23.5% (upper right) to 72% (lower left). The specificity for US ranged from 85% (lower right) to 99.2% (upper right) and for MIBI ranged from 86.1% (lower right) to 99.1% (upper right. Positive predictive values for all gland sites were 54% and 59% for MIBI and US, respectively. The value increased for side-only prediction to 73% and 78%, respectively. Neither the parathyroid hormone level nor the calcium value level influenced the sensitivity or specificity of the two test methods. CONCLUSIONS: The validity of preoperative US and MIBI depends crucially on the specific localization of adenomas. This should be considered when planning the extent of parathyroid surgery.

Flotillin-2 expression in the human gut: from a cell model to human tissue in health and inflammatory bowel diseases.

BACKGROUND AND AIMS: The etiopathogenesis of inflammatory bowel diseases (IBD) remains largely unexplained. Flotillins (flotillin-1 and flotillin-2) are ubiquitous proteins which have been linked to inflammation and regeneration. We hypothesized that alterations in the expression of flotillin-2 in enterocytes may be related to the pathogenesis of IBD as a classical example of an inflammatory disorder of mostly unknown origin. METHODS: Cell and tissue localization of flotillin-2 (and -1) were investigated by immunofluorescent staining in 1. polarized and unpolarized CaCo-2w cells as a model of human enterocytes (native and after TNFα stimulation) and 2. intestinal biopsies from controls, patients with ulcerative colitis (UC) and patients with Crohn's disease (CD). For quantification of flotillin-2, we analyzed its expression in ileal and colonic biopsies from controls, UC patients and CD patients using real-time RT-PCR, Western blot and indirect immunofluorescence. RESULTS: In polarized CaCo-2w cells and human enterocytes in biopsies, flotillins were localized at the basolateral membrane and on subapical vesicles, but not in the apical membrane. Flotillin-2 expression did not differ between UC patients, CD patients and controls. However, it was significantly higher in colonic biopsies compared to ileal biopsies in all groups. CONCLUSIONS: By virtue of its abundant expression in enterocytes, flotillin-2 must have an essential function in intestinal physiology, especially in the colon. Yet our data could not link flotillin-2 to the pathogenesis of IBD.

Adenoma weight: the only predictive factor for multiple gland disease in primary hyperparathyroidism.

BACKGROUND: Predicting a multiple gland disease (MGD) in primary hyperparathyroidism (pHPT) remains challenging. This study aimed to evaluate predictive factors for MGD. METHODS: A retrospective chart review was performed of 1211 patients with histologically confirmed parathyroid adenoma or hyperplasia between 2007-2016. Localization diagnostics, laboratory parameters, and the weight of the resected parathyroid glands were evaluated concerning their predictive value of a multiple-gland disease. RESULTS: A number of 1111 (91.7%) had a single-gland disease (SGD), and 100 (8.3%) a multiple-gland disease (MGD). US and MIBI scans were comparable for either negative or positive adenoma localization and suspected MGD. While the PTH level was similar, the calcium level was higher in SGD (2.8 mmol/L versus 2.76 mmol/L, P=0.034). MGD had a significantly lower gland weight (0.78 g versus 0.31 g; P<0.001). A gland weight of 0.418 grams was a predictive factor for MGD with a sensitivity of 72% and a specificity of 66%. CONCLUSIONS: Only the weight of the resected parathyroid adenoma was meaningful in predicting MGD. A cut-off value of 0.418 g can differentiate SGD from MGD.

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

Immunomonitoring of nuclear factor of activated T cells-regulated gene expression: the first clinical trial in liver allograft recipients.

