Variation in the management of cT1 renal cancer by surgical hospital volume: A nationwide study.

Objectives: To analyse variation in clinical management of cT1 renal cell carcinoma (RCC) in the Netherlands related to surgical hospital volume (HV). Materials and methods: Patients diagnosed with cT1 RCC during 2014-2020 were identified in the Netherlands Cancer Registry. Patient and tumour characteristics were retrieved. Hospitals performing kidney cancer surgery were categorised by annual HV as low (HV < 25), medium (HV = 25-49) and high (HV > 50). Trends over time in nephron-sparing strategies for cT1a and cT1b were evaluated. Patient, tumour and treatment characteristics of (partial) nephrectomies were compared by HV. Variation in applied treatment was studied by HV. Results: Between 2014 and 2020, 10 964 patients were diagnosed with cT1 RCC. Over time, a clear increase in nephron-sparing management was observed. The majority of cT1a underwent a partial nephrectomy (PN), although less PNs were applied over time (from 48% in 2014 to 41% in 2020). Active surveillance (AS) was increasingly applied (from 18% to 32%). For cT1a, 85% received nephron-sparing management in all HV categories, either with AS, PN or focal therapy (FT). For T1b, radical nephrectomy (RN) remained the most common treatment (from 57% to 50%). Patients in high-volume hospitals underwent more often PN (35%) for T1b compared with medium HV (28%) and low HV (19%). Conclusion: HV is related to variation in the management of cT1 RCC in the Netherlands. The EAU guidelines have recommended PN as preferred treatment for cT1 RCC. In most patients with cT1a, nephron-sparing management was applied in all HV categories, although differences in applied strategy were found and PN was more frequently used in high HV. For T1b, high HV was associated with less appliance of RN, whereas PN was increasingly used. Therefore, closer guideline adherence was found in high-volume hospitals.

The AirSeal® insufflation device can entrain room air during routine operation.

BACKGROUND: Surgical procedures that use insufflation carry a risk of gas embolism, which is considered relatively harmless because of the high solubility of carbon dioxide. However, an in vitro study suggested that valveless insufflation devices may entrain non-medical room air into the surgical cavity. Our aim was to verify if this occurs in actual surgical procedures. METHODS: The oxygen percentage in the pneumoperitoneum or pneumorectum/pneumopelvis of eight patients operated with use of the AirSeal® was continuously measured, to determine the percentage of air in the total volume of the surgical cavity. RESULTS: Basal air percentage in the surgical cavity was 0-5%. During suctioning from the operative field air percentage increased to 45-65%. CONCLUSIONS: The AirSeal® valveless insufflation device maintains optimal distension of the surgical cavity not only by insufflating carbon dioxide, but also by entraining room air, especially during suctioning from the operative field. This may theoretically lead to air embolism in patients operated on with this device.

Available ablation energies to treat cT1 renal cell cancer: emerging technologies.

PURPOSE: An increasing interest in percutaneous ablation of renal tumors has been caused by the increasing incidence of SRMs, the trend toward minimally invasive nephron-sparing treatments and the rapid development of local ablative technologies. In the era of shared decision making, patient preference for non-invasive treatments also leads to an increasing demand for image-guided ablation. Although some guidelines still reserve ablation for poor surgical candidates, indications may soon expand as evidence for the use of the two most validated local ablative techniques, cryoablation (CA) and radiofrequency ablation (RFA), is accumulating. Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades, resulting in some new emerging types of ablations. METHODS: A literature search was conducted to identify original research articles investigating the clinical outcomes of new emerging technologies, percutaneous MWA, percutaneous IRE and SABR, in patients with primary cT1 localized renal cell cancer. RESULTS: Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades. New emerging technologies such as microwave ablation (MWA), irreversible electroporation (IRE) and stereotactic ablative radiotherapy (SABR) seem to be getting ready for prime time. CONCLUSION: This topical paper describes the new emerging technologies for cT1 localized renal cell cancer and investigates how they compare to CA and RFA.

Vimentin over-expression and carbonic anhydrase IX under-expression are independent predictors of recurrence, specific and overall survival in non-metastatic clear-cell renal carcinoma: a validation study.

