Endoscopic mucosal resection and endoscopic submucosal dissection with an external additional working channel (EMR+ and ESD+) are equivalent to using a double-channel endoscope: a systematic evaluation in a porcine ex vivo model.

BACKGROUND AND AIMS: With an external additional working channel (AWC) endoscopic mucosal resection (EMR) as well as endoscopic submucosal dissection (ESD) can be extended to techniques termed "EMR+" and "ESD+." These novel techniques are systematically compared to EMR and ESD under the use of a double-channel endoscope (DC). METHODS: Our trial was conducted prospectively in a pre-clinical porcine animal model (EASIE-R simulator) with standardized gastric lesions measuring 3 or 4 cm. RESULTS: EMR+ and EMR DC showed both good results for 3 cm lesions with no adverse events and an en bloc resection rate of 73.33% (EMR+) and 60.00% (EMR DC, p = 0.70). They came to their limits in 4 cm lesions with muscularis damages of 20.00% (EMR+), 13.33% (EMR DC, p ≥ 0.99) and decreasing en bloc resection rates of 60.00% (EMR+) and 46.67% (EMR DC, p = 0.72). ESD+ and ESD DC were both reliable concerning en bloc resection rates (100% in all groups) and adverse events (0.00% in 3 cm lesions, 12.50% muscularis damages in both ESD+ and ESD DC in 4 cm lesions). Resection time was slightly shorter in all groups with the AWC compared to DC although only reaching significance in 3 cm ESD lesions (p < 0.05*). CONCLUSIONS: With the AWC, a standard endoscope can easily be transformed to double-channel functionality. We could show that EMR+ and ESD+ are non-inferior to EMR and ESD under the use of a double-channel endoscope. Consequently, the AWC presents an affordable alternative to a double-channel endoscope for both EMR and ESD.

Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis.

Tumor grading is a robust prognostic predictor in patients with neuroendocrine neoplasms (NEN) and guides therapy, especially in tumors with high proliferation. NEN can be separated into well-differentiated and poorly differentiated types. The more aggressive NEN have been further separated into neuroendocrine tumors (NET G3) with a better prognosis and neuroendocrine carcinomas (NEC) with a worse prognosis. Despite this distinction's tremendous clinical and therapeutic relevance, optimal diagnostic biomarkers are still lacking. In this study, we analyzed the protein expression and prognostic impact of Enhancer of Zeste Homolog 2 (EZH2) by immunohistochemistry in 219 tissue samples of gastroenteropancreatic (GEP-NEN) and pulmonary NEN (P-NEN). EZH2 was almost exclusively expressed in NEN with a proliferation rate above 20% (G3), while all low-grade tumors were nearly negative. Among high-grade NEN, 65% showed high and 35% low expression of EZH2. In this group, the high expression of EZH2 was significantly associated with poor overall survival and NEC histology. Interestingly, EZH2 seems to act independently of Polycomb Repressive Complex 2 (PRC2) in NEN. In conclusion, we propose EZH2 as a robust biomarker for distinguishing between NET G3 and NEC among gastroenteropancreatic and pulmonary NEN.

Systematic Retesting for Helicobacter pylori: The Potential Overestimation of Suppressive Conditions.

Background and Aims: In contrast to guideline recommendations, endoscopic testing for Helicobacter pylori is frequently performed under Helicobacter pylori suppressive conditions, e.g., intake of proton-pump inhibitors (PPI), preceded antibiotic treatment, or recent gastrointestinal bleeding. Our study's aim was to retest patients with-under suppressive conditions-negative test results. This was carried out in order to examine the rate of false negative tests previously gathered under suppressive conditions. Methods: The trial was conducted in a large patient collective in a university hospital. Every elective esophagogastroduodenoscopy from in- and outpatients was included. Prior to endoscopy, suppressive conditions were collected via standardized questionnaire. If Helicobacter pylori testing was indicated, both helicobacter urease test and histology were performed in analogy to the Sydney classification. In case of a negative result under suppressive conditions, the patient was reinvited after, if possible, withdrawal of suppressive condition in order to perform a urea breath test (UBT). Results: 1,216 patients were included (median 59 years, 72.0% inpatients, 28.0% outpatients). Overall, 60.6% (737) were under Helicobacter pylori suppressive conditions. The main suppressive condition was intake of PPIs (54.5%). In 53.7% (653) of all included cases, Helicobacter pylori testing was performed. Of those, 14.1% (92) had a positive test, and 85.9% (561) were negative. Out of the patients with negative result, 50.8% (285) were tested under suppressive conditions and consequently invited for retesting via UBT. In 20.4% (45), suppressive conditions could not be ceased. In 22.8% (65), retesting was conducted. Of those, 98.5% (64) congruently presented a negative result again, and only 1.5% (1) was positive for Helicobacter pylori. Conclusion: Many patients undergoing esophagogastroduodenoscopy in everyday clinical practice are tested for Helicobacter pylori under suppressive conditions leading to a potentially higher risk of false negative results. However, our research shows that this issue might be overestimated.