Long-term calcineurin inhibitor (CNI) treatment can cause serious side effects in liver allograft recipients. An optimal risk-to-benefit ratio for CNI blood levels has not been established. Pharmacodynamic drug monitoring through the measurement of the CNI biological activity, that is, the expression of nuclear factor of activated T cells (NFAT)-regulated genes, seems to be a promising approach. The residual gene expression (RGE) of NFAT-regulated genes 2 and 1.5 hours after cyclosporine A (CsA) and tacrolimus (FK-506) intake was measured in 100 liver allograft recipients with 1 or more years of follow-up post-transplantation. The mean RGE in all patients was 62% ± 33%. A significant negative correlation between the CsA (P < 0.0001, r = -0.8026) and FK-506 peak levels (P < 0.0001, r = -0.6982) and the RGE of all NFAT-regulated genes was observed. Clinical reliability was proven too. In conclusion, the data presented in this pilot study reveal the applicability of the pharmacodynamic monitoring of CNI efficacy in liver allograft recipients. To confirm the advantage of individualized pharmacodynamic drug monitoring over pharmacokinetic drug monitoring with respect to clinical outcomes, controlled, prospective studies are needed.

Reduced hydrophobicity of the colonic mucosal surface in ulcerative colitis as a hint at a physicochemical barrier defect.

PURPOSE: There is increasing evidence that a defect of the gastrointestinal mucosal barrier is important for the development of inflammatory bowel diseases (IBD). The hydrophobicity of the colonic mucosal surface is a measure of its resistance to luminal antigens, e.g. of bacterial origin. Therefore, the purpose of this study was to determine this parameter in patients suffering from IBD. METHODS: Nineteen patients with ulcerative colitis (UC), ten patients with Crohn's disease (CD) and 20 controls were examined. All underwent colonic surgery at the University Hospital Heidelberg. Clinical disease activity was determined. From every subject, colonic tissue specimens were obtained, and hydrophobicity of the mucosal surface was determined with a goniometer by multiple plateau contact angle measurements. Histological evaluation of disease activity was performed in directly adjacent tissue specimens. RESULTS: Hydrophobicity of the colonic mucosal surface, expressed as plateau contact angles, was significantly reduced in patients with UC (mean ± SEM, 47.8° ± 3.4°) compared to those with CD (72.0° ± 5.2°) and controls (72.5° ± 5.6°; over-all P = 0.0004; UC versus controls, P < 0.001; UC versus CD, P < 0.05; CD versus controls, P > 0.05). Between mucosal hydrophobicity and clinical disease activity, as well as mucosal hydrophobicity and histological disease activity, no significant correlation was found. CONCLUSIONS: The results suggest a defective physicochemical barrier as an essential factor in the pathogenesis of UC, but not CD. The fact that no correlation was found between mucosal hydrophobicity and disease activity may indicate that the loss of mucosal hydrophobicity in UC is not exclusively a secondary effect due to inflammation.

Myocardial late gadolinium enhancement cardiovascular magnetic resonance in patients with cirrhosis.

BACKGROUND: Portal hypertension and cardiac alterations previously described as "cirrhotic cardiomyopathy" are known complications of end stage liver disease (ELD). Cardiac failure contributes to morbidity and mortality, particularly after liver transplantation and transjugular intrahepatic portosystemic shunt (TIPS). We sought to identify myocardial tissue characterization and evaluate cardiovascular magnetic resonance (CMR) for diagnosis of cardiac impairment. RESULTS: Twenty ELD patients underwent CMR for morphological, functional and tissue characterization by late gadolinium enhancement (LGE). Based on extent of LGE, patients were dichotomized into high and low LGE groups and analyzed regarding liver, cardiocirculatory and renal functions. CMR demonstrated hyperdynamic left ventricular function and a patchy pattern of LGE of the myocardium to a variable extent (range 2-62%) in all patients. There were no significant differences in Model for End-Stage Liver Disease (MELD), Child-Pugh score or the left ventricular ejection fraction between high and low LGE groups. QTc-interval was prolonged in 25% of the patients. E/A ratio was at the upper limit of norm; no difference between groups. Patients showing high LGE had a higher CI (p < 0.05). Biomarkers of myocardial stress were elevated. While NT-proBNP and c-Troponin-T showed no differences, PLGF and sFLT1 were lower in the high LGE group. CONCLUSION: CMR shows myocardial involvement in patients with ELD resembling appearance of myocarditis. The hyperdynamic circulation in portal hypertension may be an important factor. Larger prospective trials are warranted to confirm the association with severity and outcome of liver disease and to test the predictive power of CMR for patients listed for liver transplantation.