PURPOSE: Clinical outcomes prognostic markers are awaited in clear-cell renal carcinoma (ccRCC) to improve patient-tailored management and to assess six different markers' influence on clinical outcomes from ccRCC specimen and their incremental value combined with TNM staging. MATERIALS AND METHODS: This is a retrospective, multicenter study. One hundred and forty-three patients with pT1b-pT3N0M0 ccRCC were included. Pathology specimens from surgeries were centrally reviewed, mounted on a tissue micro-array and stained with six markers: CAIX, c-MYC, Ki67, p53, vimentin and PTEN. Images were captured through an Ultra Fast Scanner. Tumor expression was measured with Image Pro Plus. Cytoplasmic markers (PTEN, CAIX, vimentin, c-MYC) were expressed as surface percentage of expression. Nuclear markers (Ki67, p53) were expressed as number of cells/mm2. Clinical data and markers expression were compared with clinical outcomes. Each variable was included in the Cox proportional multivariate analyses if p < 0.10 on univariate analyses. Discrimination of the new marker was calculated with Harrell's concordance index. RESULTS: At median follow-up of 63 months (IQR 35.0-91.8), on multivariate analysis, CAIX under-expression and vimentin over-expression were associated with worse survival (recurrence, specific and overall survival). A categorical marker CAIX-/Vimentin+ with cutoff points for CAIX and vimentin of 30 and 50 %, respectively, was designed. The new CAIX-/Vimentin+ marker presented a good concordance and comparable calibration to the reference model. Limitations are the retrospective design, the need for external validation and the large study period. CONCLUSION: Using an automated technique of measurement, CAIX and vimentin are independent predictors of clinical outcomes in ccRCC.

Optical Coherence Tomography as a Tool for In Vivo Staging and Grading of Upper Urinary Tract Urothelial Carcinoma: A Study of Diagnostic Accuracy.

PURPOSE: Biopsies and cytology are cornerstones in the diagnosis of upper urinary tract urothelial carcinoma. However, a high rate of nondiagnostic biopsies, tumor upgrading and tumor up staging after nephroureterectomy has been observed. In this prospective in vivo study we evaluated the diagnostic accuracy of optical coherence tomography for the grading and staging of upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 26 patients underwent diagnostic ureterorenoscopy including biopsies and optical coherence tomography, followed by nephroureterectomy or segmental ureter resection. The sensitivity, specificity, negative predictive value and positive predictive value of upper tract urothelial carcinoma grading and staging by optical coherence tomography were evaluated according to the STARD (Standards for Reporting of Diagnostic Accuracy) initiative and the second stage (2a and 2b) of the IDEAL model. For tumor staging a 2×2 table for sensitivity and specificity was calculated. For tumor grading the Wilcoxon rank sum test was used to test µoct in low and high grade lesions followed by ROC analysis for sensitivity and specificity. RESULTS: In 83% the staging of lesions was in accordance with final histopathology. Sensitivity and specificity analysis for tumor invasion was 100% and 92%, respectively. Tumor size greater than 2 mm and inflammation were risks for false-positives. For low and high grade lesions median µoct was 2.1 and 3.0 mm-1, respectively (p <0.01). ROC analysis showed a sensitivity of 87% and a specificity of 90% using a µoct cutoff of 2.4 mm-1. CONCLUSIONS: This report describes optical coherence tomography as a real-time, intraoperatively diagnostic modality in the diagnostic evaluation of upper tract urothelial carcinoma. We confirmed the ability of optical coherence tomography to visualize, grade and stage urothelial carcinoma in the upper urinary tract.

Cryoablation of small kidney tumors.

INTRODUCTION: Cryoablation (CA) has been broadly used mostly in the treatment of small renal masses (SRMs). The present review aims to define the current role of CA in the treatment of SRMs by assessing clinical indications and outcomes. METHOD: A comprehensive review on patient selection, procedural details, perioperative complications, and short/long-term oncological and functional outcomes was conducted. For each section, a take-home message was formulated with level of evidence (LoE) according to Cochrane collaboration. RESULTS: Age and comorbidity drive the choice of ablation in SRMs, although hospital setting also influences the decision. Technically in adequate CA or first post-CA control occurs in 3-5% of laparoscopic cryoablation (LCA) or percutaneous cryoablation (PCA) series. Meta-analysis does not evidence differences in the rate of residual tumor per person-year between the approaches (0.033 LCA vs. 0.046 PCA, p = 0.25). Perioperative complications (8-25%) are erratically reported. LCA has significantly lower likelihood of complications than minimally invasive partial nephrectomy (MIPN). Systematic reviews indicate 30-month local tumor progression rate of 8.5% for LCA in renal cell carcinoma but low metastatic progression (1-4.4%). Few LCA long-term follow-up series (mean/media 48-98 months) report recurrence-free survival (RFS) and cancer-specific survival (CSS) ranges of 80-100%. For PCA, Kaplan-Meier local disease-free survival (DFS) of 95.6% at 3-5 years [32] and 5-year overall survival and local RFS of 86.3% were reported. The decrease in renal function after CA is minimal, and the only risk factor associated is the basal estimated glomerular filtration rate (eGFR). CONCLUSION: LoE 3a/b confirms lower CA perioperative complication rate and higher local progression rate than those for MIPN. CA preserves postoperative renal functional, without any evidence of differences in mid-/long-term follow-up compared to nephron sparing surgery.