Pathological gallbladder wall thickening is associated with advanced chronic liver disease and independent of serum albumin.

PURPOSE: Increased gallbladder wall thickness (GBWT) is a common finding. Reported causes include advanced chronic liver disease (ACLD), ascites and hypalbuminemia. GBWT is a marker for the prediction of esophageal varices. It remains unclear which of these factors is the decisive driver of GBWT. We aim to investigate whether there is a predominant factor associated with the GBWT. METHODS: We enrolled 258 patients with ascites, hypalbuminemia and/or ACLD and 98 healthy volunteers that underwent abdominal ultrasound. Differences of mean GBWT in subgroups of patients with ACLD, ascites, and/or hypalbuminemia were analyzed. Correlation between various parameters and GBWT were calculated using multiple regression analysis. RESULTS: GBWT in patients with ACLD + ascites + hypalbuminemia (n = 59; 5.70 ± 2.05 mm) was pathologically increased compared to patients with hypalbuminemia + ascites without ACLD (n = 36; 2.14 ± 0.66 mm; p < .001) and to patients with only hypalbuminemia (n = 76; 2.02 ± 0.80 mm; p < .001). GBWT of patients with ACLD + hypalbuminemia (n = 30; 3.42 ± 1.52 mm) and with ACLD and normal albumin level were not different (n = 46; 3.10 ± 1.62 mm; p > .999). Significant correlation was seen between GBWT and ACLD (r = .53; p < .001) and ascites (r = .51; p < .001) but not albumin level (r = .04; p = .510). CONCLUSION: We demonstrate that ACLD is predominantly associated with GBWT. In contrast to the current literature, serum albumin level appears not to be associated with pathological GBWT.

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19.

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver's excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality.

Tunnelled Peritoneal Catheter for Malignant Ascites-An Open-Label, Prospective, Observational Trial.

Treatment of recurrent malignant ascites in cancer patients is a challenge. Evidence based guidelines regarding the best treatment strategy are lacking. The aim of this prospective study was to investigate the safety and efficacy of a tunnelled peritoneal catheter (PleurX) in cancer patients with symptomatic ascites. Patients with symptomatic, diuretics-refractory ascites and indication for the implantation of a tunnelled peritoneal PleurX catheter were prospectively enrolled between August 2018 and July 2020. The number of catheter days, complications, amount of drained ascites and ascites-associated symptoms and hospitalization rate pre- and post-PleurX insertion were analysed. 51 Patients (64.7% male) were prospectively enrolled. The mean age was 66.6 (±7.9) years. The most common cause of ascites was pancreatic adenocarcinoma (n = 10) followed by cholangiocellular carcinoma (n = 9) and hepatocellular carcinoma (n = 8). The technical success rate of PleurX implantation was 100%. The mean volume of weakly drained ascites was 5.44l (±4.08). Major complications included cellulitis (n = 2), peritonitis and drainage dislocation (each n = 1). The mean catheter days per patient was 59.8 (±107.4) (Min 4, Max 668). Abdominal discomfort, impaired mobility, dyspnoea, fatigue, nausea and vomiting were significantly reduced 30 days after PleurX insertion (p < 0.05). Moreover, hospitalization rate was significantly reduced (p < 0.001; 27.08% of days preimplantation vs. 11.27% postimplantation). We conclude that implantation of a tunnelled ascites catheter is a safe and effective method for the treatment of refractory ascites in cancer patients with advanced disease. Serious complications are rare. Burdensome ascites-associated symptoms and hospitalization rates can be significantly reduced over a longer period of time.

Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression.

BACKGROUND: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities. PATIENTS AND METHODS: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial. RESULTS: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts. CONCLUSION: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC.

Endoscopic submucosal dissection with an additional working channel (ESD+): a novel technique to improve procedure time and safety of ESD.

BACKGROUND AND AIMS: A new external additional working channel (AWC) was recently introduced by which endoscopic submucosal dissection (ESD) can be converted to a technique termed "ESD+ ". We aim to systematically evaluate this novel technique in flat gastric lesions and compare it to classical ESD. METHODS: The study was prospectively conducted in a pre-clinical ex vivo animal model (EASIE-R simulator) with porcine stomachs. Prior to intervention, we set standardized lesions measuring 3 cm or 4 cm in antegrade as well as in retrograde positions. RESULTS: Overall, 64 procedures were performed by an experienced endoscopist. Both techniques were reliable and showed en bloc resection rates of 100%. Overall, ESD+ reduced time of procedure compared to ESD (24.5 vs. 32.5 min, p = 0.025*). Particularly, ESD+ was significantly faster in retrograde lesions with a median of 22.5 vs. 34.0 min in 3 cm retrograde lesions (p = 0.002*) and 34.5 vs. 41.0 min (p = 0.011*) in 4 cm retrograde lesions. There were 0 perforations with both techniques. In ESD+ , 1 muscularis damage occurred (3.13%) compared to 6 muscularis damages with ESD (18.75%, p = 0.045*). CONCLUSIONS: By its grasp-and-mobilize technique, ESD+ allows potentially faster and safer resections of flat gastric lesions compared to conventional ESD in an ex vivo porcine model. The potential advantages of ESD+ in terms of procedure time may be particularly relevant for difficult lesions in retrograde positions.

Diagnostic accuracy of B-Mode ultrasound and Hepatorenal Index for graduation of hepatic steatosis in patients with chronic liver disease.

BACKGROUND/AIMS: The aim of our study was to evaluate the diagnostic accuracy of B-Mode ultrasound and Hepatorenal Index (HRI) by high-end devices for the detection and classification of hepatic steatosis in patients with various causes of chronic liver disease (CLD). METHODS: We retrospectively enrolled patients with CLD who underwent liver biopsy and baseline ultrasound between March 2016 and May 2019. Sonographic graduation of steatosis (0°-III°) using B-Mode criteria and HRI were correlated with the histological graduation (S0 (<5% fat), S1 (≥5-33%), S2 (>33-66%) and S3 (>66%). Interobserver agreement was calculated. RESULTS: 157 patients were evaluated. B-Mode ultrasound had a sensitivity of 75.6% and a specificity of 76.0% to differentiate between steatosis and no steatosis (AUROC 0.758). Using B-Mode criteria for advanced steatosis (≥II°), specificity for presence of histological steatosis was ≥98.7%. For detection of advanced steatosis (≥S2), sensitivity of B-mode criteria was 90.9%. In a subgroup of patients with advanced liver fibrosis, sensitivity of B-mode criteria was 95.0% for detection of advanced steatosis (S≥2). A HRI cut-off-value of 1.46 differentiates between patients with steatosis and patients without steatosis with a sensitivity of 42.7% and a specificity of 90.7% (AUROC 0.680). Interobserver agreement of both B-Mode and HRI was good to excellent. CONCLUSION: B-Mode ultrasound using high-end devices is an excellent method to detect advanced steatosis in patients with various CLD. For diagnosis of mild steatosis, modern ultrasound devices may have higher sensitivity but at the expense of specificity. Stage of fibrosis and etiology of CLD seem not to impact on diagnostic accuracy. The additional calculation of HRI seems to have no additional benefit with regard to detect or grade hepatic steatosis in our study population.