Budd-Chiari syndrome: long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt.

BACKGROUND: Budd-Chiari syndrome (BCS) generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Treatment depends on the underlying cause, the anatomic location, the extent of the thrombotic process and the functional capacity of the liver. It can be divided into medical treatment including anticoagulation and thrombolysis, radiological procedures such as angioplasty and transjugular intrahepatic porto-systemic shunt (TIPS) and surgical interventions including orthotopic liver transplantation (OLT). Controlled trials or reports on larger cohorts are limited due to rare disease frequency. The aim of this study was to report our single centre long term results of patients with BCS receiving one of three treatment options i.e. medication only, TIPS or OLT on an individually based decision of our local expert group. METHODS: 20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome. RESULTS: 16 women and 4 men with a mean age of 34 +/- 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 +/- 2.4 revisions (range: 0-8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively. CONCLUSION: Our results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS.

Transcript levels of different cytokines and chemokines correlate with clinical and endoscopic activity in ulcerative colitis.

BACKGROUND: A definition of disease activity in ulcerative colitis (UC) is difficult. The clinical activity index (CAI) is only an indirect assessment tool of bowel inflammation and the endoscopic activity index (EAI) sometimes cannot reflect the severity of disease to the full extent. Therefore, there is a need for an objective means to quantify inflammatory activity in mucosal biopsies. In our study, we wanted to examine the correlation between transcript levels of interleukin 8 (CXCL8), interferon gamma inducible protein 10 (CXCL10), myeloid-related protein 14 (calgranulin B), macrophage inflammatory protein 2 alpha (CXCL2) with CAI and EAI in UC. METHODS: Cytokine and chemokine transcripts were quantified using real-time PCR in 49 mucosal biopsies from 27 different patients with UC. Cytokine transcript levels were correlated with CAI and EAI. RESULTS: There was a statistically significant positive correlation between CXCL8 (r = 0.30; p < 0.05), CXCL10 (r = 0.40; p < 0.02), calgranulin B (r = 0.36; p < 0.03), CXCL2 (r = 0.31; p < 0.05) and CAI. Concerning EAI significant positive correlations for CXCL8 (r = 0.37; p < 0.02), CXCL10 (r = 0.33; p < 0.04), calgranulin B (r = 0.31; p < 0.05) and CXCL2 (r = 0.44; p < 0.05) were found. Low clinical and endoscopic activity was accompanied by low cytokine levels whereas high CAI and EAI were associated with high cytokine levels. CONCLUSION: From our data, we conclude that real-time PCR quantification of CXCL8, CXCL10, calgranulin B and CXCL2 in colonic biopsies is a simple and objective method for grading inflammation of intestinal mucosa in UC. CXCL8, CXCL10, calgranulin B and CXCL2 might be used as biomarkers and thus as an objective tool especially in clinical trials to evaluate anti-inflammatory and immunomodulatory regimens.

Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation.

BACKGROUND: Decompensated cirrhosis is associated with a poor prognosis and liver transplantation provides the only curative treatment option with excellent long-term results. The relative shortage of organ donors renders the allocation algorithms of organs essential. The optimal strategy based on scoring systems and/or waiting time is still under debate. METHODS: Data sets of 268 consecutive patients listed for single-organ liver transplantation for nonfulminant liver disease between 2003 and 2005 were included into the study. The Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores of all patients at the time of listing were used for calculation. The predictive ability not only for mortality on the waiting list but also for the need for withdrawal from the waiting list was calculated for both scores. The Mann-Whitney-U Test was used for the univariate analysis and the AUC-Model for discrimination of the scores. RESULTS: In the univariate analysis comparing patients who are still on the waiting list and patients who died or were removed from the waiting list due to poor conditions, the serum albumin, bilirubin INR, and CTP and MELD scores as well as the presence of ascites and encephalopathy were significantly different between the groups (p < 0.05), whereas serum creatinine and urea showed no difference. Comparing the predictive abilities of CTP and MELD scores, the best discrimination between patients still alive on the waiting list and patients who died on or were removed from the waiting list was achieved at a CTP score of >or=9 and a MELD score of >or=14.4. The sensitivity and specificity to identify mortality or severe deterioration for CTP was 69.0% and 70.5%, respectively; for MELD, it was 62.1% and 72.7%, respectively. This result was supported by the AUC analysis showing a strong trend for superiority of CTP over MELD scores (AUROC 0.73 and 0.68, resp.; p = 0.091). CONCLUSION: The long term prediction of mortality or removal from waiting list in patients awaiting liver transplantation might be better assessed by the CTP score than the MELD score. This might have implications for the development of new improved scoring systems.