Follow-up after focal therapy in renal masses: an international multidisciplinary Delphi consensus project.

PURPOSE: To establish consensus on follow-up (FU) after focal therapy (FT) in renal masses. To formulate recommendations to aid in clinical practice and research. METHODS: Key topics and questions for consensus were identified from a systematic literature research. A Web-based questionnaire was distributed among participants selected based on their contribution to the literature and/or known expertise. Three rounds according to the Delphi method were performed online. Final discussion was conducted during the "8th International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer" among an international multidisciplinary expert panel. RESULTS: Sixty-two participants completed all three rounds of the online questionnaire. The panel recommended a minimum follow-up of 5 years, preferably extended to 10 years. The first FU was recommended at 3 months, with at least two imaging studies in the first year. Imaging was recommended biannually during the second year and annually thereafter. The panel recommended FU by means of CT scan with slice thickness ≤3 mm (at least three phases with excretory phase if suspicion of collecting system involvement) or mpMRI. Annual checkup for pulmonary metastasis by CT thorax was advised. Outside study protocols, biopsy during follow-up should only be performed in case of suspicion of residual/persistent disease or radiological recurrence. CONCLUSIONS: The consensus led to clear FU recommendations after FT of renal masses supported by a multidisciplinary expert panel. In spite of the low level of evidence, these recommendations can guide clinicians and create uniformity in the follow-up practice and for clinical research purposes.

Histopathological Outcomes after Irreversible Electroporation for Prostate Cancer: Results of an Ablate and Resect Study.

PURPOSE: Irreversible electroporation is a tissue ablation modality that uses high voltage electric energy to induce an increase in cell membrane permeability. This causes destabilization of the existing cellular transmembrane potential leading to cell death, due to the inability to maintain cellular homeostasis. This phase I-II study was designed to evaluate the histopathological outcomes of irreversible electroporation to prostate and surrounding tissue in radical prostatectomy specimens. MATERIALS AND METHODS: Sixteen patients with prostate cancer underwent an irreversible electroporation ablation without curative intent, followed by radical prostatectomy scheduled 4 weeks later. For histopathological examination of the prostate, whole mounted tissue slices were examined by dedicated genitourinary pathologists. The borders of the ablation zone and residual tumor were outlined on the slides. RESULTS: The irreversible electroporation ablation zones were characterized as areas of fibrosis, necrosis and loss of epithelial tissue in terms of denudation in the glandular structures. The ablation zone was well demarcated, showing trenchant delineations between viable and nonviable tissue. The ablated tissue showed mild to moderate inflammation, with atrophic cells in 1 case. The area was surrounded by hemorrhage at the location of the electrodes. No skip lesions or viable tissue was seen in the ablation zone. Fibrinoid necrosis of the neurovascular bundle was observed in 13 patients and denudation of the urothelium of the prostatic urethra was seen in 9. CONCLUSIONS: Histopathological assessment of the prostate 4 weeks after irreversible electroporation ablation showed sharply demarcated fibrotic and necrotic tissue in the ablation zone. No viable tissue was observed in the irreversible electroporation ablation zone.

The correlation between the electrode configuration and histopathology of irreversible electroporation ablations in prostate cancer patients.