Endoscopic mucosal resection with an additional working channel (EMR+) in a porcine ex vivo model: a novel technique to improve en bloc resection rate of snare polypectomy.

Background and study aims Recently, a new external additional working channel (AWC) was introduced by which conventional endoscopic mucosal resection (EMR) can be improved to a technique termed "EMR+". We first evaluated this novel technique in comparison to classical EMR in flat lesions. Methods The trial was prospectively conducted in an ex vivo animal model with porcine stomachs placed into the EASIE-R simulator. Prior to intervention, standardized lesions were set by coagulation dots, measuring 1, 2, 3 or 4 cm. Results Overall, 152 procedures were performed. EMR and EMR+ were both very reliable in 1-cm lesions, each showing en bloc resection rates of 100 %. EMR+ en bloc resection rate was significantly higher in 2-cm lesions (95.44 % vs. 54.55 %, P  = 0.02), in 3-cm lesions (86.36 % vs. 18.18 %, P  < 0.01) and also in 4-cm lesions (60.00 % vs. 0 %, P  < 0.01). Perforations occurred only in EMR+ procedures in 4-cm lesions (3 of 20; 15 %). Conclusions With its grasp-and-snare technique, EMR+ facilitates en bloc resection of larger lesions compared to conventional EMR. In lesions 2 cm and larger, EMR+ has demonstrated advantages, especially concerning en bloc resection rate. At 3 cm, EMR+ reaches its best discriminatory power whereas EMR+ has inherent limits at 4 cm and in lesions of that size, other techniques such as ESD or surgery should be considered.

Noninvasive assessment of liver fibrosis in a real-world cohort of patients with known or suspected chronic liver disease using 2D-shear wave elastography.

OBJECTIVES: We aimed to investigate the diagnostic accuracy of liver stiffness measurement (LSM) by 2D-shear wave elastography (2D-SWE, GE, Logiq E9) in patients with known or suspected chronic liver disease and to define cutoff values for the different stages of fibrosis. METHODS: First, we retrospectively enrolled 21 patients in a pilot study and validated the results in a prospective cohort of 70 patients between May 2017 and February 2019. In all patients, LSM and liver biopsy were performed. We analyzed the diagnostic accuracy of LSM for the different fibrosis stages and examined the impact of additional clinical parameters on LSM. RESULTS: The success rate of LSM was 88.6%. In the prospective cohort, optimal cutoff values for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 were 6.24, 7.86, 8.05 and 10.74 kPa [area under the receiver operating characteristic curve (AUROC) 0.831, 0.913, 0.996 and 0.954]. In both cohorts and in the subgroup of patients with nonalcoholic fatty liver disease (NAFLD) (n = 35), a cutoff value of 8.05 kPa differentiates patients with advanced fibrosis (F ≥ 3) and patients with no or mild fibrosis (F0-F2) with high diagnostic accuracy (AUROC 0.995-1.000). Parameters such as age, sex, BMI, bilirubin- and alanine aminotransferase-level had no significant impact on LSM. CONCLUSION: LSM by 2D-SWE is an excellent method to differentiate between patients with advanced fibrosis (F ≥ 3) and patients with no or mild fibrosis (F ≤ 2). We were able to show this also in a subgroup of patients with NAFLD.

Testing of Helicobacter pylori by Endoscopic Biopsy: The Clinical Dilemma of Suppressive Conditions.

BACKGROUND AND AIMS: Testing for Helicobacter pylori is frequently conducted during esophagogastroduodenoscopy (EGD). Suppressive conditions such as the intake of proton-pump inhibitors (PPIs), preceded antibiotic treatment or recent upper gastrointestinal bleeding impair H. pylori test quality. The aim of our study was to evaluate the frequency and pattern of H. pylori suppressive conditions in a large patient collective undergoing elective EGD in a German university hospital. METHODS: The trial was performed as a single-center study. Only elective EGD from inpatients and outpatients were included. Prior to endoscopy, H. pylori suppressive conditions were collected using a standardized questionnaire. If H. pylori testing was indicated according to the guidelines, always both histology and helicobacter urease test were performed in analogy to the Sydney classification. RESULTS: One thousand six hundred and thirty-one patients were included (median 61 years, 36.0% outpatients, 64.0% inpatients). Overall, 76.5% of patients were under H. pylori suppressive conditions. The main suppressive condition was the intake of PPIs (70.7%). In 819 (50.2%) of all included cases, H. pylori testing was performed. The following were the results: 17.3% (142) had a positive H. pylori testing and 82.7% (677) were negative. Of those with negative result, 70.0% were tested under suppressive conditions. CONCLUSION: Guidelines recommend H. pylori testing under non-suppressive conditions. However, this does not always meet the clinical practice. Our data show that de facto, many patients undergoing elective EGD are tested for H. pylori under suppressive conditions coming along with a higher risk of potentially false negative results. Particularly, concerning this issue, further research is needed to improve and clarify everyday clinical practice.