Alterations in intestinal fatty acid metabolism in inflammatory bowel disease.

Inflammatory bowel disease (IBD) constitutes a severe intestinal disorder in developed countries with increasing incidence worldwide. Upcoming evidence indicates an important role of intestinal epithelial barrier function in the development of IBD. Fatty acids exert nutritional and protective effects on enterocytes, serve as activators of transcription and constitute precursors of inflammatory mediators. The aim of this study was to investigate differential regulation of genes involved in fatty acid uptake and endogenous fatty acid biosynthesis in IBD. Mucosal biopsy specimens from non-affected regions of the intestine were subjected to DNA microarray analysis. Gene array analysis revealed a variety of genes involved in fatty acid uptake and synthesis to be differentially expressed in ileum and colon of selected IBD patients. To verify these results, real-time RT-PCR was performed for selected regulated candidate genes in larger IBD sample numbers. In single biopsy analysis long chain acyl-CoA synthetase (ACSL) 1 and 4 were upregulated in IBD (P<0.05), while a significant decrease in fatty acid synthase expression was found in ileum and colon of ulcerative colitis patients (P<0.001). Expression of the transcription factor liver X receptor (LXR) which was previously shown to induce fatty acid synthase gene expression was not altered on mRNA level in IBD. However, in cell culture experiments using the human intestinal cell line LS174T induction of fatty acid synthase by the LXR ligand T0901317 was inhibited by TNFalpha. Moreover, these experiments indicated a decrease of LXR protein levels by TNFalpha treatment. These data suggest that the decrease of fatty acid synthase expression in ulcerative colitis patients could be at least partially due to a loss of LXR expression and function in the presence of pro-inflammatory cytokines. Observed alterations in expression of genes of fatty acid metabolism may contribute to the pathophysiology of ulcerative colitis.

Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease.

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappaB (NFkappaB) binding sites in each promoter. Furthermore, NFkappaB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-alpha and transforming growth factor-beta, which could be blocked by NFkappaB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P = 0.003) polymorphism with CD and for MUC4-A585S (P = 0.025), as well as MUC13-R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFkappaB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

Aquaporin-8 expression is reduced in ileum and induced in colon of patients with ulcerative colitis.

AIM: To study susceptibility genes which may play a potential role in the pathogenesis and etiology of inflammatory bowel disease (IBD). METHODS: To identify potential susceptibility genes we performed global gene expression profiling in patients with IBD and control specimens. For determination of an intrinsic gene expression profile in ulcerative colitis (UC) and Crohn's disease (CD) compared to normal subjects, mucosal biopsies of non-inflamed regions of the colon and the terminal ileum were subjected to DNA microarray analysis. Real-time RT-PCR and immunohistochemistry were used for verification of selected regulated candidate genes and a genetic analysis was performed. RESULTS: We could show that aquaporin-8 (AQP8) mRNA and protein levels were significantly increased in the colon of UC patients compared to controls. Genetic analysis of the six exons and the promoter region of AQP8, however, revealed no mutations or polymorphisms in IBD patients. CONCLUSION: Our results suggest that upregulation of AQP8 in the colon of UC patients represents a secondary phenomenon which may, due to altered water exchange of the distal intestinal mucosa, disturb the physiologic colonic mucus barrier and thus lead to chronic inflammation and ulceration.