PURPOSE: Irreversible electroporation (IRE) is a novel minimally invasive therapy for prostate cancer using short electric pulses to ablate prostate tissue. The purpose of this study is to determine the IRE effects in prostate tissue and correlate electrode configuration with the histology of radical prostatectomy (RP) specimens. We hypothesize that the area within the electrode configuration is completely ablated and that the area within the electrode configuration is predictive for the ablated area after treatment. METHODS: A prospective phase I/II study was conducted in 16 consecutive patients with histopathologically confirmed prostate cancer scheduled for RP. Focal or extended IRE treatment of the prostate was performed 4 weeks prior to RP. The locations of the electrodes were used to calculate the planned ablation zone. Following RP, the specimens were processed into whole-mount sections, histopathology (PA) was assessed and ablation zones were delineated. The area of the tissue alteration was determined by measuring the surface. The planned and the histological ablation zones were compared, analysed per individual patient and per protocol (focal vs. extended). RESULTS: All cells within the electrode configuration were completely ablated and consisted only of necrotic and fibrotic tissue without leaving any viable cells. The histological ablation zone was always larger than the electrodes configuration (2.9 times larger for the 3 electrodes configuration and 2.5 times larger for the ≥4 electrode configuration). These ablation effects extended beyond the prostatic capsule in the neurovascular bundle in 13 out of 15 cases. CONCLUSIONS: IRE in prostate cancer results in completely ablated, sharply demarcated lesions with a histological ablation zone beyond the electrode configuration. No skip lesions were observed within the electrode configuration. CLINICAL TRIALS: ClinicalTrials.gov Identifier: NCT01790451 https://clinicaltrials.gov/ct2/show/NCT01790451.

MRI and contrast-enhanced ultrasound imaging for evaluation of focal irreversible electroporation treatment: results from a phase I-II study in patients undergoing IRE followed by radical prostatectomy.

OBJECTIVES: Irreversible electroporation (IRE) is an ablative therapy with a low side-effect profile in prostate cancer. The objective was: 1) To compare the volumetric IRE ablation zone on grey-scale transrectal ultrasound (TRUS), contrast-enhanced ultrasound (CEUS) and multiparametric MRI (mpMRI) with histopathology findings; 2) To determine a reliable imaging modality to visualize the IRE ablation effects accurately. METHODS: A prospective phase I-II study was performed in 16 patients scheduled for radical prostatectomy (RP). IRE of the prostate was performed 4 weeks before RP. Prior to, and 4 weeks after the IRE treatment, imaging was performed by TRUS, CEUS, and mpMRI. 3D-analysis of the ablation volumes on imaging and on H&E-stained whole-mount sections was performed. The volumes were compared and the correlation was calculated. RESULTS: Evaluation of the imaging demonstrated that with T2-weighted MRI, dynamic contrast enhanced (DCE) MRI, and CEUS, effects of IRE are visible. T2MRI and CEUS closely match the volumes on histopathology (Pearson correlation r = 0.88 resp. 0.80). However, IRE is not visible with TRUS. CONCLUSIONS: mpMRI and CEUS are appropriate for assessing IRE effects and are the most feasible imaging modalities to visualize IRE ablation zone. The imaging is concordant with results of histopathological examination. KEY POINTS: • mpMRI and contrast-enhanced ultrasound are appropriate imaging modalities for assessing IRE effects • mpMRI and CEUS are the most feasible imaging modalities to visualize IRE ablation zone • The imaging is concordant with results of histopathological examination after IRE • Grey-scale US is insufficient for assessing IRE ablations.

The safety and efficacy of irreversible electroporation for the ablation of prostate cancer: a multicentre prospective human in vivo pilot study protocol.

INTRODUCTION: Current surgical and ablative treatment options for prostate cancer have a relatively high incidence of side effects, which may diminish the quality of life. The side effects are a consequence of procedure-related damage of the blood vessels, bowel, urethra or neurovascular bundle. Ablation with irreversible electroporation (IRE) has shown to be effective in destroying tumour cells and harbours the advantage of sparing surrounding tissue and vital structures. The aim of the study is to evaluate the safety and efficacy and to acquire data on patient experience of minimally invasive, transperineally image-guided IRE for the focal ablation of prostate cancer. METHODS AND ANALYSIS: In this multicentre pilot study, 16 patients with prostate cancer who are scheduled for a radical prostatectomy will undergo an IRE procedure, approximately 30 days prior to the radical prostatectomy. Data as adverse events, side effects, functional outcomes, pain and quality of life will be collected and patients will be controlled at 1 and 2 weeks post-IRE, 1 day preprostatectomy and postprostatectomy. Prior to the IRE procedure and the radical prostatectomy, all patients will undergo a multiparametric MRI and contrast-enhanced ultrasound of the prostate. The efficacy of ablation will be determined by whole mount histopathological examination, which will be correlated with the imaging of the ablation zone. ETHICS AND DISSEMINATION: The protocol is approved by the ethics committee at the coordinating centre (Academic Medical Center (AMC) Amsterdam) and by the local Institutional Review Board at the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. CONCLUSIONS: This pilot study will determine the safety and efficacy of IRE in the prostate. It will show the radiological and histopathological effects of IRE ablations and it will provide data to construct an accurate treatment planning tool for IRE in prostate tissue. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov database: NCT01790451.

Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline.

There is a lack of knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty-two HBeAg-positive and 67 HBeAg-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG-IFN therapy were studied. After PEG-IFN therapy, HBeAg-negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg-positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post-treatment, 7 (13%) HBeAg-positive and 9 (14%) HBeAg-negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post-treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg-negative CHB): 71% vs 5% for HBeAg-positive (P < 0.001) and 60% vs 16% for HBeAg-negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg-positive and HBeAg-negative CHB, respectively). In conclusion, PEG-IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.

The role of imaging in the active surveillance of small renal masses.

Up to 66 % of renal cell carcinomas are detected as small renal masses before the presence of clinical symptoms. Small renal mass treatment has evolved from the exclusive use of radical nephrectomy to the use of nephron sparing procedures where possible. An increase in elderly and comorbid patients, together with the notion that just 20 % of small renal masses show high malignant potential, has prompted interest in active surveillance as a treatment option. Modern imaging techniques provide objective follow-up parameters, namely size, invasion of collecting system or perirenal fat and enhancement patterns, with minimal complication risks or patient discomfort. This review evaluates recent developments in the field of active surveillance for small renal masses. Special focus is placed on the role of imaging in the primary decision making and subsequent follow-up during active surveillance.

Duplicated ureters and renal transplantation: a case-control study and review of the literature.

INTRODUCTION: Complications of the transplant ureter are the most important cause of surgical morbidity after renal transplantation. The presence of ureteral duplication in the renal graft might result in an increased complication rate. We analyzed our data of double-ureter renal transplantations using a case-control study design. Additionally, we performed a review of the literature. METHODS: From January 1995 to April 2012, 12 patients received a donor kidney with a double ureter (0.8%). We created a control group of 24 patients matched in age, sex, donor type, and ureteral stenting. Patient charts and surgical reports were reviewed retrospectively. RESULTS: In 7 patients both ureters were separately anastomosed to the bladder. In 4 patients a common ostium was created. In 1 patient 1 of the 2 ureters was ligated. No postoperative urologic complications occured. In the single-ureter group, the urologic complication rate was 17% (P = .71). Mean creatinine levels after transplantation were comparable between both groups. DISCUSSION: A double-ureter donor kidney is not associated with an increased complication rate after renal transplantation and yields equal outcomes as compared to single-ureter donor kidneys. We conclude that transplantation of a kidney with a duplicated ureter is safe.

Prevalence of autoimmune pancreatitis and other benign disorders in pancreatoduodenectomy for presumed malignancy of the pancreatic head.

BACKGROUND: Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided. METHODS: All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked. RESULTS: A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients. CONCLUSIONS: The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy.

The importance of portal venous blood flow in ischemic-type biliary lesions after liver transplantation.

Ischemic-type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia-reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.

Results of a two-center study comparing hepatic fibrosis progression in HCV-positive liver transplant patients receiving cyclosporine or tacrolimus.

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.

Somatostatin receptor in human hepatocellular carcinomas: biological, patient and tumor characteristics.

BACKGROUND/AIM: The evidence on the efficacy of somatostatin analogues in the treatment of hepatocellular carcinoma (HCC) in humans is conflicting. A variety of human tumors demonstrate somatostatin receptors. All subtypes bind human somatostatin with high affinity, while somatostatin analogues bind with high affinity to somatostatin receptor subtype 2 (sst2). We investigated the sst2 expression in HCC and examined whether HCCs expressing sst2 are a distinct subgroup. PATIENTS AND METHODS: Forty-five human HCCs were tested for sst2 expression and biological alterations. The proliferative capacity was determined with Ki67 immunostaining and the DNA ploidy status was measured by fluorescent in situ hybridization with a chromosome 1-specific repetitive DNA probe. Expression of tumor suppressor genes (p16, p53 and Rb1) was measured by immunohistochemistry. RESULTS: sst2 expression was detected in 30 tumors (67%). No correlation existed between sst2 expression and the immunoprofiles of the tumor suppressor genes, aneuploidy, proliferation, age, gender, alpha-fetoprotein levels, tumor size, tumor grade and underlying liver disease. CONCLUSION: In 67% of the patients with HCC, sst2 could be detected in the tumor. No clinical, pathological or biological characteristics were specific for sst2-positive tumors.

Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients.

BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. AIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. PATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. METHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. RESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively. CONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.