Prospective comparison of 2D-shearwave elastography in both liver lobes in healthy subjects and in patients with chronic liver disease.

Background/aims: 2D-shearwave elastography is an established method for liver stiffness measurement (LSM). However, the success rate of LSM using the recommended standard technique in the right lobe is limited by several factors. We aimed to compare LSM in the right and left liver lobe in order to evaluate whether LSM in the left lobe could be an alternative if measurements in the right lobe are not feasible. Methods: A total of 116 subjects, 58 healthy volunteers and 58 patients with chronic liver disease (CLD), were prospectively included. LSM were performed in the right lobe and in the left lobe, both in neutral and in inspiration position. Results: LSM in the left lobe (8.39(±4.83)kPa) was significantly (p < .001) higher than LSM in the right lobe (6.27(±2.45)kPa). LSM in inspiration position (8.60(±4.33) kPa) was significantly (p = .009) higher than LSM in neutral position (7.70(±3.01)kPa). LSM in the left lobe overestimated the grade of fibrosis in 50.0% of the patients with CLD. However, correlation between LSM values right and left was strong (r = 0.856) and additional use of LSM in the left lobe increased the success rate from 106/116 (91.4%) to 112/116 (96.6%; p = .098). High skin-to-liver-capsule-distance and presence of ascites were independent risk factors for non-successful LSM. Conclusions: Despite significantly higher values, LSM in the left lobe may be an alternative if LSM in the right lobe is not feasible, and cirrhosis can be ruled out with high probability if LSM is within the normal range.

Evaluation of liver stiffness by 2D-SWE in combination with non-invasive parameters as predictors for esophageal varices in patients with advanced chronic liver disease.

Background/aims: Esophageal varices (EV) are common complications in patients with advanced chronic liver disease (ACLD). Non-invasive parameters to exclude EV in patients with ACLD would be desirable. The aim of this study was the evaluation of liver stiffness measurement (LSM) using 2D-shear wave elastography (GE Logiq E9) and other non-invasive parameters as predictors for EV. Methods: Hundred patients with ACLD were enrolled. Abdominal sonography, including measurement of gall bladder wall thickness (GBWT), spleen diameter and LSM, gastroscopy and blood test results were evaluated. Statistical analyses were performed for the association between EV and non-invasive parameters. Results: Fifty-one per cent of the patients had EV. The mean LSM (14.6 kPa) and GBWT (3.88 mm) in the group with EV were significantly higher than in the group without EV (10.6 kPa; 2.94 mm; p < .01). Performing area under the receiver operating characteristic curve, LSM has a better diagnostic performance (0.781) than GBWT (0.707), spleen diameter (0.672) and platelet count (0.635). Combining LSM (cut-off 13.58 kPa) and GBWT (cut-off 3.07 mm) resulted in a sensitivity of 86.3% and a specificity of 71.4% for the presence of EV. A sensitivity of 100% (negative predictive value 1.0) was achieved at LSM >9 kPa or GBWT >4 mm. Following these criteria in our current study population, 18% of the gastroscopies could have been avoided. Conclusions: Combining LSM with non-invasive parameters, especially GBWT, improves the diagnostic accuracy for predicting EV. We suggest reconsidering screening gastroscopy in patients with ACLD who show LSM <9 kPa and GBWT <4 mm due to the very low risk of having varices.

Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients.

Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce. Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily. Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period. Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.