Health-related quality of life correlates with clinical and endoscopic activity indexes but not with demographic features in patients with ulcerative colitis.

BACKGROUND: Inflammatory bowel disease (IBD) impairs health-related quality of life (HRQOL). Our aim was to investigate whether the improvement in the Clinical Activity Index (CAI) and Endoscopic Activity Index (EAI) is significantly correlated with the advancement of HRQOL and its dimensions in ulcerative colitis (UC) and to assess whether demographic and disease-related factors influence patients' experience of HRQOL. This examination was performed in the context of our recently published study of the anti-inflammatory effect of phosphatidylcholine in UC. METHODS: Sixty patients with chronic active UC were treated with phosphatidylcholine or placebo over 3 months. They were asked to complete the Inflammatory Bowel Disease Questionnaire-Deutschland (IBDQ-D) before and after the study. The correlations between CAI and EAI and IBDQ-D scores were calculated. Demographic and disease-related factors were obtained. RESULTS: A statistically significant lowering of CAI and EAI after treatment in the phosphatidylcholine group led to a statistically significant improvement in HRQOL (r = -0.623, P = 0.0003 for CAI; r = -0.511, P = 0.005 for EAI). Constant disease activity indexes in the placebo group accompanied constant HRQOL (r = -0.747, P < 0.0001 for CAI; r = -0.634, P = 0.0002 for EAI). Furthermore, besides a few exceptions, significant correlations between CAI and EAI and the 4 dimensions of the IBDQ-D could be shown. Demographic parameters did not significantly influence the IBDQ-D scores. CONCLUSIONS: This study points out the strong relationship between CAI and EAI and all domains of HRQOL in patients with UC. Therefore, the IBDQ-D is a valid and reliable assessment tool that reflects changes in the health status of UC patients. It is a useful measure of therapeutic efficacy and should be used in clinical trials in IBD.

Pharmacodynamic monitoring of nuclear factor of activated T cell-regulated gene expression in liver allograft recipients on immunosuppressive therapy with calcineurin inhibitors in the course of time and correlation with acute rejection episodes--a prospective study.

BACKGROUND: Due to considerable pharmacokinetic (PK) variability, immunosuppression with calcineurin inhibitors (CNIs) remains challenging. The objective of this study was to assess a pharmacodynamic (PD) approach of monitoring nuclear factor of activated T cell (NFAT)-regulated gene expression in the course of time and in correlation with rejection episodes. MATERIAL/METHODS: 22 de novo liver allograft recipients were observed for a period of up to 12 months and the residual gene expression (RGE) of NFAT-regulated genes was monitored prospectively and correlated to acute rejection episodes. RESULTS: There was a significant increase in RGEs between the time points 4-7 months and 1 month (25±7 µg/l vs. 9±5 µg/l, p≤0.0001) and 8-12 months and 1 month (50±8 µg/l vs. 10±7 µg/l, p=0.002) in the cyclosporine A (CsA) group, whereas in the tacrolimus (Tac) group a significant increase in RGEs appeared at the time point 8-12 months first. Acute rejection episodes occurred in 4 patients within 1 month after transplantation. These patients demonstrated a higher RGE of all NFAT-regulated genes compared to the other patients (CsA-treated patients: 39±0% vs. 11±5%, p=0.0001, Tac-treated patients: 48±12% vs. 18±10%, p=0.0082). CONCLUSIONS: RGE of all NFAT-regulated genes show a relation between acute rejection episodes in the early post transplant period. Thus, this PD method has the potential to aid therapeutic drug monitoring.

Mycophenolate mofetil combination therapy improves survival after liver transplantation. A single-center retrospective analysis.

BACKGROUND: Because the immunosuppressive regimen is a modifiable risk factor after orthotopic liver transplantation (OLT), physicians are nowadays aiming at an optimized and individualized strategy for each patient. The aim of this retrospective study was to examine the impact of different immunosuppressive regimens on the long-term outcome post-OLT based on routine, real-life situations, with particular focus on the subgroups of patients with HCC or HCV. MATERIAL AND METHODS: Our study included 186 patients who underwent OLT between 1999 and 2008 at the University Hospital Heidelberg, Germany with an available minimum follow-up period of 12 months. Data were collected pre-transplantation, and at 3 months, 6 months, and 12 months post-OLT and every 6 months afterwards. RESULTS: We found a statistically significant better 5-year survival in the calcineurin inhibitor (CNI) + mycophenolate mofetil (MMF) group vs. CNI - MMF (p=0.01) in the whole study group, in the HCC group (p=0.008), and in the HCV group (p=0.0163). Furthermore, there was a trend towards a prolonged HCV relapse-free 5-year survival rate in the CNI + MMF group of 85.6% vs. 70.8% in the CNI - MMF group, a trend towards a lower incidence of death secondary to infection (30.8% vs. 69.2%), and a trend towards lower rates of acute rejections (22.6% vs. 29%). The type of CNI administered was irrelevant in all respects. CONCLUSIONS: MMF added to immunosuppressive therapy improves patient survival in OLT recipients in general, as well as in patients with HCC and HCV. Prospective studies are needed to determine if a broader application of MMF post-OLT in combination with CNI-tapering could lead to further outcome improvement.

Factors influencing long-term quality of life and depression in German liver transplant recipients: a single-centre cross-sectional study.

BACKGROUND: Health-related quality of life (HRQOL) following orthotopic liver transplantation (OLT) has become increasingly important. Therefore, we aimed to identify factors affecting HRQOL after OLT. MATERIAL AND METHODS: This cross-sectional, single-centre study surveyed 281 OLT patients. Survey tools included the Short Form (SF-36) Health Survey, the Patient Health Questionnaire 9 (PHQ9), and a self-designed employment questionnaire. Patient medical records were reviewed. RESULTS: Participants included 187 men (mean age at OLT: 50 [± 11; 13-69] years). Primary indications for OLT were viral hepatitis (28%), alcoholic liver disease (35%), cholestatic liver disease (11%), and others (26%). Follow-up ranged from 2 to 136 months. Clinical factors associated with improved HRQOL were age ≤ 45 years at OLT and current MELD score <=≤ 13. Time after OLT and indication for transplantation affected SF-36 HRQOL. SF-36 physical component summary scales plateaued at 3-years post-OLT and then stabilized. For the SF-36 HRQOL, scores were the lowest in all domains for OLT recipients transplanted for chronic viral hepatitis and for unemployed patients, whereas sex and number of transplantations showed no significant differences. The PHQ9 results showed that depression was significantly more frequent among patients with current MELD score ≥ 13 or impaired liver function and those transplanted for chronic viral hepatitis or unemployed patients. Age and sex did not influence PHQ9 results. CONCLUSIONS: Medical and psychosocial support is crucial for long-term HRQOL after OLT. Developing multidisciplinary interventions to address issues such as employment, age, MELD score, and liver function may improve long-term HRQOL in these patients.

Low levels of prothrombin time (INR) and platelets do not increase the risk of significant bleeding when placing central venous catheters.

BACKGROUND AND PURPOSE: Central venous catheters are frequently placed in intensive care medicine for multiple indications. The risk of severe bleeding after cannulation is considered to be increased in patients with abnormal coagulation, common in critically ill patients. PATIENTS AND METHODS: This open prospective trial, performed at two medical intensive care units and one hematology intermediate care ward, investigated whether insertion of a central venous catheter in patients with coagulopathy (prothrombin time or= 1.5] and/or platelets

Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease.

AIM: To determine free and conjugated serum bile acid (BA) levels in inflammatory bowel disease (IBD) subgroups with defined clinical manifestations. METHODS: Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy controls by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS: Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the secondary BA lithocholic acid (LCA), was increased significantly in Crohn's disease (CD) and ulcerative colitis (UC), while most other serum BA species were decreased significantly. Total BA, total BA conjugate, and total BA glycoconjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as significantly increased as the secondary BAs LCA, ursodeoxycholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenodeoxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION: Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diagnostic characterization and differentiation of IBD subgroups with defined clinical manifestations.